Introduction

Three abstracts from the 2026 ASCO Annual Meeting speak to where acute myeloid leukemia (AML) treatment is headed: using menin inhibitors as maintenance after transplant in genetically defined subgroups, adding a targeted FLT3 inhibitor to a standard lower-intensity backbone for older or unfit patients, and combining three active agents at once for IDH1-mutated disease. Each reflects the same broader trend of matching treatment intensity, and specific mechanisms, to a patient's molecular profile.

Revumenib as Post-Transplant Maintenance in Menin-Dependent AML

Relapse remains the single most common cause of death and treatment failure after allogeneic stem cell transplant, and maintenance options remain limited. FLT3 inhibitors (gilteritinib, sorafenib, midostaurin) have shown benefit in FLT3-mutated disease, and hypomethylating agents have shown modest benefit in broader high-risk populations, but AML driven by NPM1 mutations, KMT2A rearrangements, or NUP98 rearrangements is susceptible to a different approach: menin inhibition. Revumenib is already approved for relapsed/refractory KMT2A-rearranged and NPM1-mutated AML, based on the AUGMENT-101 trial (KMT2A-rearranged: CR + CRh 22.8%, ORR 63.2%, MRD negativity 68.2%; NPM1-mutated: CR + CRh 23.4%, ORR 46.9%, MRD negativity 40.7%), and is well tolerated, with a low treatment-related discontinuation rate (4.8%) and a need to monitor for differentiation syndrome and QTc prolongation.

This single-center, pooled analysis evaluated adult and pediatric patients with KMT2A-rearranged, NPM1-mutated, or NUP98-rearranged AML who received revumenib either pre-transplant and resumed it post-transplant, compared against a historical control cohort with similar genotypes who did not receive a menin inhibitor. In the revumenib cohort, cumulative incidence of relapse was markedly lower than in the historical cohort at both 1 and 3 years (5% and 17% in the CR1 revumenib-treated group versus 46% and 80% historically, respectively, per the study's reported comparison). Overall survival at 1 and 2 years was 90% and 72% in all patients (with adults at 90% at both timepoints); event-free survival was 82% and 72% at 1 and 2 years. Non-relapse mortality was low (1% and 4% at 1 and 2 years). Thrombocytopenia was the most common adverse event, occurring in 83% of patients (grade 3 or higher in 46%).

Menin inhibitors likely represent a genuinely new post-transplant maintenance option for patients with KMT2A-rearranged, NPM1-mutated, or NUP98-rearranged AML, a population that has had few good options. Dose adjustments appear necessary to sustain patients on maintenance long-term, and how other menin inhibitors in development compare remains an open question.

Quizartinib Plus Decitabine and Venetoclax in FLT3-ITD AML

FLT3-ITD mutations confer inferior outcomes in AML, and while azacitidine plus venetoclax is standard of care for older or unfit patients, FLT3-ITD-mutated disease responds less durably to this combination because FLT3-ITD signaling activates pro-survival pathways (MCL-1 upregulation via RAS/MAPK and PI3K/AKT) that bypass BCL-2, the target of venetoclax. Azacitidine, venetoclax, and gilteritinib together have shown improved outcomes compared with historical controls, and this phase 1/2 study tested a related but distinct triplet, quizartinib (a potent, FLT3-ITD-specific type II inhibitor) with decitabine and venetoclax, in patients with relapsed/refractory AML or high-risk MDS (blasts over 10%), or newly diagnosed FLT3-ITD AML unfit for intensive chemotherapy.

Patients received decitabine 20 mg/m² for 5 days, venetoclax 400 mg for 14 days, and quizartinib 26.5 mg daily, with venetoclax/quizartinib stopped at day 14 if aplasia was present on marrow assessment. Composite complete remission (CR + CRi + MLFS) was 91% in newly diagnosed patients (N=42) and 61% in relapsed/refractory patients (N=46). MRD negativity by flow deepened with subsequent cycles in newly diagnosed patients (61% at end of cycle 1 to 71% by end of cycle 2 or later), and MRD by NGS deepened further with each cycle (17% at end of cycle 1 to 89% by end of cycle 4). Median relapse-free survival was 25 months and median overall survival 36 months in newly diagnosed patients, versus 6.3 months median overall survival in relapsed/refractory patients. Roughly a third of patients in each group proceeded to transplant. Myelosuppression was the dominant toxicity, with 40 days to ANC recovery above 500 and 35 days to platelet recovery above 50,000; grade 3 or higher non-hematologic adverse events included febrile neutropenia (37%), pneumonia (33%), and infections (17%).

Decitabine, venetoclax, and quizartinib is an effective regimen for older or unfit patients with FLT3-ITD-mutated AML, with response and survival numbers that compare favorably to historical azacitidine-venetoclax data in this genetically defined subgroup. Which FLT3-ITD triplet, this one or azacitidine-venetoclax-gilteritinib, is preferable remains unclear without head-to-head data, since these are all small, non-randomized trials.

Azacitidine, Venetoclax, and Ivosidenib in IDH1-Mutated AML

IDH1 mutations occur in 7%–8% of AML but are clinically attractive because response rates to frontline therapy tend to be better than average: 42% with IDH1 inhibitor monotherapy and 67%–93% with combination approaches. Two standard-of-care hypomethylating agent-based combinations already exist for IDH1-mutated AML, azacitidine plus venetoclax (VIALE-A: composite CR 66.4%, ORR 79%, median OS 15.2 months, median duration of response 29.5 months) and azacitidine plus ivosidenib (AGILE: composite CR 53%, ORR 63%, MRD negativity 30%, median OS 29.3 months, median duration of response 22.1 months), but with meaningfully different efficacy profiles and unclear optimal sequencing, especially since duration of response drops substantially when either doublet is used in the relapsed/refractory setting.

This phase Ib/II trial tested all three drugs together, azacitidine, venetoclax, and ivosidenib, in adults with relapsed/refractory or newly diagnosed AML, high-risk MDS, and/or MPN with an IDH1 mutation and no prior venetoclax or ivosidenib exposure. At a median follow-up of 35 months, median overall survival was not reached, with a 3-year OS of 79% (95% CI, 64%–96%); median duration of remission was also not reached, with a 3-year DOR of 83% (95% CI, 64%–100%); and 3-year cumulative incidence of relapse was 9% (95% CI, 0%–20%). Non-hematologic adverse events occurred in 80% of patients (32 of 40), with grade 3 or higher events in only 30% (12 patients), including infection (23%), QTc prolongation (5%), tumor lysis syndrome (5%), and differentiation syndrome (5%).

The triplet combination is a very effective option for patients with IDH1-mutated AML, showing better duration of response than either doublet alone with a comparable side effect profile. Whether sequencing therapies or using the combination upfront is the better long-term strategy remains unanswered, and results from the ongoing phase 3 EVOLVE-1 trial (azacitidine/ivosidenib with or without venetoclax) should help clarify this.

For Patients

For people with AML driven by specific gene changes (KMT2A rearrangements, NPM1 mutations, or NUP98 rearrangements) who have had a stem cell transplant, a drug called revumenib, taken as maintenance therapy after transplant, appears to meaningfully lower the chance of the leukemia coming back, based on a comparison with patients who did not receive it in the past.

For older adults or those unable to tolerate intensive chemotherapy who have AML with a FLT3-ITD gene change, adding a targeted drug called quizartinib to standard lower-intensity chemotherapy produced high remission rates and encouraging survival, particularly in patients newly diagnosed with this subtype.

For people with AML driven by an IDH1 gene mutation, combining three effective drugs together, azacitidine, venetoclax, and ivosidenib, produced excellent, durable remissions with manageable side effects, though whether this three-drug combination should be used upfront or the drugs given in sequence is still being studied.

Key Takeaways

  • Revumenib as post-transplant maintenance showed markedly lower relapse rates compared with historical controls in KMT2A-rearranged, NPM1-mutated, and NUP98-rearranged AML, representing a new maintenance option for a population with few prior choices.

  • Decitabine, venetoclax, and quizartinib produced a 91% composite CR rate in newly diagnosed FLT3-ITD AML unfit for intensive chemotherapy, with myelosuppression as the dominant toxicity.

  • Azacitidine, venetoclax, and ivosidenib in IDH1-mutated AML achieved a 3-year overall survival of 79% and 3-year duration of response of 83%, outperforming either doublet alone on duration of response with a comparable safety profile.

  • Across all three studies, dose modification and supportive care were central to keeping patients on effective but myelosuppressive regimens long enough to realize their benefit.

References

  1. Goulart H, Okeleji O, DiNardo CD, et al. Revumenib as maintenance for AML following allogeneic stem cell transplantation. Presented at: 2026 ASCO Annual Meeting.

  2. Yilmaz M, Muftuoglu M, Kantarjian H, et al. Quizartinib in combination with decitabine and venetoclax in FLT3-ITD mutated AML. Presented at: 2026 ASCO Annual Meeting.

  3. Marvin-Peek J, Garcia JS, Borthakur G, et al. A multicenter phase Ib/II trial of azacitidine, venetoclax, and ivosidenib in IDH1-mutated acute myeloid leukemia (AML). Presented at: 2026 ASCO Annual Meeting.