In Hawaii they Hula
They Tango in Argentina
They Reggae in Jamaica…
B. Zephaniah — “Everybody Is Doing It”
If iconic British writer and poet Benjamin Zephaniah were able to visit this year’s annual meeting, he might have added the line, “And they Jive in San Diego!” With tempo and rapid footwork in mind, here comes a whirl through a selection of acute myeloid leukemia (AML)-focused oral abstracts presented at #ASH24.
November saw the U.S. Food and Drug Administration’s approval of the first-in-class oral menin inhibitor (MI) revumenib for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements. This milestone hinged on data from the interim analysis (n=56) of the phase II AUGMENT-101 study. Updated AUGMENT-101 data (n=116) were presented in Abstract 211, which shows that in a heavily pre-treated population, 22% of patients achieved the predefined composite complete response endpoint, with a prolonged duration of response (median: 13 months), and 61% achieved MRD negativity. Key side effects are differentiation syndrome (DS) in 15%, cytopenias, and febrile neutropenia.
Other MIs are not far behind. At the same session, Abstracts 212 and 213 showcase phase 1 data for bleximenib and enzomenib as monotherapy in R/R AML with KMT2A rearrangements or NPM1 mutations, reporting response rates of greater than 30% with low treatment-related adverse events. Phase 1a data on ziftomenib and bleximenib in combination with intensive 7+3-based chemotherapy in newly diagnosed AML are reported in Abstracts 214 and 215. Notably, rapid cytoreduction appears key to averting DS, with no DS or dose-limiting toxicities observed and composite response rates as high as 80 to 100%. Abstract 216 highlights promising phase I/II data of the all-oral combination of revumenib, venetoclax, and a hypomethylating agent in R/R AML, with13 out of 39 patients responding.
Continuing our quickstep, MIs are prominent in pre-clinical sessions. Abstract 724 explores genetic and non-genetic mechanisms underlying MI resistance. Here, authors deployed and validated a CRISPR-Cas9 base editing screen in cells exposed to four different MIs currently in clinical trials to pinpoint shared and novel acquired mutations, identifying differential resistance mechanisms and providing a rationale to switch MIs when resistance occurs.
Although it's well-known that menin is part of the KMT2A/B methyltransferase complex, the factors determining the selectivity of how this complex binds DNA to drive leukemic gene expression remain poorly understood. Abstract 952 deploys multi-omic chromatin and functional genomic profiling to reveal that menin targets a subset of promoters that are adenine- and thymine-rich with a CpG island near the transcriptional start site.
Skipping beyond MIs to advances in cellular therapies in AML, Abstract 372 introduces CLL1-CD15 and CLL-CD16 inhibitory chimeric antigen receptor (CAR) T cells, which leverage the distinct expression levels of CD15 and CD16 on neutrophils and AML blasts to enhance AML cell specificity and mitigate against the granulocytopenia toxicity that has hitherto prevented CLL1-targeting CAR T cells from progressing. Abstract 371 at the same session focuses on anti-U5 snRNP200 CAR T cells, which target an antigen that is upregulated by interferon-gamma exposure and show high tumor-selectivity and efficacy in vitro and in vivo. Novel natural killer (NK) cell therapeutics also show pre-clinical promise — Abstract 915 outlines a strategy to generate “off-the-shelf” allogeneic NK cells by developing a gene construct that simultaneously downregulates major histocompatibility complex class I expression to escape host immune rejection and introduces the CAR and surface antigen molecules to avoid host NK cell killing. Abstracts 916 and 917, from the same session, highlight highly engineered, novel NK-CARs targeting AML with promising pre-clinical data.
TP53 mutations in AML portend a dire prognosis and an area of clinical need. Abstracts 61 and 330 focus on how T-cell exhaustion contributes to disease persistence, identified by single-cell, multiomic analysis of TP53-mutant primary patient samples. Abstract 637 highlights how targeting immunosuppressive T regulatory cells may help restore the function of effector CD8 T cells in AML patients with active disease.
Other new moves in AML include Abstract 327, which uses functional assays to confirm that the Y1316X mutation in the PHIP gene (recently identified as mutated in 7% of AML cases of African ancestry and rare in those of European ancestry) is an oncogenic mutation and should be included in targeted sequencing panels.
Wrapping up this whirlwind review, Abstract 450 tackles a common clinical challenge: For patients aged 60-75 with favorable-risk AML (NPM1 mutant in the absence of FLT3-ITD), does intensive chemotherapy, despite its toxicity, offer better outcomes than venetoclax and hypomethylating agents? The findings indicate comparable results between the two approaches, providing guidance for clinical decision-making in this potentially frail population.
This twirl through the latest #AML insights at ASH 2024 aims to highlight key advances in the field, though the author freely admits to struggling with the choreography required at ASH 2024! If I missed your top picks, feel free to share them at @CkBrierley
