Venetoclax-Based RIC Transplant and Maintenance Is Feasible in Poor-Risk MDS and AML

Posttransplant maintenance with venetoclax (Venclexta) plus decitabine (Dacogen) and cedazuridine (Inqovi) following a reduced-intensity conditioning (RIC) transplant regimen of venetoclax plus fludarabine and busulfan (FluBu2), along with tacrolimus (Prograf) plus methotrexate graft-vs-host disease (GVHD) prophylaxis, was safe and efficacious in patients with poor-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), according to data from a phase 1 trial (NCT03613532).¹

Findings published in Blood Advances demonstrated that among 30 patients who underwent an RIC transplant, 87% (n = 26) received venetoclax plus decitabine and cedazuridine maintenance. Reasons for not undergoing maintenance included early morphologic relapse (n = 3) and patient withdrawal due to travel logistics (n = 1). Maintenance therapy began at a median of 55 days following transplant (range, 41-106) and lasted a median of 308 days (IQR, 187-318), with a median of 8 cycles (range, 1-8). Sixty-five percent of patients who underwent maintenance completed the therapy, with discontinuation occurring due to relapse (n = 7) or GVHD (n = 2).

The most common grade 3/4 treatment-emergent adverse effects (TEAEs) during maintenance therapy included decreased neutrophil count (92%), decreased white blood cell count (81%), and decreased platelet count (54%). No treatment-related deaths were reported, and the nonrelapsed mortality (NRM) rate was 0%.

Regarding efficacy, the median progression-free survival (PFS) and overall survival (OS) were not reached at a median follow-up of 25.1 months (range, 15-33). The 2-year PFS, OS, and cumulative incidence of relapse (CIR) rates were 53% (95% CI, 33%-70%), 67% (95% CI, 47%-80%), and 47% (95% CI, 26%-65%), respectively. In the modified intention-to-treat (ITT) population, comprising only those who underwent maintenance, the respective rates were 62% (95% CI, 38%-79%), 77% (95% CI, 55%-89%), and 38% (95% CI, 18%-59%).

“The safety and promising efficacy of venetoclax/FluBu2 with tacrolimus/methotrexate GVHD prophylaxis followed by venetoclax/decitabine and cedazuridine maintenance therapy support continued development of this entire regimen in MDS/AML, particularly in poor-risk subgroups and in those with detectable pre–hematopoietic cell transplant [HCT] minimal residual disease [MRD],” lead study author Jacqueline S. Garcia, MD, and colleagues wrote in their article. “We recommend inclusion of serial next-generation sequencing–MRD measurements in transplant studies to identify patients most likely to benefit from modified transplant approaches and to elucidate treatment opportunities.”

Garcia is a physician at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

How was this venetoclax-based RIC and maintenance strategy evaluated in the trial?

Between March 2022 and October 2023, investigators enrolled patients with AML with adverse risk or MRD-positive disease (> 0.1%); those with MDS with International Prognostic Scoring System (IPSS) intermediate 2– or high-risk disease, or TP53- or RAS-mutated disease; and those with ASXL1-mutated MDS or another myeloproliferative neoplasm (MPN). Patients with AML needed to have a bone marrow blast level of less than 5% at screening, and those with MDS/MPN needed a level of no more than 10%. Notably, prior treatment with venetoclax was permitted, and all patients had to have an 8/8 HLA-matched donor.

In the open-label study, patients underwent an RIC regimen comprising venetoclax and FluBu2 prior to peripheral blood stem cell infusion on day 0. GVHD prophylaxis consisted of tacrolimus starting on day –3 and methotrexate on days 1, 3, 6, and 11.

Starting on day 28 and including a 14-day window, patients were rescreened for eligibility for maintenance therapy. To receive maintenance, patients needed to have no morphologic disease, no grade 2 to 4 acute GVHD requiring more than 0.5 mg/kg of prednisone per day, adequate organ function, an absolute neutrophil count of at least 1.0 x 10³/µL, and a platelet count of at least 50 x 10³/µL.

Maintenance therapy comprised 2 dose levels. At dose level 1, patients received venetoclax 400 mg on days 1 to 14 plus 35 mg of decitabine and 100 mg of cedazuridine on days 1, 3, and 5 every 42 days for 8 cycles. At dose level 2, decitabine and cedazuridine were administered at the same dosages, but on days 1, 2, and 3 of each 42-day cycle. Tapering of tacrolimus began on day 90 and was discontinued by 6 to 9 months for patients without GVHD.

Safety, tolerability, and determination of the recommended phase 2 dose for maintenance were the primary end points of the trial. Secondary end points included OS, PFS, CIR, NRM, and incidence of acute and chronic GVHD.

In the overall ITT population (n = 30), the median age was 69 years (range, 39-78), and 87% of patients were at least 65 years of age. Most patients were male (67%), White (90%), had an ECOG performance status of 1 (57%), and had an HCT comorbidity index of at least 3 (53%).

Disease histology included AML (50%), MDS (47%), MDS/AML by International Consensus Classification 2022 criteria (64%), and MDS/MPN (3%). Half the population had de novo or untreated disease. In the AML population (n = 15), 87% had adverse-risk disease, and the remainder had intermediate-risk disease. Those with MDS or MDS/MPN (n = 15) had intermediate 1–risk (13%), intermediate 2–risk (60%), or high-risk (27%) disease per IPSS criteria. Sixty-three percent of all patients received prior venetoclax. TP53 mutations were reported in 63% of the overall population, including in 67% of patients with MDS and 60% of patients with AML.

At screening, 70% of the overall population was in complete remission (CR) or CR with incomplete count recovery; 17% had marrow CR with hematologic improvement; 7% were in a morphologic leukemia-free state; and 7% had excess blasts at 5% to 10%.

What GVHD outcomes were reported?

No primary or secondary graft failures were reported. At 6 months, grade 2 to 4 acute GVHD occurred in 13% (95% CI, 4.1%-28%) of patients, and 3.3% (95% CI, 0.2%-15%) had grade 3 or 4 acute GVHD.

For patients undergoing maintenance therapy, moderate or severe chronic GVHD was reported in 31% (95% CI, 14%-49%) at 1 year; severe GVHD occurred in only 1 patient. Tacrolimus was tapered off at a median of 232 days (IQR, 170-301).

References

1. Garcia JS, Kim HT, Murdock HM, et al. Venetoclax/FluBu2 RIC transplant followed by all-oral venetoclax/decitabine maintenance for poor-risk MDS/AML. Blood Adv. 2026;10(5):1548-1558. doi:10.1182/bloodadvances.2025018631
2. Venetoclax added to fludarabine + busulfan prior to transplant and to maintenance therapy for AML, MDS, and MDS/​MPN. ClinicalTrials.gov. Updated December 24, 2025. Accessed March 12, 2026. https://clinicaltrials.gov/study/NCT03613532