The 66th American Society of Hematology (ASH) Annual Meeting has successfully concluded, gathering over 30,000 experts and scholars from around the world. This year’s conference featured numerous carefully curated sessions, providing profound insights into fundamental research, innovative therapies, and disease management in hematology. To highlight the key findings from ASH 2024, Hematology Frontier presents the News of ASH series, offering a concise summary of the latest breakthroughs in the field.

Menin Inhibitors: A Milestone in AML Treatment

In November 2024, FDA approved the first oral menin inhibitor, revumenib, for relapsed/refractory (R/R) acute myeloid leukemia (AML) patients with KMT2A rearrangements. This milestone was based on interim results from the Phase II AUGMENT-101 trial (n=56). Updated data (n=116), presented in Abstract 211, showed a 22% composite complete remission rate in heavily pretreated patients, with a median duration of remission of 13 months. Notably, 61% of patients achieved minimal residual disease (MRD) negativity. Key adverse events included differentiation syndrome (DS) in 15% of patients, cytopenias, and febrile neutropenia.

Other menin inhibitors are also advancing rapidly. Abstracts 212 and 213 reported promising Phase I data on bleximenib and enzomenib as monotherapies for R/R AML with KMT2A rearrangements or NPM1 mutations, demonstrating response rates exceeding 30% with manageable toxicity. Abstracts 214 and 215 presented early-phase data on ziftomenib and bleximenib in combination with intensive chemotherapy (7+3 regimen) for newly diagnosed AML. A key observation was that rapid cytoreduction appeared essential in preventing differentiation syndrome, with no cases of DS or dose-limiting toxicities observed, and composite remission rates reaching 80% to 100%.

Abstract 216 explored a novel all-oral regimen combining revumenib, venetoclax, and a hypomethylating agent in R/R AML, reporting responses in 13 out of 39 patients.

Understanding Menin Inhibitor Resistance and Molecular Mechanisms

Menin inhibitors were also a focus of preclinical studies. Abstract 724 investigated genetic and non-genetic resistance mechanisms to these agents. Researchers used CRISPR-Cas9 base-editing screening on cells treated with four different menin inhibitors to identify shared and novel resistance mutations. These findings provide a rationale for switching between menin inhibitors when resistance emerges.

Although menin is a known component of the KMT2A/B methyltransferase complex, the precise mechanisms by which this complex selectively binds DNA to drive leukemic gene expression remain unclear. Abstract 952 employed multi-omic chromatin and functional genomic analysis to reveal that menin preferentially targets promoters enriched in adenine-thymine sequences and CpG islands near transcription start sites.

Cell Therapy Innovations in AML

Advances in AML cellular therapies were another highlight at ASH 2024. Abstract 372 introduced CLL1-CD15 and CLL1-CD16 inhibitory chimeric antigen receptor (CAR) T cells, designed to exploit the differential expression of CD15 and CD16 on neutrophils and AML blasts. These modifications aim to enhance AML specificity while mitigating granulocyte depletion toxicity, a major limitation of CLL1-targeting CAR-T therapy.

Abstract 371 focused on anti-U5 snRNP200 CAR-T cells, which target an antigen upregulated in response to interferon-γ exposure. Preclinical data demonstrated strong tumor selectivity and efficacy in vitro and in vivo.

Novel natural killer (NK) cell therapies also showed promising results. Abstract 915 outlined a gene-engineering strategy to generate allogeneic “off-the-shelf” NK cells, incorporating modifications that downregulate major histocompatibility complex (MHC) class I to evade host immune rejection while integrating CAR and surface antigen molecules to prevent host NK cell-mediated elimination. Abstracts 916 and 917 presented highly engineered CAR-NK cell therapies for AML, with encouraging preclinical data.

TP53-Mutant AML: New Insights into Immune Evasion

TP53 mutations are a hallmark of poor prognosis in AML and remain a critical area of unmet clinical need. Abstracts 61 and 330 employed single-cell multi-omic analysis of primary TP53-mutant AML samples to explore how T-cell exhaustion contributes to disease persistence. Abstract 637 emphasized that targeting immunosuppressive regulatory T cells (Tregs) may help restore CD8+ T-cell function in active AML.

Additional Notable AML Findings

• Genomic Discoveries: Abstract 327 identified the Y1316X mutation in the PHIP gene as an oncogenic driver, suggesting its inclusion in targeted sequencing panels.
• Treatment Strategies for Older Patients: Abstract 450 addressed a key clinical question regarding AML management in patients aged 60-75 with NPM1 mutations but without FLT3-ITD. The study compared intensive chemotherapy with venetoclax plus a hypomethylating agent, concluding that both approaches provided comparable efficacy, offering new guidance for clinical decision-making in this patient population.

ASH 2024 presented significant advances in AML research, with menin inhibitors, cellular therapies, and novel genomic insights shaping the future of treatment. These developments continue to refine precision medicine approaches, offering hope for improved outcomes in AML.