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At the 2026 European Hematology Association (EHA) Congress, there were updates in the management of acute myeloid leukemia (AML) including novel targeted triple combinations, emerging cellular therapies, and measurable residual disease (MRD)-directed treatment strategies. During the VJHemOnc Post-EHA AML Highlights webinar, leading AML experts discussed abstracts selected by the webinar chair, Naval Daver, MD, The University of Texas MD Anderson Cancer Center, Houston, TX. From these abstracts, we have highlighted five studies with the potential to influence future clinical practice and ongoing research.

OPTI-AML trial: Evaluating 14- and 28-day venetoclax schedules in newly-diagnosed, older patients with AML

The combination of azacitidine and venetoclax is a first-line treatment option for patients with newly-diagnosed AML who are ineligible for intensive induction chemotherapy.1 However, prolonged myelosuppression frequently requires treatment interruptions or dose modifications,2 prompting investigation into whether shorter durations of venetoclax can maintain efficacy while improving treatment delivery.

During the Post-EHA AML Highlights webinar, Joshua Zeidner, MD, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, presented results from the randomized, Phase II OPTI-AML study (NCT03013998) comparing 28- and 14-day schedules of venetoclax during the first two treatment cycles in combination with azacitidine.3 

The study enrolled 169 patients aged 60 years or older with newly diagnosed AML who were considered unsuitable for intensive chemotherapy. Patients were randomized to receive azacitidine plus either 28 days (AV28, n=83) or 14 days (AV14, n=86) of venetoclax during the first two treatment cycles. The primary endpoint was complete remission (CR) after two cycles.3

The trial did not meet its primary endpoint of demonstrating non-inferiority for the shortened venetoclax schedule. Following two treatment cycles, CR rates were 49% with AV28 compared with 43% with AV14. Composite complete remission (CR/CRh/CRi) rates were also numerically higher with AV28 (81% versus 69%), while MRD negativity among responders was comparable between the treatment groups (78% versus 77%).3

Subgroup analyses suggested that outcomes differed according to molecular subtype. Patients with NPM1 or IDH1/2 mutations achieved higher CR rates with the 28-day schedule than with the 14-day schedule (61% versus 42%), whereas CR rates were the same (44%) across both treatment arms in the remaining molecular groups.3

Significantly fewer patients in the AV28 group completed the planned duration of venetoclax during Cycle 1 (68% vs 89%; p<0.01) primarily due to infection-related adverse events (AEs). However, overall toxicity profiles were comparable between the AV28 and AV14 treatment arms. In addition, Grade ≥3 treatment-emergent adverse events (TEAEs; 88% versus 87%) and early mortality events were similar. Among patients achieving complete composite remission, recovery of absolute neutrophil count (ANC) by Day 42 of Cycle 1 was more frequent with AV14, but was comparable following Cycle 2.3

The findings from the OPTI-AML study highlight the challenges of applying a uniform venetoclax schedule across a molecularly heterogeneous AML population. While shortening venetoclax exposure may remain an attractive strategy in selected settings, these prospective data support maintain the standard 28-day schedule for patients receiving azacitidine and venetoclax doublet therapy until further molecularly defined evidence becomes available.

GIMEMA AML2521 trial: MRD-directed venetoclax and azacitidine as a bridge-to-transplant in NPM1-mutated AML

Increasing use of MRD monitoring is transforming AML management, and potentially allowing intervention before overt hematologic relapse occurs. Patients with NPM1-mutated AML who develop molecular relapse or progression following intensive chemotherapy remain at high risk of subsequent disease recurrence,4,5 yet no standard treatment is currently approved in this setting.

During EHA 2026 and the Post-EHA AML Highlights webinar, Chiara Sartor, MD, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, presented results from the multicenter, Phase II GIMEMA AML2521 trial (NCT04867928) evaluating venetoclax plus azacitidine as an MRD-directed bridge-to-transplant strategy in adult NPM1-mutated AML patients with molecular failure after first-line intensive chemotherapy.6 

Thirty-four patients in morphological CR with centrally confirmed MRD positivity received venetoclax plus azacitidine. Patients received a median of three treatment cycles before proceeding to allogeneic stem cell transplantation (allo-SCT), when appropriate.6

The treatment demonstrated substantial molecular activity. Overall, 85% of patients achieved a molecular response, while 79% became MRD negative, with a median time to MRD negativity of 2.10 months (range 0.99–6.70 months). 97% of patients remained in CR through study treatment, and 85% successfully proceeded to transplant while maintaining CR.6

Reflecting on the clinical implications of these findings, Dr Sartor noted: “A centralized MRD-driven disease approach is feasible, and it allows patients to proceed to transplantation with a very low rate of adverse events.”

With a median follow-up of 13 months, one patient experienced disease relapse and subsequently died, while all patients who underwent transplantation remained in ongoing CR at the time of analysis. A total of 21 Grade ≥3 AEs were reported, the majority of which were hematologic, with neutropenia representing the most frequent toxicity (17/21). One episode of febrile neutropenia was reported, and one patient experienced an AE that prevented transplantation.6

 These findings support further evaluation of venetoclax plus azacitidine as an MRD-directed strategy capable of deepening molecular responses and acting as a bridge to transplantation for patients with NPM1-mutated AML.

Azacitidine, venetoclax, and ivosidenib: Triplet therapy achieves high MRD-negative response rates in IDH1-mutated AML

Targeted therapies have significantly improved outcomes for patients with IDH1-mutated AML, with both azacitidine-venetoclax and azacitidine-ivosidenib doublet regimens representing established treatment options.7,8 However, a proportion of patients fail to respond to treatment or eventually relapse, providing the rationale for investigating triplet approaches.9

 During EHA 2026 and the Post-EHA AML Highlights webinar, Jennifer Marvin-Peek, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, presented updated results from the multicenter, Phase Ib/II study (NCT03471260) evaluating azacitidine, venetoclax, and ivosidenib in patients with newly diagnosed IDH1-mutated AML.9

Forty patients with newly diagnosed IDH1-mutated AML who were considered unsuitable for intensive induction chemotherapy started treatment. The median age was 72 years (range 51–80); 53% had de novo AML, 10% had therapy-related AML, and 38% had secondary AML. Patients received azacitidine for seven days, venetoclax for 14 days and continuous ivosidenib, with dose modifications permitted during remission to reduce cumulative myelosuppression.9

The overall response rate (ORR) was 95%, with 93% of patients achieving a composite CR (CRc). Among evaluable responders, 91% achieved MRD negativity by flow cytometry. After a median follow-up of 35 months, median OS and duration of remission had not been reached, while estimated three-year OS was 79% (95% CI: 64–96%).9

Treatment was generally well tolerated; Grade ≥3 non-hematologic AEs occurred in 30% of patients, with infections representing the most common severe toxicity (n=7, 23%). Cases of differentiation syndrome (DS) and QTc prolongation were infrequent and were successfully managed with supportive care and dose modification. Overall, 45% of patients subsequently underwent allo-SCT, while 10 of the 22 non-transplanted patients remained on long-term study treatment.9

Discussing the study findings, Dr Marvin-Peek stated: “Triplet therapy demonstrated high MRD-negative response rates with durable remissions and comparable safety to doublet regimens.”

These findings suggest that combining azacitidine, venetoclax, and ivosidenib may provide deep and durable responses in patients with newly diagnosed IDH1-mutated AML, supporting the continued evaluation of triplet therapy in this patient population.

KOMET-007 trial: Ziftomenib plus intensive chemotherapy demonstrates deep molecular responses in newly diagnosed NPM1-mutated and KMT2A-rearranged AML

Menin inhibitors are rapidly emerging as a promising therapeutic class for genetically defined subtypes of AML. Following encouraging activity in relapsed and refractory disease, attention has shifted towards evaluating these agents in combination with standard induction chemotherapy in the frontline setting, in patients with NPM1-mutated and KMT2A-rearranged AML.10

During EHA 2026 and the Post-EHA AML Highlights webinar, Amer Zeidan, MBBS, MHS, Yale Cancer Center, New Haven, CT, presented updated results from the ongoing Phase Ia/b KOMET-007 study (NCT05735184) evaluating the menin inhibitor ziftomenib in combination with intensive induction chemotherapy (7+3) in patients with newly diagnosed NPM1-mutated or KMT2A-rearranged AML.10

At the January 2026 data cutoff, 99 patients had received ziftomenib 600 mg once daily in combination with standard 7+3 induction chemotherapy, of whom 49 had NPM1-mutated AML and 50 had KMT2A-rearranged AML. Ziftomenib was initiated on Day 8 of induction and continued throughout consolidation and, where appropriate, maintenance therapy.10

Clinical responses were observed across both molecular subgroups. CRc rates reached 96% in NPM1-mutated AML and 90% in KMT2A-rearranged AML. Local MRD negativity was achieved in 83% and 82% of evaluable responders, respectively, with 92% of patients with NPM1-mutated AML achieving MRD negativity by 20 weeks. Median CRc duration had not yet been reached for the NPM1 cohort, while one-year OS rates were 94% and 70% in the NPM1 and KMT2A cohorts, respectively.10

 Treatment was generally well tolerated. The most common (≥20%) Grade ≥3 TEAEs were febrile neutropenia (64%), thrombocytopenia (57%), and anemia (36%). Overall, 54% of patients experienced Grade ≥3 investigator-assessed ziftomenib-related AEs, most commonly (≥10%) thrombocytopenia (21%), anemia (15%), and febrile neutropenia (13%). DS occurred in 3% of patients and QTc prolongation in 4%; all events resolved following protocol-guided management.10

Taken together, these updated findings demonstrate deep molecular responses, durable remission, and a manageable safety profile with ziftomenib plus intensive chemotherapy, supporting the ongoing Phase III KOMET-017 registrational trial (NCT07007312), evaluating this combination in newly diagnosed NPM1-mutated and KMT2A-rearranged AML.11

REVSTAR-123 trial: Switchable allogeneic CAR T-cell therapy for relapsed/refractory AML

While CAR T-cell therapy has transformed the management of lymphoid malignancies, translation of this approach to AML has been limited due to the lack of leukemia-specific target antigens and concerns regarding prolonged myeloablation resulting from on-target, off-tumor toxicity.12 Novel switchable CAR T-cell platforms have been developed to address these challenges, while enabling greater control of CAR T-cell activity.13

During EHA 2026 and the Post-EHA AML Highlights webinar, Martin Wermke, MD, University Hospital Carl Gustav Carus, Dresden, Germany, presented results from the Phase Ia REVSTAR-123 study (NCT05949125), evaluating a first-in-class switchable allogeneic CD123-directed CAR T-cell therapy in patients with relapsed/refractory or MRD-positive AML with CD123 expression on at least 20% of leukemic blasts. The aims of the study were to evaluate safety and to determine the recommended dose for the Phase II study.13

Patients received the allogeneic CAR T-cell therapy together with R-TM123, a bispecific adapter that enables CAR T-cell activation against CD123. R-TM123 was administered as a continuous IV infusion during a 20-day induction cycle and subsequent 12-day consolidation cycles, separated by 7–14-day intervals. Overall, 17 heavily pretreated patients received induction therapy, and 7 completed at least one consolidation cycle.13

Overall, the treatment was well tolerated. A dose-limiting toxicity (DLT) of a Grade 2 immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome (IEC-HS) was observed in one patient, which was successfully managed through temporary CAR T-cell deactivation and immunosuppressive therapy (anakinra plus dexamethasone). Cytokine release syndrome (CRS) occurred in 12 patients and was predominantly low grade (Grade 1–3). No treatment-related mortality, neurotoxicity, or graft-versus-host disease were reported.13

CAR T-cell expansion was superior to that observed with other published autologous and allogeneic CAR-Ts in AML, with peak levels exceeding 600,000 VCN copies/μg gDNA. In addition, repeated administration of R-TM123 successfully reactivated CAR T-cells, supporting sustained biological activity without requiring additional CAR T-cell infusions.13

 Antileukemic activity was also observed. Among patients treated at the highest dose level (DL15, 500M cells and 4.8mg/day of R-TM123), investigators reported two patients with CR with full count recovery, one morphologic leukemia-free state in TP53-mutated AML, and multiple MRD conversions, with several responses ongoing at the time of analysis.13

Reflecting on the significance of the findings with the novel platform, Dr Wermke explained: “This first-in-class switchable allogeneic CAR T-cell therapy is associated with a manageable safety profile and shows promising antileukemic activity.”

These early findings have supported progression of REVSTAR into a Phase Ib expansion study, where the recommended dose is currently being evaluated in a larger cohort of patients with relapsed/refractory or MRD-positive AML.13,14

These abstracts from EHA 2026 illustrate the breadth of innovation currently taking place in AML. From optimizing established venetoclax-based regimens, to utilizing MRD-guided intervention strategies, advancing menin inhibition, and exploring next-generation cellular therapies, investigators continue to advance treatment approaches across multiple disease settings.

While several of these studies are in early phases or require longer follow-up, they collectively demonstrate how increasingly personalized treatment strategies are shaping AML management. Future insights from these trials will help define how these emerging approaches become incorporated into future standards of care.

References

  2. Shimony S, Stahl M, Stone RM, et al. Acute myeloid leukemia: 2025 update on diagnosis, risk‐Stratification, and management. Am J Hematol. 2025;100(5):860–891.
  3. Borate U, Huang Y, Lin TL, et al. OPTI-AML: Prospective randomized Phase 2 trial of 28 versus 14 day schedule of venetoclax and azacitidine for 2 cycles in newly diagnosed genomically agnostic acute myeloid leukemia patients ≥60 years. Abstract S126. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
  5. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374(5):422–433.
  6. Sartor C, Candoni A, Papayannidis C, et al. Venetoclax and azacitidine for molecular failure intervention as a bridge-to-transplant strategy for NPM1-mutated acute myeloid leukemia: The GIMEMA AML2521 Phase 2 trial. Abstract S128. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
  7. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–629.
  8. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519–1531.
  9. Marvin-Peek J, Garcia J, Borthakur G, et al. A multicenter Phase 1b/2 trial of azacitidine, venetoclax, and ivosidenib in IDH1-mutated acute myeloid leukemia (AML). Abstract S127. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
  10. Zeidan A, Wang E, Erba H, et al. Ziftomenib combined with intensive induction (7+3) for newly diagnosed NPM1 M or KMT2A-R acute myeloid leukemia (AML): Long-term results from the KOMET-007 trial. Abstract S130. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
  11. ClinicalTrials.gov. Studies to assess ziftomenib in combination with Ven+Aza or 7+3 in patients with untreated NPM1-m or KMT2A-r AML. NCT07007312. Available here. Last accessed 30 June 2026.
  12. Liu Y, Wang W, Wang C, et al. Recent advances of chimeric antigen receptor T-cell therapy for acute myeloid leukemia. Front Immunol. 2025;16:1572407
  13. Wermke M, Jongen-lavrencic M, Metzelder S, et al. First-in-class switchable allogeneic CAR-T therapy for CD123+ AML – results from the Phase Ia REVSTAR-123 (AVC-201-01) study. Abstract LB5007. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
  14. ClinicalTrials.gov. Phase 1 study of Allo-RevCAR01-T-CD123 in patients with selected CD123 positive hematologic malignancies. NCT07007312. Available here. Last accessed 30 June 2026.
Written by Raffaella Facchini
Reviewed by Thomas Southgate
Publishing date: 03/08/2026

The content of VJHemOnc is intended for healthcare professionals