a g e n d a cibmtr working committee for infection … · not for publication or presentation . a g...

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR INFECTION AND IMMUNE RECONSTITUTION Orlando, FL Saturday, February 25, 2017, 12:15 – 2:15 pm

Co-Chair: Jeffery Auletta, MD, Nationwide Children’s Hospital, Columbus, OH; Telephone: 614-722-3553; E-mail: [email protected]

Co-Chair: Caroline Lindemans, MD, PhD, University Medical Center Utrecht, Utrecht, Netherlands; Telephone: +31 622879245; E-mail: [email protected]

Co-Chair: Krishna Komanduri, MD, University of Miami; Miami, FL; Telephone: 305-243-5302; E-mail: [email protected];

Scientific Director: Marcie Riches, MD, MS, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Telephone: 919-966-3048; E-mail: [email protected]

Statistical Directors: Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-7387; E-mail: [email protected] Soyoung Kim, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-8271; E-mail: [email protected]

Statistician: Min Chen, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0710; E-mail: [email protected]

1. Introduction a. Welcome and introduction b. Minutes and Overview Plan from February 2016 meeting (Attachment 1)

2. Accrual summary (Attachment 2)

3. Published papers a. IN10-01 Karen Ballen, Kwang Ahn , Min Chen , Dr. Hisham Abdel-Azim , Ibrahim Ahmed , Dr.

Mahmoud Aljurf , Dr. Joseph Antin , Ami Bhatt , Michael Boeckh , George Chen , Dr. Christopher Dandoy , Dr. Biju George , Mary Laughlin , Dr. Hillard Lazarus , Dr. Margaret MacMillan , David Margolis , Prof. David Marks , Dr. Maxim Norkin , Dr. Joseph Rosenthal , Ayman Saad , Prof. Bipin Savani , Dr. Harry Schouten , Jan STOREK , Paul Szabolcs , Dr. Celalettin Ustun , Dr. Michael Verneris , Dr. Edmund K Waller , Dr. Daniel Weisdorf , Dr. Kirsten Williams , John Wingard , Baldeep Wirk , Tom Wolfs , Jo-Anne Young , Jeffery Auletta , Dr. Krishna Komanduri , Dr. Caroline Lindemans , Dr. Marcie Riches: Infection Rates among Acute Leukemia Patients receiving Alternative Donor Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22(9):1036-1645

d. IN09-01 Richard Maziarz, Dr. Ruta Brazauskas , Min Chen , Dr. Aleksandra McLeod , Dr. Rodrigo Martino , John Wingard , Dr. Mahmoud D Aljurf , Minnoo Battiwalla , Dr. Christopher Dvorak , Prof. Biju George , Dr. Eva Guinan , Dr. Gregory Hale , Dr. Hillard Lazarus , Prof. Jong Wook Lee , Dr. Jane Liesveld , Dr. Muthalagu Ramanathan , Dr. Vijay Reddy , Prof. Bipin Savani , Dr. Franklin Smith , Dr. Lynne Strasfeld , Dr. Randy Taplitz , Dr. Celalettin Ustun , Dr. Michael Boeckh , Dr. Juan Gea-Banacloche , Dr. Caroline Lindemans , Jeffery Auletta , Dr. Marcie

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Riches : Outcomes of allogeneic HSCT for patients with hematologic malignancies (AML, ALL, MDS, CML) with and without pre-existing fungal infections- pre-existing invasive fungal infection is not a contraindication for subsequent HSCT: a CIBMTR® study. Accepted by BMT

e. IN12-01a Pierre Teira, Minoo Battiwalla, Muthalagu Ramanathan, Kwang Woo Ahn, Min Chen,Jaime Green, Ayman Saad, Joseph H. Antin, Bipin N. Savani, Hillard M. Lazarus, MatthewSeftel, Wael Saber, Carolyn Behrendt, David Marks, Mahmoud Aljurf, Maxim Norkin, John R.Wingard, Caroline A. Lindemans, Michael Boeckh, Marcie L. Riches, Jeffery J. Auletta: EarlyCytomegalovirus reactivation remains associated with increased transplant related mortalityin the current era: a CIBMTR analysis. Blood 127(20):2427-2438

f. IN12-01b Muthalagu Ramanathan , Pierre Teira , Minnoo Battiwalla , Dr. A. Barrett , KwangAhn , Min Chen , Carolyn Behrendt , Jaime Green , Mary Laughlin , Dr. Hillard Lazarus , Prof.David Marks , Ayman Saad , Dr. Matthew Seftel , Dr. Wael Saber , Prof. Bipin Savani , Dr.Edmund K Waller , John Wingard , Jeffery Auletta , Dr. Caroline Lindemans , Michael Boeckh ,Dr. Marcie Riches : Impact of Early Cytomegalovirus Reactivation in Cord blood Stem CellRecipients in the Current Era. Bone Marrow Transplant 51(8):1113-1120

4. Studies with Preliminary Results(Attachment 3)a. IN07-01/IN11-01 Early Bacterial infection in patients undergoing allogeneic HCT (M Robien/G

Papanicolaou/Celalettin Ustun/ JA Young) (Attachment 4)b. IN13-01 Bacterial and fungal infections in patients undergoing allogeneic hematopoietic cell

transplantation following nonmyeloablative and myeloablative regimens (C Usten)(Attachment 5)

5. Studies in progressa. IN14-01 Post allogeneic hematopoietic transplant Epstein Barr Virus related

Lymphproliferative disorder following conditioning with Antithymocyte globulin orAlemtuzumab (S Naik, C Bachier, P Shaughnessy, P Hari, R Kamble) Date file preparation(Attachment 6)

b. IN16-01 Viral Encephalitis in Hematopoietic Stem cell Transplant Recipients, 2007-2013(M Abidi, P Hari) Protocol development (Attachment 7)

c. IN16-02 Determination of the burden of mucosal barrier injury-laboratory confirmedbloodstream infections (MBI-LCBI) in the first 100 days after stem cell transplant (C Dandoy, PDaniels) Protocol development(Attachment 8)

6. Future/proposed studiesa. PROP1605-01 Clinical outcomes for patients with invasive fungal infections undergoing

hematopoietic stem cell transplant, (Myeloablative vs. Nonmyeloablative/Reduced intensitystem cell transplant) in the era of newer anti-fungals, 2009-2015 (Mhaeen Abidi/Mark R. Litzow/M. Rizwan Sohail/Randall C. Walker) (Attachment 9)

c. PROP 1611-02 The Incidence of Cytomegalovirus Viremia and Disease following HLA-Haploidentical Hematopoietic Cell Transplantation Compared to HLA-Matched Related Donor,Matched Unrelated Donor, and Umbilical Cord Blood Transplantation (Rizwan Romee /Ephraim Fuchs/ Asad Bashey/ Stefan Ciurea) (Attachment 10)

d. PROP 1611-117 Impact of CMV Reactivation on Relapse of Hematological Malignancies afterHaploidentical HSCT: a CIBMTR Analysis (Anurag Singh/ Siddhartha Ganguly) (Attachment 11)

e. PROP 1611-134 Incidence and Outcomes of individuals with and without viral infections inrecipients of haploidentical versus other allogeneic hematopoietic stem cell transplantation for

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patients with hematologic malignancies (Randy Allison Taplitz/ Carolyn Mulroney/ Richard Maziarz) (Attachment 12)

Dropped proposed studies a. PROP 1611-72 CMV exposure of cord blood donor- Impact on CMV reactivation in the

recipient. Dropped due to feasibility-low number of patients. b. PROP 1611-151 Immune Reconstitution and its relation with Infectious Morbidity Post

Autologous Peripheral Blood Stem Cell Transplantation (PBSCT). Dropped due to feasibility -the CIBMTR does not capture the data required to answer the hypothesis.

c. PROP 1611-122 Outcomes from progressive multifocal leukoencephalopathy in hematopoietic stem cell transplant patients Dropped due to feasibility-low number of patients

d. PROP 1611-54 The Effect of Antibacterial Prophylaxis on Early Post-transplant Mortality in Patients with Multiple Myeloma and Lymphoma Undergoing High-dose Chemotherapy and Autologous Stem Cell Transplantation. Dropped due to feasibility

f. PROP 1611-01 Infection Density per Donor Type and Conditioning Intensity and Their Association with NRM in 3 different time points (0-33, 34-66, and 67-100 days) within 100 days after alloHCT. Dropped due to low scientific impact

7. Other Business

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Not for publication or presentation Attachment 1

A G E N D A CIBMTR WORKING COMMITTEE FOR INFECTION AND IMMUNE RECONSTITUTION Hawaii Convention Center, Honolulu, Hawaii Friday, February 19, 2016, 12:15 – 2:15 pm

Co-Chair: Jeffery Auletta, MD, Nationwide Children’s Hospital, Columbus, OH; Telephone: 614-722-3553; E-mail: [email protected] (Attended by Skype)

Co-Chair: Caroline Lindemans, MD, PhD, University Medical Center Utrecht, Utrecht, Netherlands; Telephone: +31 622879245; E-mail: [email protected]

Co-Chair: Krishna Komanduri, MD, University of Miami; Miami, FL; Telephone: 305-243-5302; E-mail: [email protected];

Scientific Director: Marcie Riches, MD, MS, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Telephone: 919-966-3048; E-mail: [email protected]

Statistical Directors: Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-456-7387; E-mail: [email protected] Soyoung Kim, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-8271; E-mail: [email protected]

Statistician: Min Chen, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0710; E-mail: [email protected]

1. Introduction

Dr. Marcie Riches moderated the introduction of the working committee followed by which all the attending co-chairs and the statisticians were introduced. Dr. Riches reviewed the goal of the working committee to publish high impact studies in a timely manner. The expectations of the meeting are review of the current status of ongoing studies and timelines and for members to assess and select proposals that will have a high impact on the field. The working committee is limited by the complicated nature of infection data (Best before day 100) including data regarding infection prophylaxis which will be the focus of the “other business” section of the meeting. The working committee Members were asked to vote on a level of scientific impact score, 1 is the highest impact and 9 is the lowest impact score for the new proposals based on the feasibility and impact on the transplant community. Dr. Riches mentioned the working committee’s membership is open to any individual willing to take an active role in study development and completion. Badge scanning will automatically add you to the Working Committee membership. She also emphasized the rules of the Authorship: 1. substantial and timely contributions to conception and design, acquisition of data, or analysis and

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mailto:[email protected]


interpretation of data; 2. drafting the article or revising it critically for important intellectual content; 3. final approval of the version to be published. All three conditions must be met.

The minutes and overview plan from the 2015 Tandem meeting held in San Diego, CA were reviewed and approved by committee members.

2. Published or submitted papers Dr. Marcie Riches mentioned, the infection working committee submitted six papers in the past year. Four of them have been published or accepted and two are undergoing revisions.

a. IN05-02 Riches ML, Trifilio S, Chen M, Ahn KW, Langston A, Lazarus HM, Marks DI, Martino R, Maziarz RT, Papinicolou GA, Wingard JR, Young J-AH, Bennett CL. Risk factors and impact of non-Aspergillus mold infections following allogeneic HCT: a CIBMTR infection and immune reconstitution analysis. Bone Marrow Transplantation. doi:10.1038/bmt.2015.263.

b IN06-01 Williams KM, Ahn KW, Chen M, Aljurf MD, Agwu AL, Chen AR, Walsh TJ, Szabolcs P, Boeckh MJ, Auletta JJ, Lindemans CA, Zanis-Neto J, Malvezzi M, Lister J, de Toledo Codina JS, Sackey K, Chakrabarty JL, Ljungman P, Wingard JR, Seftel MD, Seo S, Hale GA, Wirk B, Smith MS, Savani BN, Lazarus HM, Marks DI, Ustun C, Abdel-Azim H, Dvorak CC, Szer J, Storek J, Yong A, Riches MR.: The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: a CIBMTR analysis. Bone Marrow Transplant. 2016 Jan 4. doi: 10.1038/bmt.2015.316. [Epub ahead of print]

c. IN10-01 Karen Ballen, Kwang Ahn , Min Chen , Dr. Hisham Abdel-Azim , Ibrahim Ahmed , Dr. Mahmoud Aljurf , Dr. Joseph Antin , Ami Bhatt , Michael Boeckh , George Chen , Dr. Christopher Dandoy , Dr. Biju George , Mary Laughlin , Dr. Hillard Lazarus , Dr. Margaret MacMillan , David Margolis , Prof. David Marks , Dr. Maxim Norkin , Dr. Joseph Rosenthal , Ayman Saad , Prof. Bipin Savani , Dr. Harry Schouten , Jan STOREK , Paul Szabolcs , Dr. Celalettin Ustun , Dr. Michael Verneris , Dr. Edmund K Waller , Dr. Daniel Weisdorf , Dr. Kirsten Williams , John Wingard , Baldeep Wirk , Tom Wolfs , Jo-Anne Young , Jeffery Auletta , Dr. Krishna Komanduri , Dr. Caroline Lindemans , Dr. Marcie Riches: Infection Rates among Acute Leukemia Patients receiving Alternative Donor Hematopoietic Cell Transplantation. Submitted.

d. IN09-01 Richard Maziarz, Dr. Ruta Brazauskas , Min Chen , Dr. Aleksandra McLeod , Dr. Rodrigo Martino , John Wingard , Dr. Mahmoud D Aljurf , Minnoo Battiwalla , Dr. Christopher Dvorak , Prof. Biju George , Dr. Eva Guinan , Dr. Gregory Hale , Dr. Hillard Lazarus , Prof. Jong Wook Lee , Dr. Jane Liesveld , Dr. Muthalagu Ramanathan , Dr. Vijay Reddy , Prof. Bipin Savani , Dr. Franklin Smith , Dr. Lynne Strasfeld , Dr. Randy Taplitz , Dr. Celalettin Ustun , Dr. Michael Boeckh , Dr. Juan Gea-Banacloche , Dr. Caroline Lindemans , Jeffery Auletta , Dr. Marcie Riches : Outcomes of allogeneic HSCT for patients with hematologic malignancies (AML, ALL, MDS, CML) with and without pre-existing fungal infections- pre-existing invasive fungal infection is not a contraindication for subsequent HSCT: a CIBMTR® study. Submitted.

e. IN12-01a Pierre Teira, Minoo Battiwalla, Muthalagu Ramanathan, Kwang Woo Ahn, Min Chen, Jaime Green, Ayman Saad, Joseph H. Antin, Bipin N. Savani, Hillard M. Lazarus, Matthew Seftel, Wael Saber, Carolyn Behrendt, David Marks, Mahmoud Aljurf, Maxim Norkin, John R. Wingard, Caroline A. Lindemans, Michael Boeckh, Marcie L. Riches, Jeffery J. Auletta: Early Cytomegalovirus reactivation remains associated with increased transplant related mortality in

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the current era: a CIBMTR analysis. Blood. doi:10.1182/blood-2015-11-679639. Epub 2016 Feb 16.

f. IN12-01b Muthalagu Ramanathan , Pierre Teira , Minnoo Battiwalla , Dr. A. Barrett , Kwang Ahn , Min Chen , Carolyn Behrendt , Jaime Green , Mary Laughlin , Dr. Hillard Lazarus , Prof. David Marks , Ayman Saad , Dr. Matthew Seftel , Dr. Wael Saber , Prof. Bipin Savani , Dr. Edmund K Waller , John Wingard , Jeffery Auletta , Dr. Caroline Lindemans , Michael Boeckh , Dr. Marcie Riches : Impact of Early Cytomegalovirus Reactivation in Cord blood Stem Cell Recipients in the Current Era. Accepted by BMT.

3. Studies in progress Dr. Caroline Lindemans introduced the status of four ongoing studies.

a. IN07-01/IN11-01 Early Bacterial infection in patients undergoing allogeneic HCT (M Robien/G Papanicolaou/Celalettin Ustun/ JA Young). The study is on data file preparation stage, are expecting to finish final analysis by June 30, 2016.

b. IN13-01 Bacterial and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation following nonmyeloablative and myeloablative regimens (C Usten). The protocol has been sent to the working committee for comments, we are expecting to finish final analysis by June 30, 2016.

c. IN14-01 Post allogeneic hematopoietic transplant Epstein Barr Virus related Lymphproliferative disorder following conditioning with Antithymocyte globulin or Alemtuzumab (S Naik, C Bachier, P Shaughnessy, P Hari, R Kamble) The study is on protocol development stage, we are expecting to have dataset ready for analysis by June 30, 2016

e. IN15-01 Impact of Epstein Barr virus (EBV) infection on outcomes of allogenic hematopoietic cell transplantation (HCT) for hematologic malignancies (Pierre Teira) This study is on protocol development stage.

4. Future/proposed studies Dr. Caroline Lindemans mentioned there are total 9 proposals received this year and 5 will be presented.

a. PROP 1510-16 Viral encephalitis in hematopoietic stem cell transplant recipients, 2007-2013 (Maheen Abidi/ Parameswaran Hari) Dr. Maheen Abidi presented the proposal. The objective of this proposal are: 1. determine frequency and significance of viral DNA detection in CSF in patients screened for viral encephalitis; 2. Determine risk factors (recipient and transplant related); 3. Determine survival outcomes, encephalitis related mortality rate for different viruses, and for encephalitis due to ≥1 virus. The Hypothesis of this study is: Viral Encephalitis can have significant impact on mortality of Hematopoietic stem cell (HCT) transplant recipients, with significant variation amongst viruses on encephalitis related mortality rates. Mortality tends to be high for viral encephalitis due to more than one virus. Comments from the audience: It is an important study. There is a concern that there were no Haploidentical cases identified. Dr. Krishna Komanduri pointed out there are more than half

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of the recipient are cord blood.

b. PROP 1511-27 Impact of early gram-negative bloodstream infections on transplant outcomes in autologous and allogeneic transplant patients (Pearlie Chong/ Marcie Riches/ Krishna Komanduri) Dr. Pearlie Chong introduced the background of this study: 1. GNBSI occur in 22 – 56% of HCT recipients with high mortality, despite antimicrobial prophylaxis 2. Most data from single centers limited by local practices and resistance patterns. She also introduce the hypothesis of this study: GNBSI occurring between day 0 – day 14 after HCT negatively impacts transplant outcomes The objective of this study is to compare outcomes in HCT recipients with and without early (d0 – d14) GNBSI, overall, disease-free survival, transplant related mortality , infection related mortality from time of GNBSI and Subsequent (day+15 – day 100) BSI, viral, and fungal infections by day 100 The patient population of the study is: ≥ 18 yrs receiving 1st allo/auto HCT 2008 – 2014 for any disease and using any stem cell source, exclude patients not in CR at time of transplant and patients who die prior to day +14. The comments from committee are: 1. This should not be limited to adults only. 2. Exclude the patients not in CR. Dr. Juan Gea-Banacloche comments that the study design is not good; the center effect should be taken into consideration. He proposed a case control study. Another question from the audience is why excluded the patients who died before day14. Dr. Marcie Riches explained that we have been struggling with statistical analysis , whether or not we can account for multiple infections and early mortality, we were wanting to looking something happened early effected the outcome later. We may try to use the statistical methodology which we are using for IN0701/IN1101 and not exclude the patients who die before day 14. Also make definition, cases are had gram-negative BSI before engraftment.

c. PROP 1511-85 Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections in the first 100 days after stem cell transplant (Christopher Dandoy/ Paulina Daniels) Dr. Christopher Dandoy presented the proposal. He introduced the background of this proposal: Central line-associated bloodstream infections (CLABSIs) are a major public health issue; CLABSIs are a determinant of healthcare quality (Major focus of quality improvement efforts, hospital rankings, and reimbursement); Central venous catheter (CVC) maintenance care has been shown to be effective in reducing CLABSIs; The CDC recently modified the CLABSI definition to identify a subset of CLABSIs likely related to mucosal barrier injury termed mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI); Unlike CLABSIs, MBI-LCBIs are not prevented by improved CVC maintenance care. He mentioned, a blood stream infection is defined as an MBI-LCBI if: 1. Resulted from 1 or more of a group of organisms known to be commensals of the oral cavity or gastrointestinal tract; and 2. Occurred in a patient with signs/symptoms compatible with mucosal barrier injury such as GI-GVHD and/or neutropenia Importance. There are no reported data on the incidence, risk factors, and

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outcome of patients that develop MBI-LCBI after HSCT. High rates of MBI-LCBIs are penalizing centers that perform HSCT and care for high acuity patients. This study will lead to the identification of variables to target in future interventional studies. Dr. Christopher Dandoy mentioned the hypothesis of the proposal are: patients in the first 100 days after stem cell transplant (SCT) who develop mucosal barrier injury laboratory confirmed bloodstream infections (MBI-LCBI) have increased transplant related mortality (TRM) and decreased overall survival (OS) compared to those with no infection or an infection not classified as an MBI-LCBI. The specific aims of the study are: 1) Determine the incidence and timing of MBI-LCBIs in the first 100 days post SCT; 2) Determine the risk factors for development of a MBI-LCBI in the first 100 days; and 3) Compare TRM and OS between patients in the first 100 days post-SCT who develop a MBI-LCBI versus those with no infection or a non-MBI-LCBI. He pointed out the study strengths are: large sample size, contemporary, reflects the global reality of HSCT by including all centers. Since MBI-LCBI are identified as a burden for public health reporting with public health implications, this proposal will target major public health journal such as JAMA One concern from the committee is quantifying variability of mucosal damage, Dr. Dandoy mentioned we are going to use CDC criteria based on the organisms identified. Another concern is reporting change during time.

d. PROP 1511-103 Impact of resolved Hepatitis B infection on outcome of allogeneic hematopoietic stem cell transplant for hematologic malignancies (Carrie Yuen/ Jennifer Holter-Chakrabarty) Dr. Jennifer Holter-Chakrabarty presented the proposal. She introduced the Hypothesis of the proposal: patients with resolved hepatitis B infection have different outcomes after HSCT depending on stem cell sources. She also introduce the objective of the proposal: the primary objective: outcome (GVHD, NRM, duration of survival) in patients with resolved hepatitis B infection after allogeneic HSCT for acute leukemia as compared with control group; the secondary objective: outcome (GVHD, NRM, OS) in patients with resolved hepatitis B infection after cord blood transplant as compared with matched related and matched unrelated donor HSCT. Dr. Celalettin Ustun suggested adding variable hepatitis B serology for donor and recipient.

e. PROP 1512-02 Evaluation of post-engraftment bacterial blood stream infections occurring within the first 100 days post-transplant (Celalettin Ustun/ Jo-Anne Young/ Genovefa A Papanicolaou) Dr. Celalettin Ustun presented the proposal. He introduced hypothesis of the proposal is that later post-engraftment BSI are associated with lower overall survival and higher transplant related mortality compared to patients never developing bacterial BSI in the first 3 months after transplant.

The study objective is: To evaluate the incidence of BSI after engraftment through 100 days post-transplant (post-engraftment defined as 15 days from date of neutrophil recovery); To evaluate the effects of these infection on alloHCT outcomes (TRM, OS, DFS, secondary graft failure); To compare transplant outcomes for patients developing a first BSI after engraftment

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to patients never developing a post-engraftment BSI; To evaluate risk factors resulting in post-engraftment BSI. He mentioned the rationales are: the ongoing study (IN0701/1101) is already evaluating early BSI, and its effects on outcome (Early BSI defined as occurring from day 0 until 14 days beyond ANC recovery), with this study, we will focus on BSI occurring later after engraftment. We can share dataset of IN0701/1101, so this proposed study is an extension of IN0701/1101 and can be done rather quickly. He also explained why we want to focus on Post-engraftment Infections: 1. In the current era of improved diagnostics and HCT supportive care, more patients survive the neutropenic initial phase; 2.We will include all graft sources. Therefore, we can particularly evaluate if BSI after UCB is solely related to engraftment; 3. We will evaluate particular risk factors (GvHD etc) for this period.

One of the suggestions from the committee is to combine Prop 1512-02 and ongoing study IN0701/IN1101. Dr. Marcie Riches mentioned we can share the dataset; it will save the statistical hours and help the new study move quickly, so the committee can accept and finish more studies.

5. Dropped proposed studies Dr. Krishna Komanduri explained the reasons for the dropped proposed studies.

a. PROP 1506-06 Human Herpes Virus 6 Reactivation in Cord versus Haploidentical Hematopoietic Stem Cell Transplants, 2007-2013. Dropped due to feasibility-low number of patients.

b. PROP 1508-04 Cytomegalovirus and Effect on Early Chimerism in Patients with Myeloid Disorders Undergoing Stem Cell Transplantation using Anti-thymocyte globulin versus Alemtuzumab Dropped due to feasibility-low number of patients

c. PROP 1511-77 The efficacy and safety of high-dose valacyclovir for CMV prevention in umbilical cord blood transplant recipients. Dropped due to feasibility -the CIBMTR does not capture the data required to answer the hypothesis.

d. PROP 1511-133 Translating pharmacogenetics of antifungals into clinical outcomes. Dropped due to feasibility -the CIBMTR does not capture the data required to answer the hypothesis.

6. Other Business

Dr. Marcie Riches pointed out based on the statistical hour, the advisory working committee strongly recommended we only accept two proposals this year to proceed forward, if your proposal is not accepted, it does not mean it is not a quality proposal, it is just did not get high priority and it may be presented next year.

At the end, Dr. Riches reported the activities the infection working committee has been doing to improve the data capture. We received 9 proposals and 4 of them were dropped due to the low number of patients or lack of capture of certain data. It has been ongoing for many years. A committee of 17 persons including Dr. Riches, the WC chairs, ID specialists, and data managers are revising the forms to facilitate the collection of data for studies that require a registry (i.e. cannot be done in a single institution).

One of the changes includes revision of the antimicrobial prophylaxis data on the 2100 form. Specifically, data captured will include the first drug r the patient received (up though day 45), by

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antibacterial, antiviral, antifungal and PCP prophylaxis. Although, it is not going to give us the detail of changing a prophylaxis, it is better than the current data. The group is also working on trying to create additional supplemental data form including modify the fungal forms to capture data about diagnostic methods. The group proposed to add supplemental data form of CMV, EBV and HHV6, also will ask for drugs received for treatment, not duration of the therapy, use start date of the drug, what drugs the patient was receiving at 30 days from time of the diagnosis of the infection. It will help to capture the better information and publish the papers on high impact journals. Any comments and suggestions are welcome.

Working Committee Overview Plan for 2016-2017

a. IN07-01/IN11-01 Early bacterial infection in patients undergoing allogeneic HCT (C Ustun /J-A Young/M Robien/G Papanicolaou). We anticipate finishing final analysis by June 30, 2016 and submitted the paper by June 30, 2017.

b. IN 13-01 Bacterial and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation following nonmyeloablative and myeloablative regimens (C Usten). We anticipate finishing final analysis by June 30, 2016 and submitted the paper by June 30, 2017.

c. IN 14-01 (PROP 1303-03/PROP1311-19): Post allogeneic hematopoietic transplant Ebstein Barr Virus related lymphproliferative disorder following conditioning with antithymocyte globulin or alemtuzumab (R Kamble/ P Hari/S Naik /C Bachier/P Shaughnessy). We anticipate having a dataset ready for analysis by June 30, 2016 and submitted the paper by June 30, 2017.

d. IN 15-01 Incidence of early C. difficile infections after allogeneic hematopoietic cell transplantation over the last 12 years (C Usten). Due to the low scientific impact, the study will be dropped.

e. IN16-01 Viral encephalitis in hematopoietic stem cell transplant recipients, 2007-2013 (Maheen Abidi/ Parameswaran Hari) (PROP1510-16). We anticipate receiving the protocol by June 30, 2016 and having the data ready for manuscript by June 30 2017.

f. IN16-02 Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections in the first 100 days after stem cell transplant (Christopher Dandoy/ Paulina Daniels) (PROP 1511-85). We anticipate receiving the protocol by June 30, 2016 and having the final protocol by June 30 2017.

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Work Assignments for Working Committee Leadership (March 2016)

Jeffery Auletta IN09-01: Outcomes of allogeneic hematopoietic stem cell transplantation for patients with and without pre-existing fungal infections

Caroline Lindemans

IN10-01: Comparison of Infectious rates among alternative graft sources: single and double cord blood, matched unrelated donor and mismatched unrelated donor

Jeffery Auletta IN07-01/IN11-01: Early bacterial infection in patients undergoing allogeneic HCT

Caroline Lindemans

IN13-01 Bacterial and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation following nonmyeloablative and myeloablative regimens.

Jeffery Auletta IN14-01 Post allogeneic hematopoietic transplant Ebstein Barr Virus related lymphproliferative disorder following conditioning with antithymocyte globulin or alemtuzumab (R Kamble/ P Hari/S Naik /C Bachier/P Shaughnessy)

Krishna Komanduri

IN16-01 Viral encephalitis in hematopoietic stem cell transplant recipients, 2007-2013 (Mhaeen Abidi/ Parameswaran Hari)

Caroline Lindemans and Jeffery Auletta

IN16-02 Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections in the first 100 days after stem cell transplant (Christopher Dandoy/ Paulina Daniels) (PROP 1511-85)

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Accrual Summary for the Infection and Immune Reconstitution Working Committee Donor-recipient and Infection information reported to the CIBMTR after 2008

Variable Allogeneic

N(%) Autologous

N(%) Number of Patients 21648 9061 Infection Donor/recipient CMV status

-/- 5004 (23) N/A +/- 2505 (12) -/+ 5575 (26) +/+ 7149 (33) Missing/not tested 1415 ( 7)

Donor/recipient hepatitis B status -/- 7950 (37) N/A +/- 56 (<1) -/+ 388 ( 2) +/+ 14 (<1) Missing/not tested 13240 (61)

Donor/recipient hepatitis C status -/- 7974 (37) N/A +/- 54 (<1) -/+ 83 (<1) +/+ 4 (<1) Missing/not tested 13533 (63)

Fungal Infection history No 19839 (92) 8964 (99) Yes 1784 ( 8) 96 ( 1) Missing 25 (<1) 1 (<1)

Fungal Infection after starting of conditioning No 17333 (80) 7974 (88) Yes 3905 (18) 471 ( 5) Missing 410 ( 2) 616 ( 7)

Infection prophylaxis after starting of conditioning No 290 ( 1) 221 ( 2) Yes 21158 (98) 8664 (96) Missing 200 (<1) 176 ( 2)

Immune Reconstitution IgG at 100 day

Data not available 7977 (37) 3814 (42) Data available 13671 (63) 5247 (58)

IgM at 100 day

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Variable Allogeneic

N(%) Autologous

N(%) Data not available 14377 (66) 4400 (49) Data available 7271 (34) 4661 (51)

IgA at 100 day Data not available 14377 (66) 4362 (48) Data available 7271 (34) 4699 (52)

CD3 at 100 day Lymphocyte analyses were not performed 12663 (58) 8057 (89) Data not available 3612 (17) 545 ( 6) Data available 5373 (25) 459 ( 5)



CD20 at 100 day Lymphocyte analyses were not performed 12663 (58) 8057 (89) Data not available 7552 (35) 894 (10) Data available 1433 ( 7) 110 ( 1)


Infection Prophylaxis Antibiotics

No 6230 (29) 2862 (32) Yes 15218 (70) 6023 (66) Missing 200 (<1) 176 ( 2)

Antifungal agent No 1816 ( 8) 1720 (19) Yes 19632 (91) 7165 (79) Missing 200 (<1) 176 ( 2)

Amphotericin No 19450 (90) 8476 (94) Yes 1660 ( 8) 95 ( 1) Missing 538 ( 2) 490 ( 5)

Caspofungin No 19641 (91) 8462 (93)

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Variable Allogeneic

N(%) Autologous

N(%) Yes 1469 ( 7) 109 ( 1) Missing 538 ( 2) 490 ( 5)

Fluconazole No 8987 (42) 1768 (20) Yes 12122 (56) 6803 (75) Missing 539 ( 2) 490 ( 5)

Itraconazole No 20480 (95) 8508 (94) Yes 630 ( 3) 63 (<1) Missing 538 ( 2) 490 ( 5)

Micafungin No 16688 (77) 8287 (91) Yes 4421 (20) 284 ( 3) Missing 539 ( 2) 490 ( 5)

Posaconazole No 17583 (81) 8501 (94) Yes 3526 (16) 69 (<1) Missing 539 ( 2) 491 ( 5)

Ravuconazole No 21089 (97) 8567 (95) Yes 20 (<1) 4 (<1) Missing 539 ( 2) 490 ( 5)

Voriconazole No 12952 (60) 8238 (91) Yes 8158 (38) 333 ( 4) Missing 538 ( 2) 490 ( 5)

Other systemic antifungal agent No 20416 (94) 8431 (93) Yes 694 ( 3) 140 ( 2) Missing 538 ( 2) 490 ( 5)

Antiviral agent No 1225 ( 6) 620 ( 7) Yes 20223 (93) 8265 (91) Missing 200 (<1) 176 ( 2)

Acyclovir No 4196 (19) 1450 (16) Yes 16914 (78) 7121 (79) Missing 538 ( 2) 490 ( 5)

Foscarnet No 20432 (94) 8546 (94)

14


Variable Allogeneic

N(%) Autologous

N(%) Yes 677 ( 3) 25 (<1) Missing 539 ( 2) 490 ( 5)

Ganciclovir No 19462 (90) 8530 (94) Yes 1648 ( 8) 41 (<1) Missing 538 ( 2) 490 ( 5)

Valganciclovir No 18912 (87) 8450 (93) Yes 2196 (10) 121 ( 1) Missing 540 ( 2) 490 ( 5)

Valacyclovir No 15656 (72) 6599 (73) Yes 5454 (25) 1972 (22) Missing 538 ( 2) 490 ( 5)

Other antiviral agent No 20123 (93) 8400 (93) Yes 987 ( 5) 171 ( 2) Missing 538 ( 2) 490 ( 5)

Pneumocystis agent No 2519 (12) 3510 (39) Yes 18929 (87) 5375 (59) Missing 200 (<1) 176 ( 2)

Other prophylaxis agent No 18489 (85) 7868 (87) Yes 2620 (12) 702 ( 8) Missing 539 ( 2) 491 ( 5)

Disease Acute Leukemia/MDS 15674 (72) 167 ( 2) Chronic Leukemia 742 ( 3) 0 Non-Hodgkin Lymphoma 1361 ( 6) 2276 (25) Hodgkin Lymphoma 91 (<1) 709 ( 8) Solid tumors 16 (<1) 703 ( 8) Myeloma/Plasma Cell Disorder 137 (<1) 5148 (57) Non-malignant disorders 3627 (17) 58 (<1)

Year of transplant 2008 3313 (15) 2279 (25) 2009 3005 (14) 934 (10) 2010 1898 ( 9) 424 ( 5) 2011 1363 ( 6) 510 ( 6) 2012 1447 ( 7) 538 ( 6)

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Variable Allogeneic

N(%) Autologous

N(%) 2013 2685 (12) 1218 (13) 2014 3555 (16) 1283 (14) 2015 3344 (15) 1386 (15) 2016 1038 ( 5) 489 ( 5)

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TO: Infection and Immune Reconstitution Working Committee Members FROM: Marcie Riches, MD, MS, Scientific Director for the Infection and Immune Reconstitution

Working Committee RE: Studies in Progress Summary

Studies with Preliminary Results IN07-01/IN11-01: Early bacterial infection in patients undergoing allogeneic HCT (C Ustun /J-A Young /M Robien /G Papanicolaou) This study aims to enumerate bacterial infections occurring early (from day 0 until 14 days after neutrophil engraftment) after hematopoietic cell transplantation (HCT) by site and causative organisms over a 10 year period; Study the impact of bacterial infections on long term overall survival; Study the impact of microbiologic and transplant related factors (such as stem cell source) in relation to survival. Manuscript preparation is underway for two manuscripts: 1) very early versus later infections within the first 100 days, and 2) VRE BSI versus other BSI in the first 100 days. IN07-01/IN11-01a: VEP vs LEP vs both vs No BSI in patients undergoing allogeneic HCT (C Ustun/ J-A Young) Plan to submit to Blood by June 2017. IN07-01/IN11-01b: VRE vs other vs no BSI in patients undergoing allogeneic HCT (G Papanicolaou) Plan to submit to Blood by June 2017. IN13-01: Bacterial, viral and fungal infections in patients undergoing allogeneic hematopoietic cell transplantation (Allohct) following nonmyeloablative and myeloablative (C Ustun) This study is to compare bacterial and fungal infections between patients undergoing allogeneic hematopoietic cell transplantation (AlloHCT) following NMAR, RIC, and MAR. Manuscript preparation is underway. Plan to submit to BBMT by July 2017. Studies in Progress IN14-01: Post allogeneic hematopoietic transplant Epstein Barr Virus related Lymphproliferative disorder following conditioning with Antithymocyte globulin or Alemtuzumab (S Naik, C Bachier, P Shaughnessy, P Hari, R Kamble) This study is to determine the incidence of post allogeneic hematopoietic transplant Epstein Barr virus related lymphproliferative disorder following myeloablative or reduced intensity conditioning with including antithymocyte globulin or Alemtuzumab as conditioning or GVHD prophylaxis; To determine morbidity and outcomes associated with EBV-PTLD. Data file preparation is underway, including secondary review of pathology reports to confirm EBV association with the PTLD. Data cleaning is underway.

IN16-01: Viral Encephalitis in Hematopoietic Stem cell Transplant Recipients, 2007-2013 (M Abidi, P Hari) This study is to describe the frequency and significance of CNS viral infections in hematopoietic stem cell transplant (HCT) recipients; To determine the OS of patients with viral encephalitis after HCT. The study protocol is under development.

17


IN16-02: Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections (MBI-LCBI) in the first 100 days after stem cell transplant (C Dandoy, P Daniels) This study is to compare TRM and OS post-SCT between patients who develop a MBI-LCBI versus those with no infection or a non-MBI-LCBI in the first 100 days; To determine the incidence of MBI-LCBIs in the first 100 days post SCT; To determine the risk factors for development of a MBI-LCBI in the first 100 days; To determine the timing of MBI-LCBI after SCT. The study protocol is under development. Studies previously discontinued IN15-01 Impact of Epstein Barr virus (EBV) infection on outcomes of allogenic hematopoietic cell transplantation (HCT) for hematologic malignancies This study is to assess the impact of donor and recipient EBV serostatus on disease relapse, incidence of acute and chronic graft versus host disease (GVHD), non-relapse mortality (NRM), event-free survival (EFS) and overall survival (OS) in patients’ receiving allogeneic hematopoietic cell transplantation (HCT); To assess the impact of EBV reactivation on the same outcomes and for the same population. This study was dropped due to lower scientific impact.

18


CIBMTR IN11-01/IN07-01 IMPACT OF EARLY BACTERIAL BLOODSTREAM INFECTIONS OCCURING WITHIN 100 DAYS OF HCT ON

LONG-TERM SURVIVAL

FINAL PROTOCOL

Study Co-Chairs: Celalettin Ustun, MD University of Minnesota MMC 480 420 Delaware St SE Minneapolis, Minnesota 55455 Telephone.: 612-624-5109 E-mail: [email protected]

Jo-Anne Young, MD University of Minnesota MMC 250 420 Delaware St SE Minneapolis, Minnesota 55455 Telephone: 612-625-8462 E-mail: [email protected]

Genovefa A Papanicolaou, MD

Memorial Sloan-Kettering Cancer Center 1275 York Avenue, Box 9 New York, NY 10021 Telephone: 212-639-8361 E-mail: [email protected]

Mark A Robien, MD, MPH

NIAID (National Institute of Allergy and Infectious Diseases) Clinical Transplantation Section (HNM632)

BG 6610 RM 6225 6610 Rockledge Dr Bethesda MD 20817 Telephone: 301-496-5598 E-mail: [email protected]

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Study Statistician: Min Chen, MS CIBMTR Statistical Center Medical College of Wisconsin 9200 West Wisconsin Ave., C5500

Milwaukee, WI 53226 USA Telephone: 414-805-0710 E-mail: [email protected] PhD Statistician: Kwang Woo Ahn, PhD Division of Biostatistics Department of Population Health Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-7387

E-mail: [email protected]

Soyoung Kim, PhD, Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-8271 E-mail: [email protected]

Scientific Director: Marcie Riches, MD, MS Associate Professor of Medicine The University of North Carolina at Chapel Hill 170 Manning Drive Physician’s Office Bldg, 3rd Floor, CB#7305 Chapel Hill, NC 27599 Telephone: 919-966-3048 E-mail: [email protected] Working Committee Chair: Jeffery J. Auletta, MD

Nationwide Children’s Hospital The Ohio State University 700 Children’s Drive, ED559 Columbus, OH 43205 Telephone: 614-722-6883 E-mail: [email protected]

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Working Committee Chair: Caroline A Lindemans, MD, PhD Wilhelmina Children's Hospital University Medical Center Utrecht, Children’s hospital Lundlaan 6, PO BOX 85090 3508 AB, Utrecht, the Netherlands Telephone: 31-622879245 E-mail: [email protected]

Working Committee Chair: Krishna Komanduri, MD University of Miami; Miami, FL; E-mail: [email protected]

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1.0 HYPOTHESES: • Compared with patients who never developed bacterial bloodstream infections (BSI) in

the first 100 days after transplant, patients with BSI occurring in very early phase (BSI-VEP) (between day -10 until 14 days after neutrophil engraftment for an individual patient) and patients with BSI occurring in the late early phase (BSI-LEP) (between 15 days after engraftment until day +100) have poorer long-term survival following allogeneic hematopoietic cell transplantation (HCT).

• The impact of BSI-VEP will be different than BSI-LEP on patients’ outcomes. • BSI-VEP or BSI- LEP due to vancomycin-resistant enterococcus (VRE) have a greater

negative impact than other bacterial BSI on long-term survival following allogeneic HCT.

2.0 INTRODUCTION: This study aims to 1) enumerate bacterial BSI-VEP and BSI-LEP by site and causative organisms over a 5-year period; 2) study the impact of bacterial bloodstream infections on other infections and long-term overall survival; 3) study the impact of transplant related factors (such as stem cell source) in relation to development of bacterial BSI-VEP and BSI-LEP; 4) study the impact of conditioning regimens in relation to bacterial BSI-VEP and BSI-LEP; and 5) study the impact of center on bacterial BSI-VEP and BSI-LEP

3.0 OBJECTIVES:

The following will be evaluated for bacterial bloodstream infections (any) and VRE specifically:

3.1 Primary Objectives

3.1.1 To enumerate bacterial BSI in the first 100 days after allogeneic HCT as BSI-VEP and BSI-LEP 3.1.1.1: VEP = Very early phase, defined as the period between day -10 and 14 days

after neutrophil engraftment 3.1.1.2: LEP = Late early phase, defined as the period from 15 days after neutrophil

engraftment through 100 days post-transplant 3.1.2 To examine the association between BIS-VEP and BIS-LEP on transplant outcomes

including: 3.1.2.1 Overall survival (OS) 3.1.2.2 Disease Free survival (DFS) 3.1.2.3 Non-relapse mortality 3.1.2.4 Relapse 3.1.2.5 Acute GVHD occurring before or after an early bacterial BSI 3.1.2.6 Cause of death

3.2 Secondary Objectives:

3.2.1 To identify trends over time in microbial pathogens causing early bacterial infections.

3.2.2 To assess any differences in the incidence of bacterial BSI between pediatric and adult populations

3.2.3 To assess the effect of cell dose (CD34 and TNC) on bacterial BSI. 3.2.4 To assess the effect of conditioning regimen (e.g, myeloablative, vs. others) on early

bacterial BSI and of stem cell source

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3.2.5 To assess the effect of growth factors (e.g., administered or not.) on early bacterial BSI

4.0 SCIENTIFIC JUSTIFICATION: Over the last 10 years, changes in approaches to the management of infections in hematopoietic stem cell transplant recipients have impacted the types of early bacterial infections and the impact of infections on overall survival. The current rate of bloodstream infection for stem cell transplant recipients using match sibling or matched unrelated donor stem cell sources needs to be defined. In addition, the effect of bloodstream infection on alternative stem cell sources also needs to be defined, such as cord blood transplant. (Need to insert citations including infection risk in non-cord types of transplants.) Umbilical cord blood has been used in the pediatric population as an important graft source since the middle of the 1980s (1-4). With time, its use has been extended to adults (4-10). Despite using double cord blood units, a main problem remains low stem cell doses, which is associated with more prolonged neutropenia (approximately 3 to 4 weeks) (11-14). A recent small study (n=31) indicates that bacterial infections occur around 16% and are rarely associated with mortality (11). However, reduced intensity conditioning regimens may even further affect neutropenia and bacterial infections (12), and the effects of conditioning intensity on the rates of bacterial infections are unknown.

The current rate of bloodstream infection with MRSA needs to be defined. MRSA infections are treated with vancomycin, and vancomycin resistance is so uncommon that it is tracked by the Centers for Disease Control in Atlanta when it occurs. Since vancomycin use occurs quite frequently on a clinical basis, so one of the points of this study will be to examine infections that require treatment with agents that are not used as frequently on an empirical basis. Reports of vancomycin-resistant enterococci (VRE) emerged in the early 1990s, and quickly became a concern for HCT patients, due to increased risks of VRE acquisition associated with prolonged and severe immunosuppression, lengthy hospital stays and intensive exposure to broad-spectrum antibiotics leading to the selection of resistant flora. Additionally, allogeneic HCT is associated with disruptions in intestinal mucosal integrity caused by transplant conditioning and exacerbated by graft-versus-host disease (GVHD) which may lead to increased bacterial translocation and subsequent systemic infection. Since the documented emergence of pathogenic VRE, multiple studies over the past 15 years have described rates of early VRE bacteremia (VREB) after HCT ranging from 3.6% to 22%, with mortality ranging from 0.04% to 85% (13-25). The disparity across different reports of mortality from VRE and impact of VRE on transplant should be able to be assessed with this study. Comparing early VRE BSI with other early bacterial BSI is a clever way to address the disparity across previous reports. Given the recognized importance of VRE, numerous changes have occurred in the prevention and management of this infection; 4 new drugs with activity against VRE are now available, and screening and decolonizing strategies have been proposed. In addition, allogeneic transplant approaches have fundamentally changed, with the introduction of cord blood grafts and non-myeloablative conditioning regimens, resulting in an ever-widening group of patients, including those older than 60 years, who receive HCT. Thus, BSI VRE can occur at high rates among allogeneic HCT recipients colonized by VRE. VRE BSI is associated with high mortality rates, although it is not clear to what extent VRE infection directly contributes to this high mortality, especially in the era of antibiotics with activity against VRE.

23


Early BSI is defined as occurring up to 100 days after transplant. This will be evaluated in 2 periods: 1) Very early phase (i.e., from day 0 until 14 days after neutrophil engraftment for an individual patient) and 2) late early phase (i.e, 15 days after neutrophil engraftment until day +100). Very early phase definition in part based on the range of engraftment dates that are seen among the various stem cell sources as well as the infection analysis of the BMT CTN 0201 study, peripheral blood versus bone marrow. In that study, an exploratory analysis was done of infections and this exploratory analysis was more descriptive when the actual date of individual patient engraftment was used (26). 5.0 STUDY POPULATION: The study population will include all patients receiving first allogeneic HCT for management of AML, ALL, and MDS between January 2008 and December 2012. Study populations will include those who received a graft from either a related (including haplo-identical) or unrelated donor, and include marrow, peripheral blood or cord blood sources. Recipients of T cell depletion will be included. Patients who have had a prior transplant are excluded. Bacterial BSI will be defined as occurring between day -10 and day 100.

6.0 OUTCOMES:

6.1 Cumulative incidence of fungal infection by day +100. Death is a competing risk. 6.2 Cumulative incidence of viral infection by day +100. Death is a competing risk. 6.3 Cumulative incidence of VRE BSI by 100 days. Death is a competing risk. 6.4 Overall survival: Time to death from any cause. Patients are censored at time of last

follow-up. There are no competing risks. Event will be summarized by a survival curve. 6.5 Progression Free Survival: Time to death without relapse/persistence of underlying

disease for transplant. Patients are censored at relapse/progression or time of last follow-up. Event will be summarized by a survival curve.

6.6 Non-relapse mortality: Death without evidence of relapse or progression of underlying

malignancy. This will be estimated using the cumulative incidence function with relapse/progression as the competing risk.

6.7 Relapse/Progression: progressive disease or recurrence of disease are events. Those who

survive without recurrence or progressive disease are censored at the date of last contact. This event is summarized by the cumulative incidence estimate with NRM as the competing risk.

6.8 Cumulative incidence of chronic GVHD by 1 year. Death is a competing risk. 6.9 Causes of Death: In the event of relapse of disease for transplant, relapse is considered

the primary cause of death.

24


7.0 VARIABLES TO BE ANALYZED: Patient Related:

• Age • Gender • Performance status: ≥ 90% vs <90% • HCT-CI: 0 vs 1 vs 2 vs ≥ 3 • Fungal infection in 3 months prior to HCT: Yes vs No • WBC at start of conditioning: continuous variable (but will dichotomize based on the

data for MVA) • ANC at start of conditioning: continuous variable (but will dichotomize based on the

data for MVA) • ALC at start of conditioning: continuous variable (but will dichotomize based on the

data for MVA)

Disease Related: • Disease risk index: low vs intermediate vs high • Time from diagnosis to transplant • Disease

Transplant Related:

• Conditioning regimen intensity: myeloablative vs reduced-intensity/non-myeloablative

• TBI: yes versus no • TBI dose: ≤1200cGy vs. >1200cGy • Donor age (for unrelated recipients): 18--20y vs. 21-30y vs. 31-40y vs. 41-50y vs. 51-

60y • Donor-recipient sex: M-M vs. M-F vs. F-M vs. F-F • Donor-recipient CMV serostatus: -/- vs +/- vs -/+ vs +/+ • Donor-recipient HLA-match:

o Related: Matched versus mismatched o Unrelated: Well-matched versus partially matched vs. mismatched

• GVHD prophylaxis: calcineurin inhibitor±other vs. T-cell depletion vs. other • Source of stem cells:

o BM vs. PBSC vs. CB vs. Haplo. • Planned therapy with Growth factors (G-CSF or GM-CSF) post-transplant: yes vs. no

(defined as day-3 to day15) • Use of IVIG: yes/no

Overall infection related:

• Antiviral prophylaxis: yes versus no. • Intensive care unit affect: ICU stay vs. no ICU.

Bacterial Infections Related:

• Type of bacteria • Time from transplant to BSI within 100 days • Year of transplant: 2008 vs. 2009 vs. 2010 vs. 2011 vs. 2012

25


Post-transplant event variables: • Median time to neutrophil engraftment • Median onset of grade II – IV acute GVHD • Median onset of chronic GVHD • Median time to platelet engraftment • Mucositis yes versus no • Grade of mucositis • Steroid responsive versus steroid resistant acute GVHD therapy • Active viral infection: yes versus no (Patients who develop HSV related oral mucositis

may be more prone to translocation and thus bacterial bloodstream infection)

8.0 STUDY DESIGN: Two analyses are planned for all objectives except “Cumulative incidence of early VRE BSI” which will only be assessed in the bacterial BSI group.

8.1 Analysis 1 will compare patients with BSI-VEP vs. BSI-LEP vs. Both vs no BSI.

Patients will be categorized into 4 mutually exclusive groups: • BSI – VEP: Patients with a bacterial BSI occurring between day -10 and 14 days

after neutrophil engraftment • BSI – LEP: Patients with a bacterial BSI occurring between 15 days after

neutrophil engraftment and day 100 after transplant • Both: Patients with a bacterial BSI occurring during the VEP and a second BSI

occurring during the LEP periods • Controls: Patients without a bacterial BSI between day -10 and day 100 after

transplant.

8.2 Analysis 2 will compare early VRE BSI in 100 days vs. other early bacterial BSI in 100 days vs. no early BSI within 100 days to ascertain the impact of early VRE BSI Patients will be categorized into 3 mutually exclusive groups:

• VRE-BSI: Patients with a BSI caused by VRE occurring between day -10 and day 100 after transplant

• Other-BSI: Patients with a BSI caused by any bacteria except VRE between day -10 and day 100 after transplant

• Controls: Patients without a bacterial BSI between day -10 and day 100 after transplant.

Patient-, disease-, and transplant –related factors will be compared between groups using the Chi-square test for categorical variables and the Wilcoxon two-sample test for continuous variables. For time dependent variables (neutrophil engraftment and acute GVHD), the data are descriptive only as these events occur after transplant but may occur prior to the bacterial BSI. The probabilities of overall survival will be calculated using the Kaplan-Meier estimator. Values for other endpoints will be generated using cumulative incidence estimates to account for competing risks. A cox model for the entire population will be fit to assess the impact of early bacterial BSI on the outcomes of overall survival as a time dependent co-variate main effect variable. The proportional hazards assumption will be checked. If violated, it will be included as time-

26


dependent covariate. An interaction between the main effect and significant covariates will be examined. For TRM, relapse, PFS, and OS, the model will be constructed without acute GVHD first. After finding a final model for each outcome, acute GVHD will be examined. An interaction between the main effect and acute GVHD will be carefully investigated. The final models with and without patients with BSI who never got neutrophil recovery will be compared. Center effect will be tested using the score test of Commenges and Andersen [23].

9.0 REFERENCES: (need to update reference style so they are all consistent)

1. Gluckman E, Berger R, Dutreix J. Bone marrow transplantation for Fanconi anemia. Semin Hematol. 1984; 21:20–6.

2. Wagner JE, Broxmeyer HE, Byrd RL, et al. Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment. Blood. 1992; 79:1874–81.

3. Rocha V, Wagner JE, Sobocinski K, Klein JP, Zhang MJ, Horowitz MM, et al. Comparison of graft-versus-host disease in children transplanted with HLA identical sibling umbilical cord blood versus HLA identical sibling bone marrow transplant. N Engl J Med. 2000; 342:1846–54.

4. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007; 369:1947–54.

5. Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR, Berkowitz RL, Cabbad M, Dobrila NL, Taylor PE, Rosenfield RE, Stevens CE. Outcomes among 562 recipients of placental-blood transplants for unrelated donors. N Engl J Med. 1998; 339:1565–77.

6. Laughlin M, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE, et al. Hematopoietic engraftment and survival in adult recipients of umbilical cord blood from unrelated donors. N Engl J Med. 2001; 344:1815–22.

7. Brunstein CG, Weisdorf DJ, Defor T, et al. Favorable leukemia-free survival (LFS) for adults and children undergoing myeloablative umbilical cord blood (UCB) transplantation with cyclophosphamide (CY), fludarabine (FLU) and total body irradiation (TBI): a single center analysis of 194 patients. Blood. 2008; 112:682.

8. Michalet M, Le QH, Robin M, et al. Double cord blood cell hematopoietic stem cell transplantation after standard or reduced intensity conditioning: report of the SFGM-TC registry. Blood. 2008; 112:688.

9. Atsuta Y, Suzuki R, Nagamura-Inoue T, et al. Disease specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood. 2009; 113: 1631–8.

10. Eapen M, Rocha V, Scaradavou A, et al. Effect of stem cell source on transplant outcomes in adult patients with acute leukemia: a comparison of unrelated bone marrow, peripheral blood, and cord blood [abstract]. Blood 2008; 112:151. Lancet Oncology

11. Cahu X, Rialland F, Touzeau C, Chevallier P, Guillaume T, Delaunay J, Ayari S, Dubruille V, Le Gouill S, Mahe B, Gastinne T, Blin N, Saulquin B, Harousseau JL, Moreau P, Mohty M. Infectious complications after unrelated umbilical cord blood transplantation in adult patients with hematologic malignancies. Biol Blood Marrow Transplant. 2009; 15:1531-7.

12. N.G. Almyroudis, A. Fuller, A. Jakubowski et al. Pre- and post-engraftment bloodstream infection rates and associated mortality in allogeneic hematopoietic stem cell transplant recipients Transpl Infect Dis, 7 (2005), pp. 11–17

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13. R. Avery, M. Kalaycio, B. Pohlman et al. Early vancomycin-resistant enterococcus (VRE) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course Bone Marrow Transplant, 35 (2005), pp. 497–499

14. D. Kapur, D. Dorsky, J.M. Feingold et al. Incidence and outcome of vancomycin-resistant enterococcal bacteremia following autologous peripheral blood stem cell transplantation Bone Marrow Transplant, 25 (2000), pp. 147–152

15. D.M. Weinstock, M. Conlon, C. Iovino et al. Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant Biol Blood Marrow Transplant, 13 (2007), pp. 615–621

16. A. Zirakzadeh, D.A. Gastineau, J.N. Mandrekar, J.P. Burke, B.P. Johnston, R. Patel Vancomycin-resistant enterococcal colonization appears associated with increased mortality among allogeneic hematopoietic stem cell transplant recipients Bone Marrow Transplant, 41 (2008), pp. 385–392. (Increased mortality by 100 days after transplant correlated with the presence of VRE bacteremia)

17. Dubberke ER, Hollands JM, Georgantopoulos P, Augustin K, DiPersio JF, Mundy LM, Khoury HJ. Vancomycin-resistant enterococcal bloodstream infections on a hematopoietic stem cell transplant unit: are the sick getting sicker? Bone Marrow Transplant 2006; 38: 813-9.

18. Vydra J, Shanley RM, George I, Ustun C, Smith AR, Weisdorf DJ, Young JA. Enterococcal bacteremia is associated with increased risk of mortality in recipients of allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2012; 55: 764-70.

19. Kamboj M, Chung D, Seo SK, Pamer EG, Sepkowitz KA, Jakubowski AA, Papanicolaou G. The changing epidemiology of vancomycin-resistant Enterococcus (VRE) bacteremia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Biol Blood Marrow Transplant 2010; 16: 1576-81.

20. Rosko AE, Corriveau M, Suwantarat N, Arfons L, Treasure M, Parker P, Jacobs M, Fu P, Salata R, Lazarus HM. Vancomycin-resistant enterococci infection: not just for the transplanted. Leuk Lymphoma 2014; 55: 1320-5.

21. Tavadze M, Rybicki L, Mossad S, Avery R, Yurch M, Pohlman B, Duong H, Dean R, Hill B, Andresen S, Hanna R, Majhail N, Copelan E, Bolwell B, Kalaycio M, Sobecks R. Risk factors for vancomycin-resistant enterococcus bacteremia and its influence on survival after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2014; 49: 1310-6.

22. Young JAH, Logan BR, Wu M, Wingard JR, Weisdorf DJ, Mudrick C, Knust K, Horowitz MM, Confer D, Dubberke ER, Pergam SA, Marty FM, Strasfeld L, Anasetti C, for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0201. (2015) Infections following transplantation of bone marrow or peripheral-blood stem cells from unrelated donors. Biology of Blood and Marrow Transplant 2015; Sep 25.

23. Commenges D and Andersen PK, Score test of homogeneity for survival data, Lifetime Data Analysis 1995; 1: 145-156.

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Table 1.1 Characteristics of patients who underwent first allogeneic transplants for AML, ALL and MDS, reported to the CIBMTR, from 2008 to 2012

Variable N(%) Patient related Patients 7128 Number of centers 181 Age, median(range), years 47 (<1 - 79) Age at transplant, years

<=10 768 (11) 11-20 655 ( 9) 21-30 707 (10) 31-40 732 (10) 41-50 1125 (16) 51-60 1641 (23) >60 1500 (21)

Gender Male 3952 (55) Female 3176 (45)

Karnofsky score at transplant <90 2230 (31) >=90 4765 (67) Missing 133 ( 2)

Disease-related Disease

AML 4078 (57) ALL 1505 (21) MDS 1545 (22)

Disease stage at transplant AML/ALL Early 2961 (42) AML/ALL Intermediate 1542 (22) AML/ALL Advanced 1039 (15) MDS Early 606 ( 9) MDS Advanced 939 (13) Missing 41 (<1)

Time from diagnosis to TX, median(range), months 7 (<1 - 313) Time from diagnosis to transplant (months)

0-5 3203 (45) 6-11 1743 (24) 12-17 740 (10) 18-23 428 ( 6) >=24 1014 (14)

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Variable N(%) HCT-CI

0 3070 (43) 1 1042 (15) 2 830 (12) 3 951 (13) 4 509 ( 7) 5 584 ( 8) Missing 142 ( 2)

Fungal infection 3 month prior to TX No 6819 (96) Yes 309 ( 4)

WBC prior to preparative regimen, median(range), 10^9/L 3.9 (0.0 - 28.9) Missing 76 ( 1)

Neutrophils prior to preparative regimen, median(range), 10^9/L 2.2 (0.0 - 25.2) Missing 401 ( 6)

Lymphocytes prior to preparative regimen, median(range), months 0.9 (0.0 - 9.4) Missing 354 ( 5)

Transplant-related Conditioning regimen intensity

Myeloablative 5249 (74) RIC/NMA 1879 (26)

TBI Yes 3398 (48) No 3730 (52)

TBI dose, median(range), cGy 1200 (200 – 1500) TBI dose

No TBI 3730 (52) <=1200 cGy 2126 (30) >1200 cGy 1272 (18)

Donor/Recipient CMV status +/+ 1590 (22) +/- 592 ( 8) -/+ 2743 (38) -/- 2089 (29) Missing 114 ( 2)

Donor/recipient gender match Male-Male 2453 (34) Male-Female 1806 (25) Female-Male 1471 (21) Female-Female 1351 (19) Missing 47 (<1)

30


Variable N(%) Donor age, years Cord blood 1834 (26) Related/Other related 2118 (30)

18-20 227 ( 3) 21-30 1250 (18) 31-40 729 (10) 41-50 518 ( 7) 51-60 153 ( 2) Missing 299 ( 4)

Donor/recipient HLA match Cord blood 1834 (26) HLA-identical siblings 1990 (28) Matched related 20 (<1) Haplo 98 ( 1) Mismatched related 10 (<1) 8/8 unrelated 2302 (32) 7/8 unrelated 655 ( 9) <=6/8 unrelated 49 (<1) Unrelated (HLA match information missing) 170 ( 2)

Graft type Bone Marrow 1067 (15) Peripheral blood 4227 (59) Cord blood 1834 (26)

ATG/CAMPATH as conditioning or GVHD prophylaxis ATG alone 2155 (30) CAMPATH alone 145 ( 2) No ATG or CAMPATH 4828 (68)

GVHD prophylaxis Ex vivo T-cell depletion 67 (<1) CD34 selection 74 ( 1) Cyclophosphamide 121 ( 2) TAC + MMF +- others 1014 (14) TAC + MTX +- others 2856 (40) TAC + others 424 ( 6) TAC alone 127 ( 2) CSA + MMF +- others (except TAC ) 1345 (19) CSA + MTX +- others (except TAC , MMF) 721 (10) CSA + others (except TAC , MTX, MMF) 231 ( 3) CSA alone 99 ( 1) SIRO +/- others (Not TAC/CSA) 19 (<1) ATG/CAMPATH alone 7 (<1)

31


Variable N(%) Other GVHD prophylaxis 23 (<1)

G-CSF, GM-CSF (day-3 to day15) Yes 3983 (56) No 3145 (44)

Supplemental IVIG Yes 3058 (43) No 4070 (57)

Year of transplant 2008 2011 (28) 2009 1820 (26) 2010 1335 (19) 2011 959 (13) 2012 1003 (14)

32


Table 1.2 Bacterial blood stream infection between day 0 – day 100 and time dependent variables for patients who underwent first allogeneic transplants for AML, ALL and MDS, reported to the CIBMTR,

from 2008 to 2012

Variable N(%) Patients 7128 Type of bacteria

No BSI 4472 (63) VRE only 111 ( 2) VRE + other organisms 147 ( 2) Enterococcus Vanc Sensitive 89 ( 1) GNR, Enterobacteriaceae 256 ( 4) GNR, Non-Enterobacteriaceae 94 ( 1) Mycobacterium 7 (<1) Staphylococcus(coagulase negative) 647 ( 9) Staphylococcus(aureus/NOS) 172 ( 2) Streptococcus 197 ( 3) Anaerobes 72 ( 1) Others 116 ( 2) Polymicrobial (no VRE) 129 ( 2) 2 BSI (no VRE) 490 ( 7) 3 BSI (no VRE) 105 ( 1) 4 BSI (no VRE) 20 (<1) 5 BSI (no VRE) 4 (<1)

Time from transplant to BSI, days 11 (<1 - 100) ANC>500 after transplant

Yes 6784 (95) No 326 ( 5) Missing 18 (<1)

Time from transplant to ANC>500, days 15 (<1 - 111) Platelet>20*10^9/L after HCT

Yes 6150 (86) No 916 (13) Missing 62 (<1)

Time from transplant to platelet>20*10^9/L, days 20 (<1 - 1180) aGVHD

Yes 2847 (40) No 4218 (59) Missing 63 (<1)

Time from transplant to aGVHD, days 28 (7 - 178) cGVHD

Yes 3145 (44)

33


Variable N(%) No 3974 (56) Missing 9 (<1)

Time from transplant to cGVHD, months 6 (2 - 67) Median follow-up of survivors, months 59 (3 - 87)

*Low risk: AML and ALL: CR1; MDS:RA, RARS, RCMD, RCMD/RS, MDS Unclassifiable isolated 5q-syndrome Intermediate risk: AML and ALL: CR2, CR3+; High risk: AML and ALL: Never treated, PIF, relapse; MDS: RAEB, RAEB-T, RAEB-1, RAEB-2,

Abbreviations: ALL=acute lymphoblastic leukemia;AML=acute myelogenous leukemia; MDS =myelodysplastic syndromes; HLA=human leukocyte antigen; CP=chronic phase; CR=complete remission; BP=blast phase FK506 = tacrolimus; CSA = cyclosporine; MTX = methotrexate; TBI = total body irradiation; MMF=mycophenolate mofetil; CSA= cyclosporine A; ATG=anti-thymocyte globulin; COR=corticosteroids; ECP=extra-corporeal photopheresis; KGF=kepivance; MAB=in vivo monoclonal antibody; IVIM=in vivo immunotoxin; SIRO=sirolim us; URSO=ursodiol; OTH=other agent

34


Table 1.3 Univariate outcomes for patients who underwent first allogeneic transplants for AML, ALL and MDS, reported to the CIBMTR, from 2008 to 2012

Outcomes N Eval

Probability (95% CI)

Overall survival from transplant @100 days 7128 85 (84-86) % @6 months 74 (73-75) % @ 1 year 61 (60-62) %

Relapse 7028

@100 days 14 (13-15)% @ 6 months 23 (22-24)% @ 1 year 30 (28-31)%

Treatment related mortality 7028 @ 100 days 10 (9-11)% @ 6 months 14 (14-15)% @ 1 year 19 (18-20)%

Disease free survival 7028 @ 100 days 76 (75-77)% @ 6 months 63 (62-64)% @ 1 year 51 (50-53)%

cGVHD @ 6 month 7119 24 (23-25)% @ 1 year 39 (38-40)%

VRE infection @ 30 days 7124 2 (2-3)% @ 60 days 3 (3-3)% @ 100 days 4 (3-4)%

Fungal infection @ 30 days 7128 4 (4-5)% @ 60 days 6 (6-7)% @ 100 days 8 (8-9)%

Viral infection @ 30 days 7128 23 (22-24)% @ 60 days 39 (38-40)% @100 days 44 (43-45)%

35


Table 1.4 Cause of death for patients who underwent first allogeneic transplants for AML, ALL and MDS, reported to the CIBMTR, from 2008 to 2012

Variable N(%) Patients who died 4100 (58) Cause of death

Graft rejection 53 ( 1) Infection 550 (13) IPN 51 ( 1) Organ Failure 589 (14) GVHD 443 (11) Recurrent/Persistent Disease 1956 (48) Secondary malignancy 47 ( 1) Hemorrhage 77 ( 2) Other cause 250 ( 6) Unknown 84 ( 2)

Median follow-up of survivors, months 59 (3 - 87)

36


Table 2.1 Characteristics of patients who underwent first allogeneic transplants for AML, ALL and MDS with either VEP-BSI, LEP-BSI, Both VEP- and LEP-BSI, or without BSI by 100 day after transplant,

reported to the CIBMTR, from 2008 to 2012 Variable VEP-BSI LEP-BSI Both-BSI Without BSI p_value Patient related Number of patients 1493 824 339 4472 Number of centers 165 138 105 177 Age, median(range), years 42 (<1 - 75) 46 (<1 - 79) 42 (1 - 74) 49 (<1 - 78) <0.001 Age at transplant, years <0.001

<=10 215 (14) 93 (11) 55 (16) 405 ( 9) 11-20 179 (12) 98 (12) 40 (12) 338 ( 8) 21-30 162 (11) 84 (10) 31 ( 9) 430 (10) 31-40 163 (11) 87 (11) 30 ( 9) 452 (10) 41-50 222 (15) 120 (15) 58 (17) 725 (16) 51-60 327 (22) 175 (21) 75 (22) 1064 (24) >60 225 (15) 167 (20) 50 (15) 1058 (24)

Gender 0.833 Male 837 (56) 446 (54) 186 (55) 2483 (56) Female 656 (44) 378 (46) 153 (45) 1989 (44)

Karnofsky score at transplant 0.907 <90 471 (32) 265 (32) 102 (30) 1392 (31) >=90 995 (67) 541 (66) 233 (69) 2996 (67) Missing 27 ( 2) 18 ( 2) 4 ( 1) 84 ( 2)

Disease-related Disease <0.001

AML 870 (58) 445 (54) 180 (53) 2583 (58) ALL 372 (25) 190 (23) 99 (29) 844 (19) MDS 251 (17) 189 (23) 60 (18) 1045 (23)

Disease (Leukemia stage at transplant

<0.001

AML/ALL Early 596 (40) 325 (39) 132 (39) 1908 (43) AML/ALL Intermediate 378 (25) 192 (23) 88 (26) 884 (20) AML/ALL Advanced 255 (17) 115 (14) 56 (17) 613 (14) MDS Early 95 ( 6) 70 ( 8) 26 ( 8) 415 ( 9) MDS Advanced 156 (10) 119 (14) 34 (10) 630 (14) Missing 13 (<1) 3 (<1) 3 (<1) 22 (<1)

Time from diagnosis to TX, median(range), months

7 (<1 - 313) 7 (<1 - 173) 7 (1 - 224) 6 (<1 - 291) 0.056

Time from diagnosis to transplant (months)

0.519

0-5 646 (43) 357 (43) 142 (42) 2058 (46)

37


Variable VEP-BSI LEP-BSI Both-BSI Without BSI p_value 6-11 366 (25) 205 (25) 87 (26) 1085 (24) 12-17 170 (11) 91 (11) 40 (12) 439 (10) 18-23 93 ( 6) 60 ( 7) 19 ( 6) 256 ( 6) >=24 218 (15) 111 (13) 51 (15) 634 (14)

HCT-CI 0.525 0 651 (44) 353 (43) 139 (41) 1927 (43) 1 224 (15) 114 (14) 55 (16) 649 (15) 2 159 (11) 91 (11) 44 (13) 536 (12) 3 208 (14) 108 (13) 37 (11) 598 (13) 4 118 ( 8) 68 ( 8) 23 ( 7) 300 ( 7) 5 107 ( 7) 77 ( 9) 35 (10) 365 ( 8) 99 26 ( 2) 13 ( 2) 6 ( 2) 97 ( 2)

Fungal infection 3 month prior to TX

0.270

No 1425 (95) 796 (97) 319 (94) 4279 (96) Yes 68 ( 5) 28 ( 3) 20 ( 6) 193 ( 4)

WBC prior to preparative regimen, median(range), 10^9/L

3.8 (0.0 - 28.9) 4.0 (0.0 - 26.2) 3.8 (0.0 - 21.7)

3.9 (0.0 - 28.) 0.199

Missing 16 ( 1) 9 ( 1) 7 ( 2) 44 (<1) Neutrophils prior to preparative regimen, median(range), 10^9/L

2.1 (0.0 - 20.8) 2.2 (0.0 - 18.0) 2.1 (0.0 - 20.8)

2.2 (0.0 - 25. 0.317

Missing 83 ( 6) 46 ( 6) 12 ( 4) 260 ( 6) Lymphocytes prior to preparative regimen, median(range), months

0.9 (0.0 - 9.4) 0.9 (0.0 - 5.0) 0.9 (0.0 - 6.1) 0.9 (0.0 - 8.1 0.005

Missing 77 ( 5) 33 ( 4) 11 ( 3) 233 ( 5) Transplant-related Conditioning regimen intensity

<0.001

Myeloablative 1208 (81) 617 (75) 275 (81) 3149 (70) RIC/NMA 285 (19) 207 (25) 64 (19) 1323 (30)

TBI <0.001 No 664 (44) 430 (52) 156 (46) 2480 (55) Yes 829 (56) 394 (48) 183 (54) 1992 (45)

TBI dose, median(range), cGy 1200 (200 - 1500)

1200 (200 - 1400) 1200 (200 - 1400)

1200 (200 - 150 <0.001

TBI dose <0.001 No TBI 664 (44) 430 (52) 156 (46) 2480 (55) <=1200 cGy 454 (30) 265 (32) 110 (32) 1297 (29) >1200 cGy 375 (25) 129 (16) 73 (22) 695 (16)

38


Variable VEP-BSI LEP-BSI Both-BSI Without BSI p_value Donor/Recipient CMV status <0.001

+/+ 291 (19) 179 (22) 77 (23) 1043 (23) +/- 98 ( 7) 49 ( 6) 27 ( 8) 418 ( 9) -/+ 647 (43) 328 (40) 141 (42) 1627 (36) -/- 441 (30) 256 (31) 85 (25) 1307 (29) Missing 16 ( 1) 12 ( 1) 9 ( 3) 77 ( 2)

Donor/recipient gender match

0.783

Male-Male 523 (35) 269 (33) 107 (32) 1554 (35) Male-Female 359 (24) 231 (28) 88 (26) 1128 (25) Female-Male 310 (21) 174 (21) 78 (23) 909 (20) Female-Female 292 (20) 145 (18) 63 (19) 851 (19) Missing 9 (<1) 5 (<1) 3 (<1) 30 (<1)

Donor age, years <0.001 Cord blood 594 (40) 210 (25) 112 (33) 918 (21) Related/Other related 366 (25) 211 (26) 87 (26) 1454 (33) 18-20 43 ( 3) 28 ( 3) 8 ( 2) 148 ( 3) 21-30 193 (13) 157 (19) 43 (13) 857 (19) 31-40 118 ( 8) 98 (12) 34 (10) 479 (11) 41-50 96 ( 6) 63 ( 8) 38 (11) 321 ( 7) 51-60 28 ( 2) 24 ( 3) 4 ( 1) 97 ( 2) Missing 55 ( 4) 33 ( 4) 13 ( 4) 198 ( 4)

Donor/recipient HLA match <0.001 Cord blood 594 (40) 210 (25) 112 (33) 918 (21) HLA-identical siblings 337 (23) 196 (24) 78 (23) 1379 (31) Matched related 4 (<1) 1 (<1) 1 (<1) 14 (<1) Haplo 24 ( 2) 13 ( 2) 6 ( 2) 55 ( 1) Mismatched related 1 (<1) 1 (<1) 2 (<1) 6 (<1) 8/8 unrelated 382 (26) 277 (34) 85 (25) 1558 (35) 7/8 unrelated 114 ( 8) 98 (12) 42 (12) 401 ( 9) <=6/8 unrelated 10 (<1) 5 (<1) 7 ( 2) 27 (<1) Unrelated (HLA match information missing)

27 ( 2) 23 ( 3) 6 ( 2) 114 ( 3)

Graft type <0.001 Bone Marrow 239 (16) 114 (14) 52 (15) 662 (15) Peripheral blood 660 (44) 500 (61) 175 (52) 2892 (65) Cord blood 594 (40) 210 (25) 112 (33) 918 (21)

ATG/CAMPATH as conditioning or GVHD prophylaxis

0.241

ATG alone 443 (30) 244 (30) 101 (30) 1367 (31)

39


Variable VEP-BSI LEP-BSI Both-BSI Without BSI p_value CAMPATH alone 36 ( 2) 9 ( 1) 11 ( 3) 89 ( 2) No ATG or CAMPATH 1014 (68) 571 (69) 227 (67) 3016 (67)

GVHD prophylaxis <0.001 Ex vivo T-cell depletion 29 ( 2) 10 ( 1) 2 (<1) 26 (<1) CD34 selection 19 ( 1) 2 (<1) 5 ( 1) 48 ( 1) Cyclophosphamide 20 ( 1) 15 ( 2) 5 ( 1) 81 ( 2) TAC + MMF +- others 192 (13) 145 (18) 52 (15) 625 (14) TAC + MTX +- others 488 (33) 338 (41) 121 (36) 1909 (43) TAC + others 85 ( 6) 38 ( 5) 11 ( 3) 290 ( 6) TAC alone 30 ( 2) 11 ( 1) 5 ( 1) 81 ( 2) CSA + MMF +- others (except TAC )

349 (23) 152 (18) 76 (22) 768 (17)

CSA + MTX +- others (except TAC , MMF)

171 (11) 73 ( 9) 38 (11) 439 (10)

CSA + others (except TAC , MTX, MMF)

82 ( 5) 28 ( 3) 19 ( 6) 102 ( 2)

CSA alone 22 ( 1) 9 ( 1) 4 ( 1) 64 ( 1) SIRO +/- others (Not TAC/CSA)

3 (<1) 1 (<1) 0 15 (<1)

ATG/CAMPATH alone 0 0 0 7 (<1) Other GVHD prophylaxis 3 (<1) 2 (<1) 1 (<1) 17 (<1)

G-CSF, GM-CSF (day-3 to day15)

<0.001

No 591 (40) 326 (40) 135 (40) 2093 (47) Yes 902 (60) 498 (60) 204 (60) 2379 (53)

Supplemental IVIG <0.001 No 780 (52) 435 (53) 149 (44) 2706 (61) Yes 713 (48) 389 (47) 190 (56) 1766 (39)

Year of transplant <0.001 2008 448 (30) 248 (30) 121 (36) 1194 (27) 2009 411 (28) 240 (29) 96 (28) 1073 (24) 2010 284 (19) 158 (19) 56 (17) 837 (19) 2011 177 (12) 98 (12) 42 (12) 642 (14) 2012 173 (12) 80 (10) 24 ( 7) 726 (16)

Median follow-up of survivors, months

60 (3 - 87) 60 (3 - 81) 60 (12 - 85) 59 (3 - 87)

40


Table 2.2 Bacterial blood stream infection between day 0 – day 100 and time dependent variables for patients who underwent first allogeneic transplants for AML, ALL and MDS, with either VEP-BSI, LEP-BSI, Both VEP- and LEP-BSI, or without BSI by 100 day after transplant, reported to the CIBMTR, from

2008 to 2012 Variable VEP-BSI LEP-BSI Both-BSI Without BSI Number of patients 1493 824 339 4472 Type of bacteria

No BSI 0 0 0 4472 VRE only 82 ( 5) 29 ( 4) 0 0 VRE + other organisms 73 ( 5) 27 ( 3) 47 (14) 0 Enterococcus Vanc Sensitive 65 ( 4) 24 ( 3) 0 0 GNR, Enterobacteriaceae 186 (12) 70 ( 8) 0 0 GNR, Non-Enterobacteriaceae 48 ( 3) 46 ( 6) 0 0 Mycobacterium 2 (<1) 5 (<1) 0 0 Staphylococcus(coagulase negative) 371 (25) 276 (33) 0 0 Staphylococcus(aureus/NOS) 106 ( 7) 66 ( 8) 0 0 Streptococcus 173 (12) 24 ( 3) 0 0 Anaerobes 53 ( 4) 19 ( 2) 0 0 Others 60 ( 4) 56 ( 7) 0 0 Polymicrobial(no VRE) 84 ( 6) 45 ( 5) 0 0 2 BSI(no VRE) 165 (11) 116 (14) 209 (62) 0 3 BSI(no VRE) 24 ( 2) 17 ( 2) 64 (19) 0 4 BSI(no VRE) 1 (<1) 4 (<1) 15 ( 4) 0 5 BSI(no VRE) 0 0 4 ( 1) 0

Time from transplant to BSI, days 7 (<1 - 74) 58 (21 - 100) 8 (<1 - 36) ANC>500

Yes 1300 (87) 824 339 4321 (97) No 188 (13) 0 0 138 ( 3) Missing 5 (<1) 0 0 13 (<1)

Time from transplant to ANC>500, days 17 (<1 - 99) 15 (<1 - 42) 16 (1 - 50) 15 (<1 - 111) Platelet>20*10^9/L

Yes 1104 (74) 721 (88) 276 (81) 4049 (91) No 368 (25) 96 (12) 57 (17) 395 ( 9) Missing 21 ( 1) 7 (<1) 6 ( 2) 28 (<1)

Time from transplant to pletlet>20*10^9/L, days

27 (1 - 1180)

20 (<1 - 293) 26 (1 - 640) 19 (<1 - 753)

aGVHD Yes 546 (37) 433 (53) 195 (58) 1673 (37) No 941 (63) 387 (47) 140 (41) 2783 (62) Missing 6 (<1) 4 (<1) 4 ( 1) 16 (<1)

Time from transplant to aGVHD, days 28 (7 - 175) 27 (7 - 176) 26 (7 - 168) 29 (7 - 178)

41


cGVHD Yes 576 (39) 330 (40) 135 (40) 2104 (47) No 917 (61) 492 (60) 204 (60) 2361 (53) Missing 0 2 (<1) 0 7 (<1)

Time from transplant to cGVHD, months 6 (2 - 66) 6 (2 - 38) 5 (3 - 48) 6 (2 - 67)

42


Table 2.3.1 Univariate outcomes of patients who underwent first allogeneic transplants for AML, ALL and MDS with either VEP-BSI, LEP-BSI, Both VEP-and LEP-BSI, or without BSI by 100 day after transplant, reported to the CIBMTR, from 2008 to 2012

VEP-BSI LEP-BSI Both Without BSI Outcomes

N Eval Probability

(95% CI)

N Eval Probability

(95% CI)

N Eval Probability

(95% CI)

N Eval Probability

(95% CI) P-value

Overall survival from transplant @6 months 1493 68 (66-70)% 824 63 (60-66)% 339 63 (57-67)% 4472 79 (78-80)% <.0001 @ 1 year 55 (53-58)% 50 (46-53)% 48 (43-54)% 66 (65-67)% <.0001

Relapse 1467 815 331 4415

@ 6 months 19 (17-21)% 26 (23-29)% 22 (18-27)% 42 (22-25)% 0.0006 @ 1 year 26 (24-28)% 31 (28-35)% 27 (23-32)% 30 (29-32)% 0.0066

Non-relapse mortality 1467 815 331 4415 @ 6 months 21 (19-23)% 21 (18-24)% 25 (21-30)% 10 (9-11)% <.0001 @ 1 year 26 (23-28)% 26 (23-29)% 31 (26-36)% 15(14-16)% <.0001

Disease free survival 1467 815 331 4415 @ 6 months 60 (57-62)% 54 (50-57)% 53 (47-58)% 66 (65-68)% <.0001 @ 1 year 48 (46-51)% 43 (39-46)% 42 (36-47)% 55 (53-56)% <.0001

cGVHD @ 6 months 1493 21 (19-23)% 822 23 (21-26)% 339 23 (19-28)% 4465 25 (23-26)% 0.0554 @ 1 year 35 (32-37)% 35 (32-39)% 36 (30-41)% 41 (40-43)% <.0001

43


Table 2.3.2 Univariate outcomes of patients who underwent first allogeneic transplants for AML, ALL and MDS with either VEP-BSI, LEP-BSI, Both VEP- and LEP-BSI, or without BSI by 100 day after transplant, reported to the CIBMTR, from 2008 to 2012.*

VEP-BSI LEP-BSI Both Without BSI Outcomes

N Eval Probability

(95% CI)

N Eval Probability

(95% CI)

N Eval Probability

(95% CI)

N Eval Probability

(95% CI) P-value

Overall survival from transplant @6 months 1154 88 (64-90)% 674 77 (73-80)% 271 78 (73-83)% 3962 89 (88-90)% <.0001 @ 1 year 71 (69-74)% 60 (57-64)% 61 (54-66)% 74 (73-76)% <.0001

Relapse 1146 671 268 3929

@ 6 months 18 (15-20)% 24 (21-27)% 24 (19-29)% 22 (20-23)% 0.0015 @ 1 year 27 (24-29)% 31 (28-35)% 31 (25-36)% 29 (28-31)% 0.1236

Non-relapse mortality 1146 671 268 3929 @ 6 months 6 (5-7)% 11 (8-13)% 11 (8-15)% 4 (3-5)% <.0001 @ 1 year 12 (10-14)% 17 (14-20)% 18(14-23)% 9(8-10)% <.0001

Disease free survival 1146 671 268 3929 @ 6 months 77 (74-79)% 65 (62-69)% 65 (59-70)% 74 (73-76)% <.0001 @ 1 year 61 (59-64)% 52 (48-56)% 51 (45-57)% 62 (60-63)% <.0001

cGVHD @ 6 months 1154 27 (25-30)% 673 29 (25-32)% 271 29 (24-35)% 3960 28 (26-29)% 0.8665 @ 1 year 45 (42-48)% 43 (39-47)% 44 (38-50)% 46 (45-48)% 0.2007 *Note, patients who died before 100 day have been removed.

44


Table 2.4 Cause of death for patients who underwent first allogeneic transplants for AML, ALL and MDS with either VEP-BSI, LEP-BSI, Both VEP- and LEP-BSI, or without BSI by 100 day after transplant,

reported to the CIBMTR, from 2008 to 2012. Variable VEP-BSI LEP-BSI Both-BSI Without BSI Patients who died 921 (62) 541 (66) 235 (69) 2403 (54) Cause of death

Graft rejection 25 ( 3) 2 (<1) 2 (<1) 24 (<1) Infection 151 (16) 79 (15) 43 (18) 277 (12) IPN 17 ( 2) 7 ( 1) 3 ( 1) 24 (<1) Organ Failure 162 (18) 70 (13) 35 (15) 322 (13) GVHD 71 ( 8) 91 (17) 42 (18) 239 (10) Recurrent/Persistent Disease 364 (40) 245 (45) 91 (39) 1256 (52) Secondary malignancy 10 ( 1) 8 ( 1) 0 29 ( 1) Hemorrhage 26 ( 3) 11 ( 2) 3 ( 1) 37 ( 2) Other cause 72 ( 8) 25 ( 5) 14 ( 6) 139 ( 6) Unknown 23 ( 2) 3 (<1) 2 (<1) 56 ( 2)

45


Table 3.1 Characteristics of patients who underwent first allogeneic transplants for AML, ALL and

MDS with either VRE BSI, other BSI, or without BSI by day 100 after transplant, reported to the CIBMTR, from 2008 to 2012

Variable VRE BSI Other BSI Without BSI p_value Patient related Patients 258 2398 4472 Number of centers 76 174 177 Age, median(range), years 49 (1 - 73) 42 (<1 - 79) 49 (<1 - 78) <0.001 Age at transplant, years <0.001

<=10 20 ( 8) 343 (14) 405 ( 9) 11-20 19 ( 7) 298 (12) 338 ( 8) 21-30 30 (12) 247 (10) 430 (10) 31-40 27 (10) 253 (11) 452 (10) 41-50 36 (14) 364 (15) 725 (16) 51-60 69 (27) 508 (21) 1064 (24) >60 57 (22) 385 (16) 1058 (24)

Gender 0.667 Male 136 (53) 1333 (56) 2483 (56) Female 122 (47) 1065 (44) 1989 (44)

Karnofsky score at transplant 0.127 <90 100 (39) 738 (31) 1392 (31) >=90 153 (59) 1616 (67) 2996 (67) Missing 5 ( 2) 44 ( 2) 84 ( 2)

Disease-related Disease <0.001

AML 141 (55) 1354 (56) 2583 (58) ALL 67 (26) 594 (25) 844 (19) MDS 50 (19) 450 (19) 1045 (23)

Disease stage at transplant <0.001 AML/ALL Early 100 (39) 953 (40) 1908 (43) AML/ALL Intermediate 45 (17) 613 (26) 884 (20) AML/ALL Advanced 62 (24) 364 (15) 613 (14) MDS Early 16 ( 6) 175 ( 7) 415 ( 9) MDS Advanced 34 (13) 275 (11) 630 (14) Missing 1 (<1) 18 (<1) 22 (<1)

Time from diagnosis to TX, median(range), months 7 (1 - 224) 7 (<1 - 313) 6 (<1 - 291) 0.005 Time from diagnosis to transplant (months) 0.042

0-5 116 (45) 1029 (43) 2058 (46) 6-11 76 (29) 582 (24) 1085 (24) 12-17 23 ( 9) 278 (12) 439 (10)

46


Variable VRE BSI Other BSI Without BSI p_value 18-23 11 ( 4) 161 ( 7) 256 ( 6) >=24 32 (12) 348 (15) 634 (14)

HCT-CI 0.023 0 87 (34) 1056 (44) 1927 (43) 1 50 (19) 343 (14) 649 (15) 2 31 (12) 263 (11) 536 (12) 3 41 (16) 312 (13) 598 (13) 4 19 ( 7) 190 ( 8) 300 ( 7) 5 29 (11) 190 ( 8) 365 ( 8) Missing 1 (<1) 44 ( 2) 97 ( 2)

Fungal infection 3 month prior to TX 0.312 Yes 16 ( 6) 100 ( 4) 193 ( 4) No 242 (94) 2298 (96) 4279 (96)

WBC prior to preparative regimen, median(range), 10^9/L

3.6 (0.0 - 26.2) 3.9 (0.0 - 28.9) 3.9 (0.0 - 28.9) 0.036

Missing 6 ( 2) 26 ( 1) 44 (<1) Neutrophils prior to preparative regimen, median(range), 10^9/L

2.1 (0.0 - 20.8) 2.2 (0.0 - 20.8) 2.2 (0.0 - 25.2) 0.141

Missing 23 ( 9) 118 ( 5) 260 ( 6) Lymphocytes prior to preparative regimen, median(range), months

0.8 (0.0 - 5.7) 0.9 (0.0 - 9.4) 0.9 (0.0 - 8.1) 0.066

Missing 21 ( 8) 100 ( 4) 233 ( 5) Transplant-related Conditioning regimen intensity <0.001

Myeloablative 206 (80) 1894 (79) 3149 (70) RIC/NMA 52 (20) 504 (21) 1323 (30)

TBI <0.001 Yes 139 (54) 1267 (53) 1992 (45) No 119 (46) 1131 (47) 2480 (55)

TBI dose, median(range), cGy 1200(200 – 1400) 1200 (200 – 1500) 1200(200 – 1500) <0.001 TBI dose <0.001

No TBI 119 (46) 1131 (47) 2480 (55) <1200 cGy 78 (30) 751 (31) 1297 (29) >=1200 cGy 61 (24) 516 (22) 695 (16)

Donor/Recipient CMV status <0.001 +/+ 48 (19) 499 (21) 1043 (23) +/- 15 ( 6) 159 ( 7) 418 ( 9) -/+ 128 (50) 988 (41) 1627 (36) -/- 64 (25) 718 (30) 1307 (29) Missing 3 ( 1) 34 ( 1) 77 ( 2)

Donor/recipient gender match 0.742

47


Variable VRE BSI Other BSI Without BSI p_value Male-Male 77 (30) 822 (34) 1554 (35) Male-Female 70 (27) 608 (25) 1128 (25) Female-Male 59 (23) 503 (21) 909 (20) Female-Female 52 (20) 448 (19) 851 (19) Missing 0 17 (<1) 30 (<1)

Donor age, years <0.001 Cord blood 103 (40) 813 (34) 918 (21) Related/Other related 64 (25) 600 (25) 1454 (33) 18-20 5 ( 2) 74 ( 3) 148 ( 3) 21-30 36 (14) 357 (15) 857 (19) 31-40 16 ( 6) 234 (10) 479 (11) 41-50 21 ( 8) 176 ( 7) 321 ( 7) 51-60 5 ( 2) 51 ( 2) 97 ( 2) Missing 8 ( 3) 93 ( 4) 198 ( 4)

Donor/recipient HLA match <0.001 Cord blood 103 (40) 813 (34) 918 (21) HLA-identical siblings 59 (23) 552 (23) 1379 (31) Matched related 0 6 (<1) 14 (<1) Haplo 5 ( 2) 38 ( 2) 55 ( 1) Mismatched related 0 4 (<1) 6 (<1) 8/8 unrelated 60 (23) 684 (29) 1558 (35) 7/8 unrelated 24 ( 9) 230 (10) 401 ( 9) <=6/8 unrelated 4 ( 2) 18 (<1) 27 (<1) Unrelated (HLA match information missing) 3 ( 1) 53 ( 2) 114 ( 3)

Graft type <0.001 Bone Marrow 45 (17) 360 (15) 662 (15) Peripheral blood 110 (43) 1225 (51) 2892 (65) Cord blood 103 (40) 813 (34) 918 (21)

ATG/CAMPATH as conditioning or GVHD prophylaxis

0.289

ATG alone 79 (31) 709 (30) 1367 (31) CAMPATH alone 1 (<1) 55 ( 2) 89 ( 2) No ATG or CAMPATH 178 (69) 1634 (68) 3016 (67)

GVHD prophylaxis <0.001 Ex vivo T-cell depletion 9 ( 3) 32 ( 1) 26 (<1) CD34 selection 6 ( 2) 20 (<1) 48 ( 1) Cyclophosphamide 6 ( 2) 34 ( 1) 81 ( 2) TAC + MMF +- others 38 (15) 351 (15) 625 (14) TAC + MTX +- others 86 (33) 861 (36) 1909 (43) TAC + others 5 ( 2) 129 ( 5) 290 ( 6) TAC alone 5 ( 2) 41 ( 2) 81 ( 2)

48


Variable VRE BSI Other BSI Without BSI p_value CSA + MMF +- others (except TAC ) 62 (24) 515 (21) 768 (17) CSA + MTX +- others (except TAC , MMF) 29 (11) 253 (11) 439 (10) CSA + others (except TAC , MTX, MMF) 7 ( 3) 122 ( 5) 102 ( 2) CSA alone 1 (<1) 34 ( 1) 64 ( 1) SIRO +/- others (Not TAC/CSA) 3 ( 1) 1 (<1) 15 (<1) ATG/CAMPATH alone 0 0 7 (<1) Other GVHD prophylaxis 1 (<1) 5 (<1) 17 (<1)

G-CSF, GM-CSF (day-3 to day15) <0.001 Yes 170 (66) 1434 (60) 2379 (53) No 88 (34) 964 (40) 2093 (47)

Supplemental IVIG <0.001 Yes 122 (47) 1170 (49) 1766 (39) No 136 (53) 1228 (51) 2706 (61)

Year of transplant <0.001 2008 76 (29) 741 (31) 1194 (27) 2009 75 (29) 672 (28) 1073 (24) 2010 47 (18) 451 (19) 837 (19) 2011 34 (13) 283 (12) 642 (14) 2012 26 (10) 251 (10) 726 (16)

49


Table 3.2 Bacterial blood stream infection between day 0 – day 100 and time dependent variables for patients who underwent first allogeneic transplants for AML, ALL and MDS with either VRE BSI , other

BSI, or without BSI, reported to the CIBMTR, from 2008 to 2012 Variable VRE BSI Other BSI Without BSI Patients 258 2398 4472 Type of bacteria

No BSI 0 0 4472 VRE only 111 (43) 0 0 VRE + other organisms 147 (57) 0 0 Enterococcus Vanc Sensitive 0 89 ( 4) 0 GNR, Enterobacteriaceae 0 256 (11) 0 GNR, Non-Enterobacteriaceae 0 94 ( 4) 0 Mycobacterium 0 7 (<1) 0 Staphylococcus(coagulase nagative) 0 647 (27) 0 Staphylococcus(aureus/NOS) 0 172 ( 7) 0 Streptococcus 0 197 ( 8) 0 Anaerobes 0 72 ( 3) 0 Others 0 116 ( 5) 0 Polymicrobial(no VRE) 0 129 ( 5) 0 2 BSI(no VRE) 0 490 (20) 0 3 BSI(no VRE) 0 105 ( 4) 0 4 BSI(no VRE) 0 20 (<1) 0 5 BSI(no VRE) 0 4 (<1) 0

Time from transplant to BSI, days 11 (<1 - 99) 11 (<1 - 100) ANC>500

Yes 214 (83) 2249 (94) 4321 (97) No 44 (17) 144 ( 6) 138 ( 3) Missing 0 5 (<1) 13 (<1)

Time from transplant to ANC>500, days 18 (1 - 89) 16 (<1 - 99) 15 (<1 - 111) Platelet>20*10^9/L

Yes 1380 (75) 721 (88) 4049 (91) No 425 (23) 96 (12) 395 ( 9) Missing 27 ( 1) 7 (<1) 28 (<1)

Time from transplant to platelet>20*10^9/L, days 27 (1 - 640) 24 (<1 - 1180) 19 (<1 - 753) aGVHD

Yes 104 (40) 1070 (45) 1673 (37) No 150 (58) 1307 (55) 2761 (62) Missing 4 ( 2) 21 (<1) 38 (<1)

Time from transplant to aGVHD, days 26 (7 - 158) 27 (7 - 176) 29 (7 - 178) cGVHD

50


Variable VRE BSI Other BSI Without BSI Yes 49 (19) 992 (41) 2104 (47) No 208 (81) 1405 (59) 2361 (53) Missing 1 (<1) 1 (<1) 7 (<1)

Time from transplant to cGVHD, months 7 (3 - 57) 6 (2 - 66) 6 (2 - 67) Median follow-up of survivors, months 65 (24 - 74) 60 (3 - 87) 59 (3 - 87)

51


Table 3.3.1 Univariate outcomes of patients who underwent first allogeneic transplants for AML, ALL and MDS , with either VRE BSI, other BSI, or without BSI by day 100 after transplant, reported to the CIBMTR, from 2008 to 2012

VRE BSI Other BSI Without BSI Outcomes

N Eval Probability

(95% CI)

N Eval Probability

(95% CI)

N Eval Probability

(95% CI) P-value

Overall survival from transplant @ 100 days 258 56 (50-62)% 2398 82 (80-83)% 4472 89 (88-90)% <.0001 @ 1 year 26 (20-31)% 56 (54-58)% 66 (65-67)% <.0001

Relapse* 250 2363 4415

@ 100 days 15 (11-20)% 13 (12-15)% 14 (13-15)% 0.6211 @ 1 year 26 (21-32)% 28 (26-30)% 30 (29-32)% 0.0656

Non-relapse mortality 250 2363 4415 @ 100 days 36 (30-42)% 13 (11-14)% 7 (6-7)% <.0001 @ 1 year 51 (44-57)% 24 (22-26)% 15 (14-16)% <.0001

Disease free survival 250 2363 4415 @ 100 days 49 (42-55)% 74 (72-76)% 79 (78-80)% <.0001 @ 1 year 23 (18-29)% 48 (46-50)% 55 (53-56)% <.0001

cGVHD @ 6 months 257 9 (6-13)% 2397 24 (22-25)% 4465 25 (23-26)% <.0001 @ 1 year 17 (13-22)% 37 (35-39)% 41 (40-43)% <.0001

Note: *Death is competing risk

52


Table 3.3.2 Univariate outcomes of patients who underwent first allogeneic transplants for AML, ALL and MDS , with either VRE BSI, other BSI, or without BSI by day 100 after transplant, reported to the CIBMTR, from 2008 to 2012*

VRE BSI Other BSI Without BSI Outcomes

N Eval Probability

(95% CI)

N Eval Probability

(95% CI)

N Eval Probability

(95% CI) P-value

Overall survival from transplant @6 months 145 66 (58-73)% 1954 84 (83-86)% 3962 89 (88-90)% <.0001 @ 1 year 46 (37-53)% 68 (66-70)% 74 (73-76)% <.0001

Relapse 141 1944 3929

@ 6 months 26 (19-33)% 20 (18-22)% 22 (20-23)% 0.1783 @ 1 year 33 (25-40)% 28 (26-30)% 29 (28-31)% 0.4458

Non-relapse mortality 141 1944 3929 @ 6 months 15 (10-21)% 8 (6-9)% 4 (3-5)% <.0001 @ 1 year 26 (19-34)% 13 (12-15)% 9 (8-10)% <.0001

Disease free survival 141 1944 3929 @ 6 months 60 (51-67)% 72 (70-74)% 74 (73-76)% 0.0009 @ 1 year 41 (33-49)% 58 (56-60)% 62 (60-63)% <.0001

cGVHD @ 6 months 145 16 (11-23)% 1953 29 (27-31)% 3960 28 (26-29)% 0.0004 @ 1 year 30 (23-38)% 45 (43-47)% 46(45-48)% 0.0002 *Note: patients who died before 100 day have been removed.

53


Table 3.4 Cause of death of patients who underwent first allogeneic transplants for AML, ALL and MDS with either VRE BSI, other BSI, or without BSI by day 100 after transplant, reported to the

CIBMTR, from 2008 to 2012 Variable VRE BSI Other BSI Without BSI Patients who dead 216 (84) 1481 (62) 2403 (54) Cause of death

Graft rejection 5 ( 2) 24 ( 2) 24 (<1) Infection 34 (16) 239 (16) 277 (12) IPN 5 ( 2) 22 ( 1) 24 (<1) Organ Failure 52 (24) 215 (15) 322 (13) GVHD 29 (13) 175 (12) 239 (10) Recurrent/Persistent Disease 57 (26) 643 (43) 1256 (52) Secondary malignancy 0 18 ( 1) 29 ( 1) Hemorrhage 9 ( 4) 31 ( 2) 37 ( 2) Other cause 22 (10) 89 ( 6) 139 ( 6) Unknown 3 ( 1) 25 ( 2) 56 ( 2)

Median follow-up of survivors, months 65 (24 - 74) 60 (3 - 87) 59 (3 - 87)

54


Table 4: Variables for MVA Analysis 1 Main effect variable: No BSI (ref group) vs VEP-BSI vs LEP-BSI vs Both VEP and LEP BSI Age: ≤ 20y (ref) vs 21-40 vs 41-50 vs 51-60 vs >60 KPS: ≥ 90% (ref) vs <90% Disease stage: AML/ALL Early (ref) vs AML/ALL Intermediate vs AML/ALL Advanced vs MDS early vs MDS Advanced HCT-CI: 0 (ref) vs 1-2 vs ≥ 3 D/R CMV status: neg/neg (ref) vs any positive Conditioning Intensity: MAC (ref) vs RIC/NMA Graft type: Peripheral blood (ref) vs Marrow vs Cord Donor/HLA-match: HLA id-sib (ref) vs 8/8 unrelated vs MMUD (7/8+6/8) vs Cord vs Other

(related/haplo+unrelated HLA missing) ATG/Campath: No (ref) vs Yes GVHD prophylaxis: TAC/CSA + MTX ± others (ref) vs TAC/CSA + MMF ± others vs TCD (ex vivo + CD34

selection + ATG/Campath alone) vs Other (TAC/CSA alone, SIRO, Other) Year of HCT: 2008 – 2009 (ref) vs 2010 – 2012 Analysis 2: Main effect variable: No BSI (ref group) vs VRE-BSI vs Other BSI Age: ≤ 20y (ref) vs 21-40 vs 41-50 vs 51-60 vs >60 KPS: ≥ 90% (ref) vs <90% Disease stage: AML/ALL Early (ref) vs AML/ALL Intermediate vs AML/ALL Advanced vs MDS early vs MDS Advanced HCT-CI: 0 (ref) vs 1-2 vs ≥ 3 D/R CMV status: neg/neg (ref) vs any positive Conditioning Intensity: MAC (ref) vs RIC/NMA Graft type: Peripheral blood (ref) vs Marrow vs Cord Donor/HLA-match: HLA id-sib (ref) vs 8/8 unrelated vs MMUD (7/8+6/8) vs Cord vs Other

(related/haplo+unrelated HLA missing) ATG/Campath: No (ref) vs Yes GVHD prophylaxis: TAC/CSA + MTX ± others (ref) vs TAC/CSA + MMF ± others vs TCD (ex vivo + CD34

selection + ATG/Campath alone) vs Other (TAC/CSA alone, SIRO, Other) Year of HCT: 2008 – 2009 (ref) vs 2010 – 2012

55


Tables 5.1 – 5.4: Multivariable Analyses for Analysis 1 (VEP-BSI vs LEP-BSI vs Both VEP- and LEP-BSI vs No BSI) Table 5.1 Overall Survival (Center Effect)

99% CI 99% CI Overall

Variables N RR Lower Limit

Upper Limit p-value p-value

Main effect NoBSI 4472 1.00 <.0001 VEP 1493 1.36 1.26 1.47 <.0001

LEP 824 1.83 1.58 2.12 <.0001

BOTH 339 1.66 1.43 1.94 <.0001

Age at transplant, years <=20 1423 1.00 <.0001 21-40 1439 1.40 1.23 1.60 <.0001

41-50 1125 1.56 1.36 1.78 <.0001

51-60 1641 1.76 1.54 2.02 <.0001 >60 1500 2.02 1.76 2.33 <.0001

Karnofsky score at transplant

>=90 4765 1.00 0.0001 <90 2230 1.20 1.10 1.31 <.0001

Missing 133 1.20 0.99 1.44 0.0574

Disease-Disease stage variable

AML/ALL Early 2961 1.00 <.0001 AML/ALL Intermediate 1542 1.17 1.08 1.26 0.0002

AML/ALL Advanced 1039 2.07 1.88 2.27 <.0001 MDS Early 606 1.00 0.87 1.14 0.9747

MDS Advanced 939 1.31 1.19 1.44 <.0001

Missing 41 1.25 0.83 1.88 0.2955

HCT-CI 0 3070 1.00 <.0001

1-2 1872 1.07 0.98 1.17 0.1097 >=3 2044 1.21 1.12 1.31 <.0001

Missing 142 0.78 0.61 0.99 0.0453

Donor/Recipient CMV status -/- 2089 1.00 0.0032

Any positive 4925 1.13 1.05 1.22 0.0008 Missing 114 1.07 0.86 1.34 0.5438

Donor/recipient HLA match

56


HLA-identical siblings 1990 1.00 <.0001 8/8 unrelated 2302 1.03 0.95 1.13 0.4696

<=7/8 unrelated 704 1.31 1.16 1.48 <.0001 Cord blood 1834 1.46 1.29 1.64 <.0001

Other 298 1.26 1.04 1.52 0.0161

Year of transplant

2008-2009 3831 1.00 0.0046 2010-2012 3297 0.91 0.85 0.97 0.0046

Contrast

VEP vs LEP 0.74 0.62 0.90 <.0001 VEP vs BOTH 0.82 0.67 1.00 0.0084 LEP vs BOTH 1.10 0.88 1.37 0.2562

age 21-40 vs age 41-50 0.90 0.79 1.03 0.0430

age 21-40 vs age 51-60 0.80 0.70 0.90 <.0001

age 21-40 vs age >60 0.69 0.62 0.78 <.0001

age 41-50 vs age 51-60 0.88 0.78 1.00 0.0088 age 41-50 vs age >60 0.77 0.67 0.88 <.0001 age 51-60 vs age >60 0.87 0.79 0.96 0.0003

karnogp <90 vs Missing 1.00 0.78 1.29 0.9587

AML/ALL int vs AML/ALL Adv 0.56 0.49 0.65 <.0001

AML/ALL int vs MDS early 1.17 0.95 1.44 0.0542 AML/ALL int vs MDS Adv 0.89 0.76 1.04 0.0511

AML/ALL Adv vs MDS early 2.07 1.73 2.48 <.0001 AML/ALL Adv vs MDS Adv 1.57 1.35 1.84 <.0001

MDS early vs MDS Adv 0.76 0.64 0.90 <.0001

8/8 unrelated vs <=7/8 unrelated 0.79 0.67 0.93 0.0002 8/8 unrelated vs Cord blood 0.71 0.62 0.82 <.0001

8/8 unrelated vs Others 0.82 0.65 1.03 0.0226 <=7/8 unrelated vs Cord blood 0.90 0.74 1.09 0.1594

<=7/8 unrelated vs Other 1.04 0.78 1.39 0.7372

Cord blood vs Other 1.15 0.89 1.49 0.1467 Any positive vs Missing 1.07 0.80 1.43 0.5438

HCT-CI 1-2 vs >=3 0.89 0.80 0.98 0.0031

HCT-CI 1-2 vs Missing 1.38 0.99 1.91 0.0119

HCT-CI >=3 vs Missing 1.55 1.13 2.14 0.0004

57


Table 5.2 Disease Free Survival (Center Effect) 99% CI 99% CI Overall



Main effect NoBSI 4472 1.00 <.0001 VEP 1493 1.24 1.15 1.34 <.0001 LEP 824 1.53 1.35 1.74 <.0001

BOTH 339 1.49 1.30 1.71 <.0001

Age at transplant, years <=20 1423 1.00 <.0001 21-40 1439 1.28 1.13 1.45 0.0001 41-50 1125 1.35 1.20 1.52 <.0001 51-60 1641 1.44 1.25 1.66 <.0001 >60 1500 1.59 1.36 1.86 <.0001


>=90 4765 1.00 0.0018 <90 2230 1.18 1.08 1.30 0.0005

Missing 133 1.14 0.94 1.38 0.1978

Disease-Disease stage variable AML/ALL Early 2961 1.00 <.0001

AML/ALL Intermediate 1542 1.17 1.08 1.26 0.0001 AML/ALL Advanced 1039 2.06 1.89 2.25 <.0001

MDS Early 606 0.87 0.78 0.96 0.0087 MDS Advanced 939 1.20 1.10 1.32 0.0001

Missing 41 1.28 0.82 1.99 0.2831

HCT-CI 0 3070 1.00 0.0003

1-2 1872 1.06 0.97 1.15 0.1914 >=3 2044 1.14 1.06 1.23 0.0004

Missing 142 0.78 0.62 0.98 0.0302

Conditioning regimen intensity Myeloablative 5249 1.00 <.0001

RIC/NMA 1879 1.24 1.12 1.37 <.0001

Donor/recipient HLA match HLA-identical siblings 1990 1.00 <.0001

8/8 unrelated 2302 0.97 0.90 1.06 0.5015

58


<=7/8 unrelated 704 1.22 1.09 1.36 0.0007 Cord blood 1834 1.23 1.09 1.38 0.0007

Other 298 1.15 0.97 1.37 0.1040

Contrast VEP vs LEP 0.81 0.68 0.96 0.0017

VEP vs BOTH 0.83 0.69 1.00 0.0105 LEP vs BOTH 1.03 0.84 1.25 0.7194

age 21-40 vs age 41-50 0.95 0.84 1.07 0.2339 age 21-40 vs age 51-60 0.89 0.78 1.01 0.0175 age 21-40 vs age >60 0.80 0.70 0.93 <.0001

age 41-50 vs age 51-60 0.94 0.83 1.06 0.1922 age 41-50 vs age >60 0.85 0.73 0.99 0.0065 age 51-60 vs age >60 0.91 0.81 1.01 0.0153


8/8 unrelated vs <=7/8 unrelated 0.80 0.69 0.92 <.0001 8/8 unrelated vs Cord blood 0.79 0.69 0.91 <.0001


<=7/8 unrelated vs Other 1.06 0.83 1.35 0.5675 Cord blood vs Other 1.06 0.85 1.34 0.4784

HCT-CI 1-2 vs >=3 0.92 0.83 1.03 0.0600

HCT-CI 1-2 vs Missing 1.36 1.00 1.86 0.0106 HCT-CI >=3 vs Missing 1.47 1.08 2.00 0.0011


AML/ALL int vs MDS early 1.35 1.15 1.59 <.0001 AML/ALL int vs MDS Adv 0.97 0.83 1.13 0.6259



59


Table 5.3. Relapse (Center Effect)




Main effect NoBSI 4415 1.00 0.2337 VEP 1467 0.94 0.85 1.04 0.2068 LEP 815 1.08 0.93 1.25 0.3151

BOTH 331 1.07 0.88 1.30 0.4823

Karnofsky score at transplant >=90 4706 1.00 0.2369 <90 2190 1.20 1.07 1.34 0.0019

Missing 132 1.01 0.76 1.33 0.9562



MDS Early 595 0.57 0.47 0.69 <.0001 MDS Advanced 928 1.06 0.94 1.20 0.3664

Missing 32 1.01 0.51 2.02 0.9718


RIC/NMA 1855 1.67 1.50 1.86 <.0001

Donor/recipient HLA match HLA-identical siblings 1966 1.00 0.0005

8/8 unrelated 2272 0.84 0.77 0.92 0.0002 <=7/8 unrelated 694 0.78 0.68 0.90 0.0005

Cord blood 1802 0.82 0.72 0.94 0.0040 Other 294 0.91 0.70 1.18 0.4872

Contrast

VEP vs LEP 0.87 0.70 1.08 0.0985 VEP vs BOTH 0.87 0.69 1.11 0.1401 LEP vs BOTH 1.01 0.76 1.34 0.9588


8/8 unrelated vs <=7/8 unrelated 1.08 0.91 1.28 0.2611

8/8 unrelated vs Cord blood 1.03 0.88 1.21 0.6185

60



<=7/8 unrelated vs Other 0.86 0.61 1.21 0.2521 Cord blood vs Other 0.90 0.63 1.27 0.4266





61


Table 5.4. Treatment Related Mortality (Center Effect)




Main effect NoBSI 4472 1.00 <.0001 VEP 1493 1.82 1.63 2.04 <.0001 LEP 824 2.46 2.05 2.96 <.0001

BOTH 339 2.29 1.87 2.81 <.0001

Age at transplant, years <=20 1423 1.00 <.0001 21-40 1439 1.75 1.44 2.11 <.0001 41-50 1125 1.98 1.57 2.51 <.0001 51-60 1641 2.17 1.74 2.71 <.0001 >60 1500 2.52 2.04 3.10 <.0001


>=90 4765 1.00 0.0010 <90 2230 1.18 1.05 1.32 0.0039

Missing 133 1.38 1.09 1.74 0.0067


AML/ALL Intermediate 1542 1.06 0.92 1.23 0.4336 AML/ALL Advanced 1039 1.27 1.06 1.53 0.0100

MDS Early 606 1.32 1.10 1.58 0.0027 MDS Advanced 939 1.44 1.24 1.68 <.0001

Missing 41 1.48 0.84 2.60 0.1703

HCT-CI 0 3070 1.00 0.0012

1-2 1872 1.09 0.95 1.24 0.2121 >=3 2044 1.27 1.12 1.43 0.0001

Missing 142 1.05 0.69 1.59 0.8137




HLA-identical siblings 1990 1.00 <.0001

62


8/8 unrelated 2302 1.26 1.09 1.45 0.0017 <=7/8 unrelated 704 2.12 1.78 2.53 <.0001

Cord blood 1834 2.15 1.83 2.53 <.0001 Other 298 1.60 1.28 2.02 <.0001

Contrast

VEP vs LEP 0.74 0.57 0.97 0.0035 VEP vs BOTH 0.80 0.60 1.06 0.0393 LEP vs BOTH 1.08 0.77 1.51 0.5793




8/8 unrelated vs <=7/8 unrelated 0.59 0.47 0.74 <.0001

8/8 unrelated vs Cord blood 0.58 0.47 0.72 <.0001 8/8 unrelated vs Others 0.78 0.57 1.08 0.0513

<=7/8 unrelated vs Cord blood 0.99 0.75 1.30 0.8916 <=7/8 unrelated vs Other 1.32 0.92 1.90 0.0490

Cord blood vs Other 1.34 0.95 1.89 0.0266

Any positive vs Missing 1.11 0.66 1.87 0.6035

HCT-CI 1-2 vs >=3 0.86 0.73 1.00 0.0108 HCT-CI 1-2 vs Missing 1.03 0.59 1.80 0.8778 HCT-CI >=3 vs Missing 1.21 0.69 2.10 0.3874

AML/ALL int vs AML/ALL Adv 0.83 0.66 1.06 0.0503


AML/ALL Adv vs MDS early 0.97 0.72 1.30 0.7624 AML/ALL Adv vs MDS Adv 0.88 0.69 1.13 0.2018

MDS early vs MDS Adv 0.91 0.72 1.16 0.3301

63


TABLES 6.1 – 6.4: Multivariable Analyses for Analysis 2 (VRE-BSI vs Other BSI vs No BSI) Table 6.1. Overall Survival (Center Effect)




Main effect NoBSI 4472 1.00 <.0001 VRE 258 2.86 2.23 3.66 <.0001

OTHERS 2398 1.43 1.29 1.59 <.0001

Age at transplant, years <=20 1423 1.00 <.0001 21-40 1439 1.37 1.16 1.62 <.0001 41-50 1125 1.52 1.28 1.81 <.0001

51-60 1641 1.71 1.43 2.04 <.0001

>60 1500 1.96 1.63 2.36 <.0001

Karnofsky score at transplant >=90 4765 1.00 <.0001 <90 2230 1.19 1.07 1.33 <.0001

Missing 133 1.24 0.97 1.58 0.0238



MDS Early 606 1.01 0.85 1.21 0.8427

MDS Advanced 939 1.32 1.16 1.51 <.0001 Missing 41 1.26 0.74 2.13 0.2667

HCT-CI

0 3070 1.00 <.0001 1-2 1872 1.06 0.95 1.20 0.1703

>=3 2044 1.20 1.08 1.33 <.0001 Missing 142 0.78 0.58 1.07 0.0432

Donor/Recipient CMV status

-/- 2089 1.00 0.0084 Any positive 4925 1.12 1.02 1.24 0.0025

Missing 114 1.08 0.81 1.44 0.4858


64


8/8 unrelated 2302 1.03 0.92 1.16 0.4490

<=7/8 unrelated 704 1.32 1.13 1.54 <.0001

Cord blood 1834 1.41 1.21 1.64 <.0001 Other 298 1.28 1.01 1.61 0.0076

Year of transplant

2008-2009 3831 1.00 0.0067 2010-2012 3297 0.91 0.83 1.00 0.0067

Contrast vre vs others 1.99 1.56 2.55 <.0001

age 21-40 vs age 41-50 0.90 0.79 1.03 0.0393

age 21-40 vs age 51-60 0.80 0.71 0.91 <.0001

age 21-40 vs age >60 0.70 0.62 0.78 <.0001 age 41-50 vs age 51-60 0.89 0.79 1.01 0.0192 age 41-50 vs age >60 0.78 0.67 0.90 <.0001 age 51-60 vs age >60 0.87 0.79 0.96 0.0004

karnogp >=90 vs Missing 0.96 0.75 1.23 0.6810

HLA-identical siblings vs 8/8 unrelated 0.79 0.67 0.93 0.0002 HLA-identical siblings vs <=7/8 unrelated 0.74 0.64 0.85 <.0001

HLA-identical siblings vs Cord blood 0.81 0.65 1.01 0.0126

8/8 unrelated vs <=7/8 unrelated 0.94 0.77 1.14 0.3807 8/8 unrelated vs Cord blood 1.03 0.78 1.35 0.7736

<=7/8 unrelated vs Cord blood 1.10 0.86 1.41 0.3082 Any positive vs Missing 1.08 0.81 1.44 0.4858

HCT-CI 1-2 vs >=3 0.89 0.80 0.99 0.0044 HCT-CI 1-2 vs Missing 1.36 0.99 1.86 0.0132 HCT-CI >=3 vs Missing 1.53 1.12 2.08 0.0005





65


Table 6.2: Disease Free Survival (Center Effect)





OTHERS 2363 1.28 1.16 1.41 <.0001

Age at transplant, years <=20 1412 1.00 <.0001 21-40 1409 1.25 1.07 1.47 0.0003 41-50 1111 1.33 1.14 1.56 <.0001 51-60 1621 1.40 1.17 1.69 <.0001 >60 1475 1.54 1.25 1.91 <.0001


>=90 4706 1.00 0.0025 <90 2190 1.17 1.03 1.32 0.0010

Missing 132 1.16 0.90 1.51 0.1358


AML/ALL Intermediate 1526 1.17 1.06 1.30 <.0001 AML/ALL Advanced 997 2.04 1.82 2.29 <.0001

MDS Early 595 0.87 0.76 1.01 0.0167 MDS Advanced 928 1.21 1.07 1.37 0.0001

Missing 32 1.26 0.71 2.23 0.3042

HCT-CI 0 3030 1.00 0.0005

1-2 1846 1.05 0.94 1.17 0.2428 >=3 2011 1.13 1.03 1.25 0.0011

Missing 141 0.78 0.58 1.05 0.0287


RIC/NMA 1855 1.26 1.09 1.44 <.0001



66


Cord blood 1802 1.20 1.03 1.39 0.0028 Other 294 1.16 0.93 1.44 0.0821

Contrast

vre vs others 1.80 1.42 2.29 <.0001

age 21-40 vs age 41-50 0.94 0.83 1.06 0.1858 age 21-40 vs age 51-60 0.89 0.78 1.02 0.0254 age 21-40 vs age >60 0.81 0.70 0.94 0.0003







HLA-identical siblings vs 8/8 unrelated 0.80 0.69 0.92 <.0001 HLA-identical siblings vs <=7/8 unrelated 0.81 0.71 0.94 0.0002

HLA-identical siblings vs Cord blood 0.84 0.69 1.02 0.0238 8/8 unrelated vs <=7/8 unrelated 1.02 0.85 1.21 0.7843

8/8 unrelated vs Cord blood 1.05 0.83 1.33 0.5755 <=7/8 unrelated vs Cord blood 1.03 0.83 1.28 0.7091

HCT-CI 1-2 vs >=3 0.93 0.83 1.03 0.0738

HCT-CI 1-2 vs Missing 1.35 1.00 1.82 0.0111 HCT-CI >=3 vs Missing 1.45 1.08 1.96 0.0012

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Table 6.3 Relapse (center effect)




Main effect NoBSI 4415 1.00 0.8414 VRE 250 1.07 0.74 1.55 0.6416

OTHERS 2363 0.98 0.87 1.11 0.7308



MDS Early 595 0.57 0.44 0.73 <.0001 MDS Advanced 928 1.05 0.89 1.24 0.4515

Missing 32 1.06 0.45 2.53 0.8554

HCT-CI 0 3030 1.00 <.0001

1-2 1846 1.06 0.92 1.21 0.2959 >=3 2011 1.08 0.95 1.24 0.1176

Missing 141 0.59 0.43 0.81 <.0001


RIC/NMA 1855 1.68 1.47 1.94 <.0001

Donor/recipient HLA match HLA-identical siblings 1966 1.00 0.0004


Cord blood 1802 0.81 0.68 0.97 0.0023 Other 294 0.92 0.66 1.29 0.5271

Contrast

vre vs others 1.09 0.74 1.60 0.5795

HLA-identical siblings vs 8/8 unrelated 1.06 0.89 1.25 0.3825 HLA-identical siblings vs <=7/8 unrelated 1.04 0.89 1.21 0.5506



68






HCT-CI 1-2 vs >=3 0.98 0.84 1.13 0.6643 HCT-CI 1-2 vs Missing 1.78 1.28 2.48 <.0001 HCT-CI >=3 vs Missing 1.83 1.33 2.52 <.0001

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Table 6.4 Treatment Related Mortality (center effect) 4. TRM (center effect) 99% CI 99% CI Overall




OTHERS 2352 1.79 1.56 2.05 <.0001

Age at transplant, years <=20 1406 1.00 <.0001 21-40 1399 1.63 1.26 2.10 <.0001 41-50 1106 1.88 1.38 2.56 <.0001 51-60 1613 2.02 1.51 2.72 <.0001 >60 1474 2.41 1.82 3.21 <.0001


>=90 4685 1.00 0.0025 <90 2182 1.17 1.01 1.35 0.0060

Missing 131 1.40 0.99 1.99 0.0124

Disease-Disease stage variable AML/ALL Early 2935 1.00 0.0005

AML/ALL Intermediate 1518 1.06 0.87 1.30 0.4135 AML/ALL Advanced 994 1.23 0.96 1.57 0.0304

MDS Early 594 1.32 1.02 1.70 0.0047 MDS Advanced 926 1.39 1.14 1.71 <.0001

Missing 31 1.47 0.69 3.14 0.1900

HCT-CI 0 3015 1.00 0.0039

1-2 1837 1.07 0.90 1.27 0.3017 >=3 2005 1.24 1.06 1.45 0.0006

Missing 141 1.07 0.59 1.96 0.7666




HLA-identical siblings 1960 1.00 <.0001 8/8 unrelated 2259 1.18 0.97 1.43 0.0311

70


<=7/8 unrelated 692 1.95 1.56 2.44 <.0001 Cord blood 1795 1.89 1.52 2.34 <.0001

Other 292 1.56 1.14 2.13 0.0003

Contrast vre vs others 2.65 2.01 3.48 <.0001




AML/ALL int vs AML/ALL Adv 0.87 0.67 1.11 0.1404


AML/ALL Adv vs MDS early 0.93 0.68 1.28 0.5706 AML/ALL Adv vs MDS Adv 0.88 0.67 1.15 0.2284

MDS early vs MDS Adv 0.95 0.74 1.21 0.5657

HLA-identical siblings vs 8/8 unrelated 0.60 0.49 0.75 <.0001 HLA-identical siblings vs <=7/8 unrelated 0.62 0.50 0.78 <.0001



71


Figure 1. Overall survival curve for analysis 1 (VEP-BSI vs. LEP-BSI vs Both VEP- and LEP-BSI vs. No BSI), starting day 100 after transplant

72


Figure 2. Overall survival curve for analysis 2 (VRE-BSI vs. Others-BSI vs. No BSI), starting day 100 after transplant

73


Figure 3:

74


Appendix A Distribution of continuous variables

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Patient age 7128 0.27 1.28 4.41 25.42 47.01 58.55 67.92 72.15 79.14 Time from diagnosis to transplant, months

7128 0.43 1.84 2.73 4.34 6.68 14.97 50.92 106.64 312.96 WBC prior to preparative regimen, 10^9/L

7052 0.00 0.10 0.70 2.40 3.90 5.70 9.70 18.20 28.90 Neutrophils prior to preparative regimen, 10^9/L

6727 0.00 0.00 0.12 1.08 2.19 3.59 6.82 11.97 25.25 Lymphocytes prior to preparative regimen, 10^9/L

6774 0.00 0.00 0.19 0.56 0.90 1.34 2.24 3.43 9.43 Total TBI dose(cgy) 3397 200.00 200.00 200.00 550.00 1200.00 1320.00 1400.00 1400.00 1500.00 Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to first BSI/last follow up, days

No BSI by 100 day 4472 1.00 14.00 49.00 221.00 759.50 1610.00 2212.00 2306.00 2639.00 VEP-BSI 1832 -10.00 -7.00 -3.00 4.00 7.00 11.00 28.00 42.00 74.00 LEP-BSI 824 21.00 26.00 30.00 44.00 58.00 76.00 95.00 99.00 100.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to ANC>500/last follow up, days

Yes 6784 0.00 1.00 9.00 12.00 15.00 20.00 31.00 46.00 111.00 No 326 1.00 2.00 6.00 18.00 39.00 104.00 1812.00 2253.00 2533.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to platelet>20*10^9/L, days

No 916 1.00 4.00 11.00 34.00 65.00 119.00 802.00 2206.00 2533.00 Yes 6150 0.00 1.00 1.00 16.00 20.00 34.00 72.00 150.00 1180.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to 2-4 aGVHD, days

No 4251 1.00 10.00 31.00 157.00 624.00 1504.00 2212.00 2286.00 2459.00 Yes 2847 7.00 8.00 11.00 19.00 28.00 45.00 103.00 158.00 178.00

variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time between transplant and chronic GVHD, months

No 3974 0.03 0.33 0.95 2.89 6.97 32.04 71.74 74.54 80.89 Yes 3145 1.88 2.53 3.16 4.08 5.76 8.72 18.88 36.48 67.24

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to death/last follow-up date

Alive 3026 2.96 7.83 23.75 37.47 57.48 70.36 74.11 77.63 86.81 Dead 4100 0.03 0.33 0.99 3.19 6.97 15.59 42.04 65.30 78.98

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to relapse

75


Variable N Min 1% 5% 25% 50% 75% 95% 99% Max No 4480 0.03 0.36 1.25 7.12 36.33 60.36 73.16 75.95 86.81 Yes 2554 0.03 0.03 0.92 2.66 4.38 9.38 31.74 50.66 78.09

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to first viral infection by day100

No 4016 0.03 0.33 1.18 6.33 24.38 56.04 72.89 75.59 86.81 Yes 3112 0.00 0.03 0.16 0.56 0.95 1.48 2.40 3.06 3.29

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to first fungal infection by day 100

No 6539 0.03 0.46 1.55 6.41 24.08 52.47 72.76 75.95 86.81 Yes 589 0.00 0.00 0.13 0.43 0.99 1.97 2.96 3.26 3.29

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max First VRE by day100

No 6869 0.03 0.46 1.51 6.09 23.85 51.58 72.76 75.86 86.81 Yes 259 -0.30 -0.07 0.13 0.33 0.56 1.41 2.89 3.16 3.26

Appendix B List of other GVHD prophylaxis

GVHD_prophylaxis gvhdlist N% Other GVHD prophylaxis mmf 10 (43) mtx 5 (22) cor 3 (13) cor + mtx 2 ( 9) mab + mmf 2 ( 9) atg + cor 1 ( 4)

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IN13-01

BACTERIAL, VIRAL AND FUNGAL INFECTIONS IN PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (ALLOHCT) FOLLOWING NONMYELOABLATIVE AND

MYELOABLATIVE CONDITIONING

FINAL PROTOCOL Study Chair: Celalettin Ustun, MD University of Minnesota Medical Center Department of Medicine, Hematology, Oncology and Transplantation 420 Delaware Street SE, MMC 250 Minneapolis, MN 55455 Telephone: (612) 624-5109 E-mail: [email protected] Statistical Directors: Kwang Woo Ahn, PhD Associate Professor

8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-7387 E-mail: [email protected] Soyoung Kim, PhD, 8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-8271 E-mail: [email protected]

Study Statistician: Min Chen, MS CIBMTR Statistical Center 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI 53226 Telephone: (414) 805-0710 E-mail: [email protected]

77




Scientific Director: Marcie Riches, MD, MS University of North Carolina at Chapel Hill Associate Professor Division of Hematology/Oncology 170 Manning Drive, POB 3, #7305 Chapel Hill, NC 27599 Telephone: 919-966-3048 E-mail: [email protected] Working Committee Chairs: Jeffery Auletta, MD Nationwide Children’s Hospital Department of Hematology/Oncology and BMT 700 Children’s Drive Columbus, OH 43205 Telephone: (614) 722-3553 E-mail: [email protected]

Caroline A Lindemans, MD, PhD Wilhelmina Children's Hospital University Medical Center Utrecht, Children’s hospital Lundlaan 6, PO BOX 85090 3508 AB, Utrecht, the Netherlands Telephone: 31-622879245 E-mail: [email protected]

Krishna Komanduri, MD;

University of Miami Sylvester Cancer Center 1475 NW 12th Ave Miami; Miami, FL 33136; Telephone: (305) 243-5302 E-mail: [email protected]

78



1.0 HYPOTHESIS: Non-myeloablative regimens (NMAR) or reduced-intensity conditioning (RIC) cause less gastrointestinal (GI) toxicities, compared to myeloablative regimens (MAR) and may be associated with less severe and shorter neutropenia. Infections occurring in the early period following allogeneic transplantation are partly caused by disruption of the GI mucosal barrier due to chemotherapy and by severe neutropenia. Therefore, NMAR/RIC may be associated with fewer bacterial, viral, and fungal infections within 100 days post-transplantation compared to MAR.

2.0 OBJECTIVE: Primary Objectives:

To compare occurrence of any infection within the first 100 days post-transplant based on conditioning intensity (MAR vs RIC/NMAR) Secondary Objectives

To compare the following between MAR and RIC/NMAR allogeneic HCT 1. Occurrence of bacterial infection by 100 days 2. Occurrence of fungal infection by 100 days 3. Occurrence of viral infection by 100 days

3.0 SCIENTIFIC JUSTIFICATION: The number of patients undergoing AlloHCT for the treatment of hematologic and non-

hematologic diseases is increasing. One of the most important obstacles encountered in AlloHCT is a higher risk of morbidity and mortality due to high-dose conditioning. These risks are particularly prominent in elderly patients, and have limited the use of alloHCT in older patients and those with comorbidities.

Allogeneic stem cell transplantation (alloHCT) has been used more commonly over time for the treatment of hematologic malignant diseases. One of the main reasons is for extending alloHCT to older and patients with comorbid conditions due to nonmyeloablative (NMA) or reduced-intensity conditioning regimens (RIC).1-5 Overall survival (OS) seems to similar in patients with hematologic malignancies receiving between MAC and NMA/RIC regimens because increased relapse offset by reduced non-relapse mortality (NRM).1,6-12 Infections are one of the major contributors of morbidity and mortality after alloHCT. Less mucositis,13-16 shorter duration of neutropenia/lymphopenia,13 less severe neutropenia/lymphopenia, faster immune recovery after alloHCT were associated with decreased infections and reported to be more frequent after NMA/RIC than MAC.17,18 Therefore, the incidence of infections is expected to be lower after NMA/RIC compared to MAC, and thus contribute to the decreased NRM.19-21 However, there is no large study comparing infectious complications after alloHCT regarding conditioning intensity, therefore, we have proposed this study to CIBMTR.

79


Definition of Conditioning Intensity: We will classify the intensity of conditioning regimens per published definitions by Bacigalipo et al in this study.22

MAC: TBI≥5 Gy (single) or ≥ 8Gy fractionated

Bu > 8mg/kg oral (6.4 mg/kg IV) RIC: not MAR or NMAR

NMAC: TBI≤2Gy ± purine analog Flu+Cy ± ATG Flu+AraC+Ida Cladrabine + AraC TLI + ATG 4.0 STUDY POPULATION:

All patients ≥ 40 years of age receiving allogeneic HCT for AML in first complete remission (CR1) between January 2006 and December 2013 will be included. Patients with HIV-1 infection or who received T-cell depleted grafts will be excluded. These exclusions are intended to minimize bias that can impact infection rates, including the extent of prior chemotherapy, immunodeficiency due to lymphotropic infection and increased infection rates associated with delayed donor-derived immune recovery. Centers without patients in both MAR and NMAR/RIC categories will be excluded to minimize center bias.

5.0 VARIABLES TO BE DESCRIBED: Patient related:

• Age: 40 –44, 45- 49, 50-54, 55 – 59, 60-64, 65 – 69, ≥ 70 • Gender • Karnofsky performance score • HCT CI: 0 vs 1 vs 2 vs ≥ 3

Disease related: • Cytogenetics • Presence of prior MDS • Time from diagnosis to transplant • Disease risk: Low vs Intermediate vs High

Transplant related: • Conditioning regimen • Donor age • Donor-recipient gender match: M-M vs. M-F vs. F-M vs. F-F • Donor-recipient CMV status: +/+ vs. +/- vs. -/-, vs -/+ vs others • GVHD prophylaxis • Growth factor (use started 3 days before or 7 days after transplant: Yes/No • Donor type: HLA identical sib/matched related vs matched unrelated vs. mismatched

unrelated vs. UCB • Graft type (BM vs PBSC vs UCB) • ATG/CAMPATH • Conditioning regimen given as outpatients: all outpatient vs. some/all inpatient

80


• Recipient discharged from the hospital after HSCT: yes vs. no • TBI: yes vs no. • Year of transplant

Infection related: • Prior history of fungal infection: yes vs no • Infection at the time of transplant

Time dependent variables: • Time to neutrophil engraftment, days • Time to first bacterial infection, days • Time to first viral infection, days • Time to first fungal infection, days • Acute GVHD grade 2 -4: Yes vs No • Time to onset of acute GVHD grade 2 – 4, days

6.0 Outcomes to be analyzed:

All outcomes will be compared between patients receiving MAR or RIC/NMAR: 1. Cumulative incidence of any infection in the first 100 days. Death is a competing risk. 2. Infection rate (density) of any infection in the first 100 days. 3. Cumulative incidence of bacterial infection in the first 100 days. Death is a competing risk. 4. Infection rate (density) of bacterial infection in the first 100 days. 5. Cumulative incidence of viral infection in the first 100 days. Death is a competing risk. 6. Infection rate (density) of viral infections in the first 100 days. 7. Cumulative incidence of fungal infections in the first 100 days. Death is a competing risk. 8. Infection rate (density) of fungal infections in the first 100 days. 9. Cause of death.

7.0 STUDY DESIGN:

All patients ≥40 years old with AML in CR1 (except for HIV positive) undergoing alloHCT following MAR, NMAR or RICR (except for T cell-depleted) will be evaluated. Patient-, disease-, and treatment-related factors will be compared by using Chi-square test if variables are categorical or by using Mann-Whitney U test if variables are continuous. Poisson regression will be performed to examine infection density of each infection (multiple infections) at day 30, 100, and day 31 to 100. The cause specific hazards models will be conducted for multivariable analysis for infections to handle competing risks. For each of bacterial infection, viral infection, and fungal infection, the other two infections will be added as time-dependent covariate. Neutrophil recovery and acute GVHD will also be tested as time dependent covariates. If at least one of neutrophil recovery and acute GVHD is significant and at least one of the other two infections is significant, the interaction between them will be carefully examined. The proportional hazards assumption will be examined. If violated, it will be included as a time-dependent covariate. The center effect will also be examined by using score test (9). Interactions between the main effect and significant covariates will be examined. In particular, an interaction between the main effect and recipient age will be checked for all outcomes. Donor source, graft type, and donor age will be examined in separate models. The propensity scores will be calculated. They will be added as covariate. The main effect from the model using the propensity scores will be compared to that from the model without using the

81


propensity scores to check consistency. Adjusted cumulative incidence curves will be created based on the final cause-specific hazards model for each infection.

8.0 REFERENCES:

1. Storb R, Yu C, Zaucha JM, et al. Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant. Blood 1999;94:2523-9.

2. Giralt S, Estey E, Albitar M, et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997;89:4531-6.

3. Diaconescu R, Flowers CR, Storer B, et al. Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood. 2004;04:1550-8.

4. Bacigalupo A, Ballen K, Rizzo D, et al. Defining the Intensity of Conditioning Regimens: Working Definitions. Biol Blood Marrow Transplant. 2009; 15:1628-33.

5. Busca A, Locatelli F, Barbui A, et al. Infectious complications following nonmyeloablative allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2003;5:132-9.

6. Daly A, McAfee S, Dey, et al. Nonmyeloablative bone marrow transplantation: Infectious complications in 65 recipients of HLA-identical and mismatched transplants. Biol Blood Marrow Transplant. 2003;9:373-82.

7. Mossad SB, Avery RK, Longworth DL, et al. Infectious complications within the first year after nonmyeloablative allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant. 2001;28:491-5.

8. Junghanss C, Marr KA, Carter RA, et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant. 2002;8:512-20.

9. Commenges D, Andersen PK. Score test of homogeneity for survival data. Lifetime Data Analysis. 1995;1:145-156.

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Storb+R%22%5BAuthor%5D

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Zaucha+JM%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Busca+A%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Locatelli+F%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Barbui+A%22%5BAuthor%5D

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Carter+RA%22%5BAuthor%5D


Table 1.1 Characteristics of patients who underwent first allogeneic transplants for AML CR1, without HIV-1 and T-cell depletion, reported to the CIBMTR, from 2006 to 2013

Variable Myeloablative RIC/NMA p_value Patient related Number of patients 978 777 Number of centers 98 99 Gender 0.001

Male 489 (50) 448 (58) Female 489 (50) 329 (42)

Age, median(range), years 52 (40 - 71) 61 (41 - 81) <0.001 Age at transplant, years <0.001

40-44 174 (18) 37 ( 5) 45-49 230 (24) 50 ( 6) 50-54 226 (23) 91 (12) 55-59 225 (23) 146 (19) 60-64 85 ( 9) 211 (27) >65 38 ( 4) 242 (31)

Karnofsky performance pre-Preparative Regimen 0.269 <70 14 ( 1) 6 (<1) 70-79 68 ( 7) 52 ( 7) 80-89 218 (22) 200 (26) >=90 662 (68) 502 (65) Missing 16 ( 2) 17 ( 2)

Disease related Cytogenetics(CYTOGENE) 0.315

Favorable 26 ( 3) 20 ( 3) Intermediate 608 (62) 469 (60) Poor 285 (29) 232 (30) Not tested 22 ( 2) 12 ( 2) Missing 37 ( 4) 44 ( 6)

Presence of prior MDS 0.003 No 818 (84) 600 (77) Yes 155 (16) 173 (22) Missing 5 (<1) 4 (<1)

Time from diagnosis to TX, median(range), months 5 (2 - 12) 5 (<1 - 13) <0.001 Time from diagnosis to transplant, months 0.002

<6 714 (73) 508 (65) >=6 263 (27) 269 (35) Missing 1 (<1) 0

Transplant related HCT-CI 0.173

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Variable Myeloablative RIC/NMA p_value 0 268 (27) 190 (24) 1 111 (11) 102 (13) 2 110 (11) 77 (10) 3 106 (11) 87 (11) 4 78 ( 8) 64 ( 8) 5 43 ( 4) 36 ( 5) 6+ 36 ( 4) 49 ( 6) Not collected before 2007 216 (22) 159 (20) Missing 10 ( 1) 13 ( 2)

Donor age, median(range), years 31 (18 - 59) 31 (19 - 60) 0.886 Donor age, in decades <0.001

Cord blood 88 ( 9) 169 (22) Related donor 381 (39) 216 (28) 18-20 15 ( 2) 11 ( 1) 21-30 212 (22) 162 (21) 31-40 126 (13) 99 (13) 41-50 93 (10) 63 ( 8) 51-60 31 ( 3) 22 ( 3) Missing 32 ( 3) 35 ( 5)

Donor-recipient sex match 0.01 Male-Male 321 (33) 294 (38) Male-Female 295 (30) 181 (23) Female-Male 168 (17) 154 (20) Female-Female 193 (20) 148 (19) Missing 1 (<1) 0

Donor-recipient CMV status 0.445 +/+ 272 (28) 189 (24) +/- 92 ( 9) 76 (10) -/+ 332 (34) 300 (39) -/- 269 (28) 200 (26) +/? 4 (<1) 5 (<1) -/? 6 (<1) 4 (<1) Both missing 3 (<1) 3 (<1)

Graft type <0.001 Bone marrow 136 (14) 55 ( 7) Peripheral blood 754 (77) 553 (71) Cord blood 88 ( 9) 169 (22)

TBI <0.001 No 678 (69) 465 (60) Yes 300 (31) 312 (40)

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Variable Myeloablative RIC/NMA p_value GVHD prophylaxis <0.001

FK506 + MMF +/- others 138 (14) 168 (22) FK506 + MTX +/- others (except MMF) 556 (57) 243 (31) FK506 + others (except MTX, MMF) 53 ( 5) 35 ( 5) FK506 alone 29 ( 3) 16 ( 2) CSA + MMF +/- others (except FK506) 64 ( 7) 210 (27) CSA + MTX +/- others (except FK506, MMF) 101 (10) 47 ( 6) CSA + others (except FK506, MTX, MMF) 6 (<1) 3 (<1) CSA alone 8 (<1) 16 ( 2) MMF +/- others 2 (<1) 6 (<1) Siro +/- others 4 (<1) 9 ( 1) Other GVHD prophylaxis 17 ( 2) 24 ( 3)

Donor/recipient HLA match <0.001 Cord blood 88 ( 9) 169 (22) HLA-identical siblings 380 (39) 211 (27) matched related 1 (<1) 5 (<1) Well matched unrelated 391 (40) 299 (38) Partially matched unrelated 94 (10) 66 ( 8) Mismatched unrelated 4 (<1) 3 (<1) Unrelated (HLA match information missing) 20 ( 2) 24 ( 3)

ATG/CAMPATH as conditioning or GVHD prophylaxis <0.001 ATG alone 236 (24) 276 (36) CAMPATH alone 6 (<1) 29 ( 4) No ATG or CAMPATH 736 (75) 472 (61)

G-CSF, GM-CSF 0.297 No 612 (63) 484 (62) Yes 363 (37) 293 (38) Missing 3 (<1) 0

Preparative regimen given <0.001 All agents given as outpatient 32 ( 3) 74 (10) Some/all, agents given as inpatient 945 (97) 702 (90) Missing 1 (<1) 1 (<1)

Recipient discharged from the hospital after HSCT <0.001 No 34 ( 3) 33 ( 4) Yes 941 (96) 694 (89) NA, therapy and HSC infusion given as outpatient 3 (<1) 50 ( 6)

Year of transplant <0.001 2006 87 ( 9) 68 ( 9) 2007 129 (13) 91 (12) 2008 164 (17) 138 (18)

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Variable Myeloablative RIC/NMA p_value 2009 172 (18) 121 (16) 2010 182 (19) 62 ( 8) 2011 54 ( 6) 81 (10) 2012 66 ( 7) 57 ( 7) 2013 124 (13) 159 (20)

Infection related History of clinically significant fungal infection 0.677

No 862 (88) 674 (87) Yes 115 (12) 102 (13) Missing 1 (<1) 1 (<1)

Infection prior to preparative regimen 0.401 No 748 (76) 588 (76) Yes 38 ( 4) 39 ( 5) NA legacy cases 181 (19) 136 (18) Not done/Missing 11 ( 1) 14 ( 2)

Median follow-up of survivors, months 60 (3 - 102) 60 (3 - 105) Abbreviations:AML=acute myelogenous leukemia; HLA=human leukocyte antigen; CR=complete remission; FK506 = tacrolimus; CSA = cyclosporine; MTX = methotrexate; TBI = total body irradiation; MMF=mycophenolate mofetil; CSA= cyclosporine A; ATG=anti-thymocyte globulin; COR=corticosteroids; ECP=extra-corporeal photopheresis; KGF=kepivance; MAB=in vivo monoclonal antibody; IVIM=in vivo immunotoxin; SIRO=sirolim us; URSO=ursodiol; OTH=other agent

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Table1.2 Time dependent variables of patients who underwent first allogeneic transplants for AML CR1 , without T-cell depletion, reported to the CIBMTR, from 2006 to 2013

Variable Myeloablative RIC/NMA Patient related Number of patients 978 777 Neutrophil recovery

Yes 960 (98) 756 (97) No 18 ( 2) 21 ( 3)

Time from transplant to engraft, median(range), days 14 (1 - 111) 15 (<1 - 96) aGVHD 2-4

No 594 (61) 520 (67) Yes 384 (39) 257 (33)

Time from transplant to aGVHD grade 2-4, median(range), days 28 (7 - 161) 33 (9 - 177) cGVHD

No 430 (44) 427 (55) Yes 548 (56) 350 (45)

Time from transplant to cGVHD, median(range), months 6 (2 - 72) 6 (2 - 67) Any infection by 100 day

No 383 (39) 327 (42) Yes 595 (61) 450 (58)

Time from transplant to any first infection, median(range), days 15 (<1 - 99) 21 (<1 - 100) Bacteria by 100 day

No 529 (54) 486 (63) Yes 449 (46) 291 (37)

Time from transplant to first bacteria infection, median(range), days 12 (<1 - 100) 20 (<1 - 100) Viral by 100 day

No 642 (66) 474 (61) Yes 336 (34) 303 (39)

Time from transplant to first viral infection, median(range), days 31 (<1 - 99) 33 (1 - 100) Fungal by 100 day

No 932 (95) 738 (95) Yes 46 ( 5) 39 ( 5)

Time from transplant to first fungal infection, median(range), days 28 (<1 - 89) 30 (<1 - 99) Patient related Number of patients 978 777

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Table2 Cause of death Variable Myeloablative RIC/NMA Patient related Number of patients 978 777 Dead

No 497 (51) 313 (40) Yes 481 (49) 464 (60)

Cause of death Graft rejection 5 ( 1) 10 ( 2) Infection 70 (15) 56 (12) IPN 11 ( 2) 2 (<1) Organ Failure 63 (13) 45 (10) GVHD 71 (15) 50 (11) Recurrent/Persistent Disease 228 (47) 252 (54) Secondary malignancy 5 ( 1) 13 ( 3) Hemorrhage 3 (<1) 6 ( 1) Other cause 15 ( 3) 20 ( 4) Unknown 10 ( 2) 10 ( 2)

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Table 3 Univariate analysis Myeloablative RIC/NMA Outcomes

N Eval Probability

(95% CI)

N Eval Probability

(95% CI) P-value

Any infection by 100 day* 978 777 @ 100 days 61 (58-64) % 58 (55-61) % 0.2195

Death by 100 day** 978 777 @ 100 days 17 (15-20) % 22 (19-26) % 0.0362

Bacterial infection by 100 day* @ 100 days 978 46 (43-49)% 777 37 (34-41)% 0.0004

Fungal infection by 100 day* @ 100 days 978 5 (3-6)% 777 5 (4-7)% 0.7599

Viral infection by 100 day * @ 100 days 978 34 (31-37)% 777 39 (36-42)% 0.0459

Note: *Death as a competing risk **Any infection as a competing risk

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Table 4. Infection density* Infection Myeloablative RIC/NMA p_value Number of patients 978 777 Infection per patient in the first 100 days 1.00 (0.00 - 17.14) 1.00 (0.00 - 12.00) 0.169 Infection overall density score 1.302 1.207 Bacteria per patient in the first 100 days 0.00 (0.00 - 14.29) 0.00 (0.00 - 9.52) <0.001 Bacteria overall density score 0.765 0.604 Viral per patient in the first 100 days 0.00 (0.00 - 11.11) 0.00 (0.00 - 5.26) 0.050 Viral overall density score 0.479 0.543 Fungal per patient in the first 100 days 0.00 (0.00 - 8.57) 0.00 (0.00 - 7.69) 0.762 Fungal overall density score 0.058 0.06 Note: Recurrence intervals to determine whether an infection is the same or new: Any bacteria:≤7days; Viral :≤60days; Fungal: ≤60days; * Infection density: estimate the episodes per patient per days at risk (‘rate’ of infection) Density score per patient=(# of episodes by day 100)/(days at risk(max 100per pt))*100 Overall density score=(total # of episodes by day100)/(total days at risk(max 100per pt))*100 **Kruskal-Wallis test

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Table 5. Variables to be included for the MVA of infection Main effect variable: Myeloablative (ref) vs Reduced Intensity/NMA Age: 40 – 49 years (ref) vs 50 – 59 years vs ≥ 60 years KPS: ≥90% (ref) vs <90% Cytogenetics: Favorable (ref) vs Intermediate vs Poor Time from dx to HCT: <6 months (ref) vs ≥ 6 months HCT-CI: 0 (ref) vs 1-2 vs ≥ 3 Donor/Recipient HLA Match: HLA Id sib/match related vs Well matched unrelated vs mismatched unrelated vs cord blood vs Unrelated HLA missing TBI: No (ref) vs Yes ATG/CAMPATH: No (ref) vs Yes (ATG or Campath) Prior history of fungal infection: No (ref) vs Yes Neutrophil recovery: before infection (ref) vs after infection Acute GVHD prior to infection: No (ref) vs Yes Note: The plan is also to look at propensity scoring which should incorporate KPS, HCT-CI, TBI, ATG/CAMPATH, Age

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Table 6.1 Any infection (center effect)

1. Any infection (center effect)

95% CI 95% CI

Overall



Main effect Reduced Intensity/NMA 777 1.00

0.0006

Myeloablative 978 1.28 1.11 1.48 0.0006

HCT-CI 0 458 1.00

<.0001

1-2 400 1.14 0.96 1.36 0.1318 >=3 499 1.19 1.02 1.38 0.0261 NA legacy cases 375 0.70 0.57 0.86 0.0008 Missing 23 1.29 0.77 2.14 0.3335

Donor/recipient HLA match HLA & matched related 597 1.00

<.0001

Cord blood 257 1.81 1.40 2.34 <.0001 Well matched unrelated 690 0.97 0.80 1.18 0.7708 PMU & MU 167 1.19 0.95 1.49 0.1287 Unrelated 44 1.68 1.20 2.35 0.0024

ATG/CAMPATH as conditioning or GVHD prophylaxis No 1208 1.00

0.0004

Yes 547 1.33 1.13 1.55 0.0004

Acute GVHD grade II-IV

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No 1135 1.00

<.0001 Yes 620 1.53 1.33 1.77 <.0001

Contrast

HCT-CI 1-2 vs >=3

0.97 0.84 1.11 0.6290

Cord blood vs Well matched unrelated

1.86 1.53 2.27 <.0001 Cord blood vs PMU & MU

1.52 1.20 1.93 0.0005

Cord blood vs Unrelated

1.08 0.77 1.50 0.6559 Well matched unrelated vs PMU & MU

0.82 0.67 1.00 0.0480

Well matched unrelated vs Unrelated

0.58 0.44 0.77 0.0001 PMU & MU vs Unrelated

0.71 0.52 0.96 0.0283

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Table 6.2 Bacterial infection

2. Bacterial infection

95% CI 95% CI

Overall




<.0001

Myeloablative 978 1.45 1.24 1.69 <.0001

HCT-CI 0 458 1.00

0.0544



<.0001

Cord blood 257 1.52 1.22 1.89 0.0002 Well matched unrelated 690 0.90 0.76 1.08 0.2602 PMU & MU 167 1.02 0.78 1.33 0.9082 Unrelated 44 0.83 0.47 1.44 0.5028

Neutrophil recovery No 396 1.00

0.0010

Yes 1359 0.60 0.44 0.81 0.0010

Viral before infection No 1323 1.00

<.0001

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Yes 432 1.78 1.43 2.22 <.0001

Fungal before infection No 1706 1.00

0.0004

Yes 49 2.20 1.42 3.41 0.0004

Contrast HCT-CI 1-2 vs >=3

1.10 0.91 1.34 0.3331 Cord blood vs Well matched unrelated

1.68 1.36 2.07 <.0001

Cord blood vs PMU & MU

1.49 1.11 2.01 0.0077 Cord blood vs Unrelated

1.84 1.03 3.27 0.0379

Well matched unrelated vs PMU & MU

0.89 0.68 1.16 0.3920 Well matched unrelated vs Unrelated

1.10 0.63 1.91 0.7485

PMU & MU vs Unrelated

1.23 0.68 2.22 0.4919

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Table 6.3 Viral infection (center effect)

3. Viral infection (center effect)

95% CI 95% CI

Overall




0.3590

Myeloablative 978 1.11 0.89 1.37 0.3590

Age at transplant, years 40 –-49 491 1.00

0.0649

50 –-59 688 0.97 0.81 1.16 0.7442 >= 60 576 1.24 1.01 1.51 0.0409

HCT-CI 0 458 1.00

0.0001



<.0001

Cord blood 257 2.61 2.05 3.32 <.0001 Well matched unrelated 690 1.17 0.94 1.46 0.1664 PMU & MU 167 1.45 1.10 1.91 0.0091 Unrelated 44 2.52 1.54 4.14 0.0002

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ATG/CAMPATH as conditioning or GVHD prophylaxis and <= 39 days

No 1208 1.00

<.0001 Yes 547 2.47 1.94 3.15 <.0001

ATG/CAMPATH as conditioning or GVHD prophylaxis and >39

days No 1417 1.00

0.8039

Yes 338 1.04 0.77 1.40 0.8039

Acute GVHD grade II-IV No 1116 1.00

<.0001

Yes 639 1.74 1.46 2.07 <.0001

Bacteria before infection No 1140 1.00

0.0001

Yes 615 1.41 1.18 1.67 0.0001

Contrast age 50-59 vs >=60 0.79 0.63 0.98 0.0289

HCT-CI 1-2 vs >=3 0.87 0.70 1.07 0.1914 Cord blood vs Well matched unrelated 2.23 1.74 2.86 <.0001 Cord blood vs PMU & MU

1.80 1.32 2.46 0.0002



0.81 0.63 1.04 0.1018



0.57 0.34 0.96 0.0342

overall

2.57 1.80 3.65 <.0001

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Table 6.4 Fungal infection

4. Fungal infection

95% CI 95% CI

Overall




0.9696

Myeloablative 978 0.99 0.64 1.54 0.9696

Donor/recipient HLA match HLA-identical siblings & matched related 597 1.00

0.0226

Cord blood 257 2.65 1.41 5.00 0.0026 Well matched unrelated 690 1.31 0.72 2.38 0.3684 Partially matched unrelated & Mismatched unrelated 167 1.49 0.65 3.44 0.3467 Unrelated (HLA match information missing 44 2.74 0.92 8.15 0.0708

Neutrophil recovery No 65 1.00

0.0053

Yes 1690 0.37 0.18 0.74 0.0053

Bacteria before infection No 1037 1.00

0.0119

Yes 718 1.81 1.14 2.89 0.0119

Viral before infection No 1135 1.00

0.0038

Yes 620 2.17 1.28 3.67 0.0038

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Contrast Cord blood vs Well matched unrelated

2.02 1.15 3.53 0.0139 Cord blood vs PMU & MU

1.77 0.79 3.98 0.1634



0.88 0.40 1.93 0.7501



0.55 0.16 1.82 0.3246

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CIBMTR IN14-01

Outcomes of Allogeneic hematopoietic cell transplant recipients with EBV positive and EBV

negative post transplant lymphoproliferative disorder

DRAFT PROTOCOL

Principal Investigators: Seema Naik, MD Texas Transplant Institute 4410 Medical Drive, Ste. 410 San Antonio, TX 78229 United States Telephone: (210) 575-8631 E-mail: [email protected] Carlos R. Bachier, MD Program Director Blood and Marrow Transplant Sarah Cannon Center for Blood Cancer 250 25th Avenue North, Suite 316 Nashville, TN 37203 Office: 615-342-4914 E-mail: [email protected] Paul Shaughnessy, MD Texas Transplant Institute 4410 Medical Drive, Suite 410 San Antonio, TX 78229 United States Office: (210) 575-7268 E-mail: [email protected] Parameswaran Hari, MD, MRCP, MS Medical College of Wisconsin 9200 West Wisconsin Avenue, Suite C5500 Milwaukee, WI 53226 United States Office: (414) 805-4613 E-mail: [email protected] Rammurti T. Kamble, MD Baylor College of Medicine, Methodist Hospital M970 6565 Fannin Street, Suite 1120 Houston, TX 77030 United States Office: (731) 441-1961 E-mail: [email protected]

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Study Statistician: Min Chen, MS CIBMTR 9200 West Wisconsin Ave. Milwaukee, WI 53226 USA Telephone: 414-805-0710 E-mail: [email protected]

Statistical Director: Soyoung Kim, PhD Associate Professor

8701 Watertown Plank Road Milwaukee, WI 53226 Telephone: 414-955-8271 E-mail: [email protected]

Scientific Director: Marcie Riches, MD, MS

Associate Professor University of North Carolina at Chapel Hill Physician’s Office Building, 3rd floor 170 Manning Drive, CB #7305 Chapel Hill, NC 27599 Telephone: 919-966-3048 E-mail: [email protected]

Working Committee Chairs: Jeffery Auletta, MD Nationwide Children’s Hospital Department of Hematology/Oncology and BMT 700 Children’s Drive Columbus, OH 43205 Telephone: (614) 722-3553 E-mail: [email protected]

Caroline Lindemans, MD, PhD Wilhelmina Children's Hospital University Medical Center Utrecht Telephone: 31-61-4026510 E-mail: [email protected]

Krishna Komanduri, MD

University of Miami Sylvester Cancer Center 1475 NW 12th Ave Miami; Miami, FL 33136; Telephone: (305) 243-5302

E-mail: [email protected]

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1.0 SPECIFIC AIMS:

1.1 To describe the characteristics of patients with post-transplant lymphoproliferative disorders (PTLD) following allogeneic hematopoietic cell transplantation (allo HCT)

1.2 To determine morbidity and outcomes associated with Epstein Barr virus (EBV) positive and EBV negative PTLD

2.0 ENDPOINTS:

2.1 The primary endpoints of the study will be to describe overall survival of patients

developing EBV positive and EBV negative PTLD. 2.2 The secondary endpoints will be

2.2.1 Time to onset of PTLD 2.2.2 Factors at transplant impacting outcomes following diagnosis of EBV positive

PTLD

3.0 SCIENTIFIC JUSTIFICATION: Post-transplant lymphoproliferative disorder (PTLD) after allo HCT is predominantly derived from donor B cells and typically occurs within the first 6 months after transplantation, usually associated with EBV and occurring before reconstitution of the EBV specific cytotoxic T lymphocyte (CTL) response. It can, however, occur later in the most severely immunocompromised patients. Risk factors include the degree of mismatch between donor and recipient, manipulation of the graft to deplete T cells, and the degree and duration of immunosuppression used to prevent and treat GVHD. 1,2 PTLD occurs more commonly in pediatric patients than in adults. The higher incidence in children is thought to result from the fact that they have a greater likelihood of being EBV-naïve recipients. In solid organ transplant (SOT) patients, approximately 50% of the patients develop detectable elevated EBV DNA. In allo HCT patients, EBV reactivation is detected in 31% and 65% of un manipulated and TCD HCT patients in a retrospective analysis of 150 patients.3 SOT patients also develop PTLD later than HCT patients. The median length of time between transplant and diagnosis of PTLD for SOT patients is 2.8 years versus 121 days for HCT patients. PTLD is most likely to develop in the first year following allo HCT, with an incidence of 224 per 100,000 but falls to 54 per 100,000 in the 2nd year and 31 per 100,000 in the 6th year.22 Late-onset PTLD, occurring years after transplantation is often associated with more monoclonal lesions and a worse prognosis. In adults, rates range from 1%–3% in kidney and liver transplants, 2%–6% in heart–lung transplants, and in up to 20% of small intestine transplants 10, 15, 16, 18. The variation is likely related to the degree and duration of immunosuppression as well as the number of EBV-positive donor lymphocytes in the graft. PTLDs represent a heterogeneous group of EBV positive non-Hodgkin’s lymphomas that vary clinically and are ill-defined morphologically 9. A spectrum of B-cell proliferative states are classified as polymorphic PTLD or monomorphic PTLD. Most early lesions are polymorphic. The monomorphic PTLD is further characterized as diffuse large B-cell lymphoma (DLBCL), the commonest form of PTLD, Burkitt’s lymphoma/Burkitt’s-like lymphoma, and Hodgkin-like lymphoma10. Late onset PTLDs can occasionally be EBV negative and unknown factors such as other viral reactivations may likely be related to these EBV negative PTLDs.9

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An overall incidence of EBV PTLD in severe aplastic anemia patients is 6% and is 13% with ATG exposure. The majority of EBV infections that occur after transplantation, especially in adults, are clinically silent reactivations. This leads to a subsequent delay in the diagnosis of PTLD. Studies have shown a positive correlation between the degree of EBV DNAemia and the development of PTLD.24 EBV DNAemia is significantly more commonly seen in SOT recipients than HSCT patients. Also, more SOT patients develop PTLD than HSCT, and also significantly later than HSCT recipients. Since the occurrence of PTLD is significantly related to the viral load, constant quantification of EBV-DNA load is a prognostic marker for the development of PTLD.11,12,13

A large systemic analysis for progression to PTLD is lacking. Table-1 summarizes published data for post-transplant PTLD. In a study by Buyck, et al 4 in 89 patients with severe aplastic anemia reported an overall incidence of 6.3% for EBV PTLD. A marked increase in the incidence was noted (13.3%) in patients exposed to ATG with 5 of 43 patients developing EBV PTLD. Some information on ATG and or Alemtuzumab related EBV PTLD is available as case reports and retrospective analyses of small number of patients.5-8 A descriptive analysis of an all patients from the Center for International Blood and Marrow Transplant Research (CIBMTR) would be able to answer some of the questions surrounding EBV-PTLD such as effect of viremias including EBV/CMV/HSV/HHV6 on the onset of PTLD and also impact of various conditioning regimens and GVHD prophylaxis on outcome of both EBV positive and EBV negative PTLD.

4.0 STUDY POPULATION:

All patients undergoing allogeneic HCT reported to the CIBMTR between 2002 and 2014 and subsequently reported to have PTLD (q430-432 on 2100 form v3.0 or analogous question on retired forms). Patients with prior lymphomas, prior chronic lymphoid leukemia (CLL/PLL), SCID, other inherited immune system disorders, and autoimmune disease are excluded. For the purposes of this study, patients will be divided based on the presence/absence of EBV in the associated PTLD

5.0 OUTCOMES:

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5.1 Overall survival from diagnosis of EBV+ PTLD: time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up.

5.2 Overall survival from diagnosis of EBV- PTLD: time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up.

6.0 VARIABLES TO BE DESCRIBED:

6.1. Patient related: • Gender: male or female • Age by decades • Karnofsky performance status: <90 or > or = to 90 • HCT-CI • Race and ethnicity

6.2. Disease related prior to transplant:

• Disease status at transplantation • Prior XRT: yes or no • Time from diagnosis to transplant

6.3. Transplant related: • Conditioning intensity: myeloablative or nonmyeloablative/reduced-intensity • TBI: yes vs. no • Dose of TBI • Donor type (HLA identical sib vs. matched related vs. mismatched related vs.

haploidentical vs. matched unrelated vs. mismatched unrelated vs. cord) • Stem cell source (bone marrow, peripheral blood, umbilical cord) • Donor-recipient gender mismatch for transplants excluding cord transplants • Donor/Recipient CMV serostatus • Recipient EBV serostatus • GVHD prophylaxis • ATG/CAMPATH: ATG alone vs CAMPATH alone vs ATG+CAMPATH vs neither

6.4. Post-transplant variables occurring prior to the diagnosis of PTLD

• Acute GVHD grade 2 – 4: yes vs no • Chronic GVHD: yes vs. no • Day 100 WBC • Day 100 absolute lymphocyte count (calculated variable) • CMV viremia by day 100: yes vs no • EBV viremia by day 100: yes vs no • HSV viremia by day 100: yes vs no • HHV-6 viremia by day 100: yes vs no • Adenovirus viremia by day 100: yes vs no • Number of infections (any) by day 100: yes vs no

6.5. PTLD related:

• Time from HSCT to development of PTLD

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7.0 (POTENTIAL) VARIABLES FOR MULTIVARIABLE ANALYSIS IMPACTING OS FOR THE EBV +

PTLD GROUP • Conditioning Intensity : MAC vs RIC/NMA • Age: 0 – 20 years vs 21 – 50 years vs ≥ 51 years • Disease: Malignant vs SAA vs Other non-malignant disease • Donor: UCB vs. Related vs. Unrelated • GVHD prophylaxis: T-cell depletion (ex vivo or CD34 selection) vs. Other GVHD prophylaxis • In vivo TCD: Campath/ATG vs neither • TBI: Yes vs No • Viremia (any vs individual?) prior to the diagnosis of PTLD • GVHD prior to the diagnosis of PTLD

8.0 STUDY DESIGN: Definition of PTLD as well as determination of EBV positive or EBV negative PTLD will be as reported by the center. The demographics and baseline features will be assessed for statistically significant differences using the Chi-square test, Fisher’s exact test or the Kruskal Wallis test, as appropriate. Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. The probability of survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. The EBV negative group will be a descriptive study. To calculate infection density, the number of infections will be counted up to either 1) PTLD if time from transplant to PTLD <= 100 days or ii) up to day 100 if time from transplant to PTLD > 100 days. The number of infections will be divided by smaller number of days between time from transplant to PTLD and day 100 to calculate infection density. Cox regression modeling will be applied to analyze OS of EBV positive from the time from the time of PTLD. The proportional hazards assumption will be tested. If it is violated, it will be added as time-dependent covariate. Interactions between significant covariates will be investigated. Because of the difference in the age distribution between MA and RIC/NMA, we would add age to the model and check whether it has an interaction with the main effect. We would also add control cohort for case cohort analysis for PTLD From 40859 patients without PTLD from center who had either EBV positive or EBV negative PTLD and apply all inclusion criteria to create matched control cohort.

9.0 References: 1. Heslop HE. How I treat EBV lymphoproliferation. Blood. 2009; 114:4002-8. 2. Gottschalk S, Rooney CM, Heslop HE Post-

transplant lymphoproliferative disorders. Annu Rev Med 2005; 56:29-44. 3. Van Esser JW, van der HB, Meijer E, et al. Epstein-

Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV lymphoproliferative disease following T-cell–depleted SCT. Blood 2001; 98(4):972-978.

4. Buyck HC, Ball S, Junagade P, Marsh J, Chakrabarti S. Prior immunosuppressive therapy with antithymocyte globulin increases the risk of EBV-

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related lymphoproliferative disorder following allo-SCT for acquired aplastic anaemia. Bone Marrow Transplant 2009; 43:813-6.

5. Brunstein CG, Weisdorf DJ, DeFor T, Barker JN, Tolar J, van Burik JA, Wagner JE.Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood. 2006; 108:2874-80. 6.Viola GM, Zu Y, Baker KR, Aslam S. Epstein-Barr virus-related lymphoproliferative disorder induced by equine anti-thymocyte globulin therapy. Med Oncol. 2011; 28:1604-8.

6. Islam MS, Anoop P, Gordon-Smith EC, Rice P.Datta-Nemdharry P, Marsh JC. Epstein -Barr virus infections after allogeneic stem cell transplantation: a comparison between non-malignant and malignant hematological disorders.Hematology.2010; 15:344-50.

7. Coppoletta S, Tedone E, Galano B, Soracco M, Raiola AM, Lamparelli T, Gualandi F, Bregante S, Ibatici A, di Grazia C, Dominietto A, Varaldo R, Bruno B, Frassoni F, Van Lint MT, Bacigalupo A. Rituximab treatment for Epstein-Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2011; 17:901-7.

8. Pervez S, Raza MQ, Mirza A, Pal A. Strong BCL2 expression in Burkitt lymphoma is not uncommon in adults. Indian J Pathol Microbiol Apr-Jun; 54(2):290-3.

9. Carbone A, Gloghini A, Dotti G. EBV-associated lymphoproliferative disorders: classification and treatment. Oncologist2008 May; 13(5):577-85.

10. van der Velden WJ, Mori T, Stevens WB, de Haan AF, Stelma FF, Blijlevens NM, et al. Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab. Bone Marrow Transplant Nov; 48(11):1465-71.

11. Orii T, Ohkohchi N, Kikuchi H, Koyamada N, Chubachi S, Satomi S, et al. Usefulness of quantitative real-time polymerase chain reaction in following up patients with Epstein-Barr virus infection after liver transplantation. Clin Transplant2000 Aug;14(4 Pt 1):308-17.

12. Merlino C, Cavallo R, Bergallo M, Giacchino F, Bollero C, Negro Ponzi A, et al. Epstein Barr viral load monitoring by quantitative PCR in renal transplant patients. New Microbiol2003 Apr; 26(2):141-9.

13. Holman CJ, Karger AB, Mullan BD, Brundage RC, Balfour HH, Jr. Quantitative Epstein-Barr virus shedding and its correlation with the risk of post-transplant lymphoproliferative disorder. Clin Transplant Mar 4.

14. Gross TG, Orjuela MA, Perkins SL, Park JR, Lynch JC, Cairo MS, et al. Low-dose chemotherapy and rituximab for post transplant lymphoproliferative disease (PTLD): a Children's Oncology Group Report. Am J Transplant Nov; 12(11):3069-75.

15. Heslop HE. Equal-opportunity treatment of EBV-PTLD. Blood Mar 15; 119(11):2436-8. 16. Schiffer L, Henke-Gendo C, Wilsdorf N, Hussein K, Pape L, Schmitt C, et al. CXCL13 as a

novel marker for diagnosis and disease monitoring in pediatric PTLD. Am J Transplant Jun; 12(6):1610-7.

17. Dvorak CC, Bollard CM, El-Bietar J, Filipovich A. Complications of transplant for nonmalignant disorders: autoimmune cytopenias, opportunistic infections, and PTLD. Biol Blood Marrow Transplant Jan; 18(1 Suppl):S101-10.

18. Dharnidharka VR, Lamb KE, Gregg JA, Meier-Kriesche HU. Associations between EBV serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National Registry Data in the United States. Am J Transplant Apr; 12(4):976-83

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19. Montserrat E. PTLD treatment: a step forward, a long way to go. Lancet Oncol Feb; 13(2):120-1.

20. Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol Feb; 13(2):196-206.

21. De Pasquale MD, Mastronuzzi A, De Vito R, Cometa A, Inserra A, Russo C, et al. Unmanipulated donor lymphocytes for EBV-related PTLD after T-cell depleted HLA-haploidentical transplantation. Pediatrics Jan; 129(1):e189-94.

22. Wiesmayr S, Webber SA, Macedo C, Popescu I, Smith L, Luce J, et al. Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. Eur J Immunol Feb; 42(2):541-50.

23. Eckrich MJ, Frangoul H, Knight J, Mosse C, Domm J. A case of pediatric PTLD following autologous stem cell transplantation and review of the literature. Pediatr Transplant Feb; 16(1):E15-8.

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Table 1 Characteristics of patients who underwent first ALLO transplants with PTLD , reported to the CIBMTR, from 2002 to 2015

Variable EBV positive

N(%) EBV negative

N(%) Patient related Number of patients 236 34 Number of centers 95 29 Gender

Male 144 (61) 21 (62) Female 92 (39) 13 (38)

Age, median(range), years 32 (<1 - 76) 48 (1 - 70) Age at transplant, years

0-10 45 (19) 5 (15) 11-20 45 (19) 4 (12) 21-30 27 (11) 2 ( 6) 31-40 27 (11) 3 ( 9) 41-50 27 (11) 6 (18) 51-60 35 (15) 6 (18) >60 30 (13) 8 (24)

Karnofsky performance pre-Preparative Regimen <90 54 (23) 10 (29) >=90 178 (75) 20 (59) Missing 4 ( 2) 4 (12)

Disease related Disease

AML 77 (33) 8 (24) ALL 33 (14) 5 (15) CML 11 ( 5) 2 ( 6) MDS 42 (18) 8 (24) Other acute leukemia 1 (<1) 0 Plasma cell disorder 1 (<1) 0 Severe aplastic anemia 46 (19) 7 (21) Inherit.abnorm.erythrocyte diff/funct. 12 ( 5) 2 ( 6) Inherit.disord. of metabolism 9 ( 4) 1 ( 3) Histiocytic disorders 3 ( 1) 1 ( 3) Other, specify 1 (<1) 0

Disease Status at transplantation Early 78 (33) 10 (29)

Intermediate 34 (14) 3 ( 9) Advanced 42 (18) 6 (18) Unknown 11 ( 5) 4 (12)

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N(%) EBV negative

N(%) Non-Malignant disease 71 (30) 11 (32)

Time from diagnosis to TX, median(range), months 9 (<1 - 327) 8 (1 - 150) Time from diagnosis to transplant, months

<6 78 (33) 15 (44) 6-11 61 (26) 7 (21) 12-17 26 (11) 4 (12) 18-23 11 ( 5) 3 ( 9) >=24 53 (22) 5 (15) Missing 7 ( 3) 0

HCT-CI 0 96 (41) 12 (35) 1 21 ( 9) 3 ( 9) 2 14 ( 6) 3 ( 9) 3 19 ( 8) 4 (12) 4 12 ( 5) 3 ( 9) 5 10 ( 4) 1 ( 3) Legacy cases, no HCT-CI information 63 (27) 8 (24) Missing 1 (<1) 0

Prior XRT No 145 (61) 18 (53) Yes 7 ( 3) 1 ( 3) Non-Malignant disease 71 (30) 11 (32) Missing 13 ( 6) 4 (12)

Transplant related Conditioning regimen intensity

Myeloablative 112 (47) 17 (50) RIC 43 (18) 4 (12) NMA 9 ( 4) 1 ( 3) Non-Malignant disease 71 (30) 11 (32) TBD/missing 1 (<1) 1 ( 3)

TBI No 126 (53) 17 (50) Yes 109 (46) 15 (44) Missing 1 (<1) 2 ( 6)

Donor-recipient HL match HLA identical sib 30 (13) 6 (18) Matched other related 2 (<1) 0 Haploidentical 2 (<1) 0 Mismatched other related 10 ( 4) 2 ( 6) Unrelated well matched 62 (26) 13 (38)

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N(%) EBV negative

N(%) Unrelated partially matched 24 (10) 4 (12) Unrelated mismatched 4 ( 2) 1 ( 3) Unrelated HLA missing 30 (13) 4 (12) Cords 72 (31) 4 (12)

Donor-recipient sex match Cords 72 (31) 4 (12) Male-Male 60 (25) 15 (44) Male-Female 34 (14) 8 (24) Female-Male 26 (11) 4 (12) Female-Female 21 ( 9) 1 ( 3) Missing 23 (10) 2 ( 6)

Donor-recipient CMV status +/+ 29 (12) 11 (32) +/- 24 (10) 2 ( 6) -/+ 81 (34) 10 (29) -/- 78 (33) 7 (21) ?/+ 9 ( 4) 3 ( 9) ?/- 14 ( 6) 0 Missing 1 (<1) 1 ( 3)

Donor-recipient EBV status +/+ 23 (10) 5 (15) +/- 3 ( 1) 0 -/+ 52 (22) 1 ( 3) -/- 11 ( 5) 2 ( 6) +/? 3 ( 1) 0 -/? 19 ( 8) 2 ( 6) ?/+ 82 (35) 9 (26) ?/- 13 ( 6) 3 ( 9) Missing 30 (13) 12 (35)

Stem cell source BM 64 (27) 12 (35) PB 100 (42) 18 (53) Cords 72 (31) 4 (12)

ATG/CAMPATH as conditioning or GVHD prophylaxis ATG + CAMPATH 1 (<1) 0 ATG alone 173 (73) 20 (59) CAMPATH alone 17 ( 7) 1 ( 3) No ATG or CAMPATH 45 (19) 13 (38)

GVHD prophylaxis Ex vivo T-cell depletion 19 ( 8) 2 ( 6)

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N(%) EBV negative

N(%) CD34 selection 10 ( 4) 2 ( 6) Cyclophosphamide 1 (<1) 2 ( 6) FK506 + MMF +- others 28 (12) 7 (21) FK506 + MTX +- others 46 (19) 7 (21) FK506 + others 12 ( 5) 2 ( 6) FK506 alone 6 ( 3) 0 CSA + MMF +- others (except FK506) 38 (16) 2 ( 6) CSA + MTX +- others (except FK506, MMF) 42 (18) 7 (21) CSA + others (except FK506, MTX, MMF) 19 ( 8) 2 ( 6) CSA alone 11 ( 5) 0 Other GVHD prophylaxis* 4 ( 2) 1 ( 3)

Year of transplant 2002 7 ( 3) 1 ( 3) 2003 19 ( 8) 1 ( 3) 2004 11 ( 5) 2 ( 6) 2005 19 ( 8) 2 ( 6) 2006 20 ( 8) 4 (12) 2007 29 (12) 3 ( 9) 2008 30 (13) 1 ( 3) 2009 18 ( 8) 7 (21) 2010 21 ( 9) 2 ( 6) 2011 13 ( 6) 3 ( 9) 2012 8 ( 3) 0 2013 22 ( 9) 6 (18) 2014 19 ( 8) 2 ( 6)

PTLD related Time from transplant to PTLD, median(range), months 3 (<1 - 53) 5 (1 - 110)

Missing 3 ( 1) 1 ( 3) Time from diagnosis of PTLD to last follow up, median(range), months 9 (<1 - 127) 12 (<1 - 111)

Missing 3 ( 1) 2 ( 6) Events before PTLD AGVHD grade 2-4 before PTLD

No 160 (68) 25 (74) Yes 75 (32) 9 (26) Missing 1 (<1) 0

Time from transplant to aGVHD grade 2-4, median(range), days 28 (8 - 151) 21 (11 - 47) CGVHD before PTLD No 204 (86) 24 (71) Yes 32 (14) 10 (29)

Time from transplant to cGVHD, median(range), months 4 (3 - 12) 4 (3 - 24)

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N(%) EBV negative

N(%) CMV before PTLD and before day100 after TX

No 186 (79) 22 (65) Yes 48 (20) 12 (35) Missing 2 (<1) 0

Time from transplant to first CMV, median(range), days 32 (5 - 95) 45 (10 - 85) EBV before PTLD and before day100 after TX

No 164 (69) 30 (88) Yes 70 (30) 4 (12) Missing 2 (<1) 0

Time from transplant to first EBV, median(range), days 61 (17 - 100) 53 (48 - 78) HSV before PTLD and before day100 after TX

No 221 (94) 31 (91) Yes 13 ( 6) 3 ( 9) Missing 2 (<1) 0

Time from transplant to first HSV, median(range), days 12 (<1 - 98) 55 (20 - 65) HHV6 before PTLD and before day100 after TX

No 217 (92) 32 (94) Yes 17 ( 7) 2 ( 6) Missing 2 (<1) 0

Time from transplant to first HHV6, median(range), days 28 (8 - 82) 27 (24 - 29) Adenovirus before PTLD and before day100 after TX

No 226 (96) 32 (94) Yes 8 ( 3) 2 ( 6) Missing 2 (<1) 0

Time from transplant to first Adenovirus, median(range), days 25 (14 - 58) 64 (34 - 94) Total number of infections before PTLD and before day100 after TX

0 65 (28) 12 (35) 1 70 (30) 7 (21) 2 42 (18) 6 (18) 3 42 (18) 5 (15) 4 8 ( 3) 1 ( 3) 5 7 ( 3) 0 6 1 (<1) 3 ( 9) 7 1 (<1) 0

Median follow-up of survivors, months 60 (3 - 132) 73 (6 - 121) Abbreviations: ALL=acute lymphoblastic leukemia;AML=acute myelogenous leukemia; MDS =myelodysplastic syndromes; HLA=human leukocyte antigen; CP=chronic phase; CR=complete remission; BP=blast phase FK506 = tacrolimus; CSA = cyclosporine; MTX = methotrexate; TBI = total body irradiation; MMF=mycophenolate mofetil; CSA= cyclosporine A; ATG=anti-thymocyte globulin; COR=corticosteroids; ECP=extra-corporeal photopheresis; KGF=kepivance; MAB=in vivo monoclonal antibody; IVIM=in vivo immunotoxin; SIRO=sirolim us; URSO=ursodiol; OTH=other agent

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*GVHD_prophylaxis gvhdlist EBV positive EBV negative total Other GVHD prophylaxis 4 0 4 cor 0 1 1 *30 patients with PTLD missing; **49 patients with tumor EBV missing Quarantine centers from research studies were excluded. ** centers being queried to obtain information if available Distribution of continuous variables Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Patient age

EBV negative 34 1.12 1.12 2.48 18.79 48.22 59.61 67.79 69.97 69.97 EBV positive 236 0.44 0.70 2.60 12.74 31.57 52.23 67.83 71.55 75.90

Time from diagnosis to transplant(month)


Time from transplant to PTLD(month) (longer than 12 month will be reviewed)


Time from diagnosis of PTLD to last follow up (months)


Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time from transplant to death/last follow-up date

Alive 118 3.49 5.79 11.22 25.23 52.57 88.42 119.01 124.28 132.11 Dead 151 1.35 1.48 2.07 3.85 7.50 15.00 42.01 75.07 117.11

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time between transplant and aGVHD before PTLD (days)

No 181 12.00 18.00 35.00 62.00 102.00 156.00 732.00 2540.00 3346.00 Yes 84 8.00 8.00 10.00 18.50 28.00 42.00 90.00 151.00 151.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max

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Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time between transplant and chronic GVHD before PTLD(month)

No 224 0.39 0.66 1.25 2.11 3.08 4.87 17.17 35.72 52.70 Yes 42 2.96 2.96 3.22 3.32 4.05 6.09 11.02 24.01 24.01

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time between transplant to first CMV by day 100 before PTLD(days)

No 205 12.00 20.00 37.00 69.00 100.00 100.00 100.00 100.00 100.00 Yes 60 5.00 5.00 14.00 26.00 33.50 45.50 67.50 95.00 95.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time between transplant to first EBV by day 100 before PTLD(days)

No 191 12.00 18.00 44.00 77.00 100.00 100.00 100.00 100.00 100.00 Yes 74 17.00 17.00 23.00 43.00 59.50 76.00 97.00 100.00 100.00

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Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time between transplant to first HSV by day 100 before PTLD (days)

No 249 12.00 30.00 41.00 71.00 100.00 100.00 100.00 100.00 100.00 Yes 16 0.00 0.00 0.00 7.50 17.00 54.00 98.00 98.00 98.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time between transplant to first HHV-6 by day 100 before PTLD(days)

No 246 12.00 20.00 40.00 66.00 100.00 100.00 100.00 100.00 100.00 Yes 19 8.00 8.00 8.00 22.00 28.00 35.00 82.00 82.00 82.00

Variable N Min 1% 5% 25% 50% 75% 95% 99% Max Time between transplant to first Adenovirus by day 100 before PTLD (days)

No 255 12.00 20.00 40.00 69.00 100.00 100.00 100.00 100.00 100.00 Yes 10 14.00 14.00 14.00 23.00 27.50 57.00 94.00 94.00 94.00

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CIBMTR IN16-01 Viral Encephalitis in Hematopoietic Stem cell Transplant Recipients, 2007-2013

DRAFT PROTOCOL

Study Chair: Maheen Z. Abidi

University of Colorado Hospital 12700 E. 19th Avenue Research Complex 2, Mail Stop B168 Aurora, CO 80045 United States Telephone: (303) 724-4922 E-mail: [email protected] Parameswaran Hari, MD, MS Medical College of Wisconsin Milwaukee, WI 53226 USA Telephone: 414-805-4604 E-mail: [email protected]

Statistical Directors: Kwang Woo Ahn, PhD Associate Professor


Study Statistician: Min Chen, MS CIBMTR Statistical Center 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI 53226 Telephone: (414) 805-0710 E-mail: [email protected]

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Scientific Director: Marcie Riches, MD, MS University of North Carolina at Chapel Hill Associate Professor Division of Hematology/Oncology 170 Manning Drive, POB 3, #7305 Chapel Hill, NC 27599 Telephone: 919-966-3048 E-mail: [email protected] Working Committee Chairs: Jeffery Auletta, MD Nationwide Children’s Hospital Department of Hematology/Oncology and BMT 700 Children’s Drive Columbus, OH 43205 Telephone: (614) 722-3553 E-mail: [email protected]

Caroline A Lindemans, MD, PhD Wilhelmina Children's Hospital University Medical Center Utrecht, Children’s hospital Lundlaan 6, PO BOX 85090 3508 AB, Utrecht, the Netherlands Telephone: 31-622879245 E-mail: [email protected]

Krishna Komanduri, MD;

University of Miami Sylvester Cancer Center 1475 NW 12th Ave Miami; Miami, FL 33136; Telephone: (305) 243-5302 E-mail: [email protected]

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1.0 Objectives: 1.1 To describe the frequency and significance of viral DNA detection in cerebrospinal fluid (CSF) in hematopoietic stem cell transplant (HCT) recipients screened for viral encephalitis. 1.2 To determine the OS of patients with viral encephalitis after HCT

2.0 Scientific Justification:

Limited data exists on characteristics of viral encephalitis in hematopoietic stem cell transplant (HCT) recipients. Viral CNS infections have been reported infrequently after allogeneic stem cell transplant even though they are the most common type of acute encephalitis in the Western hemisphere(1-5). Diagnosis remains challenging and can often only be established by autopsy. Review of literature on viral encephalitis after allogeneic HCT is Human Herpes Virus 6 (HHV6) focused, where as other viruses such as Epstein Barr virus (EBV), Cytomegalovirus (CMV), Varicella zoster virus (VZV), Herpes simplex virus (HSV), JC virus, adenovirus and BK virus have been less frequently reported(2, 3, 6-13). Rare reports exist for Human Herpes Virus 7 (HHV-7), and West Nile virus encephalitis. In a study conducted by Schmidt-Heiber et al, 2,628 allogeneic HCT recipients were analyzed to identify risk factors and characteristics of viral encephalitis (14). Only 32 HCT recipients fulfilled the criteria of viral encephalitis; HHV6 was the identified cause in 9 patients (28%) and non HHV-6 viruses (including patients with more than one identified virus) occurred in 23 patients (72%). Non-HHV6 viruses as noted were EBV (19%), HSV (13%), JC virus (9%), VZV (6%), CMV (6%) and adenovirus (3%). More than one virus was identified in 16% of the patients. Median onset of time was 106 days after HCT; HHV6 encephalitis was noted to occur earlier than non-HHV6 encephalitis. Median survival time after the onset of viral encephalitis as calculated by Kaplan- Meier method was 94 days and was comparable among patients with HHV6 and non-HHV6 encephalitis. Overall mortality rates for deaths attributed to viral encephalitis were noted to be highest for encephalitis secondary to more than one virus (80%), 33% each for HHV6 and EBV, and 67% for JC virus. No death was reported secondary to HSV encephalitis. First line treatments for HCT recipients with HHV-6 encephalitis are Foscarnet and Ganciclovir. Cidofovir is a second-line agent because of the nephrotoxicity associated with the drug. In the above study, antiviral treatment was foscarnet based on all HHV6 encephalitis patients and resulted in 63% response rate(14). Combination antiviral treatment with Ganciclovir and Foscarnet was done in 3 cases of HHv6 encephalitis and was found to be efficacious. In vivo T-cell depletion (particularly with Alemtuzumab), graft-versus host disease (GvHD) prophylaxis with mycophenolate mofetil and fludarabine-based conditioning prior to allogeneic HCT have been implicated as potent risk factors for development of systemic viral infections such as CMV viremia, but the impact of these variables on the occurrence of viral encephalitis has not been studied at large(15, 16). In the above study the authors found a significant association between viral encephalitis and prior use of OKT-3 or Alemtuzumab for T cell depletion (p<0.001) (14). Amongst HCT recipients with CMV encephalitis, they further observed that 4/5 HCT recipients were CMV seropositive and were allografted from CMV-Seronegative donors suggesting an exceptionally high risk for CMV encephalitis (14).

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Different viruses are noted to have distinct characteristics such as onset time, response to treat and outcome. The reasons for the observed difference in encephalitis onset times amongst different causative viruses remain unclear. Both host factors (e.g. reconstitution of virus-specific T cells) and virus specific characteristics (e.g. replication kinetics, level of neuroviruelnce) might be responsible for this (14).

3.0 Study Population:

All patients undergoing first allogeneic hematopoietic stem cell transplant for acute leukemia, myelodysplastic syndrome, CML, CLL, or lymphoma and reported to CIBMTR from 2007-2013. Included patients will be those with documented CNS viral infection occurring in the first 100 days after transplantation.

4.0 Variables to be described:

Patient-related variables: • Age as continuous variable • Gender (male vs. female) • Karnofsky performance score (>90% vs 80 – 89% vs <80% • HCT-CI (0 versus 1-2 versus ≥ 3) • Region

Disease-related variables: • Disease • Lines of chemotherapy (1 vs. 2. vs. >2) • Disease status at transplant (early vs intermediate vs advanced)

Transplant-related variables: • Interval from diagnosis to transplant: <12m vs. ≥ 12m; continuous • Donor type (Matched Related vs Matched Unrelated vs Mismatched Unrelated vs

Umbilical cord vs Haploidentical) • Graft type (bone marrow, cord blood, peripheral blood stem cell) • Donor age (for unrelated only) • Donor-recipient gender match: M-M vs M-F vs F-M vs F-F • Donor recipient CMV status: +/+ vs +/- vs -/- • Recipient EBV serostatus: Positive vs Negative • G-CSF use (Y/N) • ATG or ALG Y/N • Campath Y/N • Conditioning intensity • Total Body Irradiation Y/N • GVHD prophylaxis

Time dependent variables occurring prior to the diagnosis of encephalitis • Acute graft-versus-host disease (GVHD) Y/N • Time to neutrophil engraftment • CMV reactivation Y/ N

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Infection Related • Viremia: Yes/No • Organism specific criteria: HHV6, EBV, VZV, CMV, JC Virus (PML), Adenovirus,

Multiple viruses 5.0 Outcomes:

5.1 Overall survival of patients developing viral encephalitis: Defined as time from onset of viral encephalitis to death of any cause. Surviving patients are censored at the time of last contact. Events will be plotted on a survival curve.

5.2 Cumulative Incidence of viral encephalitis for specific viruses and separately for polyviral encephalitis: This will be assessed as the CI function with death and relapse as competing risks.

5.3 Causes of Death: In the event of relapse of disease for transplant, relapse is considered the primary cause of death.

6.0 Study Design: Patient, disease, transplant-related factors will be compared using Chi-square test if variables are categorical or by using Mann-Whitney U test if variables are continuous. Univariate analysis will be performed for primary or secondary end points. Kaplan-Meier estimates will be used for OS of patients with viral encephalitis. “Survival after onset of viral encephalitis” will be calculated from time of diagnosis of viral encephalitis to death or last follow up. “Viral encephalitis related survival” will be calculated from time of onset of viral encephalitis to deaths directly attributed to viral encephalitis. Cumulative incidence will be used to calculate the incidence of viral encephalitis.

7.0 References: 1. Koskiniemi M, Rantalaiho T, Piiparinen H, von Bonsdorff CH, Farkkila M, Jarvinen A,

et al. Infections of the central nervous system of suspected viral origin: a collaborative study from Finland. J Neurovirol. 2001;7(5):400-8.

2. Muta T, Fukuda T, Harada M. Human herpesvirus-6 encephalitis in hematopoietic SCT recipients in Japan: a retrospective multicenter study. Bone Marrow Transplant. 2009;43(7):583-5.

3. Reddy SM, Winston DJ, Territo MC, Schiller GJ. CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency. Bone Marrow Transplant. 2010;45(6):979-84.

4. Schmidt-Hieber M, Zweigner J, Uharek L, Blau IW, Thiel E. Central nervous system infections in immunocompromised patients: update on diagnostics and therapy. Leuk Lymphoma. 2009;50(1):24-36.

5. Whitley RJ. Herpes simplex encephalitis: adolescents and adults. Antiviral Res. 2006;71(2-3):141-8.

6. Battiwalla M, Paplham P, Almyroudis NG, McCarthy A, Abdelhalim A, Elefante A, et al. Leflunomide failure to control recurrent cytomegalovirus infection in the setting of renal failure after allogeneic stem cell transplantation. Transpl Infect Dis. 2007;9(1):28-32.

7. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative

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patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113(20):4834-40.

8. Davis D, Henslee PJ, Markesbery WR. Fatal adenovirus meningoencephalitis in a bone marrow transplant patient. Ann Neurol. 1988;23(4):385-9.

9. Kharfan-Dabaja MA, Ayala E, Greene J, Rojiani A, Murtagh FR, Anasetti C. Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature. Bone Marrow Transplant. 2007;39(2):101-7.

10. Pruitt AA. Central nervous system infections in cancer patients. Semin Neurol. 2004;24(4):435-52.

11. Romee R, Brunstein CG, Weisdorf DJ, Majhail NS. Herpes simplex virus encephalitis after allogeneic transplantation: an instructive case. Bone Marrow Transplant. 2010;45(4):776-8.

12. Tauro S, Toh V, Osman H, Mahendra P. Varicella zoster meningoencephalitis following treatment for dermatomal zoster in an alloBMT patient. Bone Marrow Transplant. 2000;26(7):795-6.

13. Zerr DM, Gooley TA, Yeung L, Huang ML, Carpenter P, Wade JC, et al. Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients. Clin Infect Dis. 2001;33(6):763-71.

14. Schmidt-Hieber M, Schwender J, Heinz WJ, Zabelina T, Kuhl JS, Mousset S, et al. Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents. Haematologica. 2011;96(1):142-9.

15. Chakrabarti S, Mackinnon S, Chopra R, Kottaridis PD, Peggs K, O'Gorman P, et al. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Blood. 2002;99(12):4357-63.

16. Schmidt-Hieber M, Schwarck S, Stroux A, Ganepola S, Reinke P, Thiel E, et al. Immune reconstitution and cytomegalovirus infection after allogeneic stem cell transplantation: the important impact of in vivo T cell depletion. Int J Hematol. 2010;91(5):877-85.

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Table 1.1 Characteristics of patients who underwent first ALLO transplants with AML, ALL, MDS, CML, CLL, NHL or HL , developed CNS viral infection within 100 days reported to the

CIBMTR, from 2007 to 2013 Variable N(%)

Patient related Number of patients 93 Gender

Male 54 (58) Female 39 (42)

Age, median(range), years 45 (3 - 74)

Age at transplant, years <=10 10 (11) 11-20 16 (17)

21-30 6 ( 6) 31-40 10 (11) 41-50 10 (11)

51-60 21 (23) >60 20 (22)

Karnofsky performance status at HCT

<80 9 (10) 80-89 22 (24) >=90 62 (67)

Region US 84 (90)

Europe 4 ( 4) Australia/New Zealand 2 ( 2) Mideast/Africa 1 ( 1)

Central/South America 2 ( 2) Disease-related Disease

AML 29 (31) ALL 20 (22) CLL 7 ( 8)

CML 7 ( 8) MDS 19 (20) NHL 11 (12)

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Variable N(%)

HCT-CI 0 32 (34) 1 14 (15)

2 5 ( 5) 3 18 (19) 4 7 ( 8)

5 10 (11) Legacy cases, no HCT-CI information 7 ( 8)

Time from diagnosis to TX, median(range), months 11 (3 - 164)

Time from diagnosis to transplant (months) 0-5 22 (24) 6-11 29 (31)

12-17 13 (14) 18-23 5 ( 5) >=24 24 (26)

Transplant-related Graft type

Bone Marrow 7 ( 8) Peripheral blood 32 (34) Cord blood 54 (58)

Donor type Cord 54 (58) HLA-identical Sib 5 ( 5)

Related 2 ( 2) 8/8 unrelated 19 (20) 7/8 unrelated 9 (10)

<6/8 unrelated 1 ( 1) Missing 3 ( 3)

Donor/recipient gender match

Cord 54 (58) Male-Male 15 (16) Male-Female 10 (11)

Female-Male 6 ( 6) Female-Female 7 ( 8) Missing 1 ( 1)

Donor age, years

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Variable N(%)

Cord blood 54 (58) Related/Other related 7 ( 8) 21-30 9 (10)

31-40 6 ( 6) 41-50 11 (12) Missing 6 ( 6)

Donor/Recipient CMV status +/+ 4 ( 4) +/- 4 ( 4)

-/+ 47 (51) -/- 33 (35) -/? 1 ( 1)

?/+ 4 ( 4) Conditioning regimen intensity

Myeloablative 61 (66)

RIC 12 (13) NMA 12 (13)

TBD 8 ( 9) TBI

No 33 (35)

Yes 60 (65) GVHD prophylaxis

Ex vivo T-cell depletion 1 ( 1)

Cyclophosphamide 1 ( 1) TAC + MMF +- others 29 (31) TAC + MTX +- others 17 (18)

TAC + others 11 (12) TAC alone 2 ( 2) CSA + MMF +- others (except TAC ) 19 (20)

CSA + MTX +- others (except TAC , MMF) 3 ( 3) CSA + others (except TAC , MTX, MMF) 6 ( 6) CSA alone 1 ( 1)

Other GVHD prophylaxis* 3 ( 3) ATG received

No 61 (66)

Yes 32 (34)

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Variable N(%)

Campath received No 88 (95) Yes 5 ( 5)

G-CSF, GM-CSF (day-3 to day 7) No 27 (29) Yes 66 (71)


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Table 1.2 Time dependent variable and infection

Variable N(%)

Number of patients 93

Infection-related Viral infection by day100

HHV6: CNS only 39 (42)

HHV6: CNS + Viremia 29 (31) HHV6: CNS + Viremia + Other 4 ( 4) HHV6: CNS + other 1 ( 1)

CMV: CNS only 1 ( 1) CMV: CNS + viremia 2 ( 2) EBV: CNS Only 5 ( 5)

EBV: CNS + Viremia 4 ( 4) Adeno: CNS only 1 ( 1)

VZV: CNS only 3 ( 3) HSV: CNS only 1 ( 1) Polyoma virus: CNS + viremia + Other 1 ( 1)

Multi: HHV6 CNS only AND CMV CNS + Viremia 1 ( 1) Multi virus: CMV CNS + Viremia AND HSV CNS 1 ( 1)

GVHD_prophylaxis* gvhdlist n

Other GVHD prophylaxis cor + mmf + siro 1 (33)

mmf 1 (33)

mmf + siro 1 (33)

Distribution of continuous variables Variable N Min 1% 5% 25% 50% 75% 95% 99% Max

Patient age

93 2.81 2.81 5.83 19.64 45.03 58.43 72.06 73.64 73.64

Time from diagnosis to transplant (months)

93 3.09 3.09 3.59 6.12 10.89 24.84 87.57 164.44 164.44

Total tbi dose(cgy)

Yes 60 200.00 200.00 200.00 200.00 1200.00 1320.00 1400.00 1400.00 1400.00 Variable N Min 1% 5% 25% 50% 75% 95% 99% Max

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Time from transplant to ANC>500, days

Yes 9 7.00 7.00 10.00 13.00 19.00 24.00 37.00 54.00 54.00

No 3 41.00 41.00 41.00 41.00 65.00 72.00 72.00 72.00 72.00


Time from transplant to aGVHD, days

No 36 0.00 0.00 0.00 63.50 141.00 641.50 2218.00 2342.00 2342.00

Yes 57 7.00 7.00 9.00 17.00 28.00 46.00 95.00 158.00 158.00


Survival

No 27 11.22 11.22 18.78 36.12 59.80 72.80 77.04 95.99 95.99

Yes 66 1.02 1.02 1.18 2.34 3.60 7.70 32.63 73.62 73.62

Selection Criteria Removed Remained First allo transplant for AML, ALL, CML, CLL, MDS NHL, HD2007-2013

16637

BM, PM or CB only (PB + UCB, n=110; BM + UCB, n=11; 'Other, specify', n=1; ' PB + OTH , n=2; missing, n=2) 126 16511 Excluded if twin or multiple donor 155 16356 Any viral infection at CNS 16246 110 Developed Viral Encephalitis within 100day after HCT 15 95 Excluded if NMDP legacy cases (no infection information) 2 93 Excluded if no consent 0 93

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CIBMTR IN16-02

Determination of the burden of mucosal barrier injury-laboratory confirmed bloodstream infections

(MBI-LCBI) in the first 100 days after stem cell transplant

DRAFT PROTOCOL Study Chair(s): Christopher Dandoy, MD, MSc Assistant Professor of Clinical Pediatrics Cincinnati Children’s Hospital Medical Center 3333 Burnet Avenue, MLC 11027

Cincinnati, Ohio 45229-3039 Telephone: (513) 636-7287 E-mail: [email protected]

Paulina Daniels, DO Bone Marrow Transplant Physician Cincinnati Children’s Hospital Medical Center 3333 Burnet Avenue, MLC 11027

Cincinnati, Ohio 45229-3039 Telephone: (513) 636-7287 E-mail: [email protected] Statistical Directors: Kwang Woo Ahn, PhD Associate Professor


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Study Statistician: Min Chen, MS CIBMTR Statistical Center 9200 W. Wisconsin Ave. CLCC, Suite C5500 Milwaukee, WI 53226 Telephone: (414) 805-0710 E-mail: [email protected] Scientific Director: Marcie Riches, MD, MS University of North Carolina at Chapel Hill Associate Professor Division of Hematology/Oncology 170 Manning Drive, POB 3, #7305 Chapel Hill, NC 27599 Telephone: 919-966-3048 E-mail: [email protected] Working Committee Chairs: Jeffery Auletta, MD Nationwide Children’s Hospital Department of Hematology/Oncology and BMT 700 Children’s Drive Columbus, OH 43205 Telephone: (614) 722-3553 E-mail: [email protected]

Caroline Lindemans, MD, PhD. Wilhelmina Children's Hospital University Medical Center Utrecht Telephone: 31-61-4026510 E-mail: [email protected] Krishna Komanduri, MD; University of Miami Sylvester Cancer Center 1475 NW 12th Ave Miami; Miami, FL 33136; Telephone: (305) 243-5302 E-mail: [email protected]

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1.0 Hypothesis: Patients in the first 100 days after stem cell transplant (SCT) who develop mucosal barrier injury laboratory confirmed bloodstream infections (MBI-LCBI) have increased transplant related mortality (TRM) and decreased overall survival (OS) compared to those with no infection or an infection not classified as an MBI-LCBI.

2.0 Specific Aims: 2.1. Compare TRM and OS post-SCT between patients who develop a MBI-LCBI versus those with no

infection or a non-MBI-LCBI in the first 100 days 2.2. Determine the incidence of MBI-LCBIs in the first 100 days post SCT 2.3. Determine the risk factors for development of a MBI-LCBI in the first 100 days 2.4. Determine the timing of MBI-LCBI after SCT

3.0 Scientific Justification

Patients undergoing SCT are at increased risk of a bacterial infection. The majority of patients have a central venous catheter (CVC) for medication administration, transfusions and frequent blood draws. Central line-associated bloodstream infections (CLABSIs) are among the most serious complications in SCT patients and lead to prolonged hospitalization, intensive care admissions, prolonged antibiotic treatment and increased mortality1-3. CVC maintenance care has been shown to be effective in reducing CLABSIs4-6. Recently, concern has been raised regarding immunocompromised patients including SCT patients who are at risk of developing blood stream infections classified as CLABSIs that do not result from the presence of the central line but instead from other mechanisms, such as translocation of bacteria through non-intact mucosa7,8. On the basis of literature review and expert opinion, the Centers for Disease Control and Prevention developed a modification of the CLABSI definition, termed “mucosal barrier injury laboratory-confirmed bloodstream infection” (MBI-LCBI). This definition was recently integrated into National Healthcare Safety Network (NHSN) methods for primary blood stream infection surveillance to aid in identifying a subset of blood stream infections reported as CLABSIs that are likely related to mucosal barrier injury and not the presence of a central line7. Unlike CLABSIs, MBI-LCBIs are not prevented by improved CVC maintenance care. A blood stream infection is defined as an MBI-LCBI if: (1) it resulted from 1 or more of a group of selected organisms known to be commensals of the oral cavity or gastrointestinal tract and (2) occurred in a patient with certain signs or symptoms compatible with the presence of mucosal barrier injury such as gastrointestinal graft-versus-host disease and/or neutropenia7. There is very little data describing MBI-LCBIs. There is no data on the incidence, risk factors, and/or outcome of patients that develop an MBI-LCBI after SCT. Currently, SCT is a known risk factor for MBI-LCBIs, but there is little investigation in risk stratification and prevention of these infections. This study will determine the burden of MBI-LCBIs after SCT by comparing the outcome of patients who develop a MBI-LCBI to patients with no infection or with an infection that is not classified as a MBI-LCBI. Additionally, we will determine the risk factors for MBI-LCBI development.

4.0 Patient Eligibility Population: The following patients will be included in this study

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• The study population will consist of all patients (pediatric and adult) undergoing first allogeneic stem cell transplant reported to the CIBMTR between 2009 and 2014

• Any stem cell source including bone marrow, peripheral or cord blood • Any source including matched or mismatched related and unrelated donors

5.0 Outcomes • Overall survival: Time to death, patients will be censored at last follow-up. • Transplant related mortality (TRM): time to death without evidence of disease

relapse/progression. This event will be summarized as cumulative incidence estimate with relapse/progression as the competing risk.

• Incidence of MBI-LCBI within the first 100 days: This will be assessed as the cumulative incidence function with death and relapse/progression as competing risks.

o A bloodstream infection will be classified as a MBI-LCBIs if it meets both the organism criteria and the patient criteria from the NHSN9: Organism Criteria:

• Eligible organisms include Candida species, Enterococcus species, Enterobacteriaceae, viridans group, Streptococcus species, and certain anaerobes without isolation of additional recognized pathogens or common commensal organisms.

Patient Criteria: • Grade 3-4 gastrointestinal graft versus host disease

Or • ANC < 500 within 7 days of the positive culture

• Incidence of bloodstream infections (bacterial and fungal) not meeting criteria for MBI-LCBI: This will be assessed as the cumulative incidence function with death and relapse as competing risks.

• Infection as primary or secondary cause of death by day 100 and by 1 year.

6.0 Varaible to be described 6.1. Patient-related variables

• Age at transplant (continuous, <18 vs. >18 years) • Gender: male vs. female

6.2. Transplant related

• Disease • Donor type: related vs. unrelated • HLA match status: well matched vs. partially matched • Graft type: BM vs. PBSC vs. CB • Conditioning: Myeloablative vs. RIC/non-ablative; type of conditioning regimen • GVHD prophylaxis: CSA +/- others vs. FK-506 +/- others vs. T cell depletion vs. others • ATG use at transplant: yes vs. no

6.3 Time dependent variables • Acute GVHD grades 2-4 post-transplant: yes or no • Chronic GVHD at any time post-transplant: yes or no

7.0 Study Design:

Using the criteria listed in section 5.1, patients will be categorized as (a) having developed at least one MBI-LCBI in the first 100 days post-SCT, (b) having developed a bloodstream infection not

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meeting MBI-LCBI criteria in first 100 days post-SCT, (c) having not developed a MBI-LCBI in the first 100 days post-SCT. The Kaplan-Meier method will be used to estimate the probability of overall survival after day 100. The cumulative incidence will be calculated for treatment related mortality after day 100. The Log-Rank test will be used to assess differences in survival and Gray’s test for competing risks will be used for differences in TRM (treating relapse and death from disease as competing risks) among the groups. Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. Multivariable Cox regression analysis will be used to evaluate for potential risk factors and their interactions for development of MBI-LCBI following transplant in OS and TRM. The main effect will be added as time-dependent covariate. The proportional hazards (PH) assumption will be tested. The covariates that violate the PH assumption will be added as time-dependent covariates. A stepwise selection procedure will be used to identify the final model.

8.0 References: 1. Wilson MZ, Rafferty C, Deeter D, Comito MA, Hollenbeak CS. Attributable costs of central line-

associated bloodstream infections in a pediatric hematology/oncology population. Am J Infect Control. 2014;42(11):1157-1160.

2. Cecinati V, Brescia L, Tagliaferri L, Giordano P, Esposito S. Catheter-related infections in pediatric patients with cancer. Eur J Clin Microbiol Infect Dis. 2012;31(11):2869-2877.

3. Poutsiaka DD, Price LL, Ucuzian A, Chan GW, Miller KB, Snydman DR. Blood stream infection after hematopoietic stem cell transplantation is associated with increased mortality. Bone Marrow Transplant. 2007;40(1):63-70.

4. Bundy DG, Gaur AH, Billett AL, et al. Preventing CLABSIs among pediatric hematology/oncology inpatients: national collaborative results. Pediatrics. 2014;134(6):e1678-1685.

5. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006;355(26):2725-2732.

6. Miller MR, Griswold M, Harris JM, et al. Decreasing PICU catheter-associated bloodstream infections: NACHRI's quality transformation efforts. Pediatrics. 2010;125(2):206-213.

7. See I, Iwamoto M, Allen-Bridson K, Horan T, Magill SS, Thompson ND. Mucosal barrier injury laboratory-confirmed bloodstream infection: results from a field test of a new National Healthcare Safety Network definition. Infect Control Hosp Epidemiol. 2013;34(8):769-776.

8. Freeman JT, Elinder-Camburn A, McClymont C, et al. Central line-associated bloodstream infections in adult hematology patients with febrile neutropenia: an evaluation of surveillance definitions using differential time to blood culture positivity. Infect Control Hosp Epidemiol. 2013;34(1):89-92.

9. Central Line–Associated Bloodstream Infection (CLABSI) Event. National Healthcare Safety Network website: http://www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf.

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Table 1.1 Characteristics of patients who underwent first ALLO transplants with MBI-LCBI and without MBI-LCBI by day 100 after transplant, reported to the CIBMTR, from 2009 to 2014

Variable MBI-LCBI

N(%) BSI

N(%) Control

N(%)

Patient related

Number of patients 1513 2907 10450 Number of centers 183 205 241 Gender

Male 869 (57) 1731 (60) 6092 (58) Female 644 (43) 1176 (40) 4358 (42)

Age, median(range), years 41 (<1 - 82) 44 (<1 - 82) 49 (<1 - 83)

Age at transplant, years <=10 309 (20) 579 (20) 1383 (13) 11-20 179 (12) 281 (10) 895 ( 9)

21-30 129 ( 9) 225 ( 8) 883 ( 8) 31-40 125 ( 8) 253 ( 9) 919 ( 9) 41-50 220 (15) 376 (13) 1335 (13)

51-60 298 (20) 602 (21) 2285 (22) >60 253 (17) 591 (20) 2750 (26)

Karnofsky performance pre-Preparative Regimen <80 136 ( 9) 323 (11) 1058 (10) 80-89 346 (23) 649 (22) 2275 (22)

>=90 1009 (67) 1875 (64) 6928 (66) Missing 22 ( 1) 60 ( 2) 189 ( 2)

Disease-related

Disease AML 545 (36) 1038 (36) 3595 (34) ALL 271 (18) 402 (14) 1201 (11)

CLL 31 ( 2) 79 ( 3) 328 ( 3) CML 54 ( 4) 102 ( 4) 331 ( 3) MDS 270 (18) 597 (21) 2410 (23)

Other acute leukemia 22 ( 1) 26 (<1) 90 (<1) NHL 79 ( 5) 164 ( 6) 792 ( 8) HL 2 (<1) 23 (<1) 165 ( 2)

Plasma cell disorder/Multiple Myeloma 9 (<1) 21 (<1) 129 ( 1) Other Malignancies 0 2 (<1) 8 (<1)

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Variable MBI-LCBI

N(%) BSI

N(%) Control

N(%) Severe aplastic anemia 65 ( 4) 88 ( 3) 380 ( 4)

Inherited abnormalities erythrocyte differentiation or function

53 ( 4) 91 ( 3) 397 ( 4)

SCID and other immune system disorders 49 ( 3) 117 ( 4) 379 ( 4) Inherited abnormalities of platelets 2 (<1) 6 (<1) 9 (<1) Inherited disorders of metabolism 31 ( 2) 94 ( 3) 120 ( 1)

Histiocytic disorders 26 ( 2) 48 ( 2) 99 (<1) Autoimmune Diseases 2 (<1) 5 (<1) 6 (<1) Other, specify 2 (<1) 4 (<1) 11 (<1)

Transplant-related Graft type

Bone Marrow 275 (18) 553 (19) 2054 (20) Peripheral blood 641 (42) 1404 (48) 6430 (62) Cord blood 597 (39) 950 (33) 1966 (19)

Donor/recipient HLA match Cord blood 597 (39) 950 (33) 1966 (19) HLA-identical siblings 333 (22) 639 (22) 3207 (31)

Other matched related 8 (<1) 17 (<1) 102 (<1) Mismatched related 1 mismatched 3 (<1) 0 9 (<1) Mismatched related >=2 mismatched 25 ( 2) 51 ( 2) 167 ( 2)

Mismatched related, mismatch unknown 30 ( 2) 59 ( 2) 217 ( 2) 8/8 unrelated 364 (24) 858 (30) 3549 (34) 7/8 unrelated 105 ( 7) 238 ( 8) 749 ( 7)

<=6/8 unrelated 12 (<1) 18 (<1) 30 (<1) Unrelated (HLA match information missing) 35 ( 2) 76 ( 3) 443 ( 4) Missing 1 (<1) 1 (<1) 11 (<1)

Conditional regimen intensity Myeloablative 1034 (68) 1800 (62) 5312 (51) RIC 253 (17) 546 (19) 2761 (26)

NMA 107 ( 7) 301 (10) 1193 (11) TBD 114 ( 8) 246 ( 8) 1079 (10)

Missing 5 (<1) 14 (<1) 105 ( 1) GVHD prophylaxis

No GVHD prophylaxis (forms under review) 16 ( 1) 52 ( 2) 289 ( 3)

Ex vivo T-cell depletion 18 ( 1) 28 (<1) 83 (<1)

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Variable MBI-LCBI

N(%) BSI

N(%) Control

N(%) CD34 selection 23 ( 2) 32 ( 1) 172 ( 2)

Cyclophosphamide 58 ( 4) 98 ( 3) 351 ( 3) TAC + MMF +- others 274 (18) 566 (19) 1730 (17) TAC + MTX +- others 461 (30) 898 (31) 3813 (36)

TAC + others 72 ( 5) 144 ( 5) 657 ( 6) TAC alone 31 ( 2) 44 ( 2) 236 ( 2) CSA + MMF +- others (except TAC ) 306 (20) 588 (20) 1530 (15)

CSA + MTX +- others (except TAC , MMF) 138 ( 9) 225 ( 8) 934 ( 9) CSA + others (except TAC , MTX, MMF) 86 ( 6) 141 ( 5) 288 ( 3)

CSA alone 12 (<1) 46 ( 2) 184 ( 2) Other GVHD prophylaxis 17 ( 1) 42 ( 1) 177 ( 2) Missing 1 (<1) 3 (<1) 6 (<1)

ATG No 1010 (67) 1883 (65) 7103 (68) Yes 500 (33) 1015 (35) 3289 (31)

Missing 3 (<1) 9 (<1) 58 (<1) Year of transplant

2009 391 (26) 842 (29) 2038 (20)

2010 246 (16) 461 (16) 1285 (12) 2011 147 (10) 310 (11) 999 (10) 2012 161 (11) 267 ( 9) 1112 (11)

2013 257 (17) 481 (17) 2146 (21) 2014 311 (21) 546 (19) 2870 (27)

Median follow-up of survivors, months 39 (3 - 85) 47 (2 - 86) 36 (1 - 88)

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Table 1.2 Infection and time dependent variables

Variable MBI-LCBI

N(%) BSI

N(%) Control

N(%)

Number of patients 1513 2907 10450

Infection-related Infection type

Candida 55 ( 4) 44 ( 2) 0

Entrerococcus 321 (21) 221 ( 8) 0 Strep all except pneumoniae 396 (26) 108 ( 4) 0 Enterobacteriaceae 591 (39) 367 (13) 0

Anaerobes 150 (10) 128 ( 4) 0 Other BSI 0 2039 (70) 0 No BSI 0 0 10450

Time from transplant to MBI-LCBI/BSI, median(range), days 8 (<1 - 99) 38 (<1 - 100) Time dependent variable

ANC engraftment Yes 1509 (>99) 2586 (89) 10092 (97) No 4 (<1) 308 (11) 315 ( 3)

Missing 0 13 (<1) 43 (<1) Time from transplant to ANC>500, days 18 (1 - 122) 15 (<1 - 88) 15 (<1 - 203) Acute GVHD grade II-IV

No 788 (52) 1728 (59) 6752 (65) Yes 718 (47) 1157 (40) 3454 (33) Missing 7 (<1) 22 (<1) 244 ( 2)

Time from transplant to aGVHD, days 28 (7 - 174) 29 (7 - 176) 33 (7 - 178) Chronic GVHD(any severity)

No 1007 (67) 1870 (64) 6201 (59)

Yes 505 (33) 1029 (35) 4215 (40) Missing 1 (<1) 8 (<1) 34 (<1)

Time from transplant to cGVHD, months 6 (1 - 66) 6 (1 - 72) 6 (<1 - 73)

Selection Criteria (IN1602 ) November 2016 Removed Remained First Allo transplant 2009-2014 16200 BM, PM or CB only 184 16016 Excluded if twin or multiple donor 179 15837 Excluded if no 100day follow up form (no infection information) 527 15310 Excluded if no consent 438 14872*

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MBI-LCBI: # with GI GVHD (only) = 204 # with ANC <500 (only) =1164 # GI GVHD + ANC <500 =145

*Selection for MBI-LCBI Regrouped Remained Organisms Candida (200 – 209), Enterococcus (135, 177), Strep Viridans (167), Enterobacteriacecae (130, 134, 136, 146, 155, 160, 161), or Anaerobes (122, 124, 123, 129, 131, 139, 147, 148, 154, 166) and Site in Bloodstream/Central line draw (1, 60, 61)

2367

GI GVHD (stage 3 or stage 4) OR BSI prior to or +7 days of date of ANC engraftment OR BSI +/- 7 days of decline in ANC <500 for 3 days

854 1513

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Proposal 1605-01 Title: Clinical outcomes for patients with invasive fungal infections undergoing hematopoietic stem cell transplant, (Myeloablative vs. Nonmyeloablative/Reduced intensity stem cell transplant) in the era of newer anti-fungals, 2009-2015 Maheen Z. Abidi, MD, Medical College of Wisconsin, [email protected] Mark R. Litzow, MD, Mayo Clinic College of Medicine, [email protected], M. Rizwan Sohail, MD, Mayo Clinic College of Medicine, [email protected], Randall C. Walker, MD, Mayo Clinic College of Medicine, [email protected] Hypothesis: Clinical outcomes and mortality rates in patients with pre-existing invasive fungal infections are improved in the current era of newer available anti-fungal agents for patients undergoing reduced intensity (RIC) and non-myeloablative transplant (NMA) vs. myeloablative stem cell transplant (SCT). Specific Aims:

• To determine long-term clinical outcomes and mortality rates of patients with leukemia and other hematologic malignancies with and without pre-existing invasive fungal infections (IFI) i.e. invasive aspergillosis, mucormycosis and fusariosis that undergo hematopoietic stem cell transplant (HSCT).

• Determine impact of IFIs on the incidence and severity of Graft versus host disease and on leukemia/underlying hematological disease relapse rates.

• The incidence is to be examined over 2009-2015 in the era of newer antifungal agents and newer formulations (Voriconazole, Intravenous Posaconazole, delayed release Posaconazole tablets 2014, Isavuconazole 2015 availability era). Compare results with outcome of molds that underwent SCT 1995-2009, (Era of Ambisome, Echinocandin, Voriconazole, Posaconazole suspension) CIBMTR study IN09-01.

Variables to be analyzed: Recipient Related:

• Underlying hematological disease for HSCT Transplant Related Factors:

• Conditioning regimen (non-myeloablative, reduced intensity vs. myeloablative) • Stem cell source: cord blood, bone marrow, and peripheral stem calls

Complications of Transplant • Acute and Chronic GVHD treatment/prophylaxis • Prolonged and/ or high dose corticosteroid use • Graft failure • Co-infections (e.g. CMV reactivation)

Scientific justification: Patients with acute leukemia are frequently diagnosed with invasive fungal infections (IFI), during induction therapy or post-remission. Many of these patients subsequently undergo HSCT. IFI’s particularly invasive aspergillosis (IA) and invasive mucormycosis (IM), are important causes of morbidity and mortality in HSCT recipients. Lack of reliable data on long-term impact of pre-existing IFI’s on

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allogeneic HSCT, complicates evidence based-decision making whether or not to proceed with HSCT. What also remains unclear in this clinical scenario is how soon to proceed with HSCT after anti-fungal therapy has been initiated. Duration and type of immune suppression also remains unclear. Given the advancements in the field of anti-fungal agents in the last 10-15 years, patients with pre-existing IFI have more promising prospects for a successful subsequent HSCT. Reduced intensity and NMA HSCT further helps in minimizing opportunistic infections. It is therefore of interest, in the current era of more effective anti-fungal therapy and less myeloablative regimens to re-examine post- transplant outcomes of patients with IFI. The CIBMTR study IN09-01, studies outcomes of patients with hematological malignancies with and without pre-existing fungal infections (yeasts and IFIs) in patients undergoing HSCT from 1995-2009. This time era would capture treatment of fungal infections in the era of conventional and lipid-base Amphotericin formulations, Voriconazole (2002), and Posaconazole suspension (2006). To be noted Posaconazole oral suspension was noted to have poor bioavailability, particularly in HSCT with mucositis, diarrhea and gastro-intestinal graft versus host disease. Thus sub-therapeutic posaconazole levels were noted with breakthrough IFIs and decrease likelihood of successful treatment for fungal infections. In 2014, delayed-release posaconazole tablets and intravenous formulation of posaconazole were introduced. In a retrospective comparison of posaconazole levels in patients taking delayed-release posaconazole vs. oral suspension, a significant high proportion of patients receiving delayed-release posaconazole were noted to achieve therapeutic serum levels than the cohort receiving oral posaconazole suspension(1). Due to sustained higher drug concentrations the new posconazole formulations hold promise for greater efficacy in treatment of IFIs(2). In March 2015, based on the results of the VITAL study, the FDA approved a new extended spectrum triazole called isavuconazole for treatment of invasive aspergillosis and mucormycosis. An open-label non-comparative study evaluating isavuconzole (VITAL) as first-line or salvage treatment was carried out in 37 patients with invasive mucormycosis(3). A hematologic malignancy was present in 59%; 35% had received a hematopoietic stem cell transplant, and 27% were neutropenic. The endpoints of this study were all cause mortality and overall response at day. Mortality at day 42 was 38%; this was noted to be lower in patients with primary IM (33.3%) versus patients who were intolerant or refractory to prior antifungal treatment (43.7%). Mortality data was noted to be consistent with published data showing mortality rates of 35-45% using Amphotericin B or posaconazole salvage regimens. In this analysis the patients treated with isavuconazole vs. amphotericin B had similar mortality rates (33.3% vs. 41.3% respectively). There has been much interest as well in use of combination anti-fungal therapy in the treatment of IFIs. More recently, in 2015 Marr et al, performed a randomized, multi-center trial comparing combination anti-fungal therapy (voriconazole and echinocandin) than voriconazole alone(4). Patients with hematological malignancies and HCT with invasive aspergillosis were noted to have better survival outcomes when treated with combination anti-fungal therapy. In 2015, Penack et al, presented the results from the EBMT Database; a large multi-center European database involving 28,352 patients with leukemia who underwent first allogeneic HSCT between 2005- 2010(5). Information regarding pre-existing invasive aspergillosis was available on 1,150 patients. There were 689 patients who had pre-existing IA. Interestingly, there were no significant differences between patients with and without pre-transplant IA in terms of overall survival, non-relapse mortality, relapse free survival, incidence and severity of acute GvHD, incidence of chronic GvHD and pulmonary complications. While there was a trend in lower overall survival in patients with preexisting IA, it was not statistically significant (p=0.078). The authors concluded that a history of IA should not generally be considered a contra-indication for HSCT. In this study, the authors recognize that they may have underestimated the effect of IA on HSCT outcomes, as they were unable to assess if the patients with

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pre-existing IA had proven or probable IA. Due to lack of high-quality microbiology data, they were unable to verify that some of the patients in the non-IA group, had possible IA thus leading to possible bias. Furthermore. Lack of high quality microbiology data, made it difficult to distinguish between IA and other IFIs. This makes it possible that some of the IA cases in this study, were mis-diagnosed cases of non-aspergillus molds. In contrast to the above study, in 2014 Girmenia et al published the results of their multi-center GITMO study conducted in 1,858 allogeneic HSCT recipients between 2008 - 2010(6). 93 of these patients who underwent HSCT had proven/probable and possible IFI in the 180 days prior to allogeneic HSCT. The authors noted that patients with IFIs before transplant had a higher risk f proven or probable IFIs in the early post-transplant period and significantly poorer 1-year survival. Currently, there is a paucity of literature on this subject. Thus, there is a critical need for high-quality, multicenter studies to determine the clinical outcomes in patients with IFIs undergoing HSCT in the era of newer more effective antifungal agents and less myeloablative conditioning regimens. Important questions that need more to be studied is the timing of HSCT following diagnosis of IFIs, duration and specific anti-fungal agents used for pre and post-transplant antifungal therapy, as well as measurable indicators (clinical/microbiologic/radiologic resolution) before HSCT. It would also be of interest to examine the impact of IFIs on the incidence and severity of GvHD and leukemia relapse notes as it is a common strategy to reduce immunesuppression in patients with IFIs undergoing HSCT. Study population:

• Adult and Pediatric Patients undergoing first allogeneic hematopoietic stem cell transplant reported to CIBMTR from 2009-2015

• Diagnoses – Acute leukemia, MDS, CML, CLL and Lymphoma • Organism specific criteria

o Mucorales, Aspergillus and Fusarium - Histopathological evidence - Microbiologic evidence - Aspergillus galactomanan assay - 1, 3 B-D-Glucan

Data requirements: Patient-related variables:

• Age as continuous variable • Gender (male vs. female) • Race • Karnofsky performance score (<80, ≥80) • Geographical differences/origin. (Ref. form 2000)

Disease-related variables: • First day of diagnosis of underlying cancer for which HSCT was done • Type of cancer for which HSCT was done • First date of chemotherapy • Number of chemotherapy cycles prior to HSCT • Number of lines of chemotherapy • Neutropenia/ Hematopoeitic recovery following HSCT (Ref. form 2100) • WBC transfusion Y/N (Ref. Form 2100)

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Transplant-related variables: • Interval from diagnosis to transplant: <12m vs. ≥ 12m; continuous • Type of first transplant (Allogeneic) • Donor type (Matched Related vs Matched Unrelated vs Allogeneic Mismatched Unrelated vs

Umbilical cord vs Haploidentical) • Graft type (bone marrow, cord blood, peripheral blood stem cell) • Donor age • Donor-recipient gender match: M-M vs M-F vs F-M vs F-F • Donor recipient CMV status: +/+ vs +/- vs -/- • T-cell depletion (yes vs no) • Conditioning regimen (Myeloablative vs. Non Myeloablative vs Reduced intensity) • GVHD prophylaxis • Therapy given after start of preparative regimen to prevent acute GVHD or graft rejection Y/N

o ATG y/N o Campath Y/N o Steroids o Tacrolimus o Cellcept o Sirolimus

• Acute graft-versus-host disease (GVHD) rate and severity within 60 days of onset (Grade I-II, Grade III-IV) Y/N (Ref. Form 2100) o Biopsy proven Y/N o Clinical evidence Y/N

• Therapy Given for Acute GVHD Y/N o ATG y/N o Campath Y/N o Steroids o Tacrolimus o Cellcept o Sirolimus

• Chronic graft-versus-host disease (GVHD) rate and severity within 100 days post SCT Y/N (Form 2100)

• Grade/Severity • Therapy Given for Acute GVHD Y/N

o ATG y/N o Campath Y/N o Steroids o Tacrolimus o Cellcept o Sirolimus

• Systemic steroids use • G-CSF use (Yes/No) • Engraftment Y/N (Ref. Form 2100)

o Date of engraftment o Was engraftment treated with steroids Y/N

• Time to platelet engraftment • Graft failure (yes vs no)

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Infection-related variables: • Actual date of diagnosis of invasive fungal infection • Kind of invasive fungal infection (Invasive Aspergillosis, Invasive Mucormycosis, Fusarium)

o Aspergillus species o Mucorales specie o Other Molds (e.g. Fusarium)

• Site of infection (Pulmonary, CNS, abdominal/GI, disseminated or other e.g. skin/ wound) • Co-existing viral infection Y/N (Ref. Form 2100)

o Cytomegalovirus • Co-existing bacterial infection Y/N

o Antifungal prophylaxis regimen(s): o Antifungal(s) regimen details: Type of antifungal used e.g. echinocandins, voriconazole, posaconazole, isavuconazole,

Amphotericin B Start and stop dates for each antifungal used (Ref. form 2146) Reason antifungal therapy started

♦ Prophylaxis ♦ Empiric therapy due to suspected infection ♦ Documented infection ♦ Planned post-HSCT therapy

Reason antifungal therapy was stopped ♦ Toxicity ♦ Infection worsened ♦ Therapy complete

o Pre-HSCT Antifungal prophylaxis Antifungal regimen used in Neutropenic vs. Non-neutropenic phase

o Post HSCT Antifungal prophylaxis Secondary (Planned post-HSCT therapy for suspected IFI diagnosed in pre-HSCT period) Antifungal regimen used in Pre-engraftment vs. Post-engraftment phase. (Ref. Form

2100). History of Fungal infection prior to receipt of preparative regimen Y/N (Ref. Form 2000) History of Fungal infection being active in 2 weeks prior to receipt of preparative

regimen Y/N History of more than one fungal infection prior to preparative regimen Y/N (Form 2000)

♦ Kind of fungal infection (Aspergillus, Mucor etc) ♦ Date of infection ♦ Site of infection

Outcome-related variables: • Overall survival • Relapse rate • Non-relapse mortality: death without evidence of disease relapse. This will be assessed using

cumulative incidence function with relapse as competing risks • Infection as primary or secondary cause of death by day 100 and by 1 year. • Date of Death for cases that died secondary to invasive fungal infection

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• Cumulative incidence of invasive fungal infections: This will be assessed as the cumulative incidence function with death and relapse as competing risks

• Infection density of invasive fungal infection during the first year post-transplant. Study design: This study will analyze patient outcomes of all HSCT recipients in the CIBMTR database 2009-2015, with and without pre-existingIFI. Patients will be stratified by the graft source. Conditioning regimens, anti-fungal prophylaxis and post-transplant follow-up will be studied. Using the survival data of entire population of allogeneic HCST patients, the CI of IA and IM will be determined, with stratification by graft source, risk factors, and by era of transplantation. Using patients within strata as controls, the relative frequencies of risk factors in patients with IA, IM, Fusariosis will be analyzed. Patient, disease, transplant-related factors will be compared using Chi-square test if variables are categorical or by using Mann-Whitney U test if variables are continuous. Univariate and multivariate analysis will be performed for primary or secondary end points. Overall survival will be calculated from both diagnosis and time of HSCT. References: 1. Durani U, Tosh PK, Barreto JN, Estes LL, Jannetto PJ, Tande AJ. Retrospective Comparison of

Posaconazole Levels in Patients Taking the Delayed-Release Tablet versus the Oral Suspension. Antimicrobial agents and chemotherapy. 2015;59(8):4914-8.

2. Gurascio-Howard L, Malloch K. Centralized and decentralized nurse station design: an examination of caregiver communication, work activities, and technology. Herd. 2007;1(1):44-57.

3. Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR, 3rd, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. The Lancet Infectious diseases. 2016.

4. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Annals of internal medicine. 2015;162(2):81-9.

5. Penack O, Tridello G, Hoek J, Socie G, Blaise D, Passweg J, et al. Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties. Bone marrow transplantation. 2016;51(3):418-23.

6. Girmenia C, Raiola AM, Piciocchi A, Algarotti A, Stanzani M, Cudillo L, et al. Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014;20(6):872-80.

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Table 1 Characteristics of patients who underwent first ALLO transplants with AML, ALL, MDS or CMLreported to the CIBMTR, from 2010 to 2015

Variable

With both form 2046 and 2146*

N(%)

Without form 2046 and/or 2146

N(%)

Patient related

Number of patients 390 8573 Number of centers 128 128 Gender

Male 232 (59) 4949 (58) Female 158 (41) 3624 (42)

Age, median(range), years 50 (1 - 76) 55 (<1 - 82)

Age at transplant, years <=10 30 ( 8) 569 ( 7)

11-20 37 ( 9) 500 ( 6) 21-30 30 ( 8) 649 ( 8) 31-40 38 (10) 726 ( 8)

41-50 61 (16) 1067 (12) 51-60 88 (23) 1959 (23) >60 106 (27) 3103 (36)

Disease AML 199 (51) 3796 (44) ALL 72 (18) 1407 (16)

CML 11 ( 3) 314 ( 4) MDS 108 (28) 3056 (36)


<90 84 (22) 1422 (17) >=90 152 (39) 2916 (34) Missing 154 (39) 4235 (49)

Graft type Bone Marrow 58 (15) 1236 (14) Peripheral blood 245 (63) 5816 (68)

Cord blood 87 (22) 1521 (18) Donor/recipient HLA match

Cord blood 87 (22) 1521 (18) HLA-identical siblings 100 (26) 2488 (29)

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Variable


N(%)


N(%)

matched related 1 (<1) 55 (<1) Mismatched related, 1 mismatch 0 7 (<1)

Mismatched related,>=2 mismatch 7 ( 2) 95 ( 1) Mismatched related, mismatch unknown 12 ( 3) 319 ( 4) Other related, match unknown 0 1 (<1)

8/8 unrelated 126 (32) 3170 (37) 7/8 unrelated 31 ( 8) 639 ( 7) <=6/8 unrelated 0 21 (<1)

Unrelated (HLA match information missing) 26 ( 7) 257 ( 3) Conditioning regimen intensity

Myeloablative 220 (56) 4696 (55)

RIC 104 (27) 2439 (28) NMA 29 ( 7) 682 ( 8)

TBD 37 ( 9) 724 ( 8) Missing 0 32 (<1)

CMV Donor/Recipient Serostatus

Cord blood 87 (22) 1521 (18) +/+ 88 (23) 1805 (21) -/- 47 (12) 1197 (14)

+/- 23 ( 6) 551 ( 6) -/+ 72 (18) 1513 (18) Missing 73 (19) 1986 (23)

Year of transplant 2010 77 (20) 1220 (14) 2011 43 (11) 886 (10)

2012 44 (11) 932 (11) 2013 91 (23) 1599 (19) 2014 64 (16) 2054 (24)

2015 71 (18) 1882 (22) Aspergillus day0-day100 after transplant

No 325 (83) 8475 (99)

Yes 65 (17) 97 ( 1) Missing 0 1 (<1)

Fusarium day0-day100 after transplant

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Variable


N(%)


N(%)

No 385 (99) 8565 (>99) Yes 5 ( 1) 7 (<1)

Missing 0 1 (<1) Mucorales day0-day100 after transplant

No 378 (97) 8559 (>99)

Yes 12 ( 3) 13 (<1) Missing 0 1 (<1)

Median follow-up of survivors, months 36 (3 - 73) 25 (1 - 79) *189 patients with both form 2046 and 2146, 3 patients with 2046 only, 198 patients with 2146 only.

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Proposal 1611-02 Title: The Incidence of Cytomegalovirus Viremia and Disease following HLA-Haploidentical Hematopoietic Cell Transplantation Compared to HLA-Matched Related Donor, Matched Unrelated Donor, and Umbilical Cord Blood Transplantation. Rizwan Romee, MD, [email protected], Washington University in Saint Louis Ephraim Fuchs, MD, [email protected], Johns Hopkins School of Medicine Asad Bashey, MD, PhD, [email protected], Northside Hospital, Atlanta Stefan Ciurea, MD, [email protected], MD Anderson Cancer Center Hypothesis: We hypothesize that the incidence of cytomegalovirus (CMV) reactivation and disease are higher among patients who received haploidentical hematopoietic cell transplantation (haploHCT) with post-transplant cyclophosphamide (PTCy) compared to patients after HLA-matched related donor (MRD), matched unrelated donor (MUD), and umbilical cord blood (UCB) transplantation. Specific aims: Primary Aim: Compare the incidence of CMV reactivation and CMV disease among patients who received haploHCT with PTCy versus those who received MRD. Secondary Aims:

• Compare CMV reactivation and disease with respect to use of peripheral blood vs. bone marrow grafts in haplo-HCT

• Analyze if there is an association between CMV reactivation and decreased cumulative incidence of relapse following haploHCT with PTCy for hematologic malignancies. o Subset analysis for those who have received transplants for AML

• Determine if there is a statistical difference in graft-versus-host disease and relapse free survival (GRFS) between those patients who experience CMV reactivation and those who do not following haploHCT with PTCy

• Analyze if there is a correlation between donor/recipient CMV serostatus and relapse following haploHCT with PTCy

• Analyze if there is a correlation between donor/recipient CMV serostatus and development of CMV disease following haploHCT with PTCy

Scientific impact: We hope to conduct this CIBMTR study in order to better characterize the incidence of CMV reactivation and disease among recipients of haploHCT with PTCy with either bone marrow (BM) or peripheral blood stem cell (PBSC) grafts, in comparison to MRD. If we were to identify a higher incidence of disease or earlier reactivation, this would allow us to design CMV surveillance and preemptive treatment protocols that may be better suited to the specific immunosuppressive aspects of haploHCT with PTCy. Additionally, we intend to analyze a large cohort of haploHCT recipients to determine if CMV reactivation has any effect on relapse and mortality especially in the context of haplo-HCT, which would help provide prognostic information.

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Scientific justification: Cytomegalovirus has long been associated with increased morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT).1–3 A recent CIBMTR analysis demonstrated that even in the current era of preemptive surveillance and treatment protocols, early CMV reactivation was associated with significantly increased non-relapse mortality (NRM) among recipients of alloHCT for AML, ALL, MDS, and CML, which translated to decreased overall survival (OS) among those with AML and ALL.4 The association of CMV reactivation and improvement in relapse-free survival (RFS) is a well-published phenomenon among patients who received HLA-matched alloHCT for hematologic malignancies, however this CIBMTR study failed to identify any effect of CMV reactivation on relapse.5,6,4,7 This registry study was incredibly impactful, however haploidentical hemaotpoeitic cell transplantation (haploHCT) were underrepresented, and less than 1% of all patients from the registry had received post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. This is likely due to the fact that the records utilized in this registry study were of those who underwent alloHCT prior to 2010, and the utilization of haploHCT has really only accelerated on an international level over the past five years.8,9 Recently we conducted a single-center, retrospective cohort study on 138 patients who underwent haploHCT with PTCy, receiving T-cell replete PBSC grafts, and did not detect a significant difference in cumulative incidence of relapse (CIR) or overall survival (OS) between those who did and those who did not have CMV viremia.10 Notably, our virmeia cohort experienced very early CMV viremia (median time to viremia of 24d), and an incidence of CMV disease that was higher than expected in the era of preemptive antiviral strategies. A large, registry study with similar endpoints would assess the validity of these results, and identify whether there is fundamental difference between HLA-haploidentical and HLA-matched transplantation that would predispose haploHCT recipients to a higher risk of CMV disease and negate the relapse protection seen previously with CMV viremia. Such results could lead to tailoring of preemptive treatment strategies and aid in prognosis of disease relapse. Study population: Inclusion Criteria:

• Patients who received haploidentical HCT (peripheral blood or bone marrow as graft source) using PTCy for a hematologic malignancy between 2008 and 2016

• Patients who received MRD, MUD, or UCB transplantation between 2008 and 2016 to serve as the control arm

• Age ≥ 18 years Exclusion Criteria:

• Patients who received haploHCT for a benign hematologic condition • Patient information that lacks post-transplant infection information • Lack of donor/recipient CMV serostatus

Data requirements: Data would be obtained via that reported to the CIBMTR. Any patient who received haploHCT with PTCy for a hematologic malignancy between 2008 and 2016 would be assessed to see if he/she met inclusion criteria. The following variables would be collected and analyzed:

• Patient age • Patient gender • Patient race • Time to CMV reactivation • Time to CMV end-organ disease (if developed) • Recipient and donor cytomegalovirus serostatus (positive versus negative)

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• Time from hematologic diagnosis to HCT • Recipient performance score (KPS 90-100 versus <90) • Recipient HCT-CI (0-1 vs. ≥2) • Disease risk index (low or intermediate, or high risk) • Cytogenetic risk category (Low, Intermediate, or High) • De novo vs. secondary AML • Disease status at the time of transplant (active disease vs. CR) and CR number • Donor gender • Donor age • Conditioning intensity (ablative vs. reduced-intensity/non-ablative) • TBI-based conditioning (yes vs. no) • Graft source for haploidentical transplants (peripheral blood vs. marrow) • GvHD prophylaxis regimen (calcineurin inhibitor-based or not)

Study design: The first analysis would be the cumulative incidence analysis using the Fine and Gray’s method in order to determine the cumulative incidence of CMV reactivation among haploHCT, and MRD transplant recipients. In this analysis, death without CMV reactivation would be considered a competing risk event. CMV reactivation would be coded as a time-dependent covariate. Multivariate analysis using a step-wise selection approach, and any variables with a p-value <0.05 will be deemed significant and included in the model. Transplant type and CMV reactivation will be forced into the model. Among all patients with CMV reactivation, a cumulative incidence analysis would be conducted to determine cumulative incidence of CMV disease following reactivation, with death without CMV disease considered a competing risk event. Similar multivariate analysis would be conducted using step-wise selection. The Kaplan-Meier estimator would be used to compare overall survival (OS) among haploHCT and MRD transplant recipients individually, with each transplant type analyzed by dividing each into two cohorts based on presence or absence of CMV reactivation. This would identify whether CMV reactivation has a significant effect on overall survival in some transplant types but not others. With a similar stratification based on CMV reactivation, the next analysis would address cumulative incidence of hematologic disease relapse, treating death without relapse as a competing risk event. Similar analysis would be conducted for non-relapse mortality, treating disease relapse as a competing event. Stratified by CMV reactivation, the Kaplan-Meier estimator will be used to calculate the 1-year unadjusted probability of GRFS, as defined by Holtan et al., for all transplant types individually, Cox regression models will be used to identify significant covariates to GRFS, and will be used to compute the 1-year adjusted overall probability GRFS. 11 All of the previous analyses would be repeated with stratification based on donor/recipient CMV serostatus combination in place of CMV reactivation to determine its impact on CMV reactivation, disease, OS, relapse, and NRM. References: 1. Ariza-Heredia EJ, Nesher L, Chemaly RF. Cytomegalovirus diseases after hematopoietic stem cell

transplantation: A mini-review. Cancer Lett. 2014;342(1):1-8. doi:10.1016/j.canlet.2013.09.004. 2. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients.

Infect Dis Clin North Am. 2010;24(2):319-337. doi:10.1016/j.idc.2010.01.008. 3. Mori T, Kato J. Cytomegalovirus infection/disease after hematopoietic stem cell transplantation. Int J

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Hematol. 2010;91(4):588-595. doi:10.1007/s12185-010-0569-x. 4. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated

with increased transplant related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-2438. doi:10.1182/blood-2015-11-679639.

5. Elmaagacli AH, Steckel NK, Hegerfeldt Y, et al. Early Cytomegalovirus Replication After Allogeneic Stem Cell Transplantation Is Associated With a Decreased Relapse Risk in Acute Myeloid Leukemia Patients: Evidence for a Putative Virus-Versus-Leukemia Effect. Blood. 2011;118(5):1403-1412. doi:10.1016/j.bbmt.2010.12.034.

6. Takenaka K, Nishida T, Asano-Mori Y, et al. Cytomegalovirus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation is Associated with a Reduced Risk of Relapse in Patients with Acute Myeloid Leukemia Who Survived to Day 100 after Transplantation. Biol Blood Marrow Transplant. 2015;21(11):2008-2016. doi:10.1016/j.bbmt.2015.07.019.

7. Green ML, Leisenring WM, Xie H, et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood. 2013;122(7):1316-1324. doi:10.1182/blood-2013-02-487074.

8. Bashey A, Zhang X, Sizemore CA, et al. T-Cell-Replete HLA-Haploidentical Hematopoietic Transplantation for Hematologic Malignancies Using Post-Transplantation Cyclophosphamide Results in Outcomes Equivalent to Those of Contemporaneous HLA-Matched Related and Unrelated Donor Transplantation. J Clin Oncol. 2013;31(10):1310-1316. doi:10.1200/JCO.2012.44.3523.

9. Solomon SR, Sizemore C a., Sanacore M, et al. Haploidentical Transplantation Using T Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who Lack Conventional Donors is Well Tolerated and Produces Excellent Relapse-Free Survival: Biol Blood Marrow Transplant. 2012;18(12):1859-1866. doi:10.1016/j.bbmt.2012.06.019.

10. Goldsmith SR, Slade M, DiPersio JF, et al. Cytomegalovirus viremia, disease, and impact on relapse in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. Haematologica. 2016. doi:10.3324/haematol.2016.149880.

11. Holtan SG, DeFor TE, Lazaryan A, et al. Composite endpoint of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125(8):1333-1339. doi:10.1182/blood-2014-10-609032.

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Table 1 Characteristics of adult patients who underwent first ALLO transplants with Acute leukemia, MDS/MPS, CML, CLL/PLL, NHL, HL, Plasma cell disorder/MM, reported to the CIBMTR, from 2008 to

2015

Variable Mismatched related

N(%) Other donor type

N(%)

Number of patients 334 10286

Number of centers 62 219 Gender

Male 201 (60) 6012 (58)

Female 133 (40) 4274 (42) Age, median(range), years 59 (18 - 78) 53 (18 - 81) Age at transplant, years

11-20 6 ( 2) 181 ( 2) 21-30 31 ( 9) 1002 (10) 31-40 25 ( 7) 1157 (11)

41-50 40 (12) 1821 (18) 51-60 72 (22) 3097 (30) >60 160 (48) 3028 (29)

Disease AML 140 (42) 4285 (42) ALL 43 (13) 1186 (12)

Other leukemia 9 ( 3) 456 ( 4) CML 9 ( 3) 457 ( 4) MDS/MPS 84 (25) 2622 (25)

Other acute leukemia 4 ( 1) 82 (<1) NHL 35 (10) 918 ( 9)

HL 9 ( 3) 125 ( 1) Plasma cell disorder/Multiple Myeloma 1 (<1) 155 ( 2)


<90 30 ( 9) 2796 (27) >=90 81 (24) 5283 (51) Missing 223 (67) 2207 (21)

Graft type Bone Marrow 175 (52) 1098 (11) Peripheral blood 159 (48) 7765 (75)

Cord blood 0 1423 (14) Donor/recipient HLA match

151




N(%)

Cord blood 0 1423 (14) HLA-identical siblings 0 4896 (48) matched related 0 70 (<1)

Mismatched related, 1 mismatch 3 (<1) 0 Mismatched related,>=2 mismatch 114 (34) 0 Mismatched related, mismatch unknown 217 (65) 0

Other related, match unknown 0 10 (<1) 8/8 unrelated 0 3887 (38)

Conditioning regimen

Myeloablative 91 (27) 5549 (54) RIC 24 ( 7) 2694 (26) NMA 195 (58) 970 ( 9)

TBD 23 ( 7) 1049 (10) Missing 1 (<1) 24 (<1)

CMV Donor/Recipient Serostatus Cord Blood 0 1423 (14) +/+ 138 (41) 2983 (29)

-/- 65 (19) 2358 (23) +/- 39 (12) 1003 (10) -/+ 92 (28) 2519 (24)

Median follow-up of survivors, months 14 (3 - 97) 50 (1 - 102)

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Protocol 1611-117 Title: Impact of cmv reactivation on relapse of hematological malignancies after haploidentical HSCT: a CIBMTR analysis Anurag Singh, MD, [email protected], University of Kansas Medical Center Siddhartha Ganguly, MD, [email protected], University of Kansas Medical Center Hypothesis: To study the relationship between CMV reactivation and relapse rates/mortality after haploidentical allogeneic stem cell transplants performed between 2000-2015

Specific aims:

• To assess the impact of donor and recipient CMV serostatus on disease relapse and mortality in patients receiving haploidentical hematopoietic stem cell transplantation.

• To assess the impact of CMV reactivation on disease relapse and mortality following haploidentical transplantation.

Scientific justification: Cytomegalovirus (CMV) infections have been reported to impact donor engraftment [1]and to cause severe diseases after allogeneic hematopoietic stem cell transplantation (SCT), including pneumonia, hepatitis, gastroenteritis, retinitis, and encephalitis . [2] CMV has also been associated with an increased risk for acute graft-versus-host disease (GVHD) in patients receiving T cell–depleted grafts and for chronic GVHD. Because of this detrimental impact of CMV disease on the prognosis of patients after SCT, preventive measures against active CMV infection after hematopoietic SCT were introduced to allow early interventions and to reduce mortality and morbidity mediated through CMV-associated diseases. Early interventions include the preemptive antiviral therapy with, for example, ganciclovir and valganciclovir as soon as the viral load in plasma or whole blood exceeds a predefined cut-off value during close monitoring .[3] More recently, there has been several reports of decreased relapse rates associated with early CMV reactivation.[4, 5] A few studies have also reported improvement in overall survival. [6] The most common hypothesis for this phenomenon is that CMV reactivation leads to an expansion of Natural killer cells which play an important role in graft vs tumor responses.[7] Recently, a CIBMTR study looked at the data for cord blood transplantation and found that CMV reactivation and positive CMV serology were associated with increased non-relapse mortality (NRM) among both AML and ALL CB recipients. [8] There is no large data set looking at the effect of CMV serostatus and reactivation to outcomes after a haploidentical transplant. In a recently published paper from two institutions in Italy, effect of CMV serostatus on transplant outcomes were analyzed. In this analysis conducted on 207 consecutive adult patients receiving haplo-HSCT with PT-Cy for a hematological malignancy, higher NRM and worse survival were noted among CMV+ patients compared with CMV− ones. [9] However, this paper did not analyze the effect of CMV reactivation on disease relapse. In view of this, it would be important to confirm these findings with multi-institutional data which will help to identify better stem cell donor and also identify those who are at higher risk of CMV reactivation after haploidentical transplant.

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Study population: All patients receiving a first allogeneic transplantation for any AML, MDS, ALL and lymphomas from a haploidentical donor with any conditioning intensity between 2000 and 2015 and reported to the CIBMTR will be included. Outcomes: Patients will be analyzed separately for each disease. Relapse: death is the competing risk. Overall survival: time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up. Disease Free survival: time to relapse or death from any cause. Non-relapse mortality: death without evidence of disease relapse. Relapse is the competing risk. aGVHD grade 2 – 4: Death is the competing risk cGVHD, any severity: Death is the competing risk Variables to be analyzed: CMV Related

• CMV reactivation: Yes vs No • Time to onset of CMV reactivation, days post-transplant

Patient Related • Age: in decades (≤ 10, 11-20, 21-30, 31-40, 41-50, 51-60, ≥ 60) • Gender: Male vs Female • : CMV serostatus • Race (White vs. Hispanic vs. Black vs. Other) • Karnofsky performance score at transplant: < 90 vs. 90-100 • Time from transplant to diagnosis, months

Transplant Related • disease risk category: Low vs Intermediate vs High • Year of transplant: 2000 – 2007 vs 2007 – 2015 • Graft type: Bone marrow vs peripheral blood • Donor Type: 1st degree vs second degree relatives • Conditioning intensity: Myeloablative vs RIC/NMA • TBI-based conditioning: Yes vs No • T-cell depletion: Yes (in vivo/ex vivo) vs No • GVHD prophylaxis: Post transplant CY+ tac + MMF vs Others • Acute GVHD: grade 0-1 vs. 2-4 (as time-dependent variable)

Study design: This is a retrospective study of CIBMTR data between 2000 and 2015. This study aims to determine if CMV reactivation post-transplant has a protective value after haploidentical transplant. It also aims to assess if specific donor/recipient CMV serostatus combinations have protective value as far as the disease response is concerned. Patient-, disease-, and transplant –related factors will be compared between groups using the Chisquare test for categorical variables and the Wilcoxon two sample test for continuous variables.

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The probabilities of disease-free and overall survival will be calculated using the Kaplan Meier estimator. Values for other endpoints will be generated using cumulative incidence estimates to account for competing risks. We will first analyze outcomes based on pre-transplant serostatus combinations. We will then compare the effect of CMV-reactivation in those patients with CMV reactivation post-transplant as a time-dependent covariate. Interactions between CMV reactivation and GVHD will also be examined incorporating both CMV reactivation and GVHD as time-dependent covariates to assess impact on relapse. References: 1. Steffens, H.P., et al., Cytomegalovirus inhibits the engraftment of donor bone marrow cells by

downregulation of hemopoietin gene expression in recipient stroma. J Virol, 1998. 72(6): p. 5006-15. 2. Peggs, K.S. and S. Mackinnon, Cytomegalovirus: the role of CMV post-haematopoietic stem cell

transplantation. The International Journal of Biochemistry & Cell Biology, 2004. 36(4): p. 695-701. 3. Boeckh, M. and P. Ljungman, How we treat cytomegalovirus in hematopoietic cell transplant

recipients. Blood, 2009. 113(23): p. 5711-5719. 4. Elmaagacli, A.H., et al., Early human cytomegalovirus replication after transplantation is associated

with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood, 2011. 118(5): p. 1402-12.

5. Green, M.L., et al., CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood, 2013. 122(7): p. 1316-24.

6. Manjappa, S., et al., Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen. Biol Blood Marrow Transplant, 2014. 20(1): p. 46-52.

7. Foley, B., et al., Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood, 2012. 119(11): p. 2665-74.

8. Ramanathan, M., et al., Impact of early CMV reactivation in cord blood stem cell recipients in the current era. Bone Marrow Transplant, 2016. 51(8): p. 1113-1120.

9. Crocchiolo, R., et al., The patient/'s CMV serological status affects clinical outcome after T-cell replete haplo-HSCT and post-transplant cyclophosphamide. Bone Marrow Transplant, 2016. 51(8): p. 1134-1136.

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Table 1 Characteristics of patients who underwent first ALLO transplants with AML, ALL, MDS/MPS, NHL or HL, reported to the CIBMTR, from 2000 to 2015

Variable N(%) Number of patients 717 Number of centers 104 Gender

Male 452 (63) Female 265 (37)

Age, median(range), years 56 (1 - 82) Age at transplant, years

<=10 40 ( 6) 11-20 60 ( 8) 21-30 64 ( 9) 31-40 45 ( 6) 41-50 65 ( 9) 51-60 144 (20) >60 299 (42)

Disease AML 330 (46) ALL 112 (16) MDS/MPS 185 (26) NHL 73 (10) HL 17 ( 2)

Graft type Bone Marrow 284 (40) Peripheral blood 433 (60)

Donor/recipient HLA match Mismatched related, 1 mismatch 22 ( 3) Mismatched related,>=2 mismatch 242 (34) Mismatched related, mismatch unknown 453 (63)

Conditioning regimen Myeloablative 259 (36) RIC 111 (15) NMA 293 (41) TBD/Missing 54 ( 7)

CMV Donor/Recipient Serostatus +/+ 292 (41) -/- 127 (18) +/- 83 (12) -/+ 179 (25) Missing 36 ( 5)


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Proposal 1611-134: Title: Incidence and Outcomes of individuals with and without viral infections in recipients of haploidentical versus other allogeneic hematopoietic stem cell transplantation for patients with hematologic malignancies Randy Allison Taplitz, MD, [email protected], University of California, San Diego Carolyn Mulroney,MD, [email protected], University of California, San Diego Richard Maziarz,MD, [email protected], Oregon Health and Sciences University Specific aims: 1. To determine the incidence of viral infections (including parainfluenza virus, influenza virus, RSV,

adenovirus, hMPV, BK, CMV, EBV, HHV-6, VZV, and HSV) during the first 100 days after haploidentical versus non-haploidentical allogeneic hematopoietic stem cell transplant • Viral load quantitation • Evidence of end organ disease

2. To compare the clinical outcomes between patients with and without viral infections at one year after haploidentical versus other allogeneic hematopoietic stem cell transplantation for hematologic malignancies in regards to the following: • Treatment-related mortality • GVHD • Bronchiolitis obliterans/cryptogenic organizing pneumonia (COP) • Relapse Rates • Leukemia free survival • Overall survival • Length of stay • Co-infection (yeast/mold etc) • Surgical intervention (observation only)

3. To determine patient-, disease- and transplant-related variables associated with worse outcomes after allogeneic transplantation patients for patients with and without viral infection during haploidentical and other allogeneic hematopoietic stem cell transplantation • Primary hematologic malignancy and stage at transplant • Preparative regimen (including prior exposure to Campath, ATG) • Graft source

o Marrow o PB stem cells

• Mechanism of T cell depletion o CD34 selection o Total CD3 depletion o ATG or Campath o other

• Immunosuppressant regimen o Post-transplant Cytoxan o Other o None

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Scientific justification: Haploidentical stem cell transplantation (SCT) has had wider application as an alternative source for stem cells in patients without matched donors with the reported success of post transplant high dose Cytoxan used with T-cell replete (TCR) stem cell infusions from peripheral blood or bone marrow. Prior to the development of the Post-Transplant Cytoxan strategy for haploidentical SCT, these transplants were limited by severe GVHD, graft rejection, and infectious complications. When TCR strategies have been compared to T cell depleted (TCD) strategies (CD34 selection, in-vivo T cell depletion with ATG or Campath) in haploidentical transplant, TCR regimens showed improvements in NRM in TCR group accompanied by better immune reconstitution of T cell subsets in the first 6 months’ post-transplant. High rates of viral infections after haploidentical stem cell transplant in recent years continue to be reported despite excellent survival particularly in the setting of post transplant Cytoxan. One recent single center series reported in 2015 looked specifically at Post transplant Cytoxan strategy in patients who underwent transplant between 2009 and 2014, but multicenter, comparative data is lacking. Infection rates in this setting have been reported in the range of 70% at 100 days and 77% at 1 year for viral infections. CMV reactivation has been reported in up to 54% of recipients, and polyomavirus associated cystitis 19%. Bacterial and fungal infections were reported in 63 % and 12 % respectively. The CIBMTR database provides an ideal opportunity to take a broader look at viral and other infections after haploidentical transplants, particularly in recipients of post transplant Cytoxan, and identify the burden of viral and other infectious diseases, risk factors and outcomes. Study population:

• All patients >2 years of age receiving an allogeneic HSCT for AML, ALL, MDS, CML, Aplastic Anemia, CLL, Hodgkin’s and non-Hodgkin’s Lymphoma and Multiple Myeloma (haploidentical vs. other) with documented viral infection within the first 100 days who have been reported to the CIBMTR between 2010 -2015

• All patients >2 years of age receiving an allogeneic transplant for AML, ALL, MDS, CML, Aplastic Anemia, CLL, Hodgkin’s and non-Hodgkin’s Lymphoma and Multiple Myeloma without documented prior viral infection within the first 100 days who have been reported to the CIBMTR between 2010-2015

Outcomes:

• Treatment-related mortality: death within the first 100 days of transplant for any cause or death in complete remission of primary disease.

• Overall survival: time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up.

• Relapse rate • Graft vs. Host disease • Diagnosis of Bronchiolitis Obliterans/COP • Leukemia free survival • Total number of inpatient hospital days within the first 100 days (LOS) • Co-infection (yeast/mold)

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Variables: Patient related:

• Age at transplant (continuous) • Karnofsky performance at transplant: <90% vs. ≥90% • Gender: male vs. female • CMV status

Disease related: • Disease: AML, ALL, MDS, CML, Aplastic Anemia, CLL, Hodgkin’s and non-Hodgkin’s Lymphoma

and Multiple Myeloma • Disease risk: low, intermediate, high • Disease status: PIF vs. CR1/2 vs. >CR2 vs. refractory relapse vs. untreated relapse • Time from diagnosis to transplant

Transplant related: • Conditioning regimen: NMA vs. RIC vs. conventional myeloablative • Source of stem cells: bone marrow vs. peripheral blood • Donor source: pooled: sibling, unrelated (well-matched, partial match, mismatched) vs. cord

blood vs. haploidentical • ABO mismatch • Donor CMV status • Age of Donor • Degree of Donor match

Data requirements: Data for this study can be extracted from the standard data collection forms, specifically Forms 2000, 2004-2006, 2100, 2110-2014, 2116, 2118, 2128, 2146 Study design: Statistical analysis will be done under the guidance of the CIBMTR Working Committee Statistician as well as medical director. The goal of this study is to establish incidence and risk factors for viral infections in recipients of haploidentical versus other transplants. Moreover, the study will compare the clinical outcomes between patients with and without viral infections in the first 100 days of HSCT while adjusting for significant patient-, disease-, and transplant-related variables. Patient-, disease- and transplant- related factors will be compared between groups using the Chi-square test for categorical variables and the Wilcox on two sample test for continuous variables. The probabilities of progression-free and overall survival will be calculated using the Kaplan Meier estimator, with the variance estimated by Greenwood’s formula. Values for other endpoints will be generated using cumulative incidence estimates to account for competing risks. Cox proportional hazards regression will be used to compare the two groups. The variables to be considered in the multivariate models are listed. The assumption of proportional hazards for each factor in the Cox model will be tested using time-dependent covariates. When this indicates differential effects over time (non-proportional hazards), models will be constructed breaking the post-transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. A backwards stepwise model building procedure will be used to identify significant risk factors which associated with the outcomes. Each model will contain the main effect with and without viral infections since it is the main interest of this study. Factors significantly associated with the outcome variable at a 5% level will be kept in the final model. First order interactions between main effect and significant covariates will be tested. Epidemiologic changes in incidence will be reported descriptively.

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References: 1. Ciurea SO1, Mulanovich V, Saliba RM, et al. Biol Blood Marrow Transplant. Improved early outcomes

using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation, 2012. Dec;18(12):1835-44. doi: 10.1016/j.bbmt.2012.07.003. Epub 2012 Jul 11.

2. Perruccio, K., Topini, F., Tosti, A., Gazzola, M. V., Messina, C., Martelli, M. F., Caniglia, M., Velardi, A. and Cesaro, S. Differences in Aspergillus-specific immune recovery between T-cell-replete and T-cell-depleted hematopoietic transplants. Eur J Haematol, 2015. 95: 551–557

3. Tishcer, J, engel N, Fritsch et al. Virus Infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings. Ann Hematol, 2015 94: 1677-1688

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https://www.ncbi.nlm.nih.gov/pubmed/?term=Ciurea%20SO%5BAuthor%5D&cauthor=true&cauthor_uid=22796535

https://www.ncbi.nlm.nih.gov/pubmed/?term=Mulanovich%20V%5BAuthor%5D&cauthor=true&cauthor_uid=22796535

https://www.ncbi.nlm.nih.gov/pubmed/?term=Saliba%20RM%5BAuthor%5D&cauthor=true&cauthor_uid=22796535

https://www.ncbi.nlm.nih.gov/pubmed/22796535


Table 1 Characteristics of patients who underwent first ALLO transplants with AML, ALL, MDS, CML, CLL, NHL, HL, plasma cell disorder and severe aplastic anemia, reported to the CIBMTR, from 2010 to

2015

Variable First viral infection by

day100 N(%) No viral infection by

day100 N(%)

Number of patients 5822 7273 Number of centers 202 223

Gender Male 3307 (57) 4387 (60) Female 2515 (43) 2886 (40)

Age, median(range), years 51 (2 - 82) 54 (2 - 83) Age at transplant, years

2-10 490 ( 8) 349 ( 5)

11-20 544 ( 9) 493 ( 7) 21-30 482 ( 8) 617 ( 8) 31-40 556 (10) 630 ( 9)

41-50 745 (13) 949 (13) 51-60 1257 (22) 1773 (24) >60 1748 (30) 2462 (34)

Disease AML 2235 (38) 2718 (37) ALL 987 (17) 892 (12)

Other leukemia (including CLL) 152 ( 3) 230 ( 3) CML 162 ( 3) 233 ( 3)

MDS 1456 (25) 2148 (30) NHL 430 ( 7) 525 ( 7) HL 83 ( 1) 96 ( 1)

Plasma cell disorder/Multiple Myeloma 67 ( 1) 71 (<1) Severe aplastic anemia 250 ( 4) 360 ( 5)

Graft type

Bone Marrow 1024 (18) 1207 (17) Peripheral blood 3310 (57) 5183 (71) Cord blood 1488 (26) 883 (12)

Donor/recipient HLA match Cord blood 1488 (26) 883 (12) HLA-identical siblings 1258 (22) 2606 (36)

matched related 39 (<1) 53 (<1)

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Variable First viral infection by

day100 N(%) No viral infection by

day100 N(%)

Mismatched related, 1 mismatch 3 (<1) 6 (<1)

Mismatched related,>=2 mismatch 78 ( 1) 86 ( 1) Mismatched related, mismatch unknown 276 ( 5) 241 ( 3) Other related, match unknown 5 (<1) 2 (<1)

8/8 unrelated 1973 (34) 2650 (36) 7/8 unrelated 484 ( 8) 448 ( 6) <=6/8 unrelated 19 (<1) 21 (<1)

Unrelated (HLA match information missing) 198 ( 3) 275 ( 4) Missing 1 (<1) 2 (<1)

Conditioning regimen intensity

Myeloablative 3142 (54) 3342 (46) RIC 1261 (22) 2307 (32) NMA 650 (11) 610 ( 8)

TBD 499 ( 9) 610 ( 8) N/A(Non malignant disease) 250 ( 4) 360 ( 5)

Missing 20 (<1) 44 (<1) CMV Donor/Recipient Serostatus Cord blood 1488 (26) 883 (12)

+/+ 1227 (21) 1597 (22) -/- 431 ( 7) 1368 (19) +/- 222 ( 4) 614 ( 8)

-/+ 1096 (19) 1076 (15) Missing 1358 (23) 1735 (24)


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Table 2 Infection



N(%)

Number of patients 357 5465

Herpes Simplex No 344 (96) 5178 (95) Yes 13 ( 4) 287 ( 5)

Varicella No 352 (99) 5417 (99)

Yes 5 ( 1) 48 (<1) CMV

No 115 (32) 2307 (42)

Yes 242 (68) 3158 (58) Adenovirus

No 339 (95) 5164 (94)

Yes 18 ( 5) 301 ( 6) Enterovirus

No 355 (99) 5417 (99)

Yes 2 (<1) 48 (<1) 5Hepatitis A

No 357 5464 (>99)

Yes 0 1 (<1) Hepatitis B

No 357 5452 (>99)

Yes 0 13 (<1) Hepatitis C

No 357 5459 (>99)

Yes 0 6 (<1) HIV

No 357 5465

Influenza No 351 (98) 5354 (98)

Yes 6 ( 2) 111 ( 2) Measles

No 357 5465

Mumps

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N(%)

No 357 5465 PML

No 357 5465

RSV No 348 (97) 5294 (97) Yes 9 ( 3) 171 ( 3)

Rubella No 357 5465

Parainfluenza

No 347 (97) 5259 (96) Yes 10 ( 3) 206 ( 4)

HHV-6

No 311 (87) 4594 (84) Yes 46 (13) 871 (16)

EBV No 343 (96) 4875 (89) Yes 14 ( 4) 590 (11)

Polyoma virus No 245 (69) 3964 (73) Yes 112 (31) 1501 (27)

Rotovirus No 356 (>99) 5423 (99) Yes 1 (<1) 42 (<1)

Rhinovirus No 340 (95) 5032 (92) Yes 17 ( 5) 433 ( 8)

HPV No 356 (>99) 5461 (>99) Yes 1 (<1) 4 (<1)


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