Hematology · Medical Literature
Integration of venetoclax into a fludarabine and melphalan conditioning regimen in patients aged 50 years and older with acute myeloid leukemia and myelodysplastic syndrome: Results from a phase 2 clinical trial.
Abstract
The optimal regimens for older adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain uncertain. The authors conducted a multicenter phase 2 trial to evaluate the novel venetoclax, fludarabine, and melphalan (VFM) regimen in patients with AML or MDS aged 50 years and older. The VFM regimen consisted of venetoclax (400 mg daily on days -8 to -2), fludarabine (30 mg/m2 daily on days -7 to - 3), and melphalan (120-140 mg/m2 daily on day -2). Sixty patients (median age, 58 years; age range, 51-66 years) received the novel VFM conditioning regimen. The 2-year disease-free survival (DFS) rate was 75.0% (95% confidence interval [CI], 64.8%-86.8%), which was the primary end point. Two-year rates of overall survival, graft-versus-host disease (GVHD)-free and recurrence-free survival, nonrelapse mortality, and relapse were 78.3% (95% CI, 68.6%-89.5%), 61.6% (95% CI, 50.5%-75.3%), 13.3% (95% CI, 6.1%-23.3%), and 11.7% (95% CI, 5.1%-21.3%), respectively. Treatment-related grade 2-3 nonhematologic adverse events occurred in 58% of patients, with no grade 4-5 nonhematologic toxicities. The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at day 100 was 5.0% (95% CI, 1.3%-12.7%) and 1.7% (95% CI, 0.1%-7.9%), respectively. The 2-year cumulative incidence of moderate-to-severe chronic GVHD was 16.7% (95% CI, 8.5%-27.3%). These findings support the feasibility of incorporating venetoclax into a fludarabine and melphalan conditioning regimen in older adults with AML/MDS. Notably, the low rates of GVHD and relapse associated with this venetoclax-based conditioning regimen support further study of this platform [ClinicalTrials.gov Identifier: NCT05084027].
Clinical relevance
In patients aged 50 years and older with AML or MDS undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), does a novel conditioning regimen combining venetoclax, fludarabine, and melphalan (VFM) provide acceptable disease-free survival with manageable toxicity? __SNAPSHOT__ {"studyDesign":"Multicenter, single-arm phase 2 clinical trial","setting":"Multicenter; specific country and institution types not reported in the abstract","sampleSize":"n=60 (single arm)","population":"Adults aged ≥50 years (median age 58 years; range 51–66 years) with AML or MDS undergoing allo-HSCT","intervention":"VFM conditioning regimen: venetoclax 400 mg orally daily on days −8 to −2; fludarabine 30 mg/m² daily on days −7 to −3; melphalan 120–140 mg/m² on day −2","comparator":"Not applicable (single-arm study; no concurrent control or comparator group)","primaryOutcome":"2-year disease-free survival (DFS) rate","followUp":"Minimum follow-up duration not reported; outcomes reported at 2 years","fundingSource":"Not reported"}
Key findings
Among 60 patients who received the VFM conditioning regimen, the 2-year DFS rate — the primary endpoint — was 75.0% (95% CI, 64.8%–86.8%). Secondary outcomes at 2 years were as follows: overall survival (OS) 78.3% (95% CI, 68.6%–89.5%); GVHD-free and relapse-free survival (GRFS) 61.6% (95% CI, 50.5%–75.3%); nonrelapse mortality (NRM) 13.3% (95% CI, 6.1%–23.3%); and relapse rate 11.7% (95% CI, 5.1%–21.3%). P-values for any of these outcomes are not reported in the abstract. No NNT or NNH can be calculated from a single-arm study without a comparator. Regarding safety, treatment-related grade 2–3 nonhematologic adverse events (AEs) occurred in 58% of patients; no grade 4–5 nonhematologic toxicities were reported. The abstract appears truncated ('The cumulative…'), and additional safety data, engraftment data, and subgroup analyses — if any — are not available from the abstract alone.
Practice implications
This single-arm phase 2 trial suggests that the VFM conditioning regimen is feasible and associated with encouraging 2-year DFS (75%) and OS (78.3%) in patients aged ≥50 years with AML or MDS, populations for whom myeloablative conditioning is often considered prohibitive. The 2-year relapse rate of 11.7% and NRM of 13.3% compare favorably with published benchmarks for reduced-intensity conditioning in this age group, though no direct statistical comparison to a control group was made and no formal inferential testing against a historical control is described in the abstract. The composite GRFS of 61.6% is clinically meaningful but reflects ongoing GVHD and relapse events that limit cure rates. The absence of grade 4–5 nonhematologic toxicities is reassuring. However, the following remain unestablished: (1) whether these outcomes are superior to standard Flu/Mel or busulfan-based regimens without venetoclax; (2) efficacy and safety in patients outside the 51–66 year age range; (3) outcomes stratified by disease risk (ELN/IPSS-R category), MRD status at transplant, donor type, or GVHD prophylaxis approach; (4) the full safety profile, including hematologic toxicities, infectious complications, and organ toxicity (abstract is truncated). Because only an abstract is available, complete methods, statistical analysis plan, pre-specified historical comparator, and full results tables cannot be assessed — this is a critical limitation for interpreting study validity. Results should be interpreted as hypothesis-generating and not immediately practice-changing. __LIMITATIONS__ Single-arm design without a concurrent control group precludes causal inference or direct efficacy comparison to standard conditioning (e.g., Flu/Mel or Bu/Flu alone),No p-values or formal statistical comparisons reported; it is unclear whether a historical control DFS threshold was pre-specified,Small sample size (n=60) limits power for subgroup analyses, rare adverse event detection, and generalizability,Abstract is truncated; complete safety data (hematologic toxicity, infectious complications, hepatic/renal AEs, engraftment kinetics) are unavailable for review,Narrow age range (51–66 years) and uncharacterized comorbidity burden limit generalizability to the broader older adult transplant population,Disease heterogeneity (AML and MDS combined) without apparent reporting of disease-specific outcomes,Donor type, GVHD prophylaxis strategy, MRD status at transplant, and cytogenetic/molecular risk distribution are not described in the abstract,Funding source and potential conflicts of interest are not reported, precluding assessment of sponsorship bias,Duration of follow-up for individual patients is not specified; 2-year landmark rates may be influenced by maturity of the dataset,No comparison of melphalan dose tiers (120 vs. 140 mg/m²) or venetoclax dosing rationale relative to antifungal coadministration is addressed in the abstract __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ In this small, single-arm phase 2 trial, the venetoclax + fludarabine + melphalan (VFM) conditioning regimen demonstrated a 2-year DFS of 75% and OS of 78.3% with no grade 4–5 nonhematologic toxicities in adults aged 50–66 years with AML or MDS undergoing allo-HSCT — results that appear clinically promising for a population in whom intensive conditioning is often limited. However, the absence of a concurrent comparator, the truncated abstract, and the small sample size preclude definitive conclusions; randomized or registry-controlled studies are needed before VFM can be recommended as a standard conditioning platform.