Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: A Retrospective Multicenter Analysis on 285 Procedures Performed between 2000 and 2020

Background. Refractory/relapsed B-cell non-Hodgkin Lymphoma (R/R B-NHL) carries a dismal prognosis. In about 40% of patients CAR-T cell therapy is an effective and potentially curative salvage treatment that has curtailed the indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, outside clinical trials, real-life data about the long-term efficacy of allo-HSCT are still lacking; moreover, additional information is required to look at the possible combination of allo-HSCT and CAR-T cells. Thus, a multicenter study among six Italian Hematology Centers was performed to assess the outcome of patients with R/R B-NHL undergoing allo-HSCT.

Patients and Methods. Data from 285 allo-HSCT procedures performed during 2000 and 2020 in 281 R/R B-NHL patients aged ≥ 18 yrs. have been collected. All patients signed the informed consent for sharing their data with the GITMO and EBMT Registry for scientific purposes. The retrospective analysis was approved by the Institutional Review Board (IRB) of the coordinating Center (IEO, Milan), additional approval was obtained according to the specific policies of each participating Institution. Primary endpoint of the study was progression-free survival (PFS) from allo-HSCT until lymphoma progression or death from any cause; secondary endpoints included: i. overall survival (OS), defined as the time from allo-HSCT to death from any cause; ii. cumulative incidence (CI) of disease-related death; iii. CI of non-relapse mortality (NRM); iv. CI of acute and chronic GVHD. The patient median age was 50 years (19-70), 94 (33%) were female, main histological subsets included 123 (43.3%) indolent lymphoma (primarily follicular lymphoma, 108 cases), 124 (43.7%) aggressive B-cell lymphoma (primarily diffuse large B-cell lymphoma, 91 cases) and 37 (13%) mantle-cell lymphoma. At the time of allo-HSCT, 135 (47.7%) patients were in Complete Remission (CR), 63 (22.3%) in partial response, 30 (10.6%) with stable disease and 55 (19.4%) with progressing disease. Myeloablative regimen (MAC) was employed in 86 (30.2%) procedures; 70 (24.6%) patients were transplanted from a haploidentical donor. The median follow-up (FU) for the whole series is 16 (PFS) and 24 (OS) months, while the median FU for the surviving patients is 8.7 years (0.3-22), with less than 10% of patients lost to FU at 5 years.

Results. The 3 and 5-yr PFS was 43.9 (95% CI 38.1-49.6) and 41.2% (35.4-46.9); the 3 and 5-yr OS was 50.4% (44.5-56.1) and 48.8% (42.9-54.5). Positive predictors of PFS were: i. histology, i.e. indolent lymphoma (3-yr PFS: 55.6%, 46.3-63.9) compared to aggressive (37.9 %, 29.4-46.3) and to MCL (27.0%, 14.1-41.8); ii. CR at allo-HSCT (3-yr PFS 52.7%, 43.9-60.8) vs non-CR (3-yr PFS ranging between 30.9 and 43.3%). These were the only pre-transplant variables associated with a significant benefit on PFS in both univariate and multivariate analysis. Similar features were observed for OS. Considering patients in CR, there were no significant differences among histological subtypes; when patients not in CR were considered, indolent lymphoma did significantly better (3-yr PFS 54%) compared to aggressive (26%), and MCL that showed the poorest outcome (0% PFS at 2 yrs). No significant differences were seen with regard to type of donor. Overall, 58 (20.4%) patients died for lymphoma progression, with a CI of disease related death of 15.9% (11.9-20.4) at 12 mos and 19.2% (14.9-24.1) at 5 years; 74 patients died for early toxic events occurring within the first year since allo-HSCT, with a 12-mo CI of 26.1% (21.1-31.3), and additional 25 cases of late (> 1 year) non-disease related deaths, for a CI at 5 yrs of 31.9% (26.5-37.4). Overall, the CI for gr. 3-4 a-GVHD was 9.1% (6.1-12.8) at 1 yr and the CI for c-GVHD requiring therapy was 13.5% (9.8-17.8) at 3 yrs. At present, 98 patients (35%) are very long survivors at a minimum of 5 years up to 22 years since transplant, 80 of them in continuous CR of their previous lymphoma.

Conclusions. i. allo-HSCT is an effective option for high-risk, R/R B-NHL, with PFS expectancy around 40% at 5 years and a good proportion of long-term survivors; ii. most favorable results are achieved in patients undergoing allo-HSCT in CR; iii. indolent lymphoma mostly benefits from allo-HSCT while MCL have the worst outcome. Allo-HSCT remains a potentially curative option for patients who fail or cannot have access to CAR-T cells or bispecific monoclonal antibodies.