Allo-SCT, Myeloablative Conditioning With Busulfan/Fludarabine Improves Survival in Myelofibrosis

Patients with myelofibrosis (MF) who underwent allogeneic-stem cell transplantation (allo-SCT) from matched donors using busulfan and fludarabine (BuFlu) myeloablative conditioning (MAC) in conjunction with thiotepa and posttransplant cyclophosphamide (PTCy) had very encouraging survival rates and promising disease control at 2 years follow-up, according to results from a large study published in Transplantation and Cellular Therapy.¹

New methods of stem cell transplantation are essential to elucidate better patient outcomes. | Image Credit: © atipong - stock.adobe.com

In clinical practice, allo-SCT has been known as the only potentially curative treatment for MF, though it is associated with an intense treatment burden and associated side effects. Correspondingly, Janus kinase (JAK) inhibitors have begun to revolutionize the treatment space for patients with MF, providing more options for sustained symptom control, though some have been linked to adverse outcomes, including anemia. Given these hurdles, it remains imperative for research to continue to focus on novel allo-SCT conditioning regimens that can be safe and effective in patients.^1,2

Busulfan (Myleran; GSK) and fludarabine (Fludara; Bayer Healthcare) are each chemotherapeutic agents designed for use in hematological malignancies. In a large study, investigators led by Murthy et al found that the BuFlu combination was associated with better outcomes in both reduced-intensity conditioning (RIC) and MAC. The improved outcomes included better overall survival (OS), lower early non-relapse mortality (NRM), and lower acute graft-versus-host disease (GVHD).³

The investigators of the current study discussed these results in the context of expanding treatment options for patients, especially those with severe disease and older patients. According to these experts, fractionation of Bu over a 3-week period allows for heightened conditioning and allows for new agents, such as JAK inhibitors, to improve efficacy while sustaining a positive safety profile. Furthermore, thiotepa, an agent used to lower the risk of graft rejection in combination with medicines such as BuFlu or cyclophosphamide, is known for its antileukemia effects.^1,4

In this study, the investigators aimed to assess the efficacy of a myeloablative fractionated BuFlu and thiotepa combination (BFT) in patients with MF. Patients at their center with intermediate- and high-risk MF who underwent allo-SCT between 2019 and 2024 at the investigator’s center were included. All patients were treated with PTCy and tacrolimus-based GVHD prophylaxis. The primary end points of the trial were progression-free survival (PFS) and OS, with secondary end points including cumulative incidence of relapse (CIR), NRM, and GVHD.¹

Study investigators identified a total of 74 patients during the study period; 53% of these patients had primary MF, while 47% had post-essential/posy polycythemia vera MF. Patient demographics included 32 (43%) patients being aged 65 years and older at the time of transplant. Furthermore, 42 (56%) of patients had intermediate-2-risk disease, and 23 (31%) had high-risk disease, as per criteria from the Dynamic International Prognostic Scoring System Plus.¹

No primary graft failures were reported across the patient population. Median follow-up was 26 months; according to the investigators, median PFS and OS were not reached in the cohort, with 2-year PFS and OS rates measured at 71% and 72%, respectively. In addition, 2-year CIR and NRM were reported to be 6% and 23%, respectively. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was utilized as a predictor for outcomes; an HCT-CI greater than 3 was the only predictor for PFS (HR: 2.6; 95% CI, 1.1-6.5; P = .03), OS (HR: 2.9; 95% CI, 1.2-7.5; P = .02), and NRM (HR: 2.8; 95% CI, 1.03-7.7; P = 0.04), the investigators found.¹

The study authors noted that this was the largest study to date that reported on the outcomes of patients with MF who underwent this combination regimen. In their discussion, they explained how encouraging survival rates and positive disease control were observed in this population, with a less than 10% relapse rate at 2 years. Importantly, the MAC platform was observed to be tolerable in patients up to 74 years, a promising result that is hopeful for patients in this population who often experience more severe disease.¹

REFERENCES

1. Srour SA, Saliba RM, Ramdial RM, et al. Fractionated busulfan, fludarabine and thiotepa myeloablative conditioning to improve transplant outcomes for myelofibrosis. Transplantation and Cellular Therapy. 2025;31(2):S63. doi:10.1016/j.jtct.2025.01.100

2. Halpern L. Patients with myelofibrosis face long-term treatment and hospitalization despite improvements in therapy. Pharmacy Times. Published January 23, 2025. Accessed March 20, 2025. https://www.pharmacytimes.com/view/patients-with-myelofibrosis-face-long-term-treatment-and-hospitalization-despite-improvements-in-therapy

3. Murthy GSG, Kim S, Estrada-Merly N, et al. Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis. Haematologica. 2023;108(7):1900-1908. doi:10.3324/haematol.2022.281958

4. Mayo Clinic Staff. Thiotepa (injection route). Mayo Clinic. Last Updated March 1, 2025. Accessed March 20, 2025. https://www.mayoclinic.org/drugs-supplements/thiotepa-injection-route/description/drg-20066363