Chronic neutrophilic leukemia with concurrent CSF3R and SETBP1 mutations: single colony clonality studies, in vitro sensitivity to JAK inhibitors and lack of treatment response to ruxolitinib

Lasho, T. L.; Mims, Alice S.; Elliott, Michelle A.; Finke, Christy; Pardanani, Animesh; Tefferi, Ayalew

doi:10.1038/leu.2014.39

Cited by 50 publications

(42 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other therapies included interferon a or its pegylated form (n 5 4), hypomethylating agents (n 5 4), ruxolitinib (n 5 2), thalidomide (n 5 2), cladribine (n 5 2), and imatinib (n 5 1). None induced remission and provided primarily palliative and transient benefit, including ruxolitinib, which produced an initial reduction in leukocytosis but required the addition of hydroxyurea in both cases treated, details of one have been previously published [10]. Only one patient with leukemic evolution proceeded to hematopoietic stem cell transplantation (HSCT) after achieving BM aplasia after standard 7 1 3 induction chemotherapy.…”

Section: Resultsmentioning

confidence: 99%

“…Central review of the peripheral blood smears, bone marrow (BM) aspirates, and biopsies was performed to confirm that all cases [1]. The methods of mutation analysis of CSF3R, SETBP1, JAK2, MPL, ASXLI, and CALR have been previously published, as have the details of initial CSF3R-mutation discovery of these cases [3,[8][9][10] Statistical analysis considered clinical and laboratory features from diagnosis. The Stat View (SAS Institute, Cary, NC) statistical package was used for calculations.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

et al. 2015

View full text Add to dashboard Cite

*Colony stimulating factor 3 receptor gene (CSF3R) mutations have recently been associated with chronic neutrophilic leukemia (CNL). Fourteen patients with CSF3R-mutated CNL (median age 67 years; 57% males) were screened for additional mutations; 8 (57%) and 5 (38%) harbored an ASXL1 and/or SETBP1 mutation (two patients expressed both), respectively. Two patients developed blastic transformation, both SETBP1-mutated and ASXL1-unmutated, whereas two other cases evolved into chronic myelomonocytic leukemia (CMML), both ASXL1-mutated and SETBP1-unmutated. Median survival was 23.2 months (10 deaths documented). On multivariable analysis mutated ASXL1 (P 5 0.009; HR 19.6, 95% CI 2.1-184.1) and thrombocytopenia (P 5 0.005; HR 28.8, 95% CI 2.8-298.2) were independently predictive of shortened survival. This study provides information on the natural history of CSF3R-mutated CNL and identifies mutant ASXL1 and thrombocytopenia as risk factors for survival. The study also suggests pathogenetic roles for SETBP1 and ASXL1 mutations in disease evolution into blast phase disease and CMML, respectively.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In vitro studies of this patient's double-mutant myeloid cells also showed resistance to the application of specific JAK inhibitor treatment. Although, currently unknown if the co-expression of SETBP1 in this CSFR3T618I-mutated patient with CNL contributed to the ineffectiveness of JAK inhibitor therapy, a subsequent case report by Ammatuna et al of a WHO-defined aCML patient coexpressing CSFR3T618I and SETBP1 mutations, who similarly proved refractory to ruxolitinib treatment, lends credence to that possibility [77,81]. Further support for this observation is a reported case of CSFR3T618I-positive aCML with leukocytosis, anemia, and thrombocytopenia, massive splenomegaly and severe constitutional symptoms who failed to obtain any measureable benefit from hydroxyurea.…”

Section: Novel Therapeutic Approachesmentioning

confidence: 92%

“…Other therapies included interferon a or its pegylated form (n 5 4), hypomethylating agents (n 5 4), and ruxolitinib, thalidomide, cladribine (in two cases each), and imatinib in one. None of these treatments induced remission and provided primarily palliative and transient benefit, including ruxolitinib which produced an initial reduction in leukocytosis but required the addition of hydroxyurea in both cases treated, details of one have been previously published [77]. Only one patient with leukemic evolution proceeded to hematopoietic stem cell transplantation (HSCT) after achieving BM aplasia after a standard 7 1 3 AML induction regimen.…”

Section: Clinical Course and Prognosismentioning

confidence: 99%

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

Elliott

Tefferi

2016

American J Hematol

View full text Add to dashboard Cite

Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥25 × 109/L (of which >80% are neutrophils) and with <10 and <1% circulating immature granulocytes and blasts, respectively without dysplasia, clinical, or molecular criteria for other myeloproliferative disorders, nor an identifiable cause for physiologic neutrophilia in the absence of markers of myeloid clonality. Such a pathogenic clonal marker has now been identified as a somatic activating mutation of CSF3R, most commonly CSF3R T618I, thus demanding revision of the current WHO diagnostic classification to include the molecular criterion of mutated CSF3R. The clinical presentation, disease course and prognosis of CSF‐R mutated CNL have been recently outlined. Co‐operative mutations in SETBP1 and ASXL1 appear to be of prognostic significance and correlate with disease progression. Advances in the understanding of the molecular pathogenesis of CNL, have not yet fully translated into satisfactory therapeutic strategies, but the foundations for these are strengthening. Am. J. Hematol. 91:342–349, 2016. © 2015 Wiley Periodicals, Inc.

show abstract

“…In the present study, there was insufficient time to commence treatment with JAK2 inhibitors, such as ruxolitinib, prior to the patient succumbing to the disease. However, Lasho et al (18) recently described a double-mutated CNL patient (CSF3R and SETBP1) who was refractory to treatment with ruxolitinib and hydroxyurea.…”

Section: Discussionmentioning

confidence: 99%

Chronic neutrophilic leukemia with overexpression of EVI-1, and concurrent CSF3R and SETBP1 mutations: A case report

et al. 2015

View full text Add to dashboard Cite

Abstract. Chronic neutrophilic leukemia (CNL) is a rare type of myeloproliferative neoplasm, characterized by sustained neutrophilia, splenomegaly, bone marrow granulocytic hyperplasia (without evidence of dysplasia) and an absence of the Philadelphia chromosome. Thus far, ~150 cases of CNL have been described in the literature; however, none have demonstrated overexpression of the ecotropic viral integration site-1 (EVI-1, also known as MECOM) gene. The present study describes a case that fulfilled the World Health Organization diagnostic criteria for CNL, and was associated with overexpression of EVI-1, as well as novel concurrent mutations of colony stimulating factor 3 receptor (CSF3R) and SET binding protein-1 (SETBP1). In addition, the current study briefly reviewed the relevant literature regarding novel genetic findings associated with the diagnosis and treatment of CNL. To the best of our knowledge, this is the first case report of CNL with associated EVI-1 overexpression, and concurrent CSF3R and SETBP1 mutations.

show abstract

Chronic neutrophilic leukemia with concurrent CSF3R and SETBP1 mutations: single colony clonality studies, in vitro sensitivity to JAK inhibitors and lack of treatment response to ruxolitinib

Cited by 50 publications

References 8 publications

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

Chronic neutrophilic leukemia with overexpression of EVI-1, and concurrent CSF3R and SETBP1 mutations: A case report

Contact Info

Product

Resources

About