Acute Myeloid Leukemia (AML) remains one of the most challenging hematologic malignancies to manage, with its aggressive nature, genetic heterogeneity, and high rates of relapse. Despite recent advances in targeted therapies and combination regimens, improving outcomes for patients—particularly older adults and those with relapsed or refractory disease—requires ongoing innovation. The American Society of Hematology (ASH) Annual Meeting serves as a critical forum for presenting cutting-edge research, new clinical data, and emerging therapeutic strategies in hematology. At the 2024 ASH Annual Meeting, numerous abstracts addressed key developments in AML, offering insights into novel agents, optimized treatment combinations, and mechanisms of resistance. This e-newsletter highlights summaries of the most impactful AML abstracts, providing essential takeaways for busy clinicians. For additional abstracts and in-depth analyses, visit The Practical Hematologist website. Staying current with the latest research is vital to advancing patient care and improving outcomes in this rapidly evolving landscape.

Abstracts Covered in this Issue

Click each title to jump to the abstract

Highlighted Abstract Summaries

Gemtuzumab Ozogamicin Added to Fludarabine, Cytarabine, and G-CSF (FLAG-GO) Leads to Superior Molecular Response and Survival Outcomes Than Idarubicin (FLAG-IDA): 200 Patients Long-Term Follow-Up

Authors: Jayastu Senapati, MD, DM, MBBS, Hagop M. Kantarjian, MD, Edward Ayoub, PhD, et al.

Background: Core-binding factor acute myeloid leukemia (CBF-AML) is considered favorable-risk, with high survival rates using intensive chemotherapy. FLAG (fludarabine, cytarabine, and G-CSF) regimens improve outcomes further, and adding gemtuzumab ozogamicin (GO) has shown superior molecular responses compared to FLAG with idarubicin (FLAG-IDA). This long-term follow-up reports on measurable residual disease (MRD), relapse-free survival (RFS), and overall survival (OS) from a large Phase II study.

Study Overview and Results:
The study included 200 patients with CBF-AML, median age 52 years, treated with FLAG-GO (n=92) or FLAG-IDA (n=108). Patients received up to 7 cycles of therapy, with risk stratification based on MRD assessments by PCR.

• Complete remission rates (CR/CRi) were 99% across both groups.
• FLAG-GO achieved significantly superior MRD responses, including optimal PCR response (OPR) at the end of therapy of 92% vs. 61% (p<0.01).

At a median follow-up of 102 months, FLAG-GO demonstrated durable survival benefits:

• 8-year RFS: 77% (FLAG-GO) vs. 59% (FLAG-IDA), p=0.007.
• 8-year OS: 79% (FLAG-GO) vs. 69% (FLAG-IDA), p=0.03.
• Patients aged ≥60 years particularly benefited, with a 5-year OS of 69% vs. 49% (p=0.04).

Multivariate analysis confirmed that FLAG-GO treatment and absence of KIT mutations were independent predictors of improved OPR and survival.

Relevance: This long-term follow-up highlights the superior efficacy of FLAG-GO compared to FLAG-IDA in achieving deeper molecular responses and improving survival outcomes in CBF-AML. These findings support the use of GO as part of intensive FLAG-based regimens, particularly in older patients, where the survival benefit is most pronounced. For clinicians, integrating FLAG-GO into treatment protocols offers a significant advantage in improving long-term outcomes for CBF-AML patients.

Link to Abstract: Abstract 1513

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Gilteritinib Results in Higher Remission and Transplant Rates Than Midostaurin but Does Not Increase the Post-Induction Mutational MRD Negative Rate: Results of the Phase 2 Randomized PrECOG 0905 Study in Newly Diagnosed FLT3-Mutated AML

Authors: Selina Luger, MD, FRCPC, Li Chen, MS, Keith W. Pratz, MD, et al.

Background: While midostaurin has been established as a standard addition to intensive chemotherapy for newly diagnosed FLT3-mutated AML, the more potent FLT3 inhibitor, gilteritinib, may provide added clinical benefit. The PrECOG 0905 trial compared remission rates, measurable residual disease (MRD) clearance, and transplant outcomes between gilteritinib (G) and midostaurin (M) when combined with intensive chemotherapy.

Study Overview and Results:
In this randomized, open-label Phase 2 trial, 177 newly diagnosed FLT3-mutated AML patients aged 18-70 received induction therapy with cytarabine and daunorubicin (7+3), alongside either gilteritinib (120 mg daily) or midostaurin (50 mg twice daily) on Days 8-21. Patients were stratified by FLT3 mutation type (ITD vs TKD), NPM1 mutation status, and FLT3-ITD allelic ratio. Consolidation with high-dose cytarabine (1.5-3 g/m²) was followed by the assigned FLT3 inhibitor, and patients were allowed to proceed to hematopoietic cell transplantation (HCT) at any time.

Gilteritinib resulted in higher composite complete remission (CRc) rates compared to midostaurin (85.6% vs 72.4%, p=0.042) and increased rates of HCT. However, post-induction FLT3 MRD negativity rates did not differ significantly between the gilteritinib and midostaurin arms (40% vs 47.1%, p=0.366). Subgroup analysis revealed that FLT3-TKD-only patients had improved outcomes with gilteritinib, achieving higher CRc (88.9% vs 63.2%) and MRD-negative CRc rates (72.2% vs 63.2%). In contrast, FLT3-ITD patients showed no significant difference in MRD clearance between arms.

Relevance: The PrECOG 0905 trial demonstrates that gilteritinib improves remission rates and transplant eligibility compared to midostaurin in newly diagnosed FLT3-mutated AML. While MRD negativity post-induction was not significantly different, the higher CRc rates and favorable outcomes in FLT3-TKD patients suggest gilteritinib may offer particular benefit in this subgroup. These findings have practical implications for treatment selection in newly diagnosed AML, highlighting the need for further research into optimizing MRD clearance strategies with FLT3 inhibitors.

Link to Abstract: Abstract 221

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Long-Term Survival Outcomes and Cytogenetic/Molecular Patterns of Relapse in Adults with FLT3-Mutated AML Receiving Frontline Triplet Therapy with a Hypomethylating Agent, Venetoclax, and FLT3 Inhibitor

Authors: Nicholas J. Short, Sanam Loghavi, Musa Yilmaz, et al.

Background: FLT3-mutated AML is a high-risk subtype, particularly in older adults. Triplet therapy combining a hypomethylating agent (HMA), venetoclax, and a FLT3 inhibitor (FLT3i) has shown promising outcomes in smaller studies. This large retrospective analysis investigates long-term survival and relapse patterns among newly diagnosed FLT3-mutated AML patients receiving this triplet regimen.

Study Overview and Results:
The study included 88 newly diagnosed FLT3-mutated AML patients treated with frontline triplet therapy at a single center. The median age was 70 years, with 30% of patients aged ≥75. FLT3 mutations included FLT3-ITD (77%), FLT3-TKD (17%), and other rare mutations (6%). Gilteritinib was the most commonly used FLT3 inhibitor (69%), followed by quizartinib (21%), sorafenib (8%), and midostaurin (2%).

The triplet regimen demonstrated high response rates:

• CR/CRi was achieved in 92% of patients, with 80% of responders achieving MRD negativity by flow cytometry.
• The median overall survival (OS) for the entire cohort was 28.1 months, with a 3-year OS rate of 46%.
• Patients with FLT3-ITD mutations had a median OS of 24.5 months, whereas patients with non-ITD mutations achieved a longer median OS of 39.3 months.
• RAS pathway mutations at baseline were associated with worse survival (3-year OS: 20% vs. 56%, p=0.09).

Relapse occurred in 28% of responders. Notably, 60% of relapsed patients had FLT3 wild-type clones at progression, and clonal evolution was observed in 65%, with new mutations emerging in pathways such as RAS (20%) and GATA2 (13%). Outcomes following relapse were poor, with a median OS of 4.5 months.

Relevance: This study highlights the efficacy of frontline triplet therapy with HMA, venetoclax, and a FLT3 inhibitor in newly diagnosed FLT3-mutated AML, particularly among older adults. With a median OS of over two years and high MRD negativity rates, this approach represents a significant advance over historical outcomes with HMA/venetoclax alone. However, the findings also reveal that relapses often arise from FLT3 wild-type clones, underscoring the need for strategies to address clonal evolution and emergent mutations, particularly in the RAS pathway. For practicing hematologists, these results support the integration of triplet therapy as a frontline option in older patients with FLT3-mutated AML.

Link to Abstract: Abstract 220

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A CD33-Deleted Allograft (Trem-cel) Enables Post-Hematopoietic Cell Transplant (HCT) Maintenance Dosing of Gemtuzumab Ozogamicin (GO) with Therapeutic Levels of Drug Exposure and Low Hematologic and Hepatic Toxicity in Patients with High-Risk Acute Myeloid Leukemia (AML)

Authors: John F. DiPersio, Guenther Koehne, Nirali N. Shah, et al.

Background: Post-HCT relapse remains a leading cause of mortality in high-risk AML. Gemtuzumab ozogamicin (GO), an anti-CD33 antibody-drug conjugate, is effective but limited by hematopoietic toxicity due to CD33 expression on normal myeloid cells. Tremtelectogene empogeditemcel (trem-cel) is a CD33-deleted, CRISPR/Cas9 gene-edited hematopoietic stem and progenitor cell product designed to protect myeloid cells from GO-associated toxicities and allow post-HCT GO maintenance therapy.

Study Overview and Results:
The Phase 1/2 VBP101 trial enrolled 18 patients with high-risk CD33-positive AML or MDS undergoing allogeneic HCT. Patients received trem-cel after myeloablative conditioning and began post-HCT maintenance therapy with escalating doses of GO (0.5, 1, or 2 mg/m²).

• Trem-cel demonstrated rapid engraftment, with neutrophil recovery in a median of 9 days and platelet recovery in 16 days.
• CD33 deletion efficiency was 89% (71–94%), and post-HCT flow cytometry confirmed CD33 absence on 93% of neutrophils and monocytes.
• Pharmacokinetic analysis showed GO exposures were proportionally increased, with a reduced risk of hepatotoxicity compared to standard dosing.
• Importantly, no Grade 4 neutropenia occurred during GO maintenance therapy, and hepatotoxicity was limited to transient Grade 1 transaminase elevation.
• With a median follow-up of 6 months, 10 patients completed GO maintenance therapy (median: 4 cycles), with no severe hematologic or hepatic toxicities reported. Four relapses occurred, including 2 pre-GO initiation.

Relevance: This study demonstrates that the CD33-deleted allograft (trem-cel) allows safe and effective post-HCT maintenance dosing of GO in high-risk AML. Trem-cel shields normal hematopoietic cells from GO-associated toxicities, enabling therapeutic drug exposure while reducing cytopenias and hepatotoxicity. These findings highlight a novel strategy to extend the therapeutic window of GO and improve outcomes in high-risk AML patients undergoing allogeneic HCT.

Link to Abstract: Abstract 2873

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10-Year Follow-Up of CALGB 10603/RATIFY: Midostaurin Versus Placebo Plus Intensive Chemotherapy in Newly Diagnosed FLT3-Mutant AML Patients Aged 18-60 Years

Authors: Richard M. Stone, Jun Yin, Sumithra J. Mandrekar, et al.

Background: The CALGB 10603/RATIFY trial was the first to demonstrate the survival benefit of adding the FLT3 inhibitor midostaurin to standard intensive chemotherapy for FLT3-mutated AML. This 10-year follow-up analysis assesses the durability of event-free survival (EFS) and overall survival (OS) benefits, while examining long-term relapse patterns and late toxicities.

Study Overview and Results:
A total of 717 patients (360 midostaurin arm; 357 placebo arm) with newly diagnosed FLT3-mutated AML were randomized to receive daunorubicin/cytarabine (7+3) induction and consolidation chemotherapy with or without midostaurin. Allogeneic hematopoietic cell transplantation (alloHCT) was allowed at the investigator’s discretion. Patients were followed for 10 years, regardless of subsequent therapies.

At 10 years, midostaurin demonstrated a persistent EFS benefit over placebo:

• Median EFS: 8.2 months with midostaurin vs. 3.0 months with placebo (HR 0.79, p=0.0067).
• Overall survival (OS) remained superior with midostaurin, though marginally: 10-year OS estimates were 43.7% for midostaurin vs. 38.6% for placebo.

Among the 420 patients achieving complete remission (CR) within 60 days, relapse was the most common event, occurring in 184 patients. Interestingly, the pattern of late relapses was similar between arms. Toxicities were consistent with prior reports, with no new long-term safety signals identified.

Relevance: This long-term analysis confirms the durability of the EFS and OS benefits associated with midostaurin in FLT3-mutated AML, reinforcing its role as the standard of care in combination with intensive chemotherapy. The findings highlight the importance of long-term follow-up in assessing the true impact of targeted therapies. While midostaurin remains effective, the relatively high relapse rates emphasize the need for additional strategies, such as maintenance therapies or more potent FLT3 inhibitors, to further improve long-term outcomes in this high-risk population.

Link to Abstract: Abstract 218

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Updated Results and Longer Follow-Up from the AUGMENT-101 Phase 2 Study of Revumenib in All Patients with Relapsed or Refractory (R/R) KMT2Ar Acute Leukemia

Authors: Ibrahim Aldoss, Ghayas C. Issa, James S. Blachly, et al.

Background: KMT2A rearrangements (KMT2Ar) occur in ≤10% of acute leukemias and are associated with poor prognosis, particularly in relapsed/refractory (R/R) disease. Revumenib, a selective oral menin inhibitor, demonstrated promising interim results in the AUGMENT-101 Phase 2 trial, with efficacy supporting a New Drug Application. This updated analysis reports longer follow-up data in the largest cohort of KMT2Ar patients treated with a menin inhibitor to date.

Study Overview and Results:
The study enrolled 116 patients with R/R KMT2Ar acute leukemia (82% AML, 18% ALL/MPAL). The median patient age was 35.5 years (range: 0.6–75), with 44% having received ≥3 prior lines of therapy, 63% prior venetoclax, and 51% prior allogeneic transplant.

• The CR/CRh rate was 23% (95% CI: 15%-32%), with a median duration of response (DoR) of 6.4 months.
• Notably, 59% of responders achieved MRD negativity, confirming deep remissions.
• Among 13 patients who achieved CR/CRh in the interim analysis, the median duration of CR/CRh was updated to 13 months, with 5 patients remaining in remission at 7 additional months of follow-up.

The safety profile was consistent with previous reports. Common treatment-related adverse events included differentiation syndrome (19%), which was manageable with corticosteroids and dose modifications, and cytopenias. QTc prolongation occurred in 11% but was primarily Grade 1/2 and resolved with supportive care.

Relevance: The AUGMENT-101 trial confirms that revumenib delivers durable remissions with a favorable safety profile in heavily pretreated R/R KMT2Ar leukemia patients, including those previously exposed to venetoclax or transplant. High MRD-negative response rates highlight the potential for revumenib to achieve deep, clinically meaningful responses in this high-risk population. These results reinforce revumenib’s promise as a novel targeted therapy for KMT2Ar acute leukemias and provide the foundation for further studies to optimize its use, including combination strategies.

Link to Abstract: Abstract 211

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Venetoclax Combined with "7+3" Induction Chemotherapy Induces High MRD-Negative Response Rates in Newly Diagnosed AML Patients Fit for Intensive Chemotherapy Across Ages

Authors: Ioannis Mantzaris, Matan Uriel, Mendel Goldfinger, et al.

Background: Venetoclax has revolutionized AML therapy when combined with low-intensity regimens in unfit patients. However, its role in combination with intensive "7+3" chemotherapy in newly diagnosed AML patients remains underexplored. This Phase 1b study evaluates the safety and efficacy of venetoclax plus daunorubicin and cytarabine (7+3) in newly diagnosed AML patients fit for intensive therapy across different age groups.

Study Overview and Results:
In this single-center Phase 1b trial, 34 patients aged 18–75 years with newly diagnosed AML were enrolled. Venetoclax (400 mg) was administered for escalating durations (8, 11, or 14 days) alongside daunorubicin (60 mg/m²) and cytarabine (100 mg/m²) in standard 7+3 dosing. Median age was 59 years (range: 27–71), with 62% belonging to ethnic/racial minority groups. Patients were stratified by ELN 2022 risk groups: 38% favorable, 18% intermediate, and 44% adverse-risk.

• The composite complete remission (CRc) rate was 85.3% (95% CI: 68.9%–95.1%), achieved across all venetoclax cohorts.
• Among responders, 86% achieved measurable residual disease (MRD) negativity by multiparameter flow cytometry, with 79.3% MRD-negative by any assay.
• The median time to neutrophil recovery (ANC ≥1.0K/uL) and platelet recovery (≥100K/uL) was 27 and 28 days, respectively.
• With a median follow-up of 9.6 months, median event-free survival (EFS) and overall survival (OS) were not reached. Ten patients (29%) proceeded to allogeneic stem cell transplantation in first CR.
• Patients with TP53-mutated AML and complex karyotype had poorer outcomes, with 3 of 5 experiencing primary refractory disease.

The regimen was well tolerated, with no dose-limiting toxicities (DLTs) observed. Non-hematologic adverse events included febrile neutropenia (100%), sepsis (24%), and enterocolitis (24%).

Relevance: This study highlights the potential of venetoclax combined with "7+3" chemotherapy as a safe and highly effective induction regimen in fit AML patients, inducing deep MRD-negative responses across molecular subgroups. The promising results, coupled with manageable toxicity, support further investigation to determine the optimal venetoclax duration in this regimen. For practicing oncologists, this approach offers a powerful strategy to achieve durable remissions, including in younger and older AML patients eligible for intensive chemotherapy.

Link to Abstract: Abstract 57

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Emerging Trends and Future Directions in AML

The evolving AML treatment landscape continues to explore novel agents, mechanisms, and strategies that may shape clinical practice in the future. Early-phase studies are shedding light on innovative therapeutic approaches, including next-generation targeted therapies and immunotherapies. For example, lomonitinib (Abstract #1396) introduces a dual FLT3/IRAK4 inhibitor with encouraging early safety and pharmacokinetics, while bleximenib (Abstract #212) optimizes menin inhibition in KMT2A-rearranged and NPM1-mutated AML. Additionally, advancements in CAR-T cell therapies aim to mitigate toxicities, such as the use of dual inhibitory CAR constructs in CLL1-CD15 and CLL1-CD16 iCAR-T cells (Abstract #372), a promising strategy still in preclinical stages.

Mechanistic insights are also emerging, such as venetoclax resistance pathways and immune evasion in TP53-mutated AML (Abstract #61), offering new targets for therapeutic development. Retrospective analyses (Abstract #450) continue to provide thought-provoking comparisons between venetoclax/hypomethylating agents and intensive chemotherapy in favorable-risk AML, highlighting areas for prospective validation. Furthermore, combinations like low-dose cytarabine, venetoclax, and midostaurin (Abstract #217) explore optimized regimens for older or unfit patients, while patient-reported outcomes from midostaurin/gemtuzumab-based therapies (Abstract #2907) underscore the importance of balancing efficacy and quality of life.

Together, these studies represent critical steps toward understanding AML resistance mechanisms, advancing next-generation therapies, and refining patient-centered care. While their immediate impact may be limited, they highlight promising directions for clinical trials and future therapeutic strategies.

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Click here for more detailed summaries and insights into advances in AML
as presented at ASH 2024.

References

Senapati J, et al. Gemtuzumab Ozogamicin Added to Fludarabine, Cytarabine and G-CSF (FLAG-GO) Leads to Superior Molecular Response and Survival Outcomes Than Idarubicin (FLAG-IDA): 200 Patients Long-Term Follow up. Blood. 2024;144 (Supplement 1):1513. doi: https://doi.org/10.1182/blood-2024-211599

Luger S, et al. Gilteritinib Results in Higher Remission and Transplant Rates Than Midostaurin but Does Not Increase the Post-Induction Mutational MRD Negative Rate: Results of the Phase 2 Randomized Precog 0905 Study in Newly Diagnosed FLT3 Mutated AML. Blood. 2024;144 (Supplement 1):221. doi: https://doi.org/10.1182/blood-2024-201595

Short NJ, et al. Long-Term Survival Outcomes and Cytogenetic/Molecular Patterns of Relapse in Adults with FLT3-Mutated AML Receiving Frontline Triplet Therapy with a Hypomethylating Agent, Venetoclax and FLT3 Inhibitor. Blood. 2024;144 (Supplement 1):220. doi: https://doi.org/10.1182/blood-2024-210891

DiPersio JF, et al. A CD33-Deleted Allograft (Trem-cel) Enables Post-Hematopoietic Cell Transplant (HCT) Maintenance Dosing of Gemtuzumab Ozogamicin (GO) with Therapeutic Levels of Drug Exposure and Low Hematologic and Hepatic Toxicity in Patients with High-Risk Acute Myeloid Leukemia (AML). Blood. 2024;144 (Supplement 1):2873. doi: https://doi.org/10.1182/blood-2024-205641

Stone RM, et al. 10 Year Follow-up of CALGB 10603/Ratify: Midostaurin Versus Placebo Plus Intensive Chemotherapy in Newly Diagnosed FLT3 Mutant Acute Myeloid Leukemia Patients Aged 18-60 Years. Blood. 2024;144 (Supplement 1):218. doi: https://doi.org/10.1182/blood-2024-201058

Aldoss I, et al. Updated Results and Longer Follow-up from the AUGMENT-101 Phase 2 Study of Revumenib in All Patients with Relapsed or Refractory (R/R) KMT2Ar Acute Leukemia. Blood. 2024;144 (Supplement 1):211. doi: https://doi.org/10.1182/blood-2024-194384

Mantzaris I, et al. Venetoclax Combined with “7+3” Induction Chemotherapy Induces High MRD-Negative Response Rates in Newly Diagnosed AML Patients Fit for Intensive Chemotherapy across Ages. Blood. 2024;144 (Supplement 1):57. doi: https://doi.org/10.1182/blood-2024-211685

 

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