Issa, Ghayas

Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (<0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

Abstract Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 comutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and a higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants and our clinic-ready diagnostic workflow into the CMML diagnostic framework to improve accuracy. Significance: Through comprehensive clinical and genomic profiling of a large patient cohort, alongside immunophenotypic and transcriptional cellular analyses, this study provides evidence that incorporating genomic determinants into the diagnostic criteria for OM-CMML improves diagnostic accuracy and refines the identification of early-stage CMML, thereby preventing misclassification.

Abstract Recent updates to the monocyte count thresholds for diagnosing chronic myelomonocytic leukemia (CMML) have recognized oligomonocytic CMML (OM-CMML) as an early stage within the CMML spectrum. However, the clinical validity of these revised criteria remains uncertain without considering biological factors and might misclassify myelodysplastic syndromes (MDS) with mild monocytosis as CMML. To characterize the genomic landscape of OM-CMML, we evaluated OM-CMML (n=249), MDS (n=304) and myelodysplastic CMML (MD-CMML, n=358) patients (pts) treated at three academic institutions. Targeted next-generation sequencing was performed on bone marrow (BM) at initial diagnosis or first referral. OM-CMML was characterized by lower frequencies of biallelic TET2 (biTET2) and RAS pathway (RASp) gene mutations (BRAF, CBL, KRAS, NF1, NRAS and PTPN11) compared to MD-CMML (p<0.001) but higher frequencies than MDS (p<0.001). BM monocyte frequencies, assessed morphologically, were higher in OM-CMML than in MDS (p<0.001) but lower than in MD-CMML (p<0.001), indicating that OM-CMML is a heterogenous group including true CMML and distinct MDS subsets. Unsupervised hierarchical clustering based on genomic alterations across all cases (n=911) identified three distinct clusters: 1) TP53 alterations (predominantly multihit TP53) and complex karyotype (TP53-complex); 2) biTET2 or TET2-SRSF2 co-mutation (biTET2/SRSF2); 3) a heterogenous group lacking these features (not otherwise specifiable [NOS]). Among OM-CMML pts, 11%, 34% and 55% belonged to these clusters, respectively. Model-based unsupervised clustering further identified 9 unique clusters that could be consolidated into 6 groups: 1) TP53-complex; 2) biTET2/SRSF2; 3) SF3B1 (without biTET2 or SRSF2); 4) SRSF2 without TET2 and frequent IDH2 mutations (SRSF2-IDH2); 5) ASXL1 and U2AF1 mutations and copy number alterations (CNA-ASXL1/U2AF1); 6) no somatic mutations (No mutation). biTET2/SRSF2 group exhibited monocytic bias with higher AMC, PB and BM monocyte % even among OM-CMML cases. This bias was not attributed to higher RAS pathway mutation frequencies, as biTET2/SRSF2 cases had similar RASp mutation frequencies but lower median variant allele frequencies for RASp mutations compared to NOS cases (9% vs. 21%, p=0.029). PB monocyte partitioning using flow cytometry (FC) in a subset of OM-CMML pts (n=50) demonstrated higher frequency of classical monocytosis (>94% CD14+/CD16- monocytes) in biTET2/SRSF2 vs other OM-CMML. To further determine if biTET2/SRSF2 genotype defines a distinct biological subgroup, we performed RNA-sequencing of BM CD34+ cells from healthy donors (n=15) and pts with OM-CMML (n=12), MD-CMML (n=14) and MDS (n=55). Unsupervised clustering based on gene expression profiles revealed that biTET2/SRSF2 clustered irrespective of their diagnostic group with greater dispersion being observed based on diagnosis. MDS and CMML with biTET2/SRSF2 had less differentially expressed genes compared to MDS and CMML with biTET2/SRSF2 relative to other MDS and CMML genotypes. Among 138 OM-CMML pts in whom progression to overt CMML was evaluable, 37 (27%) progressed to overt CMML of which 26 (70%) belonged to the biTET2/SRSF2 group. Competing risk analysis confirmed higher cumulative incidence and shorter time to CMML progression among biTET2/SRSF2 OM-CMML. Using ElasticNet regression we identified BM monocytosis and 14 genomic variables (including biTET2 and TET2-SRSF2) as predictors of overt CMML progression among OM-CMML. We developed a score-based model able to predict progression with high reliability (AUC 0.805, sensitivity 0.70, specificity 0.76). Model accuracy was confirmed by optimism-corrected bootstrap internal validation (AUC 0.668). Monocytic bias, BM classical monocytosis (>94% CD16- monocytes) and higher overt CMML progression in biTET2/SRSF2 was confirmed in a validation cohort (28, 66 and 22 pts with OM-CMML, MDS and MD-CMML, respectively). BM monocytosis of biTET2/SRSF2 was confirmed in this cohort with morphologic and FC monocyte frequency quantification having high concordance (r=0.737, p<0.001). Genomic subgroup analysis discriminated survival outcomes more reliably than diagnostic categories alone. Our findings suggest that the presence of biTET2 or TET2-SRSF2 co-mutations, combined with BM monocytosis, can more reliably identify true CMML cases within the OM-CMML spectrum. Integrating genomic determinants into the CMML diagnostic framework enhances diagnostic accuracy.

Abstract Introduction: Leukemogenesis is driven by nucleophosmin 1 mutations(NPM1-m) or lysine methyltransferase 2A rearrangements(KMT2A-r) in ~35–40% of acute myeloid leukemia (AML) cases. Nearly half of AML patients will develop relapsed/refractory (R/R) disease within a year, with <20% expected response rate following venetoclax/azacitidine (Ven/Aza) and progressively poorer outcomes with each subsequent line of therapy. Ziftomenib–a potent, highly selective, oral, investigational menin inhibitor–has demonstrated clinical activity as both monotherapy and in combination for adults with R/R NPM1-m or KMT2A-r AML. KOMET-007 (NCT05735184) is an ongoing, open-label, ph1a/b study of ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML. Here we present updated safety and clinical activity in patients with R/R AML treated with the recommended ph2 dose (RP2D) of ziftomenib 600 mg in combination with Ven/Aza across ph1a/b. Methods: Adults (≥18y) with R/R NPM1-m or KMT2A-r AML enrolled independently into separate arms; patients in dose escalation (ph1a) and expansion (ph1b) were treated with oral ziftomenib 600 mg once daily (QD; continuously from C1D8 onward) plus standard doses of Ven/Aza. Primary endpoints: AEs, complete remission (CR; ELN 2022), dose limiting toxicities (DLT; ph1a only). Key secondary endpoints: composite CR (CRc; CR with full, partial or incomplete hematologic recovery), overall response, duration of response. Results: As of June 25, 2025, 80 patients (51 NPM1-m, 29 KMT2A-r) with R/R AML were enrolled (20 ph1a; 60 ph1b) and treated with ziftomenib 600 mg QD + Ven/Aza. Median age was 63y (range 19–85), 50% were female, 74% had ECOG PS 0–1; 22 (28%) had FLT3 co-mutations and 7 (9%) had IDH co-mutations. Median number of prior therapies was 1 (range 1–6); 18% (14/80) had prior stem cell transplant; 25 (49%) NPM1-m and 19 (66%) KMT2A-r patients had prior Ven exposure. 71 patients (89%) had Gr ≥3 treatment-emergent AEs, most commonly (≥20% of patients) febrile neutropenia (31%), decreased platelet count (28%), decreased white blood cell count (26%) and decreased neutrophil count (23%). Gr ≥3 ziftomenib-related AEs occurred in 30 patients (38%), most commonly febrile neutropenia (9%) and anemia (8%). 6% of patients discontinued ziftomenib treatment due to AEs. Differentiation syndrome (DS) occurred in 1 (1%) NPM1-m patient (Gr 3), which lasted 1d and successfully resolved with protocol-specified DS mitigation. No ziftomenib-related QTc prolongation was reported with the combination, and no DLTs were observed in ph1a. 70 patients (43 NPM1-m; 27 KMT2A-r) were response-evaluable (≥1 response assessment or death). Median follow-up was 18.0 wks for NPM1-m and 16.4 wks for KMT2A-r. Overall response rates (ORRs) were 65% (28/43) for NPM1-m and 33% (9/27) for KMT2A-r. CRc rates were 49% (21/43) for NPM1-m and 22% (6/27) for KMT2A-r after median time to first CRc of 4.9 wks (range 2.7–15.6) and 5.5 wks (range 2.6–18.9), respectively; measurable residual disease (MRD)-negativity rates (local) among tested CRc responders were 50% (9/18) for NPM1-m and 60% (3/5) for KMT2A-r after median time to first MRD-negativity of 5.9 wks (range 2.9–15.6) and 8.1 wks (range 7.7–18.9), respectively. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 43d overall (43d for NPM1-m; 71d for KMT2A-r), and median time to platelet recovery (≥100×109/L) was 27d overall (27d for NPM1-m; 23d for KMT2A-r). As of the data cutoff, overall median duration of CRc was not estimable; median overall survival was not estimable for NPM1-m and 21.1 wks for KMT2A-r. In Ven-naive patients, CRc rates were 71% (15/21) for NPM1-m and 33% (3/9) for KMT2A-r; CR rates were 48% (10/21) and 11% (1/9); and ORRs were 81% (17/21) and 56% (5/9), respectively. The study is ongoing with 44% (19/43) of NPM1-m and 11% (3/27) of KMT2A-r patients still on treatment, with responses continuing to evolve.Updated data to be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg QD + Ven/Aza was well tolerated with robust clinical activity in patients with R/R NPM1-mor KMT2A-rAML. No ziftomenib-related QTc prolongation was reported. One case of DS (NPM1-m, Gr 3) successfully resolved with protocol-specified mitigation. These data support further investigation of ziftomenib-based combinations in R/R NPM1-mand KMT2A-rAML.

Abstract Introduction: Nucleophosmin 1 mutations (NPM1-m) drive leukemogenesis in approximately 30% of acute myeloid leukemia (AML) cases. Ziftomenib is a potent, highly selective, oral, investigational menin inhibitor that has demonstrated clinical activity as both monotherapy and in combination for adults with NPM1-m or lysine methyltransferase 2A-rearranged (KMT2A-r) AML. KOMET-007 (NCT05735184) is an ongoing, open-label, dose-escalation (phase 1a) and expansion (phase 1b) study of ziftomenib in combination with standard chemotherapies in NPM1-m or KMT2A-r AML. Here we present phase 1b safety and clinical activity in patients with newly diagnosed NPM1-m AML who received the recommended phase 2 dose (RP2D) of ziftomenib 600 mg in combination with venetoclax and azacitidine (Ven/Aza). Methods: Adults (≥18 years) with newly diagnosed NPM1-m AML who were not eligible for intensive chemotherapy were enrolled in phase 1b and received ziftomenib 600 mg once daily plus standard doses of Ven/Aza. Ziftomenib was orally administered once daily continuously from Cycle 1 Day 8 onward. Phase 1b primary endpoints were adverse events (AEs) and complete remission (CR) per ELN 2022. Secondary endpoints included composite CR (CRc; defined as CR with full, partial, or incomplete hematologic recovery), overall response, and duration of response. Local measurable residual disease (MRD) was assessed by next-generation sequencing, RT-qPCR, and multiparameter flow cytometry. Results: As of June 25, 2025, 39 patients with newly diagnosed NPM1-m AML were enrolled and treated with ziftomenib 600 mg once daily plus Ven/Aza in phase 1b. Median age was 75 years (range 53–93), 54% were female, 46% had ECOG PS 0–1; 12 (31%) had FLT3 co-mutations and 9 (23%) had IDH co-mutations. Median duration of follow-up was 16.3 weeks (range 1.6–41.1). Twenty-nine patients (74%) had grade ≥3 treatment-emergent AEs, most commonly (≥20% of patients) decreased neutrophil count (31%) and decreased platelet count (23%). Grade ≥3 ziftomenib-related AEs occurred in 14 patients (36%), most commonly decreased neutrophil count (15%) and decreased platelet count (13%). No ziftomenib treatment discontinuations occurred due to AEs. Differentiation syndrome occurred in 1 (3%) patient (grade 2), which successfully resolved with protocol-specified mitigation. One patient (3%) had investigator-assessed ziftomenib-associated QTc prolongation (grade 3); however, there were concomitant significant electrolyte abnormalities and event resolved with electrolyte repletion. At time of data cutoff, 31 NPM1-m patients were response-evaluable (≥1 response assessment or death). CRc rate was 84% (26/31) after a median time to first CRc of 3.5 weeks (range 2.4–9.4), with local MRD-negativity rates among tested CRc responders of 54% (13/24) after a median time to first MRD-negativity of 8.4 weeks (range 2.9–17.4). CR rate was 58% (18/31) and overall response rate was 94% (29/31), with responses and MRD-negativity rates continuing to evolve. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 36 days, and median time to platelet recovery (≥100×109/L) was 28 days. The median duration of response and median overall survival were not reached as of the data cutoff, at a median follow-up of 16.3 weeks. The study is ongoing, with 81% (25/31) of NPM1-m patients still on-study and 77% (24/31) still on ziftomenib treatment. Updated safety and clinical activity results will be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg once daily combined with Ven/Aza was well tolerated and demonstrated robust clinical activity in patients with newly diagnosed NPM1-m AML, including 84% CRc after a median of 3.5 weeks and 54% CRc MRD-negativity after a median of 8.4 weeks. Low rates of ziftomenib-related cytopenia and no additional myelosuppression were observed with this combination. One case each of differentiation syndrome (grade 2) and investigator-assessed QTc (grade 3) were successfully resolved. Taken together, these data support the RP2D determination and advancement of this ziftomenib-based combination in the KOMET-017 (NCT07007312) randomized phase 3 study in patients with newly diagnosed NPM1-m AML.

PURPOSE Ziftomenib—a potent, highly selective, oral menin inhibitor—was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1 -mutated ( NPM1 -m) and KMT2A -rearranged AML in the KOMET-001 phase I trial. METHODS In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1 -m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh). RESULTS From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events. CONCLUSION Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1 -m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.

Abstract RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal events (75%, 64%, and 59%, respectively). CBL mutations frequently occurred in codominance with SRSF2 and multihit TET2, and were enriched for KIT mutations. PTPN11 mutations more frequently co-occurred with SETBP1 and DNMT3A mutations, and were infrequently codominant with TET2 or ASXL1. RASp mutations predicted for shorter overall survival (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.15-2.07; P = .0075) and leukemia-free survival (LFS; HR, 1.67; 95% CI, 1.26-2.20; P = .0011), influenced outcomes of myelodysplastic and TET2 mutant CMML, and cooperated with IDH2 and RUNX1 mutations to induce shorter LFS. These data set the bases for refined genomic classifications of CMML, and underscore the need to develop RAS-directed therapies for patients with CMML.

6506 Background: NPM1 -m drives leukemogenesis in ~30% of AML. Despite current risk stratification, nearly half will have R/R disease within a year, after which outcomes are poor with <10% complete response following chemotherapy. Ziftomenib – a potent, highly selective, oral, investigational menin inhibitor – has shown clinical activity as monotherapy and in combination for adults with R/R NPM1 -m and KMT2A -r AML, with 600 mg once-daily (QD) as the recommended phase 2 monotherapy dose for NPM1 -m. Here we present the primary analysis for NPM1 -m patients (pts) treated with ziftomenib 600 mg QD in the pivotal KOMET-001 study. Methods: KOMET-001 (NCT04067336) is a multicenter, open-label phase 1/2 study of ziftomenib in adults with R/R AML. In phase 2, pts with NPM1 -m R/R AML received ziftomenib 600 mg QD. Phase 2 primary endpoint: complete remission with full/partial hematologic recovery (CR/CRh); key secondary endpoints: composite complete remission (CRc), durations of CR/CRh and CRc, and safety. The analyses below include NPM1 -m pts pooled from phase 1b/2. Results: The phase 2 primary endpoint was met ( p =0.0058). As of 20 Dec 2024, 112 pts were enrolled (51% US/Canada, 49% Europe/UK) in phase 1b/2 and treated with ziftomenib 600 mg QD, with a median follow-up of 4.2 months. Median age was 69 yrs (range 22–86), 56% female, 83% ECOG PS 0–1, median of 2 prior therapies (range 1–7), including 60% prior venetoclax (VEN) and 23% prior transplant. CR/CRh rate in all phase 1b/2 pts was 25% (28/112; 95% CI 17–34) and overall response rate was 35% (39/112; 95% CI 26–44). In phase 2 pts, 23% (21/92; 95% CI 15–33) achieved CR/CRh (Table), with 67% (10/15) MRD negativity among CR/CRh responders tested (local). Comparable CR/CRh rates were observed in both VEN-naïve and exposed pts (21% vs. 24%). Ziftomenib was well tolerated with 3% (3/112) discontinuing due to treatment-related adverse events (TRAEs). 40% (45/112) of pts had Grade (Gr) ≥3 TRAEs, including 13% differentiation syndrome (all Gr3), ≤5% each anemia, febrile neutropenia and thrombocytopenia, and 2% QTc prolongation (Gr3). Updated clinical activity and safety data will be presented. Conclusions: In the pivotal KOMET-001, the phase 2 primary endpoint was met: Ziftomenib achieved deep and durable responses in R/R NPM1 -m AML, regardless of prior VEN. Ziftomenib was well tolerated with limited myelosuppression and only 3% ziftomenib-related discontinuations. Taken together, these data support the potential use of ziftomenib monotherapy as a new treatment option for R/R NPM1 -m AML. Clinical trial information: NCT04067336 . Response, n (%) Phase 2600 mg QDN=92 Phase 1b/2600 mg QDN=112 CR 13 (14) 20 (18) CR/CRh 21 (23) 28 (25) CRc 24 (26) 32 (29) Median duration, months (95% CI) CR/CRh 3.7 (1.9–NE) 3.7 (1.9–7.7) CRc 4.6 (2.8–11.4) 5.1 (2.8–8.1) Restricted mean duration, months (95% CI) CR/CRh 4.3 (3.1–5.6) 5.2 (3.6–6.7) CRc 5.9 (4.0–7.7) 6.4 (4.6–8.1)

Introduction: Somatic mutations in RAS pathway genes are present in ~30% of patients with chronic myelomonocytic leukemia (CMML) and are usually associated with myeloproliferative features. Whether mutations in distinct RAS pathway genes share similar genomic context and have similar implications remains unknown. Such an understanding might inform future studies evaluating genotype-specific therapies (RAS-codon specific and pan-RAS inhibitors) or cooperative leukemogenic mechanisms. This multicenter study examines the landscape of RAS pathway mutations (RASMT) in CMML. Methods: Newly diagnosed CMML patients evaluated at MD Anderson Cancer Center (n=449, 54%) and Mayo Clinic (n=383, n=46%) were included after IRB approval. Clonal relationships were tested using Pearson goodness-of-fit. Clones with the highest variant allele frequency (VAF), or with VAF close to 40% were defined as dominant, and those present at VAF &lt;20% in the presence of another dominant clone were defined as subclonal. RASMT genes included NRAS, KRAS, BRAF, CBL, CBLC, PTPN11 and NF1. Standard statistical measures were applied. Results: Among 832 CMML patients (median age 71 years, 68% male) 387 (47%) had myeloproliferative (MP) and 445 (53%) had myelodysplastic (MD) CMML. A total of 350 (42%) patients had RASMT with higher prevalence among MP-CMML compared to MD-CMML (55% vs 31%, p&lt;0.001). Among patients with RASMT, 262 (32%), 59 (7%), 20 (2%), 6 (&lt;1%) and 3 (&lt;1%) had 1, 2, 3, 4 or 5 distinct RASMT, respectively. Importantly, 17 patients harbored a RASmt as the only detectable somatic mutation, with KRASMT being the most frequent (n=10, 59%), including 3 (18%) patients with &gt;1 RASMT. Among RASMT patients, a trend for higher hemoglobin (12.7 vs 10.8 g/dL, p=0.054) was observed in NF1MT CMML and lower WBC (14.4 vs 27.9 x109/L, p=0.067) values in CBLMT CMML. In total, 479 somatic mutations in RAS pathway genes were identified the most frequent involving NRAS (n=169, 35%) followed by CBL (n=120, 25%), KRAS (n=102, 21%), PTPN11 (n=38, 8%), NF1 (n=34, 7%), BRAF (n=11, 2%) and CBLC (n=5, 1%). Most frequently involved codons for each RAS pathway gene were as follows: G594 (n=3) for BRAF, R420 (n=22) and C404 (n=15) for CBL, G12 (n=41; G12D: 13, G12C: 3) and A146 (n=16) for KRAS, G12 (n=116; G12D: 74, G12C: 5) for NRAS and A72 (n=8) for PTPN11. CBLMT CMML had higher ASXL1 (58% vs 44%, p=0.011), BRAF (8% vs 4%, p=0.017), IDH2 (10% vs 4%, p=0.024), KIT (5% vs 1%, p=0.038), SRSF2 (54% vs 40%, p=0.004), TET2 (59% vs 47%, p=0.019) and ZRSR2 (10% vs 4%, p=0.014) co-mutation frequency. Of note, DNMT3A mutations were mutually exclusive of CBLMT CMML (0% vs 7%, p=0.007), and multihit TET2 was more common among TET2MT/CBLMT vs TET2MT/CBLWT CMML (82% vs 67%, p =0.039). CMML with NF1 mutations had higher BCORL1 (8% vs 0%, p=0.005), PTPN11 (15% vs 3%, p=0.014) and SETBP1 (23% vs 8%, p=0.022) mutational cooccurrences. NRASMT CMML was enriched for ASXL1 (53% vs 43%, p=0.042), ETNK1 (5% vs 1%, p=0.004), GATA2 (4% vs 1%, p=0.034) and STAG2 (4% vs 1 %, p=0.023) mutations but had lower JAK2 (1% vs 6%, p=0.036) and TP53 (1% vs 5%, p=0.022) mutational frequency. PTPN11 mutations were associated with higher NF1 (29% vs 7%, p=0.014), SETBP1 (27% vs 9%, p=0.01) and WT1 (6% vs &lt;1%, p=0.014) mutational cooccurrences and lower SRSF2 (23% vs 42%, p=0.05) frequency. We evaluated RAS mutant clonal dominance in 253 (72%) RASMT patients. NRAS (63% vs 38%), KRAS (63% vs 38%) and CBL (65% vs 35%) mutations were more frequently observed as dominant clones while PTPN11 (44% vs 56%), BRAF (25% vs 75%) and NF1 (35% vs 65%) mutations were more frequently subclonal events, particularly of TET2, ASXL1 or SRSF2 mutant clones. Presence of a RAS pathway mutation was associated with shorter LFS (36 vs 53 months, HR 1.5, 95% CI 1.1-2.2, p=0.020), with presence of multiple RAS mutations shortening LFS further (53, 43, 27 months for 0, 1 and &gt;1, p=0.017). PTPN11 mutations predicted for shorter OS (18 vs 39 months, HR 1.7, 95% CI 1.0-2.8, p=0.035) and LFS (14 vs 36 months, HR 1.9, 95% CI 1.2-2.9, p=0.008). Presence of &gt;1 RAS pathway mutation was associated with shorter OS in ASXL1MT/TET2MT CMML compared to those with no RAS mutations (24 vs 53 months, HR 4.2, 95% CI 1.6-10.8, p=0.004). Conclusions: RAS mutations exhibit distinct genomic features and clonal hierarchy in CMML and cooperate with other somatic mutations to drive clinical outcomes. This study forms the foundation for assessment of novel RAS pathway inhibitors in CMML.

Background: The potent and selective oral menin-histone-lysine N-methyltransferase 2A (KMT2A) inhibitor revumenib (SNDX-5613) induced complete remissions with clearance of residual disease in acute leukemias refractory to multiple previous lines of therapy ( Nature. 2023;615:920-924). Here we report outcomes following the resumption of revumenib after hematopoietic stem cell transplant (HSCT). Methods: Patients aged ≥30 days with relapsed or refractory (R/R) acute leukemias with genetic alterations associated with HOXA overexpression, including KMT2A-rearranged ( KMT2Ar) or nucleophosmin 1 ( NPM1)-mutated leukemias, were enrolled in the AUGMENT-101 phase 1/2, multicenter, open-label, dose-escalation study (NCT04065399). Patients received revumenib every 12 hours (q12h) in 28-day continuous cycles. Patients who achieved a complete response (composite definition [CRc]), morphological leukemia-free state, or partial response could undergo HSCT without leaving the study. Revumenib was stopped before the HSCT conditioning regimen but, per a protocol amendment, could be resumed after HSCT if the patient was in CRc. Measurable residual disease (MRD) was assessed using multiparameter flow cytometry and/or polymerase chain reaction. Results: Between November 5, 2019, and June 28, 2023, a total of 131 phase 1 patients were enrolled and treated in the AUGMENT-101 study. Nine patients with acute myeloid leukemia (AML) from the AUGMENT-101 study resumed revumenib (8 after transplant and 1 after a stem cell boost [Table 1]). Seven patients had KMT2Ar and 1 patient each had nucleoporin 98 rearranged (NUP98r) and mutated NPM1. Revumenib was resumed 59 to 180 days after HSCT (Table 2). Dose was reduced for 4 of 9 patients to mitigate adverse events of thrombocytopenia (n=3) and leg pain (n=1), and revumenib was discontinued in 4 of 9 patients because of progressive disease (n=2), cytopenias (n=1), and not reported (n=1). Revumenib duration of treatment (DOT) in the maintenance setting at the time of this analysis ranged from 23 to 588 days, with treatment ongoing for 5 of the 9 patients. CRc was maintained in 6 of 9 patients after HSCT and maintenance revumenib. One patient with reported MRD after HSCT converted to MRD-negative status following initiation of revumenib maintenance therapy. Overall, MRD-negative remissions were maintained in 5 patients as of the data cut off. Conclusions: With 3 patients on revumenib maintenance therapy for more than a year, long-term responses, including conversion to MRD-negative status, were seen in these heavily pretreated patients with AML. Resuming revumenib post HSCT had a tolerable safety profile consistent with that previously reported for the AUGMENT-101 study.