Reference Detail

Ref Type

Journal Article

PMID

(31880950)

Authors

Dao KT, Gotlib J, Deininger MMN, Oh ST, Cortes JE, Collins RH, Winton EF, Parker DR, Lee H, Reister A, Schultz, Savage S, Stevens, Brockett C, Subbiah N, Press RD, Raess PW, Cascio M, Dunlap J, Chen Y, Degnin C, Maxson JE, Tognon CE, Macey T, Druker BJ, Tyner JW

Title

Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology	38	10	2020 Apr 01	1006-1018	J Clin Oncol

URL

Abstract Text

Colony-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.We 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.ORR 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.Ruxolitinib 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CSF3R T640N	chronic neutrophilic leukemia	predicted - sensitive	Ruxolitinib	Case Reports/Case Series	Actionable	In a Phase II trial, Jakafi (ruxolitinib) treatment resulted in an overall hematologic response rate of 35% (15/43, 4 complete and 11 partial responses) and a median overall survival of 18.8 months in patients with chronic neutrophilic leukemia (CNL) or atypical chronic myeloid leukemia harboring CSF3R mutations T618I (n=20), T640N (n=1), and T615A (n=1), including a complete response in a CNL patient harboring CSF3R T640N (PMID: 31880950; NCT02092324).	31880950
CSF3R T618I	chronic neutrophilic leukemia	predicted - sensitive	Ruxolitinib	Case Reports/Case Series	Actionable	In a Phase II trial, Jakafi (ruxolitinib) treatment resulted in an overall hematologic response rate of 35% (15/43, 4 complete and 11 partial responses) and a median overall survival of 18.8 months in patients with chronic neutrophilic leukemia (CNL) or atypical chronic myeloid leukemia harboring CSF3R mutations, including T618I (n=20), T640N (n=1), and T615A (n=1), with 2 complete and 9 partial responses in CNL patients harboring CSF3R T618I (PMID: 31880950; NCT02092324).	31880950