ORIGINAL ARTICLE

Reduced intensity allogeneic hematopoietic celltransplantation can induce durable remission in heavilypretreated relapsed Hodgkin lymphoma

Robert Chen & Joycelynne M. Palmer & Leslie Popplewell & Jessica Shen &

Eileen Smith & Maria Delioukina & Neil Kogut & Joseph Rosenthal & Stephen Forman &

Auayporn Nademanee

Received: 3 November 2010 /Accepted: 20 December 2010 /Published online: 6 January 2011# Springer-Verlag 2011

Abstract Hodgkin lymphoma (HL) can be aggressive andintractable in some cases. Patients who relapse afterautologous HCT (auto-HCT) have limited treatmentoptions. City of Hope reports our experience in the use ofreduced intensity allogeneic hematopoietic cell transplanta-tion (allo-HCT) in 24 heavily pretreated patients withrelapsed HL, between January 2003 and December 2008.The median number of prior therapies was 5; 20/24 patientshad prior auto-HCT. The conditioning regimen for allpatients was fludarabine and melphalan. With a medianfollow-up for living patients of 39.0 months, at 2 years theoverall survival (OS) was 60% (95% CI 42, 72) and theprogression-free survival was 27% (95% CI 22, 32). Non-relapse mortality was 13.1% (95% CI 5.1, 31.4) at 2 years.The incidence of grade II–IV aGVHD was 45.8% and 8.3%for grade III–IV. Allo-HCT in heavily pretreated relapsed

Hodgkin lymphoma is feasible, tolerable, and can inducedurable clinical remissions.

Keywords Allogeneic transplant . Reduced intensity .

Hodgkin lymphoma . Relapsed . HL

Introduction

In 2008, it was estimated that approximately 8,220 newcases of HL were diagnosed in the USA [1]. For patientswith advanced disease at presentation, ABVD is the goldstandard first-line therapy, with a 3-year event-free survivalof 75% as reported by Johnson et al. [2] and a 5-yearprogression-free survival of 68% as reported by Federicoet al. [3]. The majority of these patients can be curedwith conventional chemotherapy (±radiation therapy), butapproximately 20–35% of patients have either primaryrefractory disease or relapse shortly after induction chemo-therapy treatment [2–5]. The standard of care for patientswith relapsed HL is salvage chemotherapy followed byauto-HCT. There are a variety of salvage chemotherapyregimens (ICE, DHAP, GDP, and GVD) that have beenpublished as phase 2 trials with overall response ratesbetween 69% and 89% [6–9].

Although high-dose chemotherapy followed by autologoustransplant can effectively achieve long-term remission, about50% of these patients will relapse post auto-HCT [10–13]. Forthese patients, allo-HCT remains the only curative option.Previous studies of allo-HCT utilizing myeloablative condi-tioning regimens yielded poor results due to high regimen-related toxicities, but a minority of these heavily pretreatedpatients (15%) were able to achieve long-term remissions[14–16]. Sureda et al. from the European Group for Blood

R. Chen (*) : L. Popplewell : E. Smith :M. Delioukina :S. Forman :A. NademaneeDepartment of Hematology/Hematopoietic Cell Transplantation,City of Hope National Medical Center,Duarte, CA 91010, USAe-mail: rchen@coh.org

J. M. Palmer : J. ShenDivision of Biostatistics, City of Hope National Medical Center,Duarte, CA 91010, USA

N. KogutCity of Hope–Kaiser Permanente,Los Angeles, CA, USA

J. RosenthalDepartment of Pediatric Hematopoietic Cell Transplantation,City of Hope National Medical Center,Duarte, CA 91010, USA

Ann Hematol (2011) 90:803–808DOI 10.1007/s00277-010-1146-3

and Marrow Transplantation (EBMT) directly comparereduced intensity conditioning (RIC) to a standardmyeloablative regimen in 168 patients with relapsed/refractory HL [17]. This study reports the 3 month and1-year incidence of non-relapse mortality (NRM) to be28% and 46%, respectively, in the standard myeloablativegroup and 15% and 23% in the reduced intensity group.This demonstrates that RIC decreases NRM andtransplant-related complications. Few centers have inves-tigated the use of RIC regimens to treat relapsed HL postauto-HCT and all are retrospective. Data from the EBMT,Dana Farber Cancer Institute, and MD Anderson areconsistent and show a relatively high overall survivaland low non-relapse mortality [17–19].

Here, we report the results of RIC allo-HCT performedin 24 patients with HL at the City of Hope between 2003and 2008.

Patients and methods

Between 2003 and 2008, 24 patients with relapsed/refractory HL underwent RIC allo-HCT from either anHLA-matched sibling donor or an HLA-matched (≥5/6)unrelated donor using stem cells collected from the bonemarrow (n=3), peripheral blood (n=20), or umbilical cordblood (n=1) at the City of Hope (COH). The COHInstitutional Review Board approved the retrospectiveanalysis of data from this consecutive case-series; anonym-ity of all patient information was maintained. Acute andchronic GVHD were graded according to establishedcriteria [20]. Patients were considered evaluable for GVHDif they achieved engraftment. Pathology and pretransplantstaging were reviewed at the City of Hope. Post-transplantevaluation of disease status with imaging studies, bonemarrow biopsies, and engraftment analysis occurred at 30and 100 days, 1 year post-transplant, and yearly thereafter,or as clinically indicated. International Working Groupcriteria were used to define disease response post-transplant, as some patients were treated prior to imple-mentation of revised response criteria.

Patient characteristics

Details regarding patient, disease, and treatment character-istics are provided in Table 1. The median age of thepatients is 35 years (range, 14–63). Median time fromdiagnosis to allo-HCT was 35.5 months (range, 13.6–213.9). Sixteen (66.7%) of the 24 patients had chemo-sensitive disease at the time of transplant, 20 (83.3%)patients had a prior auto-HCT, five (20.8%) had priortandem auto-HCT, and 18 (75%) had prior radiation as partof induction/salvage treatment. The median number of prior

regimens was 5 (range, 3–8). The median PretransplantAssessment of Mortality Score was 21 (range, 19–34) [21].Disease status in this study was evaluated by CT scans aspatients before 2005 did not uniformly receive functionalPET imaging prior to allo-HCT.

Eligibility criteria

Patients with relapsed HL were offered allo-HCT after thefollowing criteria were met: histologically confirmed HLbeyond 1st complete remission with no active or uncon-trolled infection and adequate cardiac, pulmonary, renal,

Table 1 Patient, disease, and transplant characteristics

Characteristics Number (%) or median(range)

Gender

Male 13 (54.2%)

Female 11 (45.8%)

Age at transplant 35 (14–63)

Donor type

Sibling 12 (50%)

Matched unrelated 10 (41.7%)

Mismatched unrelated 2 (8.3%)

Time from diagnosis to transplant(months)

35.5 (13.6–213.9)

Responsiveness to chemotherapy

Sensitive 16 (66.7%)

Resistant 8 (33.3%)

Prior autologous transplant

Yes 20 (83.3%)

No 4 (16.7%)

PAM Score 21 (19–34)

Stem cell source

Peripheral Blood 20 (83.3%)

Bone Marrow 3 (12.5%)

Cord Blood 1 (4.2%)

Prior radiation

Yes 18 (75%)

No 6 (25%)

Median number of prior regimens 5 (3–8)

GVHD prophylaxis

Tacro/Siro 12 (50%)

Tacro/Siro/MTX 4 (16.7%)

Tacro/MTX 1 (4.2%)

CSA/MMF 3 (12.5%)

CSA/MMF/MTX 2 (8.3%)

CSA/MMF/ATG 2 (8.3%)

Tacro tacrolimus, Siro sirolimus, MTX methotrexate, CSA cyclospor-ine A, MMF mycophenolate mofetil, ATG anti-thymocyte globulin,PAM Pretransplant Assessment of Mortality Score

804 Ann Hematol (2011) 90:803–808

and hepatic function. In addition, patients must haverelapsed after prior auto-HCT, been unable to collectsufficient stem cells to undergo auto-HCT, or had chemo-refractory disease deemed inappropriate for auto-HCT.Eligibility also required availability of an HLA-identicalrelated donor, HLA-matched unrelated donor, or single-antigen mismatch unrelated donor, who was able to donatefilgrastim-mobilized peripheral blood stem cells or bonemarrow, or double umbilical cords.

Conditioning regimen and GVHD prophylaxis

All patients were conditioned with an RIC regimenconsisting of fludarabine and melphalan and received stemcells from a fully matched sibling (n=12, 50%) or fullymatched unrelated donor (n=10, 41.7%), excepting twopatients who were transplanted using a mismatchedunrelated donor; one of these was transplanted using doubleumbilical cords (Table 1). Fludarabine/melphalan has beenthe standard RIC regimen at City of Hope since January of2003. Fludarabine 25 mg/m2 is administered daily for5 days intravenously, and melphalan 140 mg/m2 is givenintravenously daily for 1 day.

Cyclosporine plus mycophenolate mofetil was theGVHD prophylaxis regimen of choice per institutionalguidelines prior to 2006, after which tacrolimus andsirolimus became the standard GVHD prophylaxis regimenat City of Hope. All patients receiving tacrolimus intrave-nously started on day −2 and were dosed to maintain atherapeutic serum level of 4–12 ng/ml and switched to oraladministration as soon as oral intake was feasible. Metho-trexate was either added or substituted for sirolimus forsome of the patients who received a matched unrelateddonor transplant. ATG was also added for a minority ofpatients who received a matched unrelated donor transplant.For the two patients that underwent a single-antigen mis-matched unrelated donor transplant, one received cyclospor-ine, mycophenolate mofetil, and mini-methotrexate forGVHD prophylaxis and the other received tacrolimus,sirolimus, and mini-methotrexate.

Statistical methods

Survival estimates were calculated using the Kaplan–Meierproduct-limit method, 95% confidence intervals werecalculated using the logit transformation and the Green-wood variance estimate [22]. Differences between Kaplan–Meier curves were assessed by the log-rank test. Patientswho were alive at the time of analysis were censored at thelast contact date. Overall survival (OS) was measured fromstem cell infusion to death from any cause. Progression-freesurvival (PFS) was defined as time from stem cell infusionto recurrence, progression, or death from any cause,

whichever occurred first. The relapse/progression rate(RPR) was defined as time from stem cell infusion torecurrence or progression. Non-relapse mortality (NRM)was measured from transplant to death from any causeother than disease relapse or disease progression. Non-relapse-related mortality and relapse-related mortality wereconsidered competing risks for mortality. The cumulativeincidence of NRM and relapse-related mortality wascalculated using the method described by Gooley et al.[23]. Differences between cumulative incidence curves inthe presence of a competing risk were tested using the Graymethod [24]. The significance of demographic, disease, andtreatment features were assessed using univariate Coxregression analysis [25]. Univariate Cox proportionalhazard models were used to model time to event endpoints(e.g., OS, PFS, RPR, and NRM), as a function of theprognostic variables. The list of prognostic variables wasdetermined from a literature review that identified factorsassociated with survival and/or disease relapse/recurrencein patients treated with allo-HCT. These variables were:number of prior regimens, prior auto-HCT, chemosensitivedisease at time of transplant, donor type, and priorradiation. All calculations were performed using SAS 9.2(SAS Institute, Cary, NC) and R (version 2.4.1; http://www.r-project.org). Statistical significance was set at the p<0.05level; all p values were 2-sided. The data were locked foranalysis on July 21, 2009 (analytic date).

Results

Engraftment

All patients achieved engraftment. The median time toneutrophil recovery was 16 days (range, 10–42) as definedby absolute neutrophil count ≥500. The median time toplatelet recovery was 13.5 days (range 8–56) as defined byplatelet count >20 without transfusion support. Chimerismstudies were available in 20 patients by day 100. All 20patients exhibited full donor hematopoiesis.

Graft-versus-host disease

All patients were evaluable for acute GVHD, whichoccurred in 14 out of 24 patients (58.3%). The incidenceof aGVHD grades II–IV and III–IV was 45.8% and 8.3%,respectively. With a median follow-up for all patients of27.2 months (range, 1.4–68.5), the incidence of extensivecGVHD was 58.3% (14/24 patients). Donor type wasevaluated as a risk factor for development of GVHD. Therewas no significant difference between matched siblingdonors and matched unrelated donors with regard toGVHD. The impact of GVHD on OS, PFS, and relapse

Ann Hematol (2011) 90:803–808 805

rate was also evaluated. There were no statisticallysignificant differences with regard to OS, PFS, or relapse/progression rate.

OS, PFS, and disease relapse/progression

With a median follow-up of 27.2 months (range, 1.4–68.5)for all patients, 12 patients were alive at the analytic date(50%); seven in CR (58.3%); and five patients in relapse(41.7%). OS at 1 and 2 years was 75% (CI 59, 85) and 60%(CI 42, 72), respectively (Fig. 1a). PFS at 1 and 2 years was50% (CI 40, 60) and 27% (CI 22, 32; Fig. 1a). The relapse/progression rate (cumulative incidence) at 1 and 2 yearswas 48% (CI 38, 59) and 63% (CI 56, 71). The day 100 and1-/2-year non-relapse mortality rates were 4.2% (CI 0.6,24.3; n=2) and 13.1% (CI 5.1.8, 31.4; n=5), respectively

(Fig. 1b). The primary causes of death were: progressivedisease PD (n=6), GVHD (n=3), and other (n=3).

Univariate analysis

Donor type, number of prior regimens, prior auto-HCT,prior radiation, and response status prior to allo-HCT wereevaluated as prognostic factors. By univariate analysis, forboth OS and PFS endpoints, the number of prior regimensshowed no statistically significant differences in OS (HR0.35; 95% CI 0.09–1.29, p=0.11) or PFS (HR 0.59, 95% CI0.21–1.59, p=0.29). OS and PFS were also analyzed toexplore possible differences given the patients’ transplanthistory (prior auto-HCT) and type of donor. There werealso no statistically significant differences with regard toOS (HR 0.5, 95% CI 0.14–1.89, p=0.31) or PFS (HR 0.44,95% CI 0.13, 1.43, p=0.17) for prior auto-HCT or fordonor type: OS (HR 0.72, 95% CI 0.22–2.29, p=0.57) andPFS (HR 0.49, 95% CI 0.19–1.31, p=0.15).

Lymphoma relapse/progression

Disease relapse or progression occurred in 16 out of 24patients (66.7%) and resulted in death for seven patients.The median time to disease progression was 181 days afterallo-HCT (range, 103–436). The 1- and 2-year relapse/progression rates were 48% (95% CI 38–59) and 63% (95%CI 56–71), respectively. By univariate analysis, no signifi-cantly predictive factors emerged. Although not statisticallysignificant, the relapse rate was 50% for patients withchemosensitive disease at the time of allo-HCT as comparedto 75% for the patients with chemorefractory disease at thetime of allo-HCT.

Discussion

Conventional myeloablative allo-HCT is not a standardsalvage treatment for patients with HL due to its hightreatment-related mortality and toxicities. Patients withrelapsed HL often have been exposed to prior radiation,multiple prior chemotherapy regimens, and high-dosechemotherapy with auto-HCT, all of which potentiate therisks of a myeloablative allo-HCT. Reduced intensity allo-HCT has become the standard treatment for many elderlypatients with hematologic malignancies and is also poten-tially toxicity-sparing in refractory Hodgkin patients. In thisanalysis, we have described the City of Hope experiencewith the use of reduced intensity allo-HCT for relapsed HL.

Our sample size of 24 patients is small but allows us todraw preliminary conclusions. The patients in this studyrepresent a heavily pretreated population in which 69% hadprior radiation therapy, 83.3% had undergone previous

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Time Post-transplant (years)0 1 2 3 4 5 6

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OSPFS

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Fig. 1 Outcomes for both panels, n=24 and median follow-up ofsurviving patients was 39 months. a Overall survival (OS) andprogression-free survival (PFS) probabilities as a function of timepost-transplant in years. Two-year overall survival point estimate was60% (95% CI 47, 72) and progression-free survival was 27% (95% CI22, 32). b Non-relapse mortality (NRM) and relapse/progression rate(RPR) as a function of time post-transplant in years. Two-year NRMpoint estimate was 13.1% (95% CI 5.1, 31.4) and RPR (cumulativeincidence) was 63% (CI 56, 71)

806 Ann Hematol (2011) 90:803–808

high-dose chemotherapy and auto-HCT, 20.8% had under-gone tandem auto-HCT, and the median number of priorregimens was 5. Approximately half of the patients did nothave a matched related sibling (45.8%) and underwent amatched unrelated donor or single-antigen mismatchedunrelated donor allo-HCT. Despite the high-risk patientgroup, the non-relapse mortality was only 4.2% at 100 daysand 13.1% at 2 years. This is similar to non-relapsemortality data from MD Anderson of 15% at 2 years, andslightly better than EBMT’s 23% at 1 year, Fred Hutch-inson’s 21% at 2 years, and Dana Farber’s 23% at 3 years[15, 18, 19, 26] (see Table 2). It is important to note thatdonor type did not adversely affect non-relapse mortality inour study and may indicate that lack of a sibling donorshould not prevent consideration of a reduced intensity allo-HCT.

Patients in this study had a high-risk profile, with 33.3%chemoresistant disease at the time of transplant. Despite sucha high percentage of patients with chemoresistant disease, wewere able to obtain a 1-year PFS of 50% and 2-year PFS of27%. This is comparable to the 3-year PFS of 22% reported byDana Farber, 2-year PFS of 23–29% reported by FredHutchinson, and 2-year PFS of 32% reported by MDAnderson [18, 19, 26] (Table 2). Also, the PFS curve inFig. 1 shows that there is a definite plateau suggesting thatdurable remission can be achieved. The 1-year OS of 75%and 2-year OS of 60% is also comparable with prior resultsof 3-year OS of 56% reported by Dana Farber, 2-year OS of53–58% reported by Fred Hutchinson, and 2-year OS of64% reported by MD Anderson [18, 19, 26] (Table 2). Thereis no prospective clinical trial using allo-HCT for HD.However, the volume and the consistency of retrospectiveresults shown by several major transplantation centers canjustify the use of allo-HCT for relapsed HD.

Due to the limited number of patients and the retrospec-tive nature of our study, we cannot conclusively identifyrisk factors that adversely affect OS or DFS. Historical datashow that PFS and relapse can be affected by disease statusat the time of allo-HCT. Disease status in this study wasevaluated by CT scans as patients (before 2005) did notuniformly receive functional PET imaging prior to allo-HCT. Sixteen of the patients in this study had chemo-sensitive disease at the time of allo-HCT and 8/16 (50%)have relapsed at this time. Of the eight patients withchemorefractory disease at the time of allo-HCT, 6/8 (75%)have relapsed. Despite the small dataset, there is a tendencytoward higher efficacy of allo-HCT for HL patients withchemosensitive disease.

While allo-HCT is a reasonable option, relapse rates forrelapsed/refractory Hodgkin patients are still high with alltested salvage therapies and strategies to improve efficacyshould be explored. One reasonable approach would bemaximal cytoreduction of disease burden prior to allo-HCTwith effective salvage therapy. Novel therapeutics such asSGN-35 (brentuximab vedotin) and vorinostat are beingstudied in phase 1/2 trials for relapsed HL and preclinicaldata are encouraging [27, 28]. Besides being effectivesalvage therapies, these agents could serve as bridgetherapies to allo-HCT, improving its efficacy.

Historically, evidence for a graft versus HL effect hasbeen limited and has been the subject of controversialdebate. A few reports have associated lower relapse ratewith graft versus host disease and this has been used asevidence of a graft versus HL effect. Further support for agraft versus HL effect has been demonstrated by observa-tions of disease response to donor lymphocyte infusion[29]. In our study, acute and chronic GVHD have nosignificant impact on DFS, OS, or relapse rate. Our

Table 2 Summary of reduced intensity allo-HCT in prior studies

Study Conditioningregimen

Cell source Follow-up(months)

NRM OS PFS

EBMT [15] BEAM PB 75 3 years, 24% 5 years, 28% 5 years, 18%Flu/TBI

Flu/Mel BMBu/Mel/Cy

Fred Hutchinson [26] TBI PB 25 MRD: 2 years, 21% MRD: 2 years, 53% MRD: 2 years, 23%

Flu/TBI MUD: 2 years, 8% MUD: 2 years, 58% MUD: 2 years, 29%

Dana Farber [18] Bu/Flu PB 26 3 years, 23% 3 years, 56% 3 years, 22%BM

MDACC [19] Flu/Mel PB 24 2 years, 15% 2 years, 64% 2 years, 32%BM

COH (this study) Flu/Mel PB 26 2 years, 13.1% 2 years, 60% 2 years, 27%1 DCBT

Flu fludarabine, Mel melphalan, TBI total body irradiation, Bu busulfan, BEAM carmustine, etoposide, cytarabine, melphalan, PB peripheralblood, BM bone marrow, DCBT double cord blood transplant, MRD matched related donor, MUD matched unrelated donor

Ann Hematol (2011) 90:803–808 807

observation that patients with matched unrelated donorshad a reduced relapse rate as compared to those withmatched related donors is consistent with the scientificprinciple of graft versus HL.

As a single institution study with a limited patient numbers,we are not able to identify with certainty the clinicalparameters that predict transplant outcomes. However, wehave shown that allo-HCT with reduced intensity condition-ing regimen is safe in heavily pretreated patients with relapsedHL and has a low treatment-related mortality. Our report isconsistent with other retrospective series on the use of reducedintensity allo-HCT in HL. Furthermore, we have also shownthat reduced intensity allo-HCTcan induce durable remission.

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