Clinical response to ruxolitinib in CSF3R T618-mutated chronic neutrophilic leukemia.
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ABSTRACT:
SUBMITTER: Stahl M
PROVIDER: S-EPMC7479634 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
Clinical response to ruxolitinib in CSF3R T618-mutated chronic neutrophilic leukemia.
Stahl Maximilian M Xu Mina L ML Steensma David P DP Rampal Raajit R Much Melissa M Zeidan Amer M AM
Annals of hematology 20160411 7
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Project description:BackgroundThe molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms.MethodsTo identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies.ResultsWe identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib.ConclusionsMutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.).
| S-EPMC3730275 | biostudies-literature
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| S-EPMC5451352 | biostudies-literature
Project description:PurposeColony-stimulating factor-3 receptor (CSF3R)-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of CSF3R mutation status.MethodsWe conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival.ResultsORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic CSF3R mutations. The mean absolute allele burden reduction of CSF3R-T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed.ConclusionRuxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring CSF3R-T618I were most likely to respond.
| S-EPMC7106977 | biostudies-literature
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| S-EPMC5477626 | biostudies-literature
Project description:Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that includes only 150 patients described to date meeting the latest World Health Organization (WHO) criteria and the recently reported CSF3R mutations. The diagnosis is based on morphological criteria of granulocytic cells and the exclusion of genetic drivers that are known to occur in others MPNs, such as BCR-ABL1, PDGFRA/B, or FGFR1 rearrangements. However, this scenario changed with the identification of oncogenic mutations in the CSF3R gene in approximately 83% of WHO-defined and no monoclonal gammopathy-associated CNL patients. CSF3R T618I is a highly specific molecular marker for CNL that is sensitive to inhibition in vitro and in vivo by currently approved protein kinase inhibitors. In addition to CSF3R mutations, other genetic alterations have been found, notably mutations in SETBP1, which may be used as prognostic markers to guide therapeutic decisions. These findings will help to understand the pathogenesis of CNL and greatly impact the clinical management of this disease. In this review, we discuss the new genetic alterations recently found in CNL and the clinical perspectives in its diagnosis and treatment. Fortunately, since the diagnosis of CNL is not based on exclusion anymore, the molecular characterization of the CSF3R gene must be included in the WHO criteria for CNL diagnosis.
| S-EPMC4562747 | biostudies-literature
Project description:Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm, which is characterized by sustained peripheral leukocytosis with neutrophilia, hepatosplenomegaly, and hypercellularity of the bone marrow, with less than 5% myeloblasts along with normal neutrophil maturation and no dysplasia. In 2016, World Health Organization (WHO) included activating mutations in the gene for colony-stimulating factor 3 receptor (CSF3R) as one of the diagnostic criteria with CSF3RT618I being the most common mutation. We report a rare case of CNL (JAK2V617F negative, BCR-ABL1 negative, CSF3RT618I positive) in an elderly female who had an aggressive clinical course of the disease.
| S-EPMC6248686 | biostudies-literature
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| S-EPMC10567908 | biostudies-literature
Project description:Mutations in CSF3R (colony-stimulating factor 3 receptor) are frequent oncogenic drivers in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). Here we describe a 75 year old man who was diagnosed with CSF3R-T618I-positive atypical CML. He presented with leukocytosis, anemia, and thrombocytopenia and developed massive splenomegaly and severe constitutional symptoms. Hydroxyurea was given over a 6 month period but failed to provide any measureable clinical benefit. Eventually, he was treated with ruxolitinib, an FDA-approved JAK1/2 inhibitor, which resulted in dramatic improvement of his blood counts. He also had significant reduction of spleen volume and constitutional symptoms. This case highlights the need for a clinical trial to interrogate JAK1/2 as a potential molecular target in CNL and aCML in patients with or without CSF3R mutation. A clinical trial evaluating the safety and efficacy of ruxolitinib for this patient population is registered at ClinicalTrials.gov (NCT02092324).
| S-EPMC4145163 | biostudies-literature
Project description:Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization guidelines have been updated to include CSF3R mutations as part of the diagnostic criteria for CNL. Because of the high prevalence of CSF3R mutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion. However, recent additional genomic characterization demonstrates that CNL has much in common with other chronic myeloid malignancies at the genetic level, such as the clinically related diagnosis atypical chronic myeloid leukemia. These commonalities include mutations in SETBP1, spliceosome proteins (SRSF2, U2AF1), and epigenetic modifiers (TET2, ASXL1). Some of these same mutations also have been characterized as frequent events in clonal hematopoiesis of indeterminate potential, suggesting a more complex disease evolution than was previously understood and raising the possibility that an age-related clonal process of preleukemic cells could precede the development of CNL. The order of acquisition of CSF3R mutations relative to mutations in SETBP1, epigenetic modifiers, or the spliceosome has been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population.
| S-EPMC5301820 | biostudies-literature
Project description:Chronic neutrophilic leukemia (CNL) represents a rare disease, that has been classified among the BCR/ABL-negative myeloproliferative neoplasms. The disease is characterized by marked leukocytosis with absolute neutrophilia and its clinical presentation may vary from asymptomatic to highly symptomatic with massive splenomegaly and constitutional symptoms. CNL prognosis remains relatively poor, as most patients succumb to disease complications or transform to acute myeloid leukemia. Recent studies have demonstrated that CSF3R mutations drive the disease, albeit the presence of other secondary mutations perplex the genetic landscape of the disease. Notably, the presence of CSF3R mutations has been adopted as a criterion for diagnosis of CNL. Despite the vigorous research, the management of the disease remains suboptimal. Allogeneic stem cell transplantation represents the only treatment that could lead to cure; however, it is accompanied by high rates of treatment-related mortality. Recently, ruxolitinib has shown significant responses in patients with CNL; however, emergence of resistance might perturbate long-term management of the disease. The aim of this review is to summarize the clinical course and laboratory findings of CNL, highlight its pathogenesis and complex genetic landscape, and provide the context for the appropriate management of patients with CNL.
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