[Reduced intensity or nonmyeloablative conditioning] followed by haplo-hematopoietic cell transplantation with [post-transplantation cyclophosphamide] should be considered an acceptable option for patients with lymphoma without matched sibling donors.— Nilanjan Ghosh, MD, PhD, and colleagues
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In an analysis of the observational database of the Center for International Blood and Marrow Transplant Research reported in the Journal of Clinical Oncology, Nilanjan Ghosh, MD, PhD, of Levine Cancer Institute, Carolinas Healthcare System, Charlotte, North Carolina, and colleagues found that lymphoma patients undergoing reduced-intensity conditioning had similar outcomes with related-donor haploidentical hematopoietic cell transplantation (HCT) and post-transplantation cyclophosphamide compared with human leukocyte antigen (HLA)-matched sibling-donor HCT, with the former approach being associated with a reduced risk for chronic graft-vs-host disease.1
The study involved 987 adult patients undergoing either haplo-HCT (n = 180) or matched sibling-donor–HCT (n = 807) after reduced-intensity conditioning regimens. The haplo-HCT group received conditioning with fludarabine, cyclophosphamide, and 200-cGy total-body irradiation, and the matched sibling-donor–HCT group received conditioning with fludarabine plus either an alkylator and/or 200-cGy total-body irradiation. The haplo-HCT group received graft-vs-host disease prophylaxis with post-transplantation cyclophosphamide with or without a calcineurin inhibitor and mycophenolate, and the matched sibling-donor–HCT group received calcineurin inhibitor–based prophylaxis.
There were no significant differences between the haplo-HCT and matched sibling-donor–HCT groups with regard to sex (64% and 61% male), number of prior therapy lines (median of three in both), bone marrow (12% and 6%) or extranodal involvement (35% and 25%) at HCT, presence of bulky disease (10% and 8%), HCT comorbidity index (eg, 0 for 43% and 41%, 1–2 for 27% and 24%), chemotherapy sensitivity at HCT (6% and 12% refractory), and interval between diagnosis and HCT (median of 31 and 34 months).
The haplo-HCT group had a significantly (P < .05) higher proportion of patients with advanced age (35% vs 24% ≥ 60 years), African American ethnicity (15% vs 4%), and Karnofsky performance score (KPS) ≥ 90 (79% vs 68%). The matched sibling-donor–HCT group had significantly more patients with stage III or IV disease (67% vs 47) but fewer with disease risk index of intermediate or high (63% vs 75%) at the time of HCT. Histology significantly differed between the groups; the most common histologies in the haplo-HCT and matched sibling-donor–HCT groups were diffuse large B-cell lymphoma (36% and 23%), follicular lymphoma (16% and 25%), and Hodgkin lymphoma (24% and 22%).
Median follow-up for survivors was 3 years. The 28-day neutrophil recovery was similar in the haplo-HCT and matched sibling-donor–HCT groups (95% vs 97%, P = .31), whereas 28-day platelet recovery was delayed in the haplo-HCT group (63% vs 91%, P = .001). The cumulative incidence of grade 2 to 4 acute graft-vs-host disease at day 100 was 27% vs 25% (P = .84), and the rate of grade III or IV acute graft-vs-host disease at day 100 was 8% in both groups; on multivariate analysis, relative risks (RRs) were 1.40 (P = .06) for grade 2 to 4 acute graft-vs-host disease and 0.50 (P = .45) for grade 3 or 4 acute graft-vs-host disease. The cumulative incidence of chronic graft-vs-host disease at 1 year was 12% after haplo-HCT vs 45% after matched sibling-donor HCT (P < .001), with the benefit confirmed on multivariate analysis (RR = 0.21, P < .001); haplo-HCT was also associated with a reduced risk of moderate/severe chronic graft-vs-host disease (RR = 0.06, P = .005) on multivariate analysis.
For haplo-HCT vs matched sibling-donor–HCT, the 1-year rate for nonrelapse mortality was 10% vs 9% (P = .57). Three-year rates were 15% vs 13% for nonrelapse mortality (P = .41), 37% vs 40% for relapse/disease progression (P = .51), 48% vs 48% for progression-free survival (P = .96), and 61% vs 62% for overall survival (P = .82). On multivariate analysis, the relative risks for the haplo-HCT vs matched sibling-donor–HCT groups were 1.52 (P = .06) for nonrelapse mortality, 0.80 (P = .10) for relapse/disease progression, 0.98 (P = .83) for progression-free survival, and 1.14 (P = .34) for overall survival.
Independent of transplant type, significant predictors of outcomes included KPS < 90 and HCT comorbidity index ≥ 3 for nonrelapse mortality; histology other than follicular lymphoma, not being in complete remission at HCT, presence of bulky or extranodal disease at HCT, HCT performed before 2010, and intermediate or high disease-risk index for disease progression/relapse; and, in addition to the other independent factors for progression-relapse, histology other than follicular lymphoma or T-cell non-Hodgkin lymphoma for mortality.
The investigators concluded:
[C]ompared with [reduced intensity conditioning] matched sibling donor-hematopoietic cell transplantation, haplo-hematopoietic cell transplantation with [post-transplantation cyclophosphamide] significantly reduces the risk of chronic graft-vs-host disease without compromising relapse and survival. [Reduced intensity or nonmyeloablative conditioning] followed by haplo-hematopoietic cell transplantation with [post-transplantation cyclophosphamide] should be considered an acceptable option for patients with lymphoma without matched sibling donors. As such, this strategy can broaden the timely applicability of [allogeneic] hematopoietic cell transplantation without compromising efficacy and limit the racial barriers for receiving this potentially curative treatment option. Additional analyses in collaboration with European Group for Blood and Marrow Transplantation are being planned to validate these results in a larger international patient cohort. The results of our study warrant confirmation in prospective, randomized, controlled trials.
The Center for International Blood and Marrow Transplant Research is supported by grants or contracts from the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration; Office of Naval Research; and numerous corporate and other sponsors. ■
Disclosure: For full disclosures of the study authors, visit www.jco.ascopubs.org.
1. Ghosh N, Karmali R, Rocha V, et al: Reduced-intensity transplantation for lymphomas using haploidentical related donors versus HLA-matched sibling donors: A Center for International Blood and Marrow Transplant Research analysis. J Clin Oncol. June 6, 2016 (early release online).
For a commentary on this study by Matt Kalaycio, MD, FACP, see here.
If chronic graft-vs-host disease rates are reduced without an increase in relapse rates, post-transplant cyclophosphamide may not only extend a transplant option to virtually everybody who stands to benefit from it, but it may also replace standard graft-vs-host disease...!-->!-->