Tefferi, Ayalew

SummaryAmong 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non‐ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A‐mutated cases less likely (p < 0.01) to be affected. Treatment‐emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.

AbstractOverviewEssential thrombocythemia is a Janus kinase 2 (JAK2) mutation‐prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia.DiagnosisIn addition to thrombocytosis (platelets ≥450 × 109/L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature‐appearing megakaryocytes distributed in loose clusters.Genetics: Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%–11%), ASXL1 (7%–20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q−/13q‐.Survival and PrognosisLife expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high‐, intermediate‐1‐, intermediate‐2‐, and low‐risk disease with corresponding median survivals of 8, 14, 21, and 47 years.Risk Factors for ThrombosisFour risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild‐type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation).Mutations and PrognosisMPL and CALR‐1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF‐free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2‐mutated patients with extreme thrombocytosis and those with abnormal karyotype.TreatmentThe main goal of therapy is to prevent thrombosis. In this regard, once‐daily low‐dose aspirin is advised for all patients and twice daily for low‐risk disease. Cytoreductive therapy is advised for high‐risk and optional for intermediate‐risk disease. First‐line cytoreductive drugs of choice are hydroxyurea and pegylated interferon‐α and second‐line busulfan.Additional ContentThe current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post‐essential thrombocythemia MF, as well as new investigational drugs.

Abstract Among 281 patients with essential thrombocythemia and calreticulin (CALR) mutation, we found a variant allele frequency of ≥60% to be associated with significantly shortened myelofibrosis-free survival, mostly apparent with CALR type-1 and CALR type-indeterminate mutations.

AbstractThe primary objective of treatment in myelofibrosis (MF) is prolongation of life, which is currently accomplished only by allogeneic hematopoietic stem cell transplantation (AHSCT). Determination of optimal timing for AHSCT is facilitated by molecular risk stratification. Non‐transplant treatment options in MF are palliative in scope and include Janus kinase 2 (JAK2) inhibitors (JAKi): momelotinib (FDA approved on September 15, 2023), ruxolitinib (November 16, 2011), fedratinib (August 16, 2019), and pacritinib (February 28, 2022); all four JAKi are effective in reducing spleen size and alleviating symptoms, considered a drug class effect and attributed to their canonical JAK–STAT inhibitory mechanism of action. In addition, momelotinib exhibits erythropoietic effect, attributed to alleviation of ineffective erythropoiesis through inhibition of activin A receptor type‐I (ACVR1). In transplant‐ineligible or deferred patients, the order of treatment preference is based on specific symptoms and individual assessment of risk tolerance. Because of drug‐induced immunosuppression and other toxicities attributed to JAKi, we prefer non‐JAKi drugs as initial treatment for MF‐associated anemia that is not accompanied by treatment‐requiring splenomegaly or constitutional symptoms. Otherwise, it is reasonable to consider momelotinib as the first‐line JAKi treatment of choice, in order to target the triad of quality‐of‐life offenders in MF: anemia, splenomegaly, and constitutional symptoms/cachexia. For second‐line therapy, we favor ruxolitinib, over fedratinib, based on toxicity profile. Pacritinib and fedratinib provide alternative options in the presence of severe thrombocytopenia or ruxolitinib‐resistance/intolerance, respectively. Splenectomy remains a viable option for drug‐resistant symptomatic splenomegaly and cytopenia.

SummaryAmong 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy‐related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10‐year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia‐free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision‐making in MDS‐del(5q) regarding allogeneic stem cell transplant.

Abstract Venetoclax + hypomethylating agent (Ven‐HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND‐AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND‐AML was to identify molecular predictors of treatment response to Ven‐HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, “favorable” predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and “unfavorable” TP53 (40% vs. 67%), FLT3‐ ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy‐related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow‐up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5–4.8), adverse karyotype (1.6, 1.1–2.6), TP53 mutation (1.6, 1.0–2.4), and absence of IDH2 mutation (2.2, 1.0–4.7); these risk factors were subsequently applied to construct an HR‐weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low ( n = 130; median survival 28.9 months), intermediate ( n = 105; median 9.6 months), and high ( n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3‐tiered, CR/CRi‐based, and genetics‐enhanced survival model for AML patients receiving upfront therapy with Ven‐HMA.