Post-transplant bendamustine (PT-BEN) with or without cyclophosphamide for gvhd prophylaxis after haplo-identical or matched unrelated donor transplants: A phase I/II trial Free

Background: Graft-versus-host disease (GVHD) is a major complication following allogeneic hematopoietic stem cell transplantation (alloSCT), especially when using haploidentical (haplo) or matched unrelated donors (MUDs). PT-Cy is the current standard for GVHD prophylaxis in these settings. However, in preclinical studies, bendamustine (BEN) has shown promise as an alternative or adjunct. This Phase I/II clinical trial evaluates the safety, and efficacy of post-transplant bendamustine (PT-BEN) as GVHD prophylaxis in patients undergoing alloSCT from either haplo or MUDs.

Patients and Methods: The eligibility criteria were age 18-70 years with hematologic malignancies requiring alloSCT. The other inclusion criteria were an ECOG PS of 0-2 and adequate organ function. The conditioning regimen consisted of reduced intensity fludarabine (40 mg/m² iv daily on days -5 to -2), melphalan (50 mg/m² iv daily on days -5, -4), total body irradiation (200 cGy) on day -1 prior to alloSCT Day 0. PT-BEN was given on days 3 and 4 after transplant. Day 4 dose was fixed at 100mg/m²iv. Four doses' levels of PT-BEN were explored for Day 3: DL1 consisted of CY 50 mg/kg iv and no BEN; DL2:CY 30 mg/kg+BEN 30 mg/m²; DL3: CY 20 mg/kg+ BEN 60 mg/m²; DL4: BEN 100 mg/m² and no CY. Additional standard GVHD prophylaxis included tacrolimus and mycophenolate mofetil daily starting Day 5 (moved to Day 0 after July 2024. Maintenance therapy with standard-of-care azacitidine plus venetoclax or tyrosine kinase inhibitors (TKIs) was permitted post-alloSCT.

Results: Twenty-six patients (median age: 52 years; range, 31–69) were enrolled, with 21 (81%) male. HCT-CI ≥3 was present in 40% of patients. Diagnoses included hi-risk AML by ELN criteria (n=10; 38%), MDS (n=5; 19%), ALL (n=4; 15%—including 1 Ph+, 1 Ph−, and 2 ETP-ALL), lymphoma/CLL with Richter's transformation (n=4; 15%), and CML (n=3; 12%). In the phase 1 dose-escalation portion, BEN was administered at four dose levels: DL1 (n=4), DL2 (n=3), DL3 (n=5), and DL4 (n=3). Due to increased toxicity at higher doses—including GVHD, infections, and cytokine release syndrome—DL2 was selected for expansion in phase 2 (n=12). Donor sources included haploidentical (n=12; 46%), matched unrelated (n=9; 35%), matched sibling (n=2; 8%), and 9/10 mismatched unrelated donors (n=3; 11%). Graft sources were evenly split between bone marrow (n=13) and peripheral blood (n=13). The median donor age was 34.5 years (range, 15–74), and 38% of transplants were female-to-male. All patients received unmanipulated grafts and achieved engraftment. Neutrophil recovery (>0.5 × 10⁹/L) occurred at a median of 13 days (range, 10–17), and platelet recovery (>20 × 10⁹/L) at 15 days (range, 7–26). Treatment-related mortality (TRM) at day 100 and at 6 months was 8% in both instances. Four patients died: two due to acute GVHD, and two from infection. Seven patients received maintenance therapy. With a median follow-up of 12 months (range, <1–55 months), the 1-year overall survival (OS) and progression-free survival (PFS) rates were 80% and 75%, respectively. These survival rates remained unchanged at the time of patients' last follow-up. Notably, patients with acute leukemia (AML or ALL) demonstrated 100% 1-year OS.

The incidence of grade II–IV acute GVHD by dose level (DL) was as follows: DL1 – 25%, DL2 – 21%, DL3 – 40%, and DL4 – 100%. By univariate analysis, patients treated at DL3 and DL4 or those receiving peripheral blood stem cell grafts had a significantly higher risk of developing grade II–IV acute GVHD compared to those treated at DL1 and DL2 (67% vs 0%, P = 0.029; and 80% vs 14%, P = 0.027, respectively). The 1-year incidence of extensive chronic GVHD was 19%.

Two patients experienced cytokine release syndrome (CRS) of grade 3 and 4 severity. They were both treated at DL4. Cytomegalovirus viremia of grade 2 was observed in four patients, with no cases exceeding grade 2. Similarly, four patients developed acute cystitis of grade 2, including one case associated with BK virus; no higher-grade cystitis was reported.

Conclusions: PT-BEN is a promising GVHD prophylaxis strategy in haplo and MUD alloSCT, particularly at DL2 (30 mg/kg+BEN 30 mg/m² on Day 3 and BEN 100 mg/m2 on day 4 post-transplant). Lower GVHD rates were observed with marrow grafts. The safety profile, engraftment, and encouraging survival—especially the 100% 1-year OS in acute leukemia—support further evaluation in ongoing phase II studies.