Background: Patients with high-risk acute myeloid leukemia (AML) continue to experience poor outcomes despite undergoing stem cell transplantation (SCT). The primary causes of SCT failure are non-relapse mortality (NRM) and disease relapse. NRM is often driven by infections, conditioning regimen toxicity, and graft-versus-host disease (GVHD). To mitigate conditioning-related toxicity, we extended the schedule of myeloablative busulfan to three weeks. To reduce GVHD-associated morbidity and mortality, we incorporated post-transplant cyclophosphamide (PTCy). To address relapse risk, in addition to myeloablative dose of busulfan, we added cladribine, thiotepa, and venetoclax—agents with known activity in AML. We evaluated this novel regimen in a prospective phase 2 trial in patients with high-risk AML.

Patients and Methods: High-risk AML was defined by one or more of the following: primary refractory or relapsed disease, measurable residual disease (MRD) positivity, ELN22 adverse-risk classification, or secondary AML. Eligible patients were aged 18–70 years and had a matched or haploidentical related donor, or a 7/8 or 8/8 HLA-matched unrelated donor. The conditioning regimen included outpatient busulfan (Bu) 100 mg/m² on days -20 and -13, fludarabine 10 mg/m², cladribine 10 mg/m², and Bu pharmacokinetically dosed to achieve a total systemic exposure of 20,000 ±12% µmol/min on days -6 to -3. Venetoclax 400 mg was administered daily from days -22 to -3. GVHD prophylaxis consisted of PTCy 50 mg/kg on days +3 and +4, tacrolimus ± mycophenolate mofetil. The primary endpoint was progression-free survival (PFS). A sample size of 50 patients provided >80% power to detect an increase in 1-year PFS from 30% (historical) to 47%, with a 5% Type I error rate (ClinicalTrials.gov: NCT04708054).

Results: Fifty patients (22 female, 28 male) with a median age of 55 years (range: 18–70) were enrolled between December 2021 and August 2023. Disease characteristics included: primary refractory/relapsed AML (32%), MRD+ (74%), ELN22 adverse risk (66%), and secondary AML (22%). TP53 and FLT3 mutations were each present in 24% of patients. Donor types included matched unrelated (52%), matched sibling (26%), haploidentical (14%), and mismatched unrelated (8%). Median HCT-CI score was 2 (range: 0–7); 38% had a Karnofsky performance score ≤80%.

At a median follow-up of 28 months, median PFS was not reached (95% CI: 11 months–NR). One-year and three-year PFS were 60% (95% CI: 48–75) and 58% (46–73), respectively. Three-year overall survival (OS), NRM, and relapse rates were 64% (52–79), 16% (6–26), and 26% (14–38), respectively. TP53 wild-type patients demonstrated superior outcomes, with 3-year OS of 74%, PFS of 68%, NRM of 18%, and relapse rate of 13%.

Median time to neutrophil and platelet engraftment was 15 days (range: 12–31) and 21 days (range: 5–50), respectively. No graft failures occurred. At day 30, donor chimerism was 100% for both T-cell and myeloid lineages. Grade 2–4 acute GVHD occurred in 20% (8.8–31), grade 3–4 in 6% (0–13), chronic GVHD at 3 years in 13% (2–19), and moderate-to-severe chronic GVHD at 3 years in 11% (0–16).

Conclusion: This study met its primary endpoint, demonstrating a promising 3-year PFS of 58% in a cohort of patients with very high-risk AML. Outcomes were particularly favorable in TP53 wild-type patients, with a low relapse rate of 13% and 3-year OS of 74%. These findings support further investigation of this novel conditioning regimen.

This content is only available as a PDF.
2025
Sign in via your Institution