Lymphoma

Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor

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Abstract

Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000–2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.

Introduction

Allogeneic hematopoietic cell transplantation (HCT) has been shown to be a valuable and potentially curative strategy to treat patients with high-risk lymphoma.1, 2, 3, 4, 5, 6 Reduced-intensity conditioning (RIC) regimens have further extended the use of allogeneic HCT to those who relapse after autologous HCT, older patients and persons with significant pre-transplant comorbidities.6, 7, 8, 9, 10

Donor availability is a potential barrier for patients who are candidates for allogeneic HCT, but lack an adequately HLA matched and clinically suitable sibling donor. While Caucasian patients have a 60–70% probability of identifying an 8/8 allele level HLA matched unrelated donor (MUD), for ethnic minority groups fewer than 30% find a well-matched donor.11 In the past 10 years, a growing number of reports supported an expanding usage of HLA mismatched unrelated donors (MMUD), umbilical cord blood (UCB) and partially HLA matched family donors (haploidentical) as valuable alternatives to fill the gap in donor availability.12, 13, 14

However, data on the relative efficacy of alternative donor HCT for adults with high-risk lymphoma are limited and there are no data on comparison of 7/8 HLA MUDs vs 8/8 HLA MUDs and UCB.7, 9, 15, 16, 17, 18, 19, 20 Thus, we performed a retrospective registry-based analysis studying the outcomes of patients with advanced lymphoma who received an allograft from MUD, MMUD or UCB using data from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Patients and methods

Data source

The CIBMTR, a voluntary working group of >450 transplantation centers worldwide, collects data on consecutive allogeneic HCTs at a statistical center housed at both the Medical College of Wisconsin (Milwaukee, WI, USA) and the National Marrow Donor Program (Minneapolis, MN, USA). Patients are observed longitudinally with yearly follow-up. Computerized checks for errors and onsite audits of participating centers ensure data quality. The present study was conducted with a waiver of informed consent and in compliance with Health Insurance Portability and Accountability Act regulations as determined by the Institutional Board and the Privacy Officer of the Medical College of Wisconsin.

Study population

In this comparative study, we included patients 18 years old with non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma who underwent transplant with an 8/8 allele HLA MUD, 1 Ag or allele MMUD and UCB transplanted in the United States between 2000 and 2010. We verified HLA matching for all cases included in this study. Forty-nine percent were retrospectively typed using stored samples for NMDP/CIBMTR research repository;21 43% were NMDP-facilitated transplants and 9% had HLA typing reported by the transplant center. A contemporary haploidentical-related donor cohort had only 39 patients with a short median follow-up of 14 months and was excluded from this analysis. Patients with planned second transplants, ex-vivo manipulated grafts and those with rare aggressive histologies (that is, aggressive NK cell neoplasms, lymphoblastic lymphoma, Burkitt lymphoma and primary central nervous system lymphoma) were excluded. Preparative regimens were classified either as RIC or myeloablative conditioning (MAC) according to the published consensus definitions.22 RIC regimens included melphalan 140 mg/m2, BU 9 mg/kg orally, TBI <5 Gy, fludarabine-TBI combinations or fludarabine-based conditioning. The MAC preparative regimens included mostly TBI- or BU-based combinations.

Definitions, study end points and statistical analysis

The primary objective was to compare OS after HCT between patients undergoing MUD, MMUD and UCB transplants, while adjusting for patient, disease and transplant-related characteristics. Patient, disease and transplant-related factors were compared between groups using the Chi-square test for categorical variables and the Wilcoxon sample test for continuous variables. Surviving patients were censored at the time of last contact. Secondary end points were PFS, relapse, non-relapse mortality (NRM), grade II–IV acute GVHD and chronic GVHD.23, 24 Adjusted survival probabilities of OS and PFS for the three donor groups were estimated based on Cox proportional hazards models.25 Adjusted cumulative incidence rates were calculated for relapse and NRM to accommodate competing risks.26 Acute and chronic GVHD were defined calculated using cumulative incidence function. Multivariate analysis used Cox’s proportional hazard model.27 All clinical variables were tested for proportional hazards assumptions. Factors violating the proportional hazards assumption were adjusted through stratification. We stratified models for OS, PFS, relapse and NRM based on same set of variables (that is, Karnofsky performance score, lymphoma subset, GVHD prophylaxis and disease status). Stepwise model building procedures used a significance threshold of 0.05 for both entry and retention in the models. The main effect variable of donor type (MUD vs MMUD vs UCB) was forced into the models, and a random effect in the model was used to adjust for the center effect. Interactions between the main effect variable and adjusted covariates were tested at a significance level of 0.01. No significant interactions between the donor type variable and adjusted covariates were detected in any of the models. The results are reported at 3 years post transplant.

Results

Patients, disease and transplant characteristics

We studied 1593 patients with NHL and Hodgkin lymphoma treated at 119 centers. Baseline patient, disease and transplant-related characteristics of UCB (n=142), MMUD (1 allele mismatched n=106; 1 Ag mismatched n=169) and MUD (n=1176) recipients are summarized in Table 1. The median age at transplant was 50 (MUD), 45 (MMUD) and 45 (UCB) years. The MUD cohort included more males, more often had mantle cell NHL and less often had HL. Both MUD and MMUD graft types were mostly peripheral blood male–male donor–recipient sex matched (Table 1). About half of recipients in three donor groups were CMV sero-positive. More UCB recipients were non-Caucasian, had higher Karnofsky performance score, more had chemotherapy-sensitive disease and received prior radiation therapy. Sixty-three percent (n=90) of UCB transplants used two UCB unit grafts. The median TNC dose of combined UCB units was 2.8 × 10e7/kg (range, 0.2–9.5) and were mostly HLA locus 5/6 (28%) or 4/6 (55%) matched. Notably, 45% (n=23) of single and 29% (n=26) of double UCB grafts were small providing <2.5 × 10e7 TNC/kg. UCB HCT had the shortest interval from diagnosis to transplant (median 27 months). In each donor group, about 70% received a RIC transplant. The proportion of patients with prior autograft, chemosensitive disease and type of conditioning in different lymphoma subsets were similar in each donor group. Recipients of MUD and MMUD were more likely to receive a tacrolimus-based GVHD prophylaxis regimen and antithymocyte globulin (ATG) or alemtuzumab than UCB recipients. GVHD prophylaxis for UCB transplants more often included CYA plus mycophenolate mofetil. Donor/recipient sex, donor/recipient CMV status and graft type (marrow vs blood) were similar in adult unrelated donors. The median follow-up of survivors in the MUD, MMUD and UCB groups was 57 months (range, 6–129), 65 months (range, 12–125) and 25 months (range, 6–73; P<0.001), respectively.

Table 1 Characteristics of patients who underwent allogeneic hematopoietic cell transplantation for NHL and HL reported to the CIBMTR between 2000 and 2010 by graft type

Neutrophil and platelet engraftment

Neutrophil engraftment at day 28 and day 100 was significantly more frequent in MUD and MMUD recipients as compared with UCB (Table 2). Platelet recovery to 20 × 109/L at day 100 was also significantly better in MUD and MMUD than UCB (Table 2). In MUD, MMUD and UCB groups, median time to neutrophil recovery was 13 (0–106), 16 (1–75) and 21 (0–66) days and median time to platelet recovery was 16 (0–394), 25 (1–49) and 45 (0–334) days, respectively.

Table 2 Outcomes after hematopoietic cell transplantation by donor type

Non-relapse mortality

The adjusted cumulative incidences of NRM at 3 years were 35% (MUD 95% confidence interval (CI) 32–38%), 44% (MMUD 95%CI 39–50%) and 37% (UCB 95%CI 28–46%) (Table 3; Figure 1a). In multivariate analysis, the NRM risk was significantly higher in MMUD compared with MUD recipients, while there was no difference between MMUD vs UCB and MUD vs UCB groups (Figure 1a; Table 4). UCB graft cell dose did not significantly impact the NRM risk (UCB NC <2.5x10e7 vs 2.5 × 10e7 hazard ratio 1.37; P=0.13). The most common non-relapse cause of death among MUD and MMUD patients was infections (n=16 and 16), followed by GVHD (n=14 and 13). Organ failure (n=15 and 13) and non-engraftment were infrequent (n=3 and 1). In the UCB group, the most frequent causes of NRM were infection (n=15), organ failure (n=11), non-engraftment (n=11), GVHD (n=4) and lymphoproliferative disorder (n=4). Graft failure was managed by second (n=10) or third transplant (n=1); only two patients with graft failure survived, both UCB recipients following second HCT.

Table 3 3-year adjusted probabilities
Figure 1
figure1

(a) NRM: Adjusted 3-year NRM by donor groups. (b) Relapse: Adjusted 3-year relapse rate by donor groups. (c) PFS: Adjusted 3-year PFS by donor groups. (d) OS: Adjusted 3-year OS by donor groups.

Table 4 Multivariate analysis of factors associated with risk of NRM, acute GVHD, chronic GVHD, relapse, PFS and OS

GVHD

Grade II–IV acute GVHD was more frequent in MMUD and MUD as compared with UCB recipients (Table 2). Grade III and IV occurred at similar rate (Table 2). The cumulative incidence of chronic GVHD at 3 years was twofold higher in MMUD and MUD cohorts as compared with UCB (Table 2). In multivariate analysis, the risk of acute GVHD was significantly lower in UCB recipients as compared with MUD and MMUD (Table 4). The risk of chronic GvHD was highly significantly decreased in UCB recipients (Table 4).

Relapse/progression

The 3-year risk of relapse/progression was lower in MMUD transplants but was not different in recipients of MUD and UCB grafts (Tables 3 and 4; Figure 1b). Relapse was not influenced by single or double unit UCB grafts or by total UCB TNC dose infused (data not shown). Relapse was the most frequent cause of death in all three donor groups affecting 285 (39%) in MUD, 64 (32%) in MMUD and 22 (29%) in UCB recipients. Twenty-five patients received DLI for relapse, 23 (MUD) and 2 (MMUD). Only eight MUD recipients survive between 16 and 96 months after DLI.

Survival

Adjusted PFS at 3 years was 33% (MUD 95%CI 30–36%), 30% (MMUD 95%CI 25–35%) and 31% (UCB 95%CI 23–39%) (Table 3, Figure 1c) with the risk of treatment failure not significantly associated with graft source (Table 4). Due to higher NRM and lower relapse risks in the MMUD group, the OS in three groups were similar (Table 4). Adjusted OS at 3 years in the three groups was 43% (95%CI 40–46%) in MUD, 37% (95%CI 32–43%) in MMUD and 41% (95%CI 33–50%) in UCB recipients (Figure 1d). In UCB group, overall mortality was not influenced by TNC dose (low vs high hazard ratio 1.24; P=0.42).

Discussion

In this large registry-based study, we analyzed the differences in transplant risks and clinical benefits in adults with Hodgkin lymphoma and NHL receiving transplants from alternative donors. Comparative data are increasingly needed by the patients and their physicians to guide the decision making regarding hematopoietic transplant donor options. The main findings of our study were as follows: (1) survival was similar for three donor types; (2) the risk of acute and, in particular, chronic GVHD was significantly lower in recipients of UCB; (3) there was quicker hematopoietic recovery in recipients of MUD and MMUD as compared with UCB, yet without significant influence on NRM and 4) MMUD recipients had lower risk of relapse as compared with MUD; however, this benefit was offset by increased NRM.

Overall, between 37 and 43% patients with relapsed or refractory lymphoma using alternative donors survived beyond 3 years and the graft source did not significantly influence PFS or OS. These promising results compare favorably even with HLA matched sibling donor transplants, yet the heterogeneity in subjects and lymphoma histology likely contribute to modest differences.1, 4, 28, 29 It is important to recognize that our cohort of lymphoma patients undergoing allograft is heterogeneous and skewed with high proportion of patients who were chemorefractory (27%), had failed autologous HCT (50%) and radiation therapy (70%). Thus, some patients were heavily pre-treated and these unrelated donor HCTs were delayed and used after other modalities failed to control their disease. Furthermore, the UCB HCTs were more recent and follow-up was shorter. Because some critical prognostic variables such as disease status and lymphoma subtype violated the proportional hazard assumption in three donor groups, we controlled for them by stratified analysis to answer the donor source risk association; thus the analysis was not designed to address influence of disease and patient-related factors on outcomes. Some potentially important variables such as comorbidity index were not available in this cohort. Despite several adverse features and heterogeneity of this cohort, these encouraging results clearly suggest that allotransplantation offers potentially curative therapy which can be extended to almost all patients with high-risk lymphoma, even those without an available HLA matched sibling. Future studies investigating different lymphoma subsets are needed to refine our conclusions.

Importantly, our results highlight the acceptable transplant outcomes of MMUD and UCB HCT.9, 15, 28 In MMUD, the HLA mismatch seems to have driven greater alloreactivity as evidenced by higher incidences of acute GVHD and chronic GVHD and a lower risk of relapse. The benefit of lower relapse was offset by higher risk of NRM resulting to similar survival as compared with UCB and MUD. Future efforts to improve MMUD HCT need to focus on better patient selection and innovative strategies to reduce GVHD. Recent much larger registry studies demonstrated impairment of survival after single allele mismatch and adverse effect of HLA-C Ag mismatching, therefore we acknowledge that our results may be impacted by smaller cohort size.30, 31, 32 Validation in a larger study and cautious interpretation are therefore warranted.

We observed a lower risk of acute and chronic GVHD in UCB recipients as compared with MUD and MMUD, although in vivo T-cell depletion that can reduce the risk for acute GVHD was used frequently in MUD and MMUD. Lower risk of GVHD and greater HLA mismatch in UCB HCT did not compromise the alloreactivity against lymphomas. As GVHD contributes to morbidity and mortality and can compromise the quality of life of long-term survivors, a lower risk of both acute and chronic GVHD after UCB HCT may be an additional favorable feature influencing donor choice. UCB transplant was used more frequently for ethnic minorities since suitable UCB units mismatched in one or two HLA loci can provide a graft for 90–95% of patients with minority backgrounds, who less often identify a MUD.33

These data demonstrate that successful allogeneic donor HCT can be available for all adult lymphoma patients including those of minority ethnic groups with rare HLA haplotypes. Our study supports prospective testing of UCB and MMUD in lymphoma such as randomized CTN trial comparing UCB with haploidentical donor. Our results mandate that patients with lymphoma in whom allograft is indicated have wider access to alternative donor options.

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Acknowledgements

The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics Inc.; *Amgen Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech Inc.; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research Inc. Roswell Park Cancer Institute; HistoGenetics Inc.; Incyte Corporation; Jeff Gordon Children’s Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick’s Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.

*Corporate members.

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Bachanova, V., Burns, L., Wang, T. et al. Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor. Bone Marrow Transplant 50, 197–203 (2015) doi:10.1038/bmt.2014.259

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