Jabbour, Elias

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 The past decade has witnessed remarkable advances in deciphering the pathophysiology of acute lymphoblastic leukemia (ALL) and in developing novel targeted therapies. Basic research and genomic mapping have identified new prognostic biomarkers, targets, and ALL subtypes (e.g., Philadelphia‐like ALL). The ongoing therapeutic revolution in ALL is driven by the addition to the treatment arsenal of therapies that target the ABL fusions, like the BCR::ABL1 tyrosine kinase inhibitors, as well as novel agents that target CD19 and CD22: the CD22 antibody–drug conjugate inotuzumab ozogamicin, the bispecific CD3/CD19 T‐cell engager antibody blinatumomab, and CD19 chimeric antigen receptor T‐cell therapies. These combinations have improved the long‐term survival rates in B‐cell ALL to 70%, and in Philadelphia chromosome‐positive ALL to 80%–90%. The desired goals are to achieve cure rates comparable to those in pediatric ALL and to reduce or eliminate the need for prolonged intensive/maintenance chemotherapy and associated toxicities.

PURPOSE Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2 -, DUX4 -, and KMT2A -rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

AbstractThe progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was divided into a training (2790 patients) and a validation cohort (938 patients). The median age was 55 years (range, 15‐99). Among them, 442 patients (12%) had core‐binding factor AML. Binary logistic regression identified older age, worse performance status, hyperbilirubinemia, elevated creatinine, hyperuricemia, cytogenetic abnormalities other than CBF and ‐Y, and pneumonia as adverse prognostic factors for an early 4‐week mortality. This risk classification for early mortality was verified in the validation cohort of patients. In the validation cohort of more recently treated patients from 2000 to 2017, the 4‐week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low‐, high‐, and very high‐risk group, respectively. The mortality rates with low intensity therapies were 3%, 9%, and 20%, respectively. The risk classification guides treatment intensity by the assessment of age, frailty, organ dysfunction, cytogenetic abnormality, and infection to avoid early mortality.