indications for allogeneic transplantation in acute and chronic … for allogeneic... ·...

Indications for Allogeneic Transplantation in Acute and Chronic

Leukemia:What’s the evidence?

Steven Devine MDThe Ohio State University

Comprehensive Cancer Center

Large Adult AML Meta Analysis:Relapse free survival

Koreth JAMA 2009

Large Adult AML Meta Analysis:Overall Survival

Koreth JAMA 2009

ELN Cytogenetic/Molecular Classification of AML

Dohner et al, Blood, 2009

Distribution of the European LeukemiaNet genetic groups in younger (A) and older (B) adults with primary acute myeloid leukemia.

Mrózek K et al. JCO 2012;30:4515-4523

©2012 by American Society of Clinical Oncology

Outcome of patients with primary acute myeloid leukemia classified into the four European LeukemiaNet genetic groups according to the European LeukemiaNet recommendations.

Mrózek K et al. JCO 2012;30:4515-4523


HCT-Comorbidity Index and outcomes

Cornelissen et al, Nat Rev Clin Oncol, 2012

EBMT Risk Score and outcomes in AML


MA RIC

ELN Recommendations for allografts in AML CR1


Large Meta Analysis in Adult ALL

Pidala et al, Cochrane Database Syst Rev, 2011

Large Meta Analysis in Adult ALL:Impact on relapse


Large Meta Analysis in Adult ALL:Treatment related mortality


Large Meta Analysis in Adult ALL:Subset analysis


Effect of donor versus no donor on overall mortality in each trial.

Gupta V et al. Blood 2013;121:339-350

©2013 by American Society of Hematology

Descriptive curve of overall survival by donor versus no donor.



Effect of donor versus no donor on overall mortality in subgroups.



Evidence based recommendations for Allografting Adult ALL in CR1

• Ph+ and t(4;11) in first remission− Role of TKI, autografts, reduced intensity regimens?− What if matched sibling not available?

• Age 18-35 (standard and other high risk)− Matched sib transplant (myeloablative) − What if matched sibling not available?

• Age >35 (standard and other high risk)− No clear evidence to support routine use

What is the evidence for transplantation in myelodysplastic syndrome?

• Patients under age 60− Markov decision analysis (Cutler et al, Blood, 2004)

Advantage for immediate transplantation for IPSS Int-2/high risk, not lower riskThese data are getting old!Only matched siblings analyzed

• Patients aged 60-70− Markov decision analysis (Koreth et al, ASH 2011)− Analyzed quality adjusted life expectancy (QALE)

comparing immediate RIC transplant to BSC or HMAOnly advantage in Int2/high risk groupOnly matched siblings analyzed

Impact of karyotype on posttransplant relapse.

Deeg H J et al. Blood 2012;120:1398-1408


Survival by 5-group cytogenetic classification.

Deeg H J et al. Blood 2012;120:1398-1408


Comparison of Outcomes after Related and Unrelated

Hematopoietic Cell Transplantation in Adults with Myelodysplastic Syndromes: A Report from the CIBMTR

A CIBMTR Cohort Analysis for Study CK12-04

CK12-04-12_1.ppt

Abstract 353

Adjusted Probability of Overall Survival for AML after Transplant

Prob

abili

ty o

f Sur

viva

l, %

Months0 6 12 362418

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

30

MRD (N=624)

8/8 MUD (N=1,193)

7/8 MUD (N=406)

Pointwise comparison at 3 years:MRD vs. 8/8 MUD P value = 0.97 MRD vs. 7/8 MUD P value = 0.767/8 MUD vs. 8/8 MUD P value = 0.71

Saber et al. Blood 2012; 119(17):3908-16

CK12-04-12_3.ppt

Background

Due to differences in patients characteristics and disease related factors, extrapolation from AML to MDS may be inappropriate.

Therefore disease specific analysis comparing outcomes post MUD HCT vs. MRD HCT in adult MDS patients was performed.

CK12-04-12_4.ppt

Adjusted Cumulative Incidence of Treatment-related Mortality for MDS

Inci

denc

e, %

Months0 6 12 362418

100

0

20

40

60

80

0

100

20

40

60

80

30

7/8 MUD (N=413)

8/8 MUD (N=112)

MRD (N=174)

Overall P-value=0.01 (2 df)Relative Risk (95% CI):8/8 MUD vs. MRD= 1.37 (1.01-1.85) 7/8 MUD vs. MRD= 1.71 (1.17-2.47) 7/8 MUD vs. 8/8 MUD=1.24 (0.90-1.70)

CK12-04-12_10.ppt

Adjusted Probability of Overall Survival for MDS

Adj

uste

d Pr

obab

ility

, %

Months0 6 12 362418

100

0

20

40

60

80

0

100

20

40

60

80

30

8/8 MUD (N=413)

7/8 MUD (N=112)

MRD (N=174)

Overall P-value=0.005 (2 df)8/8 MUD vs. MRD= 1.24 (0.98-1.56) 7/8 MUD vs. MRD= 1.62 (1.21-2.17) 7/8 MUD vs. 8/8 MUD=1.30 (1.01-1.68)

CK12-04-12_13.ppt

Other Prognostic Factors for DFSRisk of Death/

Relapse (95% CI) P-valueKPS

≥ 90% 1.00< 90% 1.36 (1.11-1.66) 0.002

IPSS at diagnosisLow-risk 1.00Int-1 1.12 (0.77-1.64) 0.53Int-2 1.39 (0.94-2.06) 0.09High-risk 2.22 (1.37-3.58) 0.001

CK12-04-12_16.ppt

Conclusions

In adults with MDS, 7/8 MUD HCT is associated with significantly inferior outcomes compared to MRD and 8/8 MUD

8/8 MUD HCT is also associated with an unfavorable trend in mortality compared to MRD

The differences in treatment failure is determined by an excess in TRM

These results should inform the HCT community, assist in counseling MDS patients, and in the design of clinical trials

CK12-04-12_19.ppt

What are the current recommendations in myelodysplastic syndrome?

• In younger patients (<60), allograft at diagnosis for Int2/high risk patients with matched sibling and probably 8/8 matched unrelated donor

− MA or reduced intensity?− What about other alternative donors (cord, haplo)?− Influence of revised prognostic systems?− Should all first get HMA or induction?

What if they are responding to HMA?• In older patients, matched sib RIC (and by extrapolation 8/8

MUD) at diagnosis only if Int2/high − Should they all get trial of HMA?

A Multi-Center Phase III Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in

Patients Age 50 or Older with Intermediate-2 and High Risk Myelodysplastic Syndrome

BMT CTN 1102

January 2013

Ryotaro Nakamura, MDCorey Cutler, MD MPH

Hypothesis

• RIC Allogeneic Stem Cell Transplantation Offers a Survival Advantage over Non-Transplant Therapy in Patients Considered Candidates for Transplantation

Basic Design

• Donor vs. No Donor Comparison of Patients Referred for Transplantation– “Does Transplant Help”

• Intention to Treat • No mandate of transplant or non-transplant

regimen

Primary Objective- Compare the three-year overall survival probability between the two study arms using an intent-to-treat analysis

Arm 1: RIC alloHCT Arm 2: Non-Transplant Therapy / Best Supportive Care

Secondary Objectives- Compare leukemia-free survival (LFS) at 3 years from

enrollment- Compare QOL measures between treatment arms

Study Objectives

Eligibility• De novo MDS with CURRENT or PRIOR

Intermediate-2 / High-risk IPSS Score • Aged 50-75 years• Marrow (30 days) with < 20% blasts• Any therapy prior to registration• KPS > 70 / ECOG ≤ 1• NO specific lab testing eligibility

– Available tests + gestalt at transplantation consultation • No formal MUD search activated.

– Sibling donor search or with a known MRD or no MRD donor is allowed

• Treatment Compliance Planned– Intent to proceed to RIC transplantation if a donor is found– No intent to pursue alternative donor transplantation at the

time of enrollment

MDS Study Design

Significant and Rapid Improvement in Survival After Unrelated Donor

Hematopoietic Cell Transplantation: Analysis of National Marrow Donor Program

Facilitated Transplants from 2000 to 2009

Navneet S Majhail, MD, MSMedical Director, Health Services Research,

National Marrow Donor Program, Minneapolis, MN

Adjunct Associate Professor of Medicine, University of Minnesota, Minneapolis, MN

Abstract 234

Study Population

• 15,040 unrelated donor HCT recipients• Analyses stratified by age and diagnosis

Cohort 2000-2004N

2005-2009N

Malignant diseases, age <18 yrs 906 1017

Malignant diseases, age 18-59 yrs 3808 5745

Malignant diseases, age ≥60 yrs 412 1783

Non-malignant diseases 476 893

36

Practice Changes Over Time

3745 49

40

5968 74

64

0

20

40

60

80

100

%

Increased use of HLA 8/8 matched donor

37

*** *

2000-20042005-2009

* P < 0.05

23

47

77

2133

7887

26

0

20

40

60

80

100

%

Increased use of PBSC as graft source

Malignant ds, age <18 yrs

Malignant ds, age 18-59 yrs

Malignant ds, age ≥ 60 yrs

Non-malignant diseases

*

**

*

Overall Survival, 3-years

38

45 (42-48)%

55 (52-58)%

Malignant diseases, age <18 yrs

Non-malignant diseasesMalignant diseases, age ≥ 60 yrs

Malignant diseases, age 18-59 yrs

P<0.001 P<0.001

25 (21-30)%

35 (33-37)%

60 (55-64)%

69 (66-72)%

P<0.001

2000-2004

2005-2009

Treatment Related Mortality, 3-years

39

Malignant diseases, age <18 yrs

Malignant diseases, age ≥ 60 yrs

Malignant diseases, age 18-59 yrs

28 (25-31)%

2000-2004

2005-2009

21 (18-23)%

P<0.001

37 (35-38)%

28 (27-29)%

P<0.001

34 (30-39)%

31 (29-33)%

P=0.20

Multivariate Analyses for Overall Survival

CohortHazard Ratio (95% CI); Referent 2000-04

Adjusted for patient factors P-value Adjusted for patient

+ practice factors P-value

Malignant ds,age <18 yrs 0.75 (0.66-0.86) <0.001 0.82 (0.71-0.95) 0.008

Malignant ds,age 18-59 yrs 0.78 (0.74-0.82) <0.001 0.86 (0.80-091) <0.001

Malignant ds,age ≥60 yrs 0.76 (0.67-0.86) <0.001 0.78 (0.68-0.90) <0.001

Non-malignant diseases 0.68 (0.56-0.82) <0.001 0.78 (0.63-0.95) 0.01

40

20

05

-20

09

Patient factors: Age at HCT, gender, race/ethnicity, KPS/Lansky score, CMV status, coexisting diseases, time from diagnosis to HCT, diagnosis, disease risk (malignant ds.)Practice factors: Graft type, conditioning regimen intensity, HLA match, GVHD prophylaxis, T-cell depletion

Conclusions

• Significant and rapid improvement in survival following unrelated donor HCT from 2000 to 2009 for all age groups

• Survival improvements due to reduced TRM, and in certain populations, fewer relapses

• Better patient selection, increased availability of HLA-matched donors and practice changes partly explain survival improvements

• Reinforces the role of unrelated donor HCT as standard therapy for patients who need transplant and do not have HLA-matched sibling donors

41

CALGB 100103/BMT CTN 0502A Phase II Study of Allogeneic Transplant

for Older Patients with AML in First Morphologic Complete Remission Using a

Reduced Intensity Preparative Regimen

Steven M. Devine, Kouros Owzar, William Blum, Daniel DeAngelo, Richard M. Stone, Jack W Hsu, Richard E. Champlin, Yi-Bin A. Chen, Ravi Vij, James L

Slack, Robert J. Soiffer, Richard A. Larson, Thomas C. Shea, Vera Hars, Elizabeth Bennett, Sada Spangle, Sergio A Giralt, Shelly L Carter, Mary M.

Horowitz, Charles Linker, and Edwin P Alyea III on behalf of The Alliance and Blood and Marrow Transplant Clinical Trials Network

Abstract 230

Background • Outcomes in older patients with AML extremely poor

– Within CALGB, analysis of 600 AML patients age 60 and over with cytogenetics (Farag et al, Blood 2006)

• Complete remission (CR): 50%• 5-year overall survival (OS): 7%

• Results even in best CALGB group are still poor (n = 276)– CR1, Age 60-75– Received at least one consolidation cycle on trial

• 2-year disease free survival (DFS): 24%• 3-year DFS 17%

• Small series suggested relapse rates may be lower for selected older AML patients receiving reduced intensity conditioning (RIC) based allografts

CALGB 100103/BMT CTN 0502Demographics

• 9 patients cancelled; 123 Transplanted– Related: N=58; Unrelated N=65

• Patient Age– Median 65 (60-74); related: 64.5; unrelated: 66

• Patient gender– Male 76– Female: 47

• Cytogenetic risk (CALGB criteria)– Favorable: 1– Intermediate: 83– Adverse: 25– Missing: 14

• Donor age (median; range)– Related: 63 (43-81); Unrelated: 30 (19-55)

CALGB 100103/BMT CTN 0502Chronic GVHD (limited/extensive)

cGVHD at 2 yrs: 26% (95% CI: 17-34%)

CALGB 100103/BMT CTN 0502Relapse/TRM

Relapse TRM

Relapse and TRM by donor type

Relapse at 2 yrs: 47% (95% CI: 37-57%)

TRM at 2 yrs: 14%(95% CI: 7-21%)

CALGB 100103/BMT CTN 0502Disease free/Overall Survival

by donor type

DFS unrelated at 2 yrs: 38%(95% CI: 26-55%)

Prospective data is still limitedProposed new trial -Alliance/IntergroupPI Celalettin Ustun U Minnesota

AML—Age 60-75 Enroll on US Coop Group TrialCo-enroll on this trial-- Donor search

HCT by 20 Weeks if Donor found; if in CR and FitTest 2 year survival in 3 groups:

Donor/HCT allocated vs None ---- or Not fitFeasibility: How many HCTsSurvival and MorbidityQOL and Functional Recovery

Is there anything to say about CML and allografts?

• Very few patients are getting transplants• NCCN guidelines recommend consideration after failing

two lines of TKI or if T315I mutation found• If blast phase at diagnosis• Prior imatinib does not seem to worsen transplant outcomes• Relapse rates likely to be much higher• Role of MA vs RIC unclear

Indications for Allo SCT in CLL

• EBMT 2007 Dreger et al.− Consider allo transplant in:− Primary refractory CLL or early relapse (< 12 mo)

following PNA-based therapy− Relapse within 24 months following a PNA-based

regimen− Del 17p13.1 disease requiring treatment

Indications for Allo SCT in CLL

• Italian Society of Hematology− Consider if unfavorable biologic risk factors are present,

or− Non-response or early relapse following PNA-based

regimen

NCCN Guidelines

• Now basically mirror EBMT− Consider allo transplant in patients with del 17p as

consolidation after first therapy if response is demonstrated or

− In patients with early relapse (<2 years) following standard therapy

Unwritten Guidelines in CLL

• The development of novel therapeutics (b-cell receptor kinase inhibitors etc) has made the recommendation very difficult

• For patients with access to a clinical trial of a novel therapeutic, who otherwise would have been considered for allo, pursue clinical trial first

• Patients without access to a clinical trial, follow guidelines• At OSU, only transplant if failing BTK trial or if Eligible for

CALGB 100701/BMT CTN 0804

The Future of Transplant for CLL

• Will likely always have a role given the proven efficacy

• However, less toxic effective therapies must be tried and failed

• CAR-T therapies still in the wings . . .

Thank You!

Patient selection from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0303 clinical trial of transplantation with T-cell–depleted (TCD) grafts in acute myeloid

leukemia (AML) and the BMT CTN 0101 antifungal prophylaxis clinical trial (imm...

Pasquini M C et al. JCO 2012;30:3194-3201


(A) Cumulative incidence of neutrophil engraftment by treatment arm.



(A) Cumulative incidence of leukemia relapse by treatment arm.



A randomized phase III study of standard

cytarabine plus daunomycin (7+3) therapy

versus idarubicin with high dose cytarabine

(IA) with or without vorinostat in younger

patients with previously untreated acute

myelogenous leukemia

(SWOG 1203)

SWOG 1203: ObjectivesPrimary:

– To compare EFS between 7+3 vs IA vs vorinostat IA– To determine if it is possible to perform SCT in ≥ 60% of

patients in CR1 AML

Secondary:– To compare CR rates, RFS and OS between 3 arms– To compare survival at 1, 2 and 3 years between 3 arms– To study toxiciy profiles between the 3 arms– To estimate DFS in patients that receive SCT– To study impact of molecular and cytogenetic

alterations on outcome according to treatment

Design: schemaRANDOMIZATION(REG STEP 1)ARM 1: 7+3ARM 2: IAARM 3: Vorinostat IA

HR PATIENTREMISSIONREADY FOR TRANSPLANT

YES ALLO SCT(REG STEP 3)

NO

CONSOLIDATION(REG STEP 2)ARM 1 HDACARM2 IAARM 3 VORINOSTAT IA

HR PATIENTREMISSIONREADY FOR TRANSPLANT

YES

NMDP will assist on early HLA typing and accelerated search

TherapyARM 1: 7+3

– dauno 90 mg/m2 x days 1 to 3– Ara-C 100 mg/m2 CI days 1 to 7– Consolidation HDAC x 4

Arm 2: IA– Idarubicin 12 mg/m2 days 1 to 3– Ara-C 1.5 gm/m2 days 1 to 4– Consolidation IA x 6 cycles

Arm 3: Vorinostat IA– Vorinostat 500 mg po TID days 1 to 3– IA starts on day 4

Transplant per individual center

Design: StatisticsSample size

– Chemo objective: 705 eligible patients (235/arm)– Transplant objective: 53 eligible high-risk patients

in CR

Accrual– 171 patients/year– Estimate that accrual will complete is < 5 years

Accrual will continue until both objectives are met– If chemo randomization stops due to interim

analysis, accrual will continue for transplant with patients’ chemo determined by results of interim analysis

Design: Statistics, chemo objective

Cure design– Null: 35% of patients cured, median EFS for non-cured = 4.7 months– Alternative: 45% cured, median EFS for non-cured = 7.1 months

5 interim analyses– First two based on CR (at ≈1 year and 2 years). Arm(s) stopped for

harm/futility– Last three based on EFS (at ≈ 2.5, 3.5, and 4.5 years). Arm(s) stopped

for efficacy or futility

Current submission proposes proportional odds model for EFS. After discussions with CTEP, can modify to use Cox proportional hazards model (alternative average HR=1.46). Change would lead to:

– Power decrease 88% 85%– Probability stop null trial early increase 92% 97%All other #s (sample size, alpha level, type-1 error) the same

Design: Statistics

Transplant objective:– Our goal: transplant 60% eligible patients,

compared to historical rate of 40%– Estimate DFS among transplanted patients– Reasons for failure to be transplanted will be

carefully documented

CALGB 100103/BMT CTN 0502Accrual by Site

* Study suspended from 12/08 thru 11/09

Site # Registered*Dana Farber 31

Ohio State 22

University of Florida 13

MDACC 12

Mass General 10

Washington U 8

Mayo Arizona 6

14 others 1-3

132 total patients registeredTrial met accrual goal in 2/2011

CALGB 100103/BMT CTN 0502Induction/Consolidation

• Induction therapy– CR after one cycle: 73 (59%)– CR after 2 cycles: 50 (41%)– All but 9 received std 7+3 based (only 2 decitabine)

• Consolidation– None: 21 (17%)– One cycle: 62 (50%)– Two cycles: 29 (24%)– Missing: 11 (9%)

CALGB 100103/BMT CTN 0502Disease free/Overall Survival

Median follow up: 3.3 yrs (related: 3.9 yrs; unrelated: 2.9 yrs)

DFS at 2 yrs: 39%(95% CI: 30-50%)

OS at 2 yrs: 46%(95% CI: 36-57%)

CALGB 100103/BMT CTN 0502Causes of Death

Primary cause N (total 69)

Relapse 53Sepsis 6MI 2Pulmonary 3Second cancer 2HHV-6 encephalitis 1

RSV pneumonia 1

Unknown 1

Conclusions from CALGB 100103/BMT CTN 0502

• Disease free survival at 2 yrs appears to be improved compared to historical controls treated conventionally (lower limit 95% CI above historical 20%)

• Overall treatment related mortality has been relatively low (<15%) despite older age and use of unrelated donors

• Acute and Chronic GVHD incidence relatively low

• Relapse still by far the greatest cause of failure– Could ATG have contributed?

• Further prospective analysis of RIC allografts in older AML patients is planned through NCI cooperative groups and BMT CTN

CALGB 100801

• Prospective multi-center study of reduced intensity allografts in patients with MDS and older AML CR1 patients

• Attempts to optimize busulfan dosing and prevent relapse with post transplant azacytidine

• Currently actively enrolling, two thirds completed

Recent Innovations in Stem Cell Transplantation presented at ASH

• Increasing the specificity of cellular therapy– Chimeric antigen receptor (CAR) T-cells– Suicide gene transduced T-cells

• Creating viable options for patients without matched sibling donors– Improved outcomes with cord blood and

haploidentical transplantation

Recent Innovations in Stem Cell Transplantation presented at ASH

• Mitigating the risk of relapse via maintenance therapy– Lenalidomide maintnenance in myeloma– Use of PD-1 antibody to stimulate immunity– Post transplant brentuximab in Hodgkin lymphoma– Post transplant azacytidine

• Novel methods to prevent GVHD– CCR5 antagonism, bortezomib, post transplant

cyclophosphamide– Treg adoptive transfer or in vivo generation via

immunomodulating drugs

Protocol Team Members

Wael SaberJennifer Le-RademacherMary HorowitzShelly CarterBrent LoganNancy DiFronzoBill MerrittIris GerstenEric Leifer

Joe AlvarnasCorey CutlerMikkael SekeresSteve GoreRichard StoneJoe McGuirkFred AppelbaumDennis ConferJoycelynne Palmer

Stephen FormanGinna LaportRenee CarbyRyotaro Nakamura Guillermo Garcia-Manera

Coverage with Evidence Development

• CMS issued decision Aug 2010 allowing “coverage with evidence development (CED)”

Suggests insufficient evidence “..evidence does not demonstrate that the use of HCT improves health outcomes in Medicare beneficiaries with MDS.” “paucity of evidence regarding the use of HCT in patients with MDS who are 65 years or older”

Will cover costs of HCT if patients enrolled in a study that will provide CMS with data (“evidence”) to determine the value of the procedure in the Medicare population

To qualify for CED, a trial must address at least one of the following 3 questions

1. Prospectively, compared to Medicare beneficiaries with MDS who do not receive HCT, do Medicare beneficiaries with MDS who receive HSCT have improved outcomes?

2. Prospectively, in Medicare beneficiaries with MDS who receive HCT, how do IPSS score, patient age, cytopenias and comorbidities predict outcomes?

3. Prospectively, in Medicare beneficiaries with MDS who receive HCT, what treatment facility characteristics predict meaningful clinical improvement in outcomes?

Design – Treatment Assignment• Once Enrolled - 90 days maximum to

Donor/No Donor assignment– Based on likelihood of identifying donor after 90

days – NMDP data– Analysis as NO DONOR for events occurring prior

to assignment– Balances bias with those who arrive with known

donors and suffer early events– Intention to treat, even if:

• Declines transplant with known donor • Undergoes alternative donor transplant (no donor arm)

Statistics – Assumptions

Group Prob (95% CI) 2011 CIBMTR Registration

50-59 38 (27 – 50)% 265 (age 50-65)

≥ 60 33 (16 – 54)% 152 (age > 65)Combined 37 (27 – 47)% n = 417

CIBMTR 3 year OS for RIC Transplantation

Baseline Data – Azacytidine

Compassionate use program n = 282, (Itzykson et al, Blood 2011)

3 year OS = 20-25%

Donor

Availability

Total Sample size

(HCT, Non-HCT)

Three-year OS Power

HCT Non-HCT

60% 338

(203, 135)

35% 20% 84%

40% 25% 80%

70% 400

(280, 120)

35% 20% 84%

40% 25% 81%

POWER TO DETECT 15% INCREASE IN OS PROBABILITY IN THE TRANSPLANT ARM FOR VARIOUS SURVIVAL PROBABILITIES AND PROPORTIONS OF DONOR

AVAILABILITY

CIBMTR data: 420 patients/yr receive alloHCT from a MRD/MUD- Assumptions: 50% = Int-2/high risk IPSS (?underestimate)

Accrual rate = 40%- Annual enrollment: 84 patients/yr to the RIC alloHCT arm.

Donor Availability

60% 70%Donor 84 84No Donor 56 36

Total 140 120

• Estimated accrual duration: 2.5 - 3.5 years (donor/no-donor: 6:4 – 7:3)

• Accrual monitoring: Donor vs. No-donor, 50-64 vs. 65-75

Accrual

Biologic Correlates

• No planned analyses yet• Sample collection:

– Baseline: PBMCsCheek swabPossible Marrow (if avail)

– Post-Transplant: Relapse PBMCsMarrow (if avail)

- Co-enrollment on 1202 – GVHD Biomarkers

Data Collection

• Differential data collection on Transplant vs. No Transplant patients (not Donor vs No-Donor)

• CIBMTR Research Data on all Transplant recipients

• Non-Transplant Patients: Registering Transplant Center responsible for collection of:

– Vital Status– CBC data, leukemic transformation date

• SRG to perform QoL contact, obtain some info

Analysis Plan• Primary Endpoint: 3-year OS by intent-to-treat analysis

- as treated analysis

• Exploratory analyses to evaluate - Impact of hypomthelyating therapy on transplantation outcomes (i.e. OS, DFS, TRM, GVHD). The response to therapy, # of cycles, will be used in correlative analyses after RIC alloHCT.

- Subset of recently diagnosed patients who received hypomethylating therapy followed by RIC alloHCT vs. who received hypomethylating therapy not followed by RIC alloHCT

Questions this trial will not directly Answer

• What is the role of hypomethylating therapy pre-transplant?– Optimal # of cycles– Does response matter

• What is the best initial treatment for MDS?– Transplant vs. Azacytidine

• Possible subgroup analysis

Protocol Timeline• PRC Review / Approval Jan 2013

• Consent and FAQ documents included

• Needs Biomarker and Toxicity Committee Reviews

• Steps: Steering Committee ApprovalRelease to IRBsForms and Logistics being worked on now

Goal: Accrual before Q4 2013

Protocol Subject Status

CALGB 11002 Randomized phase II of decitabine-based induction for AML age ≥ 60

Active

SWOG 1117 Randomized phase II of azaciditine-based therapies for MDS

Active

SWOG 1203 Randomized phase III of standard 7+3 vs IA +/- vorinostat in AML age < 60

Approved

ECOG 1912 Randomized phase II/III of FCR vs PCI-32765 based therapies in younger CLL

Approved

Alliance 041202 Randomized phase III of bendamustine+ rituxan versus ibrutinib-based therapies in older CLL

Approved

ECOG 1910 Randomized phase III of blinatumomab in BCR/ABL-, B-cell ALL age 40-70

Approved

NCI Leukemia Steering Committee

HLA-Identical Sibling-Matched, CD34+ Selected, T cell Depleted Peripheral Blood Stem Cells Following Myeloablative

Conditioning For First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant

Clinical Trials Network

S Devine, S Carter, R Soiffer, M Pasquini, P Hari, A Stein, H Lazarus, C Linker, E Stadtmauer, E Alyea, C Keever-Taylor, and R O'Reilly

(BMT CTN) Protocol 0303

1 http://www.Cancer.gov2 Koreth, J et al. JAMA 2009

Acute Myeloid Leukemia (AML)

Most common leukemia diagnosis in adults1

Annual U.S. incidence: ~ 12,330 new cases diagnosed annuallyMortality is roughly 8,950 cases per yearAllogeneic SCT is the single most effective therapy currently available for the prevention of relapse and shows significant survival benefit in AML patients with intermediate and poor risk cytogenetics in first complete remission (CR1) 2

http://www.cancer.gov/

Reduced incidence of leukemic relapse and overall survival often not realized due to complications caused by GVHD

Acute GVHD (aGVHD) risk is 35-45%

33-67% of these patients will develop chronic GVHD (cGVHD), resulting in post transplant morbidity, mortality and reduced quality of life

Immunosuppressive agents used to prevent and treat aGVHD do not affect incidence of cGVHD; treatment options for cGVHD are poor

Graft Versus Host Disease (GVHD) Complicates Allogeneic Transplantation From Matched Related Donors (MRD)1-6

1 Ferrara J, et al. Lancet 2009 2 Chao N, et al. NEJM 1993 3 Devine S, et al. J Lab Clin Med 20034 Clift R, et al. Blood 1991 5 Nash R, et al. Blood,2000 6 Ratanatharathorn V, et al. Blood 1998

Single center studies show reduced GVHD without increased relapse rates in AML patients receiving T cell depleted (TCD) allografts in CR1,2

One randomized, prospective, multi-center TCD trial showed no increase in relapse in AML patients receiving TCD allografts3

BMT CTN 0303 Study Rationale

1 Aversa et al. Blood Cells Mol and Disease 20082 Pappadopoulos et al, Blood, 19983 Wagner, J. et al. Lancet 2005

Randomized, Prospective, Multi-center TCD trial Showed No Increase in Relapse in AML

Patients Receiving TCD Allografts

Wagner et al., Lancet 366:733, 2005

All Patients AML

BMT CTN 0303 Study Eligibility

AML in CR1 or CR2Age 18-65HLA-identical sibling availableNo more than 2 induction cycles of chemotherapy required to induce remissionNo more than six months from CR to transplant (three months for CR2)Other standard organ function criteriaNo uncontrolled bacterial/fungal/viral infectionsKarnofsky performance status > 70%

Primary endpoint:Disease-free survival at 6 months

BMT CTN 0303 Study Endpoints

Secondary Endpoints: Overall SurvivalDisease Free Survival at 2 yearsTransplant-Related MortalityRelapseAcute and chronic GVHDEngraftment/graft failureInfusional ToxicitiesProportion of grafts containing > 5 x 106 /kg CD34+

cells and < 1 x 105 /kg CD3+ cells Incidence of EBV reactivation and PTLD

BMT CTN 0303 Study Endpoints, continued

Site Patients Accrued

Dana Farber/Partners Cancer Center 18

Ohio State University 8

Memorial Sloan Kettering Cancer Center 7

Medical College of Wisconsin 7

City of Hope National Medical Center 3

University Hospitals of Cleveland 2

University of CA, San Francisco 1

University of Pennsylvania 1

TOTAL 47

Eight Centers Enrolled Patients onto BMT CTN 0303

44 patients were evaluable on study2 withdrew consent; 1 had disease progression prior to treatment

BMT CTN 0303Patient Characteristics

Patient Age Median (range) 46.3 (21-59 )

Donor age Median (range) 46.2 (16-63)

GenderMale 16 (36%)

Female 28 (64%)

Leukemia stageCR1 37 (84%)

CR2 7 (16%)

Cytogenetic Risk (CR1/CR2)

Favorable 0 / 2

Intermediate 25 / 3

Unfavorable 10 / 1

Unknown* 2 / 1

* Unknown cytogenetic risk due to lack of metaphase during testing

BMT CTN 0303 Patient Conditioning Regimen

CTN 0303 Donor Mobilization & Leukapheresis

Received daily G-CSF (16μg/kg/day subcutaneously) following screening and enrollmentLeukapheresis performed according to institutional standards commencing on Day 5 of G-CSFDaily leukapheresis with subsequent CD34+ cell selection using the CliniMACS® CD34 Reagent System continued until a post-selection target of CD34+ and CD3+ cells/kg recipient body weight was met

Primary Endpoint6 Month Disease-Free Survival of >75%

Was Met

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0

Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24

N=44

81.8% @ 6 months

Secondary EndpointsDisease-Free Survival at 2 years

All Patients By CR1/CR2*

By Stage

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0


N=44

65.7% @ 1 yr 56.4%

@ 2 yrs

61.9% @ 2 yrs

28.6% @ 2 yrs

* 2º Endpoint of >70% for CR1 and >60% for CR2 were not met. However, historical data estimate 2 Yr DFS < 60% in CR11-3

1 Suciu Blood 2003 2 Brunet et al, Hematologica 20043 Cornelissen et al, Blood 2007

Secondary Endpoint2 Year Overall Survival Was 59.4%

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0


N=44

77.3% @ 1 yr

59.4% @ 2 yrs

Secondary EndpointsNeutrophil/Platelet Engraftment

Analysis NMedian Days

to EngraftmentDay 30Estimate

Day 100 Estimate

Platelet Engraftment

>20K/µL 44 16 days

93.2% (95% CI: 85.2-100)

97.7 %(95% CI: 92-100)

Cumulative Incidence of Neutrophil

Engraftment >500/µL

44 12 days100%

(95% CI: 85.5-100)

• No primary graft failures • One secondary graft failure at Day +54 after initially engrafting on Day +12

Secondary Endpoint - Cumulative Incidence of Transplant-Related Mortality (1yr) was 13.6%

Safety endpoint of <30% TRM at 1 Year was not exceeded.

TRM at 2 years was 19.9% (95% CI: 7.1-32.7)

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0


N=44

All Patients By CR1/CR2

13.6% (95% CI: 3.4-23.8)

Secondary Endpoint - Cumulative Incidence of EBV Reactivation 18% at 2 years


13.6% (95% CI: 3.4-23.8)

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0


N=44

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0


First CR (N=37) Second CR (N=7)

18.2% @2 yrs 18.9%

14.3%

• 8 patients treated for EBV DNA levels >1000 copies/ml• One case of PTLD with subsequent death

Secondary Endpoint - Cumulative Rate of Relapse was 23.7% at 2 years

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0


N=44

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0



20.6% @ 1 yr

23.7% @2 yrs

57.1% @2 yrs

17.4%* @2 yrs


* N=7 patients treated in CR2; 4 patients relapsed(95% Confidence Interval: 14.6-99.6%)

Secondary Endpoint- Cumulative Incidence of Acute GVHD (II/IV was 22.7%)

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0

Days Post Transplant0 7 14 21 28 35 42 49 56 63 70 77 84 91 98


22.7% (95% CI: 10.2-35.2)

*No Grade IV GVHD observed


Secondary Endpoint-Cumulative Incidence of Grade III/IV Acute GVHD was 4.5%

* No Grade IV GVHD observed

4.5%(95% C.I: 0 – 10.8%)


Secondary Endpoint - Cumulative Incidence of Chronic GVHD (2 yrs) was 19%

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0



19%(95% CI: 6.8-31.1)

Includes Limited and ExtensiveAll Patients By CR1/CR2

Secondary Endpoint - Cumulative Incidence of Extensive cGVHD (2 yrs) was 6.8%

Prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0


p

N=44

6.8% (95% CI: 0-14.4)


Causes of Death at2 Year Post Transplant

Cause NRecurrence 6

Infection 4

Idiopathic Pneumonia

Organ failure

Other*

2

2

1

PTLD 1Total 16

* Possibly cardiac related

HCT following myeloablative preparative regimen for patients with AML in CR1 or CR2 can be performed in a multicenter setting using a single TCD method without additional post transplant pharmacologic GVHD prophylaxis

All 1° and most 2º endpoints were met, demonstrating:81.8% Disease Free Survival 6 months post TX No primary graft failure; Consistent neutrophil and platelet engraftment Acute GVHD <23%. No Grade IV aGVHDChronic GVHD <19% at 2 yearsTRM <20% at 2 years Low risk of relapse, but dependent on remission status

The CliniMACS® CD34 System consistently produces a graft with > 5 x 106 CD34+ cells/kg and <1 x 105 C3+ cells/kg

Conclusions BMT CTN 0303

indications for allogeneic transplantation in acute and chronic … for allogeneic... ·...

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