Abstract FLT3-internal tandem duplication measurable residual disease testing for patients in remission from acute myeloid leukemia is now recommended by the recently updated clinical standard-of-care guidelines. This companion technical note provides important laboratory and clinical recommendations regarding such testing.

ABSTRACT:QuANTUM-First was a randomized trial that demonstrated that the addition of quizartinib, a potent and selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, to induction and consolidation chemotherapy, followed by monotherapy maintenance, improved the survival for patients with newly diagnosed FLT3-internal tandem duplication (FLT3-ITD)-mutated acute myeloid leukemia. We conducted a post hoc analysis of the trial data focusing on measurable residual disease (MRD) as assayed using an amplicon-based next-generation sequencing assay, and on the impact of molecular biomarkers such as FLT3-ITD insertion length and comutations. This is, to our knowledge, the first prospective, randomized trial of an FLT3 inhibitor in newly diagnosed patients in which FLT3-ITD MRD data were collected throughout therapy. We established that quizartinib induces deeper remissions with respect to FLT3-ITD MRD vs placebo, and that the amount of MRD at the completion of induction correlates with relapse and survival. We found that longer FLT3-ITD insertion mutations correlated with worse outcome, quizartinib was beneficial irrespective of insertion mutation length, and the FLT3-ITD MRD assay was more sensitive when bone marrow was used vs peripheral blood. Regardless of the presence of NPM1 (nucleophosmin 1) comutation, quizartinib increased the rates of MRD negativity at the end of induction vs placebo. Finally, comparison of the FLT3-ITD mutation length between the polymerase chain reaction (PCR) with capillary electrophoresis assay obtained at screening and the PCR next-generation sequencing MRD assay performed at the end of induction showed a 96.2% concordance with the exact ITD length. This trial was registered at www.clinicaltrials.gov as #NCT02668653.

BMT CTN 1506 ("MORPHO") was a phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) in first remission. Subgroup analysis indicated a significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD measurable residual disease (MRD). Participants transplanted < 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved survival from post-HCT gilteritinib. Pre-HCT MRD levels were higher (P = 0.001) in participants transplanted within 120 days from diagnosis and in those treated with a FLT3 inhibitor pre-HCT and transplanted within 120 days (P = 0.008). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Time from AML diagnosis to HCT and pre-HCT FLT3 inhibitor use both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the observed regional differences in benefit from post-HCT gilteritinib. Increasing the number of courses of treatment pre-HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition, but with a presumed risk of some patients experiencing early progression. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

QuANTUM-First (ClinicalTrials.gov identifier: NCT02668653) was a randomized phase III trial in patients with newly diagnosed FLT3-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) treated with quizartinib or placebo plus standard induction and consolidation chemotherapy and/or allogeneic hematopoietic cell transplantation (allo-HCT), followed by single-agent maintenance therapy. We evaluated the impact of allo-HCT performed in first complete remission (CR1) or composite CR1 (CRc1) on overall survival (OS), considering treatment randomization. Post-hoc extended Cox regression multivariable analyses were conducted in patients who achieved complete remission/composite complete remission by the end of induction, including allo-HCT in CR1/CRc1 as a time-dependent variable to identify prognostic and predictive factors for OS. There were 297 patients with complete remission by the end of induction (quizartinib, N=147; placebo, N=150); of these, 157 (52.9%) underwent allo-HCT in CR1 (quizartinib, N=84; placebo, N=73). There were 368 patients with composite complete remission by the end of induction (quizartinib, N=192; placebo, N=176); of these, 196 (53.3%) underwent allo-HCT in CRc1 (quizartinib, N=110; placebo, N=86). Multivariable analyses revealed quizartinib treatment and allo-HCT in either CR1 (hazard ratio [HR]=0.553, 95% confidence interval [95% CI]: 0.383-0.798, P=0.0015 and HR=0.527, 95% CI: 0.349-0.796, P=0.0023, respectively) or CRc1 (HR=0.645, 95% CI: 0.470‒0.886, P=0.0068 and HR=0.557, 95% CI: 0.391-0.793, P=0.0012, respectively) as significant predictive factors for a longer OS. No new safety signals were identified. Patients who underwent protocol-specified allo-HCT in CR1/CRc1 experienced post-transplant-related complications, mostly grade ≥2 graft-versus-host disease, as expected. This post-hoc analysis further supports the use of quizartinib and allo-HCT in CR1/CRc1 as an efficacious and well-tolerated treatment strategy for newly diagnosed FLT3-ITD-positive AML patients fit for intensive chemotherapy.

Quizartinib is a potent type II inhibitor of FMS-like tyrosine kinase 3 (FLT3) that demonstrated significant survival benefit among patients with newly diagnosed (ND) acute myeloid leukemia (AML) without FLT3-internal tandem duplication (FLT3-ITD) in the randomized, Phase II QUIWI trial. Here, we present the rationale and design of QuANTUM-Wild, a double-blind, randomized, placebo-controlled, Phase III study to confirm the efficacy and safety of quizartinib plus standard induction and consolidation chemotherapy and as maintenance monotherapy in adult patients with ND FLT3-ITD-negative AML. Eligible patients are randomized 2:2:1 to one of three treatment arms. Patients in Arm A (n ≈ 280) receive quizartinib plus chemotherapy during induction and consolidation (with option for transplant without study drug), followed by up to 36 cycles of single-agent maintenance therapy. Patients in Arm B (n ≈ 280) receive placebo in all treatment phases plus chemotherapy, then as maintenance monotherapy. Patients in Arm C (n ≈ 140) receive quizartinib plus chemotherapy in the induction and consolidation phases, then placebo during the maintenance phase, to specifically assess the utility of quizartinib maintenance. The primary endpoint is overall survival. Secondary endpoints include event-free survival, remission rate, and safety.Clinical trial registration: http://www.clinicaltrials.gov identifier is NCT06578247.

This post hoc pooled analysis of ADMIRAL and COMMODORE trials aimed to determine if response kinetics differ for gilteritinib monotherapy in relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML). In total, 205 patients achieved composite complete remission (CRc). This analysis only included the 166 patients (81.0%) who achieved CRc before on-study hematopoietic stem cell transplantation (HSCT). Of these, 148 patients (89.2%) achieved CRc within 6 gilteritinib cycles, 60 patients (36.1%) after cycle 2, and 119 patients (71.7%) after cycle 4. We defined early responders (ERs; n = 60) and later responders (LRs; n = 106) as those who achieved CRc within 2 cycles and after cycle 3, respectively. Multivariate logistic regression analysis indicated that female patients and patients with nucleophosmin 1 comutations were more likely to be ERs than LRs. Median CRc duration was 2.7 months (range, 0-66) for ERs and 3.5 months (range, 0-61) for LRs. More LRs (41 of 106 patients [38.7%]) had best response of CR vs ERs (13 of 60 patients [21.7%]). Median overall survival indexed at CRc date was 9 months for ERs and 10 months for LRs. In ERs and LRs, 14 of 60 patients (23.3%) and 20 of 106 patients (18.9%) underwent HSCT respectively. The rate of drug-related grade ≥3 adverse events was 11.4 events per patient-years in ERs and 7.8 events per patient-years in LRs. Patients with R/R FLT3-mutated AML should continue gilteritinib monotherapy, if tolerated, for a minimum of 6 cycles because later responses can occur. These trials were registered at www.clinicaltrials.gov as NCT02421939 (ADMIRAL) and NCT03182244 (COMMODORE).

Abstract Patients with acute myeloid leukemia (AML) arising from antecedent myeloid neoplasms (secondary AML, sAML) continue to have poorer outcomes than those with de novo AML, characterized by a high incidence of refractory disease and relapse after initial response. Most patients with sAML are treated with combinations of hypomethylating agents, such as azacytidine, together with venetoclax, a BCL-2 inhibitor. However, RAS mutations, present in approximately 20-30% of these patients, confer resistance to venetoclax and are associated with shorter overall survival. Although RAS oncogenes were long considered “undruggable,” KRAS mutant-specific inhibitors have recently shown promise in clinical trials for solid tumors. Notably, treatment with the RAS-MultiON inhibitor RMC-7977 has been reported to sensitize AML cells to FLT3 and BCL-2 inhibition. In this study, we found that pretreatment with azacitidine enhances the sensitivity of RAS-mutated sAML cells to RMC-7977.Analysis of the BEAT AML 2.0 dataset revealed that mutations affecting RAS signaling—particularly in KRAS, NRAS, and PTPN11—rank among the top alterations associated with resistance to azacytidine treatment in AML samples. These findings suggest that combining azacytidine with RAS inhibition may represent a promising therapeutic strategy for RAS-mutated AML. To evaluate this, we compared three treatment approaches in SKM1 cells: concurrent administration of azacytidine and RMC-7977, sequential treatment with azacytidine followed by RMC-7977, and the reverse sequence. Only pretreatment with azacytidine followed by RMC-7977 produced synergistic effects. This sequential regimen also produced synergistic effects on inducing apoptosis in the MDS/sAML cell lines MDS92, MDS-L, and SKM1. Consistently, treatment of primary RAS-mutated sAML samples with azacytidine followed by RMC-7977 significantly reduced clonogenic growth compared with either agent alone, without impairing the clonogenicity of healthy hematopoietic cells. Finally, pretreatment of SKM1 xenografts with azacytidine (5 mg/kg for 5 days) markedly improved RMC-7977-mediated control of leukemic burden.We found that azacytidine treatment sensitizes RAS-mutated sAML cells to RAS inhibition by RMC-7977 in both in vitro and in vivo models. Ongoing studies aim to elucidate the underlying molecular mechanisms, including the potential role of methylation changes in modulating oncogenic signaling dependencies. Together, these findings provide a strong rationale for continued evaluation of RAS inhibitors as part of combination treatment strategies for RAS-mutated AML. Citation Format: Xinghan Zeng, Yuju An, Brandy Perkins, Tessa Seale, Erotokritos Georgantzinos, Theodora Chatzilygeroudi, Bogdan Paun, Maximillian Stahl, Mark J. Levis, Styliani Karanika, Alexander Ambinder, Sandra Misale, Theodoros Karantanos. Pre-treatment with azacytidine sensitizes RAS mutated secondary AML to the pan-RAS inhibitor RMC-7977 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1876.

Allogeneic hematopoietic cell transplantation is the only curative option for many patients with acute myeloid leukemia (AML). In the current study, we designed and implemented a personalized assay, called v96, incorporating up to 96 mutations in 30 AML patients undergoing transplantation. The assay was performed on DNA derived from cells isolated from the bone marrow as well as in cell-free plasma. All 30 (100%) of patients harbored molecular evidence of residual leukemia during remission that was detectable by the v96 assay, while only 6 (20%) had evidence of disease as assessed by conventional clinical assays. Furthermore, cell-free DNA from plasma proved to be more sensitive than DNA from cells of the bone marrow for identifying residual leukemia. The median number of mutants was 352-fold higher in plasma taken prior to transplantation for patients who relapsed compared to those who did not relapse. At 2 mo posttransplantation, 27 of the 30 patients still harbored detectable leukemia as assessed by the v96 assay. Twenty-two of these patients had a subsequent decrease in leukemic burden assessed by the v96 assay. In the majority of them (20 of 22 patients), the decrease occurred only after immunosuppression was discontinued, supporting a graft-versus-leukemia effect. These results document the feasibility of using a relatively large panel of carefully chosen mutations and a highly specific assay as noninvasive markers of therapeutic response in AML patients, minimizing the need for multiple bone marrow biopsies.

Abstract Patients with acute myeloid leukemia (AML) arising from antecedent myeloid neoplasms (secondary AML, sAML) continue to have poorer outcomes than those with de novo AML, characterized by a high incidence of refractory disease and relapse after initial response. Most patients with sAML are treated with combinations of hypomethylating agents, such as azacytidine, together with venetoclax, a BCL-2 inhibitor. However, RAS mutations, present in approximately 20–30% of these patients, confer resistance to venetoclax and are associated with shorter overall survival. Although RAS oncogenes were long considered “undruggable,” KRAS mutant–specific inhibitors have recently shown promise in clinical trials for solid tumors. Notably, treatment with the RAS-MULTI(ON) inhibitor RMC-7977 has been reported to sensitize AML cells to FLT3 and BCL-2 inhibition. In this study, we found that pretreatment with azacitidine enhances the sensitivity of RAS-mutated sAML cells to RMC-7977. Analysis of the BEAT AML 2.0 dataset revealed that mutations affecting RAS signaling, particularly in KRAS, NRAS, and PTPN11, rank among the top alterations associated with resistance to azacytidine treatment in AML samples. These findings suggest that combining azacytidine with RAS inhibition may represent a promising therapeutic strategy for RAS-mutated AML. To evaluate this, we compared three treatment approaches in SKM1 cells: concurrent administration of azacytidine and RMC-7977, sequential treatment with azacytidine followed by RMC-7977, and the reverse sequence. Only pretreatment with azacytidine followed by RMC-7977 produced synergistic effects in reducing cell viability. RAS signaling pathway analysis revealed that treatment with azacytidine increased ERK phosphorylation and DUPS6 levels in SKM1 cells, potentially sensitizing to subsequent RAS inhibition with RMC-7977. This sequential regimen also produced synergistic effects on inducing apoptosis in the MDS/sAML cell lines MDS92, MDS-L, and SKM1. Consistently, treatment of primary RAS-mutated sAML samples with azacytidine followed by RMC-7977 significantly reduced clonogenic growth compared with either agent alone, without impairing the clonogenicity of healthy hematopoietic cells. Finally, pretreatment of SKM1 xenografts with azacytidine (5 mg/kg for 5 days) markedly improved RMC-7977-mediated control of leukemic burden in vivo. In conclusion, we found that azacytidine treatment sensitizes RAS-mutated sAML cells to RAS inhibition by RMC-7977 in both in vitro and in vivo models. Ongoing studies aim to elucidate the underlying molecular mechanisms, including the potential role of methylation changes in modulating oncogenic signaling dependencies. Together, these findings provide a strong rationale for continued evaluation of RAS inhibitors as part of combination treatment strategies for RAS-mutated AML. Citation Format: Tessa Seale, Xinghan Zheng, Yuju An, Brandy Perkins, Erotokritos Georgantzinos, Theodora Chatzilygeroudi, Bogdan Paun, Maximillian Stahl, Mark J. Levis, Styliani Karanika, Alexander J. Ambinder, Theodoros Karantanos, Sandra Misale. Pre-treatment with azacytidine sensitizes RAS mutated secondary AML to the pan-RAS inhibitor RMC-7977 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B004.

Abstract Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes because of the lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML compared with healthy hematopoietic cells, and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks, leading to cancer cell death. Anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity associated with DNA damage against cell lines derived from patients with MDS/AML with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation, and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML, including TP53-mutated subsets.

Outcomes for adults with Philadelphia chromosome positive pre-B cell acute lymphoblastic leukemia (Ph + B-ALL) have improved dramatically, but questions remain regarding the optimal induction regimen and role of allogeneic hematopoietic cell transplantation (alloHCT). We analyzed 60 consecutive patients who received reduced-intensity (RII) or hyper-CVAD induction with continuous, second-generation tyrosine kinase inhibitors (TKIs). Reduced hematologic toxicity occurred after RII. Measurable residual disease (MRD) clearance by multicolor flow cytometry (MFC, 61 vs. 94%, p = 0.02) favored hyper-CVAD, but subsequent MRD-directed blinatumomab negated this difference. Four-year relapse-free survival (RFS) was 72.3% (95% confidence interval: 57.4-91.0%) and 79.8% (65.4-97.3%, p = 0.3) in RII and hyper-CVAD groups, respectively. AlloHCT, predominantly using reduced-intensity conditioning, bone marrow grafts, and post-transplant cyclophosphamide, was the only variable associated with improved overall survival on multivariate analysis. Concurrent chemotherapy and TKIs followed by blinatumomab for MRD positivity and alloHCT, all in less intensive forms, yield excellent outcomes for patients with Ph + B-ALL.

Bulk sequencing of relapsed tumors reveals mutations associated with resistance to cancer therapy but is insufficient to fully assess all causes of relapse. Due to inherent tumor heterogeneity, on-treatment tumor evolution may select for genetically distinct clones or shifts in malignant transcriptional states not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of a clinical trial cohort of acute myeloid leukemia (AML) patients treated on the Phase 1b clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Gilt) to characterize immunophenotypic, transcriptional, and genetic clonal evolution driving resistance. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, resistance was associated with RAS activation via multiple mechanisms including selection for RAS mutant clones, non-mutational upregulation of RAS transcriptional programs and a shift to RAS-associated monocytic AML differentiation. In an in vitro model of monocytic differentiation associated with non-mutational RAS transcriptional activation, we demonstrated that RAS pathway inhibition re-sensitized to Ven/Gilt. These data illustrate that convergent resistance pathways in patients can be activated via diverse genetic and non-genetic mechanisms. These results underscore that RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to AML monocytic differentiation and highlight RAS pathway inhibition as a viable clinical strategy to combat resistance. CT# NCT03625505.

ABSTRACT:QuANTUM-First demonstrated improved overall survival (OS) in patients with newly diagnosed acute myeloid leukemia with FMS-like receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD) treated with quizartinib + standard chemotherapy. Herein, we evaluated the impact of postconsolidation/posttransplant single-agent maintenance therapy on clinical outcomes in patients receiving maintenance, focusing on measurable residual disease (MRD) status at maintenance onset. OS, event-free survival, and relapse-free survival were prespecified exploratory analyses. Cumulative incidence of relapse, analyses by allogeneic hematopoietic cell transplant (allo-HCT), and analyses by MRD status were post hoc and not powered for statistical significance. Samples for FLT3-ITD MRD analysis were collected from patients with composite complete remission ≤30 days before receiving maintenance and assessed using an ultrasensitive amplicon-based assay. More patients who had received an allo-HCT and quizartinib treatment received maintenance (71%) vs placebo (55%); OS benefit was not demonstrated among these patients. In patients who did not undergo allo-HCT, quizartinib maintenance was associated with a significant OS benefit (hazard ratio [HR], 0.401; 95% confidence interval [CI], 0.192-0.838), including a benefit in patients who were MRD negative at the start of maintenance (OS HR, 0.194; 95% CI, 0.056-0.676). Patients who were MRD negative at the completion of consolidation achieved 89.1% (95% CI, 70.0-96.4) survival at 3 years with quizartinib maintenance in the absence of allo-HCT. These data suggest that for patients who achieve FLT3-ITD MRD negativity after induction and consolidation with quizartinib, maintenance with quizartinib provides a significant survival benefit and, in some patients, may eliminate the need for allo-HCT. This trial was registered at www.clinicaltrials.gov as NCT02668653.

Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition. ### Competing Interest Statement C.C.S. has provided educational talks for Astellas Pharma, served on advisory boards for Genentech/Abbvie and received research funding from Abbvie. B.C., Y.S. and J.H. are employees of Abbvie. M.S. and H.H. are or were previously employees of Genentech.

Marrow IDH1 VAF prior to Transplant and Maintenance

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by features of both myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN). Patients with CMML have dismal outcomes partially due to their poor responses to the standard treatment with hypomethylating agents, highlighting a need for new treatments. RAS mutations are detected in roughly 50% of CMML patients and in even higher frequency among patients who progress to acute myeloid leukemia (AML). These mutations contribute to a poor prognosis and are also among the most commonly acquired resistance mutations in AML patients treated with targeted therapies. The current strategy to overcome RAS in myeloid malignancies is to target downstream effectors such as MEK, but these therapies are hindered with short-lived clinical response and resistance emergence. However, recent breakthroughs in the direct inhibition of RAS have renewed enthusiasm for targeting RAS-mutant tumors. Currently, there has been little exploration of the potential efficacy and safety of RAS inhibitors in the context of myeloid malignancies. We hypothesize that the RASmulti(ON) inhibitor RMC-7977, a highly selective inhibitor of the active forms of KRAS, HRAS and NRAS, will be effective against RAS-mutated AML cell lines arising from chronic myeloid neoplasms including CMML. We first characterized the effect of RMC-7977 in various AML cell lines with mutated RAS and wild-type RAS that is activated by alternative mutations. RMC-7977 treatment suppressed proliferation in the low nanomolar range in both RAS-mutated and wild type models. The AML cell lines arising from MDS/CMML were particularly sensitive to the RAS inhibitor, with these cells also displaying increased apoptosis when treated with low nanomolar levels of RMC-7977. Cell signaling experiments revealed that low doses of RMC-7977 significantly decreased phosphorylation of MEK and ERK, as well as ERK transcriptional output. RMC-7977 treatment significantly induced apoptosis and reduced AML blasts from patients with RAS-mutated AML that arose from MDS or MDS/MPN including CMML and prolonged survival as a monotherapy in a RAS mutated secondary AML xenograft model. Additionally, treatment with RMC-7977 showed no effect on the survival and differentiation of healthy hematopoietic stem and progenitor cells taken from human donors, strengthening its potential as an effective therapy in CMML and AML with low toxicity. We have demonstrated that the pan-RAS inhibitor RMC-7977 is highly effective against RAS mutated AML cell lines arising from chronic myeloid neoplasms including CMML while sparing healthy hematopoietic stem and progenitor cells. This work provides the rationale to continue evaluating RAS inhibitors as a targeted therapy in RAS-mutated myeloid malignancies, which is a significant unmet need in the treatment of these conditions. Tessa Seale, Brandy Perkins, Theodora Chatzilygeroudi, Soren Cole, Kareem Battah, Santiago Borrego Garcia, Maximilian Stahl, Mark J. Levis, Alexander Ambinder, Theodoros Karantanos, Sandra Misale. Pan-RAS inhibitor RMC-7977 overcomes oncogenic RAS signaling and exerts antileukemic effects in CMML/AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3809.