Allogeneic Stem Cell Transplantation As Consolidation Therapy in Patients with Relapsed-Refractory B-Cell Lymphoma Exposed to Bispecific Antibodies: A Study on Behalf of Grupo Español De Transplante y Terapia Celular (GETH-TC)

Background: B-cell non-Hodgkin lymphomas (B-NHL) encompass a heterogeneous group of malignancies with diverse prognosis. Some patients (pts) achieve long-term remission with standard therapies, but many experience relapse or refractory (R/R) disease. Recently, bispecific antibodies (BsAb) have emerged as a promising therapeutic approach. Allogeneic stem cell transplantation (alloHCT) may be a consolidative strategy for high-risk pts responding to BsAb, but T-cell activation prior alloHCT could affect both efficacy and safety. This study explored the impact of BsAb on alloHCT outcomes.

Methods: We conducted a 11-center retrospective study including adult pts who received alloHCT as consolidative therapy following BsAb treatment for R/R B-NHL between February 2017 and July 2023. The primary endpoint was non-relapse mortality (NRM). Secondary endpoints included overall survival (OS), progression-free survival (PFS), relapse incidence/progression of disease (Rl/POD), acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), and hematologic recovery. Propensity score matching was performed with a contemporary cohort of B-NHL pts not previously exposed to BsAb (n=101) before alloHCT from the Grupo Español de Transplante y Terapia Celular (GETH-TC).

Results: A total number of 48 pts received BsAb prior to alloHCT. Median age was 58 years (range 22-73) and 31 (64.6%) pts were males. Thirty-six (75%) pts had stage III-IV at diagnosis, 12 (25%) had received an autologous transplant (ASCT) and 21 (43.8%), anti-CD19 CAR T-cell prior to BsAb. Median number of prior lines were 4 (range 3-11). Median time from diagnosis to alloHCT was 41 months (range 9 - 208). Glofitamab (n=22, [45.8%]) was the most used BsAb, followed by ondronextamab (n=13 [27.1%]), epcoritamab (n=11 [22.9%]), mosunetuzumab (n=1 [2.1%]) and antiCD3-CD22 (n=1 [2.1%]). Thirty-five (72.9%) BsAb were administered in monotherapy and 13 (27.1%) in combinations. The median number of BsAb’ administered doses was 14 (range 4-24) and the median time between BsAb’ last dose and alloHCT was 43 days (range 13 – 421). Disease status at alloHCT was complete response in 38 (79.2%), partial response in 7 (14.6%) and progressive disease in 3 (6.3%) pts.

Twenty-two (45.8%) pts received grafts from matched unrelated, 16 (33.3%) from haploidentical and 10 (20.8%) from matched related donors. Stem cell source was peripheral blood in all but one pts (97.7%). Reduced intensity conditioning (RIC) regimens were used in 44 (91.7%) pts and the most common GVHD prophylaxis was post-transplant cyclophosphamide-based in 40 (83.3%).

Adjusted variables included age at alloHCT, sex, number of lines (≤4 vs >4), disease status at alloHCT (chemosensitive vs chemoresistant), conditioning intensity (myeloablative vs RIC), and donor type. In the final 1:1 matched population (n=96; 48 pts treated with BsAb and 48 pts not exposed to BsAb prior alloHCT) median follow-up (FU) among survivors was 31 months (range 5-60). No differences in terms of NRM (18m NRM, 35% vs 31%, p=0.767), OS (18m OS 63% vs 48%, p=0.068), PFS (18m 56% vs 46%, p=0.147), and RI/POD (9% vs 25%, p=0.056) were observed. No differences in terms of neutrophil (91% vs 83%, p=0.727), and platelet engraftment (65% vs 63%, p=0.154) were observed among the BsAb vs no BsAb cohorts. A higher incidence of aGVHD at day +100 was observed in the BsAb cohort (47% vs 31%, p=0.046). No differences in the incidence of all grade cGVHD at 18 months were found between the two groups (24% vs 19%, p=0.123). Of the 18 pts who died during FU in the BsAb cohort, causes of death were 2 relapses and 16 transplant toxicities (9=infections, 4=GVHD, 1=cerebrovascular disease, 1=melanoma, 1=unknown).

In the multivariate analysis, age >55 was associated with worse OS (HR 2.08 [95% CI: 1.07-4.06], p=0.03) and higher NRM (HR 2.7 [95% CI: 1.19-6.13], p=0.017). Also, having received a prior ASCT was associated to higher NRM (HR 2.69 [95% CI: 1.32-5.46], p=0.006) but lower RI/POD (HR 0.13 [95% CI: 0.04 - 0.40], p<0.001]). The use of BsAb prior alloHCT was associated to lower RI/POD (HR 0.14 [95% CI: 0.04-0.05], p=0.001).

Conclusions: AlloHCT as consolidation therapy in pts exposed to BsAb is feasible and does not impact NRM. A lower incidence of RI/POD and a higher incidence of aGVHD were observed in those previously exposed to BsAb. These results should be confirmed in a larger cohort of pts with prolonged FU.