A Pilot Study of Condensed Busulfan, Melphalan, and Fludarabine Myeloablative Conditioning in Ex Vivo CD34-Selected Allogeneic Hematopoietic Cell Transplantation.

Authors

Natalia Tijaro Ovalle, Maria Bromberg, Roni Tamari, Andrew Lin, Vishwamber Talla, Danielle Lutrario, Molly Hogan, Richard Lin, Esperanza B Papadopoulos, Ann Jakubowski, Doris Ponce, Brian C Shaffer, Gagan Raju, Gunjan L Shah, Sarah Samorodnitsky, Miguel-Angel Perales, Sergio A Giralt, Michael Scordo

Published in

Transplantation and cellular therapy. Oct 15, 2026. Epub Oct 15, 2026.

Abstract

Myeloablative conditioning (MAC) with busulfan, melphalan, and fludarabine (Bu/Mel/Flu) given over 8 days in combination with rabbit antithymocyte globulin (ATG) and ex vivo CD34+-selected allogeneic hematopoietic cell transplantation (allo-HCT) leads to favorable disease control and consistently low rates of graft-versus-host disease (GVHD) in fit patients with myeloid malignancies. However, early regimen-related toxicity continues to be a major determinant of treatment tolerability, necessitating further optimization of the MAC regimen without compromising the efficacy of this platform.
We conducted a single-center pilot clinical trial evaluating the use of a condensed 5-day (Bu/Mel/Flu) regimen before ex vivo CD34+-selected allo-HCT. The primary analysis focused on patients with myeloid malignancies. A parallel cohort of patients with multiple myeloma was closed early because of slow accrual and is reported descriptively. The primary endpoint of the study was the incidence of CTCAE v5.0 grade 4 non-hematologic toxicity from the start of conditioning through day +30 post-HCT, assessed against a 20% institutional benchmark derived from prior cohorts treated with the sequential 8-day regimen. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), and rates of non-relapse mortality (NRM), CD4+ T cell immune reconstitution, and GVHD.
We enrolled 30 participants in the primary cohort of the study. Median age was 53 years (IQR 40-66), 50% were male. The most common underlying diagnosis was acute myeloid leukemia (AML) in 20 of 30 patients (67%). Two of 30 patients (7%) experienced ≥1 grade 4 toxicity from the start of conditioning until day +30 post-HCT, meeting the protocol-defined primary safety endpoint and remaining below the 20% observed rate with the 8-day regimen. With a median follow up time of 3.8 years (IQR 3.6-4.5), median OS and RFS were not reached. OS was 90% (95% CI 80-100) at 1-year and 80% (95% CI 67-96) at 2-years; RFS was 83% (95% CI 71-98) and 73% (95% CI 59-91); NRM was 6.7% (95% CI 1.1-19) at both timepoints. Median times to neutrophil and platelet engraftment were 10 days (IQR 10-11) and 16 days (IQR 15-19), respectively. The cumulative incidence of grade II-IV acute GVHD was 30%, grade III-IV acute GVHD was 10%, and moderate/severe chronic GVHD was 6.7%. CD4+ immune reconstitution by day +100 was achieved in 73% of evaluable patients.
Condensed Bu/Mel/Flu before ex vivo CD34+-selected allo-HCT was feasible and met the prespecified safety endpoint in this pilot study primarily conducted in patients with myeloid malignancies. The condensed 5-day regimen was associated with a comparable toxicity profile to the prior sequential 8-day regimen and with favorable survival outcomes supporting further study of this MAC regimen in the context of ex vivo CD34+ selection.

PMID:
42880545
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.

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