Allogeneic Hematopoietic Stem Cell Transplant for B-Cell Lymphomas in the Era of Novel Cellular Therapies: Experience from a Tertiary Canadian Center
Authors: Castonguay Mathias , Claveau Jean-Sébastien , Roy Jean , Cohen Sandra , Lachance Sylvie , Ahmad Imran , Bambace Nadia M. , Bernard Lea , Delisle Jean-Sebastien , Kiss Thomas L. , Fleury Isabelle , Mollica Luigina , Roy Denis-Claude , Sauvageau Guy , Veilleux Olivier 
Published: December 2024

Background
The role of allogeneic hematopoietic stem cell transplant (alloHSCT) for treatment of relapsed/refractory (r/r) B-cell lymphomas (BCLs) is unclear in the era of novel cellular immunotherapies. AlloHSCT can be curative for BCLs, but responses are heterogeneous across histological subtypes. Additionally, non-relapse mortality (NRM) mainly due to graft vs host disease (GVHD) limits its broad applicability. In recent years, new conditioning regimens and strategies to prevent and treat GVHD have changed the morbidity and mortality associated with transplant. We aimed to evaluate the outcomes of patients who recently received alloHSCT for BCLs to identify which patients could benefit most from alloHSCT in the era of novel therapies.
Methods
This is a retrospective single-center study in patients with BCLs treated with alloHSCT at Hôpital Maisonneuve-Rosemont between January 1st 2015 and December 31rd 2023. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included NRM, relapse and incidence of both acute and chronic GVHD (aGVHD, cGVHD). BCLs included large B-cell lymphoma (LBCL) and subtypes, mantle cell lymphoma (MCL), and indolent BCL (iBCL) defined as follicular lymphoma (FL) and marginal zone lymphoma (MZL).
Results
55 consecutive patients were treated with alloHSCT: 25 LBCLs (Richter transformation (RT): 10; transformed FL (tFL): 9; diffuse LBCL (DLBCL) NOS: 3; DLBCL ALK positive:1; DLBCL with MYC-BCL2 rearrangments:1; primary mediastinal B-cell lymphoma: 1), 16 iBCLs (FL: 15; MZL: 1), and 14 MCLs. The population was enriched for high-risk features: FLs with POD24: 43.7%; MCLs with blastoid/pleomorphic morphology or expression/mutation of P53/TP53: 42.8%. Patients had received a median of 3 (range: 1-7) prior lines of therapy and 61.8% a prior autoHSCT. No patient had received CAR-T prior to alloHSCT. Graft sources were as follows: HLA-identical (8/8) familial donor 20%, HLA-identical (8/8) unrelated donor 58%, haploidentical donor 7% and cord blood transplant 15%. Disease status remission in 88% of patients (70% complete response, 18% partial response) at time of alloHSCT. More non-myeloablative (NMA) conditioning regimens were used in iBCLs (63%) compared to the LBCLs (28%) or MCLs (29%), due to the use of a planned tandem auto/alloHSCT in iBCLs (44%). Myeloablative conditioning (MAC) was used in 36%, 13%, and 29%, and reduced intensity conditioning (RIC) in 36%, 25%, and 42% of LBCLs, iBCLs, and MCLs, respectively.
The overall 5-year PFS/OS of the entire cohort was 59.6/74.4%. After a median follow-up of 6.1, 5.8, and 2.4 years for LBCLs, iBCLs, and MCLs, their 5-year PFS/OS were 62.1/66.8%, 80.0/93.3% and estimated 39.0/68.8%, respectively. Median PFS/OS were not reached (NR) for LBCLs and iBCLs. Median PFS/OS for MCLs were 1.72 years/NR.
The overall 5-year NRM was 15.8% with a relapse incidence of 24.5%. In the subgroup analysis, the 5-year NRM for LBCLs, iBCLs and MCLs were 29.2%, 6.7% and 0%, respectively. aGVHD occurred in 43.6 % of our cohort, with grade III-IV aGVHD in 18.1% of patients (no grade IV aGVHD occurred). At 3 years, the overall cGVHD incidence (moderate or severe) was 55.8% (34.5%).
Conclusions
Our data supports the role of alloHSCT for BCLs with particularly high and prolonged response rates in iBCLs and LBCLs, where the role of alloHSCT is being challenged with new cellular immunotherapies. A potential explanation for the impressive results seen in LBCL cases is that most originated from indolent diseases (RT/tFL) which are known to be more sensitive to the graft-vs-lymphoma effect. Although NRM remains a major challenge in alloHSCT, our results demonstrate low overall rates of NRM, which are comparable to certain series of patients who receive CAR-T cell therapy for BCLs. It is important to highlight the heterogenous nature of our population and the fact that clonal relation between RT and chronic lymphoid leukemia could not be assessed. In conclusion, alloHSCT is a potentially curative option for patients with chemosensitive BCLs and patients should be promptly referred for evaluation when indicated.