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.

Association of biTET2/SRSF2 and monocytic differentiation parameters in a validation cohort.

Penalized time-to-event model for CMML progression (cumulative incidence of CMML).

Numbers at risk by survival time point by genomic group (Figure 4N).

6517 Background: Pts with R/R B-ALL and EMD have limited treatment options and are a population with an unmet need. Obe-cel is an autologous chimeric antigen receptor (CAR) T-cell therapy with a fast off-rate CAT19 binding domain and a 4-1BB-ζ co-stimulatory domain designed to improve persistence and reduce severe immunotoxicity. Here, we report a post-hoc analysis of the Phase Ib/II FELIX study (NCT04404660), evaluating efficacy and safety of obe-cel in pts with R/R B-ALL, by EMD status at lymphodepletion (LD). Methods: Following LD, adults with R/R B-ALL received obe-cel using a tumor burden-guided dosing strategy to minimize toxicity. Overall remission rate (ORR; complete remission [CR]/CR with incomplete hematologic recovery [CRi]), event-free survival (EFS), overall survival (OS), and safety are reported for pts with or without (w/o) EMD. Results: Of 127 obe-cel infused pts, 27 (21%) had EMD at LD and 100 (79%) did not. At screening, the median age (range) was 36.0 years (20–73) in pts with EMD, and 50.5 years (20–81) in pts w/o EMD. Of the pts with EMD, 13 (48%) were male and 11 (41%) were Hispanic or Latino; of those w/o EMD, 53 (53%) were male and 27 (27%) were Hispanic or Latino. The median number of prior lines of therapy (range) was 3.0 (1–6) and 2.0 (1–6) for pts with and w/o EMD at LD, respectively; prior SCT was received by 12 (44%) and 44 (44%) pts, respectively. At LD, the median bone marrow (BM) blast percentage (range) was 54% (0–100) in pts with EMD and 39% (0–100) in pts w/o EMD; Philadelphia chromosome-positive disease was observed in 6 (22%) and 30 (30%) pts, respectively. At 32.8 months’ (mos) median follow-up (range 20–53), the ORR (95% confidence interval [CI]) was 59% (39–78) in pts with EMD and 83% (74–90) in pts w/o EMD. Median DoR (95% CI) among responders was 42.5 mos (3.4–not evaluable [NE]) and NE, in those with (n=16) and w/o (n=83) EMD at LD, respectively. Overall, median EFS (95% CI) was 4.5 mos (0.0–NE) and 14.3 mos (9.0–NE) in pts with and w/o EMD at LD, respectively; however, median EFS appeared to be comparable in responders with (44.6 mos [6.0–NE]) and w/o EMD (NE). Overall, median OS (95% CI) was 15.3 mos (7.9–NE) and 21.0 mos (13.2–NE) in pts with and w/o EMD at LD, respectively. The incidence of Grade ≥3 cytokine release syndrome in pts with and those w/o EMD was 3.7% and 2.0%; the incidence of Grade ≥3 immune effector cell-associated neurotoxicity syndrome was 19% and 4.0%, respectively. Cerebrospinal fluid pharmacokinetic analyses are underway; data will be presented. Conclusions: Obe-cel treatment demonstrated favorable efficacy and safety outcomes in pts with and w/o EMD in the FELIX trial. Among responders, DoR in pts with EMD was comparable with that observed in pts w/o EMD. Overall, these findings support a positive benefit–risk profile for obe-cel, irrespective of EMD status at LD. Clinical trial information: NCT04404660 .

6531 Background: Outcomes of patients (pts) with ND AML with myelodysplasia related gene mutations (MRMs), while traditionally adverse, appear to be better with LIT regimens + venetoclax (Ven). The impact of MRMs as a minimal residual disease (MRD) marker warrants investigation. Methods: We retrospectively analyzed the impact of persistence/clearance of MRM at VAF <2% at best response of CR/CRi, in pts with LIT treated ND AML (with available genomic data), treated at our institution between 2017 – 2025 and had ≥1 MRM ( ASXL1, BCOR, EZH2, STAG2, SF3B1, SRSF2, U2AF1 , and/or ZRSR2 ) at diagnosis, at a VAF of ≥2%. We excluded pts with CBF-AML, APL, or treated secondary AML. MRM dynamics were tracked at baseline and best response (CR/CRi) and correlated with relapse free/overall survival (RFS/OS). Results: A total of 185 pts, median (med) age 69 yrs (range, 56-87 yrs), were included; 96% were ≥ 60 yrs. The common baseline MRM were SRSF2 (54%), ASXL1 (32%), STAG2 (16%) and BCOR (14%); 16% had >1 MRM. Overall, 17% had concurrent NPM1 mutation (mut), 9% FLT3 -ITD (AR>0.05), 22% RAS , 32% RUNX1 , 8% TP53 , and 32/183 pts (17%) had ELN2017 adverse cytogenetics (CTG). 171 pts (92%) were treated with LIT+Ven and 14 (8%) LIT without Ven; 105 (57%) received hypomethylating agents based, and the rest (43%) received cladribine + low-dose cytarabine based LIT. Overall, 148 (80%) achieved CR and 37 (20%) CRi. 117/168 (70%) pts with available data were MRD negative (-) by flow cytometry (FCM; <0.01%) at CR/CRi. At CR/CRi, 49 (26%) cleared their MRMs (MRM-) while 136 (74%) retained MRMs (MRM+); among pts with FCM MRD- CR/CRi, 33/117 (28%) were MRM- and 84/117 (72%) MRM+. Med cycle to CR/CRi was 1 (IQR 1-2). Pts with MRM- at CR/CRi had superior med RFS (24 [95% CI 9-18] vs. 14 mos [16-NR], p=0.008) and OS (54 [25-NR] vs. 21 mos [15-27], p=0.01) compared to MRM+ pts. Among 117 FCM MRD- pts, med RFS (NR vs. 14 mos [9-23], p=0.001) and med OS (NR vs. 19 mos [14-36], p=0.003) was still superior among MRM- pts (n=33) vs. MRM+ (n=84). 67 pts (36%) underwent a hematopoietic stem cell transplantation (HSCT) in CR1, 26/49 (53%) MRM- and 41/136 (30%) MRM+. Among FCM MRD- pts who did not undergo HSCT, 2-yr OS rate (86% vs. 48%, p=0.04) was better in MRM- pts (n=15) vs. MRM+ pts (n=58); among FCM MRD- pts who had HSCT, 2-yr OS rate trended to favor MRM- pts (n=18) (77% vs. 55%, p=.14) vs. MRM+ pts (n=26). On backward selected Cox MVA, clearance of MRMs at CR/CRi was independently associated with favorable OS (HR=0.54, 95% CI 0.31-0.95, p=0.03), along with BCOR, IDH2 mut, and HSCT, while RAS mut, FLT3 -ITD, and adverse CTG were unfavorable. Finally, among FCM-MRD- pts at CR/CRi, using the same Cox model, clearance of MRMs was independently favorable for OS (HR=0.42, 95%CI 0.20-0.93, p=0.03). Conclusions: In our analysis, the status of MRM clearance at CR/CRi in LIT treated AML with baseline MRM affected survival outcomes, including in pts FCM MRD- at CR/CRi.

Summary of L-Psi duplex ddPCR assay

Correlation between RAS pathway mutation variant allele frequencies and monocytic parameters.

Cytogenetic abnormalities and somatic mutations among all patients included in the validation cohort.

Landscape of SF3B1 mutations in the SF3B1 cluster by diagnosis.

6504 Background: Hypomethylating agents (HMAs; azacitidine/decitabine) plus venetoclax (VEN) are standard for newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy; however FMS-like tyrosine kinase-3 internal tandem duplication ( FLT3-ITD ) confers resistance and poor overall survival (OS). Addition of quizartinib (QUIZ), a potent FLT3 inhibitor, may improve outcomes. Methods: Phase I/II study of QUIZ+decitabine+VEN in two cohorts: newly diagnosed FLT3-ITD AML pts unfit for intensive chemotherapy and relapsed/refractory (R/R) FLT3-ITD AML pts. Primary endpoints were maximum tolerated dose (MTD) and overall response rate (ORR). Results: Eighty-eight patients (pts) were enrolled (frontline N=42; R/R N=46). QUIZ 26.5mg/day was selected as the recommended phase II dose (RP2D). In the frontline cohort, median age was 70y (62–85); 15 pts (36%) were ≥75y; 25 (60%), 12 (N=28%), and 5 (12%) had de novo, secondary, and therapy-related AML, respectively. DNMT3A (43%), NPM1 (33%), and RUNX1 (31%) were the most common co-mutations. Complete remission (CR), CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), end-of-cycle-1 (EOC1) measurable residual disease (MRD) negativity by multicolor flow cytometry (MFC; 0.01%), and next-generation sequencing (NGS) FLT3-ITD negativity (5×10⁻⁵) were 72% (N=29), 17% (N=7), 2% (N=1), 58% (19/32), and 27% (5/18), respectively; 2 pts in cycle 1 were not evaluable. Best MRD negativity by MFC and FLT3-NGS were 68% (23/34) and 83% (15/18). Median time to absolute neutrophil count (ANC) >500, ANC >1000, and platelets >50K were 40 (19–72), 41 (14–72), and 35 (16–71) days, respectively. The median relapse-free survival (RFS) and OS were 24.7 and 36.5mo. Fifteen pts (36%) proceeded to allogeneic stem cell transplant (ASCT) in CR1, with OS not reached vs 36.6mo without ASCT (p=0.65, landmark analysis). Median 3 cycles (1–39) were delivered; 11 pts remain on study. Thirty-one pts discontinued protocol due to ASCT (N=15), relapse (N=9), physician/pt choice (N=3), induction death (N=1), death in CR (N=1), death with disease (N=1), or hospice (N=1). Grade ≥3 non-hematologic adverse events (>5%) included febrile neutropenia (37%), pneumonia (33%), infections (17%), pain (10%), ALT increase (10%), fracture (10%), sepsis (9%), hypertension (7%), hypotension (7%), hyponatremia (7%), gait disturbance (7%), oral mucositis (7%), and pleural effusion (7%). In the R/R cohort, CR/CRi was 28% (N=13) with 33% (N=15) MLFS; 37% (N=17) proceeded to ASCT; median OS was 6.3mo (further data will be provided at the time of presentation). Conclusions: QUIZ+decitabine+VEN combination resulted in high CR/CRi, deep MRD responses, and encouraging survival in older pts with newly diagnosed FLT3-ITD AML. Clinical trial information: NCT03661307 .

The treatment landscape of B-cell acute lymphoblastic leukemia (B-ALL) has been transformed by the incorporation of immunotherapy and potent tyrosine kinase inhibitors (TKIs) into frontline regimens, resulting in meaningful improvements in long-term survival. Such advances have allowed for a reduction in both the intensity and duration of chemotherapy without compromising outcomes, a particularly important goal for older adults, who are less tolerant to intensive chemotherapy and often harbor higher-risk disease features, including TP53 mutations that confer resistance to traditional chemotherapy. Largely chemotherapy-free regimens may alleviate some of the poor outcomes that older patients experience; such regimens are under investigation. While the risk factors that portend inferior outcomes for patients with Philadelphia (Ph)-positive B-ALL are still being defined in the setting of immunotherapy-based regimens and more potent TKIs, it is evident that an elevated baseline white blood cell count is a strong predictor of relapse. The role of chimeric antigen receptor (CAR) T-cell therapy as consolidation for patients with high-risk Ph-positive B-ALL is actively being explored, alongside efforts to identify factors that influence CAR T-cell expansion and persistence as determinants of response durability. Advances in more sensitive assessments of measurable residual disease (MRD) using next generation sequencing (NGS) will help inform which patients may benefit from additional consolidative strategies. Novel agents under development include the subcutaneous (SC) form of blinatumomab, which has demonstrated efficacy even in patients with prior blinatumomab exposure. Altogether, these developments frame the next set of questions in ALL, which will be addressed in this review.

BACKGROUND:Dasatinib is approved at 100 mg/d for newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). We report outcomes with frontline dasatinib 50 mg/d in a large cohort of patients with CML-CP. METHODS:In a phase II clinical trial, patients with newly diagnosed CML-CP received dasatinib 50 mg/d alone (n = 83) or in combination with venetoclax (n = 66). We evaluated the molecular response rates, incidence of adverse events, event-free survival (EFS), and overall survival (OS). RESULTS:One hundred forty-nine patients were included; the median age at diagnosis was 46.7 years (range, 19.9-84.3); Sokal risk was high-risk in 7 patients (4.7%). By 60 months of dasatinib therapy, the cumulative rates of major molecular response, MR4, and MR4.5 were 95%, 87%, and 86%, respectively. With a median follow-up of 73 months, the 5-year EFS and OS rates were 96% and 98%, respectively. Adverse events were observed in 72 patients (48%), including pleural effusion in 19 (12.7%), of which 3 (2%) of Grade 3. Eighteen patients (12%) discontinued dasatinib due to adverse events. CONCLUSION:The long-term follow-up confirms the safety and efficacy of dasatinib 50 mg/d in patients with newly diagnosed CML-CP.

Table S1a: Representativeness of study participants. Table S1b: Response and MRD rates at 12 and 24 cycles of combination treatment in intention-to-treat population (N=79). Table S2: Response and MRD rates at 12 and 24 cycles of combination treatment in evaluable patients. Table S3a: Univariate analysis of factors associated with CR/CRi at the end of treatment. Table S3b: Multivariate analysis of factors associated with CR/CRi at the end of treatment. Table S3c: Univariate analysis of factors associated with the best CR/CRi response. Table S3d: Multivariate analysis of factors associated with the best CR/CRi response. Table S4a: Univariate analysis of factors associated with marrow UMRD4 at the end of treatment. Table S4b: Multivariate analysis of factors associated with marrow UMRD4 at the end of treatment. Table S4c: Univariate analysis of factors associated with the best marrow UMRD4 response. Table S4d: Multivariate analysis of factors associated with the best marrow UMRD4 response. Table S5a: Univariate analysis of factors associated with progression-free survival. Table S5b: Multivariate analysis of factors associated with progression-free survival. Table S6: Summary of dose modifications. Table S7: The common reasons for dose reductions and dose interruptions. Table S8a: Summary of patients with U-MRD4 at EOT who had CLL progression. Table S8b: Summary of patients with MRD at EOT who had CLL progression.

Outcomes following treatment with obe-cel in responding patients, with disease assessment by independent response review committee.

Characteristics of patients in whom bulk RNA-sequencing was performed in bone marrow CD34+ cells.

Menin inhibition leads to an antileukemic effect through hematopoietic differentiation. Treatment with the menin inhibitor revumenib results in clinical remissions in relapsed or refractory (R/R) acute myeloid leukemia (AML) with either rearrangement of lysine methyltransferase 2A (KMT2A) or mutation in nucleophosmin 1 (NPM1), leading to regulatory approval of this drug. However, determinants of response to revumenib have not been fully elucidated. We examined the immunophenotype of leukemia cells by flow cytometry, in sequential bone marrow specimens from 48 patients with R/R AML treated with revumenib. We observed dynamic changes in the immunophenotype after treatment in 16 of 31 (52%) patients, characterized by a switch from a myeloid/stem-like to a monocytic or myelomonocytic immunophenotype, or vice versa, or by substantial changes in the intensity of antigen expression or in patterns of leukemia-associated immunophenotypes. Morphologic remission with undetectable measurable residual disease (MRD) by flow cytometry following revumenib was associated with improved overall survival, with a median of 23.6 months compared with 20.8 months in patients with morphologic response and detectable MRD, and 3.2 months in non-responders. In summary, treatment monitoring of AML by flow cytometry, following menin inhibition, requires recognition of phenotypic changes associated with differentiation.

Numbers at risk by survival time point by hierarchical cluster (Figure 4L).