Fractionated Busulfan, Fludarabine and Thiotepa Myeloablative Conditioning to Improve Transplant Outcomes for Myelofibrosis

Introduction

Allogeneic stem cell transplantation (allo-SCT) remains the only curative treatment option for patients with myelofibrosis (MF). Despite the remarkable improvements in supportive care measures that led to decreased non-relapse mortality (NRM) in the more recent years, relapse remains a frequent cause of treatment failure and death for MF. A recent large registry study reported on the outcomes of busulfan and fludarabine (BuFlu) myeloablative conditioning (MAC) in MF (median age 60 years) showing a 2-year disease free survival (DFS) of 43% with a relapse rate of 41%. (Murthy et al, 2023) Outcomes were worse with reduced intensity BuFlu conditioning (median age 63) where the 2-year DFS was 24% and with a relapse rate of 50%. (Murthy et al, 2023) Fractionation of busulfan over 3 weeks allows intensification of conditioning and permits incorporation of new agents to improve efficacy while retaining a manageable toxicity profile and further expand MAC to older patients. Thiotepa improves engraftment and is known for its antileukemia effects, and hence it is frequently combined with BuFlu to improve transplant outcomes. We aimed from this study to assess the efficacy of myeloablative fractionated BuFu and thiotepa (BFT) in patients with MF.

Methods:

We included all consecutive patients with intermediate- and high-risk MF who underwent allo-SCT between 05/2019 and 03/2024. BFT regimen consisted of Bu 80 mg/m²on days -20, -13 (given outpatient) followed by thiotepa 5 mg/kg on day -7 and Flu 30-40 mg/m² and busulfan pharmacokinetically dosed to achieve total exposure for the course of 16,000 ± 12% µmol.min on days -6 to -3. All patients received posttransplant cyclophosphamide (PTCy) and tacrolimus-based graft-versus-host disease (GVHD) prophylaxis. Primary endpoints were PFS and OS. Secondary endpoints included cumulative incidence (CI) of relapse (CIR), NRM, and GVHD accounting for competing risks.

Results:

A total of 74 patients (36 males; 38 females) with a median age of 63 (range, 25-74) years were identified during the study period, of which 53% had primary MF and 47% had post essential/posy polycythemia vera MF. Thirty-two patients (43%) were at age ≥65 year at time of transplant, 40% had HCT-CI >3, and 28% with KPS <90. Most patients (80%) received ruxolitinib prior to SCT. 42 (56%) had Intermediate 2 risk disease and 23 (31%) had high-risk disease as per DIPSS-Plus criteria. 22% has massive splenomegaly ≥15 cm. Median age for donors was 35 (range, 20-75) years, 34% were matched related and 66% were 10/10 HLA matched unrelated. Peripheral blood was the graft source in all patients.

There were no primary graft failures. The median time to neutrophil engraftment was 17 (10-43) days and to platelet engraftment was 28 (10-212) days. With a median follow up of 26 (range, 3.6-53) months, the median PFS and OS were not reached, and the 2-year PFS and OS rates were 71% and 72%, respectively. The 2-year CIR and NRM were 6% and 23%, respectively. The 6-month CI of grade 3-4 acute GVHD was 10% and the 2-year moderate to severe chronic GVHD was 13%. In univariate analysis, HCT-CI >3 was the only predictor for PFS (HR 2.6, 95% CI: 1.1-6.5; p=0.03), OS (HR 2.9, 95% CI: 1.2-7.5; p=0.02) and NRM (HR 2.8, 95% CI: 1.03-7.7; p=0.04). For patients with low HCT-CI, the 2-year PFS and OS rates were 80% and 83%, respectively, and the 2-year CIR and NRM rates were 5% and 15%, respectively. In contrast, in patients with HCT-CI >3 the 2-year OS and NRM were 56% and 36%, respectively.

Conclusions:

In the largest study to report on the outcomes of MF patients who underwent allo-SCT from matched donors using MAC BFT with PTCy-based GVHD prophylaxis, our findings showed very encouraging survival rates and an excellent disease control with <10% relapse rate at 2 years. Furthermore, this our fractionated BFT MAC platform was tolerable for patients up to age 74 years with low HCT-CI, and only high HCT-CI was predictive for increased NRM.