Szuber, Natasha

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 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 seminal discovery of oncogenic driver mutations in colony‐stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL in 2013 anchored a new scientific framework, deepening our understanding of its molecular pathogenesis, providing a diagnostic biomarker, and rationalizing the use of pharmacological targeting.Diagnostic criteriaIn 2016, the World Health Organization (WHO) included the presence of activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 109/L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN.Disease updatesIncreasingly comprehensive genetic profiling of CNL has disclosed a complex genomic landscape and additional prognostically relevant mutational combinations. Though prognostic determination and therapeutic decision‐making remain challenging, emerging data on prognostic markers and the use of newer therapeutic agents, such as JAK inhibitors, are helping to define state‐of‐the‐art management in CNL.

AbstractBetween 1967 and 2017, 361 patients with myeloproliferative neoplasms (MPN), age ≤ 40 years, were seen at our institution, constituting 12% of all MPN patients (n = 3023) seen during the same time period; disease‐specific incidences were 12% in polycythemia vera (PV; n = 79), 20% in essential thrombocythemia (ET; n = 219) and 5% in primary myelofibrosis (PMF; n = 63). Compared to their older counterparts, younger patients were more likely to present with low risk disease (P < .001) and display female preponderance in ET (P = .04), lower incidence of arterial events overall (P < .001), and higher incidence of venous thrombosis in PV (P = .01). Younger patients were also more likely to express CALR mutations, in ET and PMF, normal karyotype, in PV and PMF, and lower incidence of high molecular risk mutations in PMF (P significant in all instances). Over median follow‐up of 11.3, 13, and 7.1 years for PV, ET, and PMF, leukemic transformations were respectively documented in 4%, 2%, and 10% (P values 0.1‐0.9) while incidences of fibrotic progression in PV (22%) and ET (16%) were expectedly higher in young patients, because of their longer survival (P < .001). Median survival in young patients was 37 years for PV, 35 for ET and 20 for PMF; the corresponding values were 22, 22, and 8 years for ages 41‐60 years and 10, 11, and 3 years for ages >60 years (P < .001). Young MPN patients comprise a unique disease subset defined by an attenuated‐risk cytogenetic and mutational backdrop and conspicuously longer survival compared to their older counterparts, which requires assertion during patient counseling.