Treosulfan/Fludarabine Versus Thiotepa/Busulfan/Fludarabine for Allogeneic Hematopoietic Cell Transplantation in Patients with Lymphomas in the Ptcy Era: A Study on Behalf of the Grupo Español De Trasplante y Terapia Celular (GETH-TC)

Background: The optimal conditioning regimen in allogeneic hematopoietic cell transplant (alloHCT) for lymphoid malignancies remains unclear. Standard reduced-intensity conditioning such as Flu/Mel, Flu/Cy/TBI and Bu/Flu showed acceptable results with elevated relapse rate. Reduced-toxicity regimens are frequently used to reduce disease relapse while mantaining an acceptable toxicity profile. Treosulfan/fludarabine (TreoFlu) has shown to improve alloHCT outcomes in myeloid diseases due to a reduction in non-relapse mortality (NRM) when compared to busulphan/fludarabine. However, limited information is available in lymphoid malignancies. Our aim is to compare the efficacy and toxicity prophyle of two reduced-toxicity conditionings, TreoFlu versus thiotepa/busulfan/fludarabine (TBF), in patients with lymphomas. Methods: This retrospective cohort study used data from 179 patients diagnosed with lymphoid malignancies who received a first alloHCT in 10 institutions from Spain and Italy, between March 2014 and November 2023. Inclusion criteria were: conditioning with TreoFlu or TBF regimen, transplant conditioning intensity score Low/Intermediate, use of post-transplant cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis, and peripheral-blood grafts. Primary endpoint was NRM. Secondary endpoints were overall survival (OS), progression-free survival (PFS), GVHD-free/Relapse-free Survival (GFRS), relapse incidence/progression of disease (RI/POD), cumulative incidence of acute II-IV (aGVHD) and chronic GVHD (cGVHD), and hematological recovery. Probabilities of OS, PFS and GFRS were calculated using the Kaplan-Meier estimator method, and NRM, RI, GVHD and hematological recovery as cumulative incidences. For comparisons, the log-rank test was used. Results: Sixty-five (36%) patients received alloHCT with TreoFlu conditioning and 114 (64%) with TBF. Significative differences (p<0.05) in baseline characteristics were detected in TreoFlu versus TBF regarding type of disease, Ann Arbor Stage, ECOG, type of donor, donor age, and Sorror comorbidity index. On univariate analysis, only baseline ECOG and age had a significant impact on survival and were selected for adjusting the treatment effect (TreoFlu versus TBF) on multivariate models. Median follow-up among survivors was 2.5 years (range: 0.5-3.87 years). On univariate analysis, TreoFlu was associated with a significant improvement in 2-year NRM (14% versus 33%, p=0.02), 2-year PFS (73% versus 55%, p=0.03) and 2-year GFRS probability (40% versus 14%, p=0.02). On multivariate model, we confirmed a protective role of TreoFlu on NRM (HR 0.46, 95% CI: 0.24 - 0.88, p=0.023) and GFRS (HR 0.53, 95% CI 0.33-0.81, p=0.02) but not for PFS. No differences were reported between TreoFlu and TBF regarding 2-year OS (75% versus 53%, p=0.06), 2-year RI/POD (19% versus 20%, p=0.8), 2-year aGVHD (14% versus 10% p=0.85), 2-year cGVHD (9% versus 10%, p=0.14). Day +30 neutrophil engraftment was 92% versus 94% (p=0.06) and day +30 platelet engraftment was 56% versus 52% (p=0.3). Graft Failure was not observed in TreoFlu while it was reported in 3/114 (3%) TBF patients. Conclusions: In our series, TreoFlu performed better than TBF in terms of NRM and GFRS in lymphoma patients receiving reduced-toxicity alloHCT. TreoFlu regimen should be considered as a potential reduced-toxicity conditioning for lymphoma patients receiving alloHCT with PTCy GVHD prophylaxis, especially for older or frail patients.