AML, MDS Allogeneic HSCT Conditioning: PFS Encouraging With Busulfan, Fludarabine Plus Cladribine, Venetoclax, Thiotepa

A clinical trial has evaluated a new regimen as conditioning for allogeneic hematopoietic stem cell transplant (HSCT) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The approach involves intensification of busulfan plus fludarabine treatment followed by addition of combination cladribine plus venetoclax and thiotepa.

The prospective phase 2 trial was conducted by a team of researchers from The University of Texas MD Anderson Cancer Center, Houston. Noteworthy among their findings were promising progression-free survival (PFS) results, which they reported at the 2025 Tandem Transplantation & Cellular Therapy Meetings of the ASTCT and CIBMTR in Honolulu, Hawai’i.

The study enrolled 49 patients with an age range of 18 to 69 years and a median age of 59 years. Twenty-five patients were women, and 22% of the cohort had TP53 mutations. For 27% of the patients, the transplant donor was a matched sibling; 55% had a matched but unrelated donor, 12% had a mismatched unrelated donor, and 6% had a haploidentical related donor.

Twenty-five patients in the cohort had AML; 40% had primary refractory or relapsed disease, and 56% had adverse risk disease per the 2022 update of the European LeukemiaNet criteria. Twenty-four patients had MDS; 58% had a revised International Prognostic Scoring System (IPSS) score greater than 3.5; and 83% had a moderately high, high, or very high molecular IPSS score. Forty-seven percent of the total cohort had comorbidity scores of 3 or higher.

The trial involved extending the busulfan plus fludarabine regimen for up to 3 weeks. The patients received outpatient venetoclax 400 mg daily on days –22 to –3 before HSCT; busulfan 100 mg/m² on days –20 and –13; thiotepa 5 mg/kg on day –7; and fludarabine 10 mg/m², cladribine 10 mg/m², and busulfan on days –6 to –3. After HSCT, graft-vs-host disease prophylaxis involved cyclophosphamide 50 mg/kg on days +3 and +4 and tacrolimus with or without mycophenolate mofetil.

The total cohort had a median follow-up of 23 months, and median PFS was not reached. The PFS of 61%, attained at 1 year and 2 years, met the trial’s primary end point. The cohort had a 2-year overall survival rate of 65%, a nonrelapse mortality rate of 22%, and a relapse rate of 16%.

The investigators’ PFS univariate analysis revealed no associations with any of the covariates tested, but their relapse univariate analysis revealed a trend toward higher relapse among patients who had mutations in TP53, with a hazard ratio of 3.693 (P=0.056).

Reference

Popat UR, Bassett RL, Alousi AM, et al. Myeloablative fractionated busulfan, fludarabine, cladribine, thiotepa and venetoclax (cladillac) conditioning regimen for allogeneic stem cell transplantation in very high-risk AML/MDS: a phase 2 trial. Abstract presented at: Tandem Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; February 12-15, 2025; Honolulu, HI.