Tefferi, Ayalew

AbstractWe retrospectively examined our experience with midostaurin therapy in 33 consecutive patients (median age 68 years; 58% females) with advanced systemic mastocytosis (adv‐SM): aggressive SM (ASM; n = 17), SM associated with another hematologic neoplasm (SM‐AHN; n = 14) and mast cell leukemia (MCL; n = 2). KITD816V mutation was detected in 84% of the patients and C findings in 91%. Eleven (33%) patients were previously treated with other cytoreductive drugs, including cladribine (n = 4) and imatinib (n = 3). Median time from diagnosis to initiation of midostaurin therapy was 2.2 months (range 0.3–41). Using modified valent criteria, overall response was 42% (53% ASM, 29% SM‐AHN, 50% MCL; p = .22), all classified as being major. Responses included ≥50% reduction in bone marrow mast cells in 40% and normalization of serum tryptase in 29%, of evaluated cases. After a median follow‐up of 14.6 months from initiation of midostaurin therapy, 7 (21%) deaths, 1 (3%) leukemic progression, and 18 (55%) treatment discontinuations were documented; median duration of midostaurin treatment was 7.9 months (range 0.5–123) and response duration 21.5 months (range 2.9–123). Most frequent side effect was gastrointestinal (51%) while grade 3/4 neutropenia or thrombocytopenia occurred in 12% of patients. Response to treatment was not predicted by KIT mutation (p = .67) or exposure to prior cytoreductive therapy (p = .44). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs. 16 months; p = .15). Findings from the current study are broadly consistent with previously published clinical trial observations.

Abstract Disease Overview Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. The 2013 seminal discovery of oncogenic driver mutations in colony‐stimulating factor 3 receptor ( CSF3R ) in the majority of patients with CNL not only established its molecular pathogenesis but provided a diagnostic biomarker and rationale for pharmacological targeting. Diagnosis In 2016, the World Health Organization (WHO) recognized activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 10 9 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN. Management There is currently no standard of care for management of CNL, due in large part to the rarity of disease and dearth of formal clinical trials. Most commonly used therapeutic agents include conventional oral chemotherapy (e.g., hydroxyurea), interferon, and Janus kinase (JAK) inhibitors, while hematopoietic stem cell transplant remains the only potentially curative modality. Disease Updates Increasingly comprehensive genetic profiling in CNL, including new data on clonal evolution, has disclosed a complex genomic landscape with additional mutations and combinations thereof driving disease progression and drug resistance. Although accurate prognostic stratification and therapeutic decision‐making remain challenging in CNL, emerging data on molecular biomarkers and the addition of newer agents, such as JAK inhibitors, to the therapeutic arsenal, are paving the way toward greater standardization and improvement of patient care.

AbstractDisease OverviewChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3–5 years).DiagnosisDiagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109/L; monocytes ≥10%), usually with accompanying bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~30% of patients, while >90% have somatic gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and the oncogenic RAS pathway (~30%) are frequent, while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact overall survival.Risk‐StratificationMolecularly integrated prognostic models include the Groupe Français des Myélodysplasies, Mayo Molecular Model (MMM), and the CMML specific prognostic model. Risk factors incorporated into the MMM include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 109/L, hemoglobin <10 g/dL, platelet count <100 × 109/L, and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups: high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively.Risk‐adapted therapyHypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ~40%–50% and complete remission rates of ~7%–17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option but is associated with significant morbidity and mortality.