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.

Heatmap of patients with active disease at study theray initiation, showing CBF subtype, ACA, treatment group and mutational groups

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

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

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

Survival outcomes of patients with acute myeloid leukemia (AML) who achieve complete remission (CR) without allogeneic stem cell transplantation (allo-SCT) remain largely undefined, yet these benchmarks are essential for developing post-remission strategies. We retrospectively analyzed 362 adults with newly diagnosed de novo AML who achieved CR/Incomplete CR (CRi) (between 2016–2023) and did not undergo allo-SCT in first remission. Patients with APL and corebinding factor AML, which are rarely consolidated with allo-SCT, were excluded. The cohort was stratified by low-intensity (LIT, n=257) and intensive therapy (IT, n=105), and survival was evaluated across predefined subgroups. Median relapse-free survival (RFS) and overall survival (OS) were 11 and 19 months, respectively. Venetoclax was associated with significantly lower 24- month relapse rates in both LIT (68% to 45%) and IT (49% to 27%) (p

Cox multivariate for overall survival in the full cohort with backward model selection not including DNMT3A-ASXL1-TET2 (DAT) and TRANSCRIPTION FACTORS

Representativeness of study participants

Comparison of SF3B1-mutated MDS with del(5q) to subclonal SF3B1-mutated MDS without del(5q). (A-F) No significant differences in baseline clinical demographics or SF3B1 VAF were observed between cases with vs. without del(5q). (G,H) Whilst survival was superior in patients with clonal SF3B1 mutations, no significant difference in leukemia-free or overall survival was identified between cases of SF3B1-mutated MDS with del(5q) vs. subclonal SF3B1-mutated MDS without del(5q), suggesting survival outcomes in such cases are influenced by alternative molecular driver events. Reported p-values utilized the cox model Wald test.

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

Cox regression univariate analysis for overall survival

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

Cox multivariate model for relapse free survival for the full cohort

Survival stratified by CBF subtype and treatment arm

Landscape of SF3B1 mutations in the SF3B1 cluster by diagnosis.

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

INTRODUCTION:Acute promyelocytic leukemia (APL) is a highly curable subtype of AML, largely due to the introduction of differentiating therapy with all-trans retinoic acid and arsenic trioxide. While intravenous arsenic trioxide (ATO) is considered the standard-of-care in the United States, its prolonged administration and monitoring requirements pose logistical challenges that require high healthcare resource utilization and negatively impact quality of life. AREAS COVERED:This review summarizes the development and clinical evaluation of intravenous and oral arsenic formulations in APL. We discuss the pharmacokinetics, safety, and efficacy of oral arsenic compared with intravenous ATO across populations, including children and patients with obesity or renal impairment. A PubMed search using the terms 'oral arsenic,' 'arsenic trioxide,' 'arsenic formulations,' 'acute promyelocytic leukemia,' and 'pharmacokinetics' was used to compile data. It draws on current pharmacokinetic and clinical evidence, including data from retrospective publications, phase 3 trials, meta-analyses, and long-term follow-up studies. EXPERT OPTION:Oral arsenic formulations achieve comparable molecular remission, long-term survival, and toxicity profiles to intravenous ATO. These oral formulations may offer meaningful advantages in quality of life, cost, and overall availability of optimal treatment. Continued clinical trials are expected to further define oral arsenic's role in frontline therapy in the United States.

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.