Transplantation and cellular therapy · 2026
Randomized Trial of Two Fractionation Schedules of Myeloablative Busulfan with Fludarabine and Cladribine in Acute Myeloid Leukemia or Myelodysplastic Syndromes.
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Popat Uday R, Lontos Konstantinos, Bassett Roland, Kawedia Jitesh, Valdez Ben C, Gulbis Alison M, Alousi Amin M, Al-Atrash Gheath, Bashir Qaiser, Hosing Chitra M, Im Jin S, Kebriaei Partow, Khouri Issa, Marin David, Mehta Rohtesh S, Nieto Yago, Oran Betul, Olson Amanda, Qazilbash Muzaffar H, Ramdial Jeremy, Saini Neeraj, Srour Samer A, Kadia Tapan, Daver Naval, Short Nicholas J, Rezvani Katayoun, Garcia-Manero Guillermo, Champlin Richard E, Andersson Borje S, Shpall Elizabeth J
Аннотация
BACKGROUND: A myeloablative busulfan (Bu) and fludarabine (Flu) regimen that includes fractionating Bu and extending its delivery time results in low toxicity, permitting its use in stem cell transplantation recipients who otherwise would receive reduced-intensity conditioning. Cladribine (Clad) is an active agent in acute myeloid leukemia (AML) that may synergize with Flu. This phase 2 randomized trial examined whether additional Bu fractionation improved the efficacy and safety of a Clad- and Flu-containing regimen.
STUDY DESIGN: Patients with AML or myelodysplastic syndrome (MDS) age 18 to 70 years with a matched donor were randomized to 2 arms. Patients in arm A received outpatient Bu 80 mg/m2 on days -13 and -12, while those in arm B received outpatient Bu 80 mg/m2 on days -20 and -13. Both groups also received Flu 10 mg/m2, Clad 10 mg/m2, and Bu pharmacokinetically dosed for a total exposure of 20,000 ± 12% µmol·minute on days -6 to -3. The primary outcome was progression-free survival (PFS).
RESULTS: A total of 116 patients were randomized, including 59 to arm A and 57 to arm B. The 3-year PFS was 48.7% (95% confidence interval [CI], 37.4% to 63.4%) in arm A and 61.3% (95% CI, 49.9% to 75.4%) in arm B (P = .19). The rate of grade ≥3 toxicities was higher in arm A compared with arm B (93.2% versus 73.7%; P = .005). Three-year nonrelapse mortality in the 2 groups was 19% (95% CI, 8.7% to 29.2%) and 7% (95% CI, 0.3% to 13.7%) (P = .066), and the 3-year relapse rate was 32.3% (95% CI, 20.2% to 44.4%) and 31.7% (95% CI, 19.4% to 43.9%) (P = .99). A multivariate Bayesian regression analysis supported an overall survival and PFS benefit in the longer-duration arm B.
CONCLUSIONS: This Bu, Flu, and Clad regimen with 3 weeks of busulfan fractionation appears to be safe and effective. Furthermore, fractionation of Bu with administration over a 3-week period reduces toxicity without increasing the relapse rate, allowing safe delivery of a myeloablative regimen to older patients.
STUDY DESIGN: Patients with AML or myelodysplastic syndrome (MDS) age 18 to 70 years with a matched donor were randomized to 2 arms. Patients in arm A received outpatient Bu 80 mg/m2 on days -13 and -12, while those in arm B received outpatient Bu 80 mg/m2 on days -20 and -13. Both groups also received Flu 10 mg/m2, Clad 10 mg/m2, and Bu pharmacokinetically dosed for a total exposure of 20,000 ± 12% µmol·minute on days -6 to -3. The primary outcome was progression-free survival (PFS).
RESULTS: A total of 116 patients were randomized, including 59 to arm A and 57 to arm B. The 3-year PFS was 48.7% (95% confidence interval [CI], 37.4% to 63.4%) in arm A and 61.3% (95% CI, 49.9% to 75.4%) in arm B (P = .19). The rate of grade ≥3 toxicities was higher in arm A compared with arm B (93.2% versus 73.7%; P = .005). Three-year nonrelapse mortality in the 2 groups was 19% (95% CI, 8.7% to 29.2%) and 7% (95% CI, 0.3% to 13.7%) (P = .066), and the 3-year relapse rate was 32.3% (95% CI, 20.2% to 44.4%) and 31.7% (95% CI, 19.4% to 43.9%) (P = .99). A multivariate Bayesian regression analysis supported an overall survival and PFS benefit in the longer-duration arm B.
CONCLUSIONS: This Bu, Flu, and Clad regimen with 3 weeks of busulfan fractionation appears to be safe and effective. Furthermore, fractionation of Bu with administration over a 3-week period reduces toxicity without increasing the relapse rate, allowing safe delivery of a myeloablative regimen to older patients.