Insights on mechanisms of clonal evolution in chronic neutrophilic leukemia on ruxolitinib therapy

Stoner, Ryan C.; Press, Richard D.; Maxson, Julia E.; Tyner, Jeffrey W.; Dao, Kim

doi:10.1038/s41375-019-0688-1

Cited by 11 publications

(9 citation statements)

References 15 publications

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“…ASXL1 mutations are associated with the premalignant condition, clonal hematopoiesis, and are often thought to be early events in myeloid leukemogenesis [ 24 ]. Indeed, serial sequencing of samples from patients with CNL on ruxolitinib therapy revealed that the CSF3R mutant clone can shrink dramatically while the ASXL1 mutant clone remains, indicating that ASXL1 mutations were antecedent in those cases [ 25 ]. Interestingly, in this case, the ASXL1 mutant clone has a lower VAF than both CSF3R mutations at all timepoints studied, consistent with it being a later genetic event.…”

Section: Discussionmentioning

confidence: 99%

Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia

et al. 2022

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Chronic neutrophilic leukemia (CNL) relates to mutational CSF3R activation with membrane proximal CSF3R mutations such as T618I as driver mutations, but the significance of truncating mutations is not clarified. In CNL, concomitant mutations promote disease progression, but insight into longitudinal acquisition is incomplete. In this study, we investigated the role of co-occurring germline and somatic CSF3R mutations in CNL, and assessed the impact of clonal evolution on transformation to acute leukemia. We employed sequential next generation sequencing and SNP array karyotyping to assess clonal evolution in CNL of early manifestation age based on a 33-year-old patient. Germline vs. somatic mutations were differentiated using a sample from the hair follicle. To investigate a potential predisposition for CNL development and progression by germline CSF3R-W791*, allelic localizations were evaluated. We detected a somatic CSF3R-T618I mutation at 46% variant allele frequency (VAF) at the time of CNL diagnosis, which co-occurred with a CSF3R-W791* truncation at 50% VAF in the germline. Evaluation of allelic localization revealed CSF3R-T618I and W791* on the same allele. A concomitant ASXL1 mutation at 39% VAF increased to 48% VAF upon transformation to mixed phenotype acute leukemia (MPAL), which has both myeloid and lymphoid features. Clonal evolution further involved expansion of the CSF3R double-mutant clone to 90% VAF via copy neutral loss of heterozygosity on chromosome 1p and the emergence of a RUNX1 mutant subclone. Allogeneic transplantation induced complete remission. This study highlights that CNL not only transforms to AML but also to MPAL. The molecular evolution is especially interesting with a CSF3R-W791* mutation in the germline and acquisition of CSF3R-T618I on the same allele compatible with increased susceptibility for mutation acquisition facilitating RUNX1-related clonal transformation.

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Section: Discussionmentioning

confidence: 99%

Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia

et al. 2022

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“…TET2 mutations have an estimated mutational frequency of 29% in CNL ( 1 , 36 ). Previous authors postulated that cooperating RUNX1 and CSF3R mutations in CNL may result in disease progression, resistance to ruxolitnib and may act as an early marker of AML transformation ( 40 , 41 ).…”

Section: Discussion and Review Of The Literaturementioning

confidence: 99%

Case report: Chronic neutrophilic leukemia associated with monoclonal gammopathies. A case series and review of genetic characteristics and practical management

Vermeersch

Delforge²,

Havelange³

et al. 2022

Front. Oncol.

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Chronic neutrophilic leukemia (CNL) is a rare but potentially aggressive BCR::ABL1 negative myeloproliferative neoplasm, characterized by sustained mature, neutrophilic leukocytosis. The discovery of key driver mutations in the colony-stimulating-factor-3 receptor (CSF3R) gene resulted in the updated World Health Organization (WHO) diagnostic criteria in 2016. A significant number of CNL cases have been associated with plasma cell dyscrasias, predominantly multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS). Compared to pure CNL, mutated CSF3R is infrequently reported in CNL cases associated with monoclonal gammopathies (MG). Until now it remains unclear whether CNL and occurring plasma cell neoplasms are clonally related or CNL is developing secondary to the underlying dyscrasia. Owing to its rarity, currently no standard of care management exists for CNL and MG-associated CNL. In this case series we report the multi-center experience of five MG-associated CNL cases with a median age of diagnosis of 69 years. Three patients (66%) showed predominance of lambda light chain expression. Four (80%) eventually evolved to MM, and one CNL-MGUS patient developed secondary acute myeloid leukemia (AML). Mutated CSF3R was present in the patient who developed AML but was absent in other cases. To assess possible associated genetic aberrations we performed recurrent analysis with next-generation sequencing (NGS). Two patients (40%) deceased with a median time of survival of 8 years after CNL diagnosis. Three (60%) are currently in follow-up with no reoccurring leukocytosis. This case series, followed by a short review, provides a long-term clinical and genetic overview of five CNL cases associated with MG.

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“…In the aforementioned phase II trial of ruxolitinib in 21 patients with CNL, changes in allele frequency were inconsistent 125 . Similarly mixed results were derived from Stoner et al's 135 report, with three patients presenting allele burden reductions while two others displayed minimal change over time.…”

Section: Managementmentioning

confidence: 98%

“…Mechanisms of clonal evolution in CNL specifically while on JAK inhibitor therapy were recently explored in a study by Stoner et al 135 Salient findings included the emergence of STAT3 mutations late in ruxolitinib treatment course with speculated contribution to JAK inhibitor resistance, and the detection of RUNX1 and STAG2 mutations at disease progression ( n = 3 each). The latter observation postulates a role for cooperative RUNX1 and CSF3R mutations in CNL progression/leukemic transformation and exposes potential value of STAG2 mutations as a late biomarker of disease progression.…”

Section: Managementmentioning

confidence: 99%

Chronic neutrophilic leukemia: 2022 update on diagnosis, genomic landscape, prognosis, and management

2022

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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 Â 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.

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Insights on mechanisms of clonal evolution in chronic neutrophilic leukemia on ruxolitinib therapy

Cited by 11 publications

References 15 publications

Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia

Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia

Case report: Chronic neutrophilic leukemia associated with monoclonal gammopathies. A case series and review of genetic characteristics and practical management

Chronic neutrophilic leukemia: 2022 update on diagnosis, genomic landscape, prognosis, and management

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