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

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Kim-Hien T Dao, Jason Gotlib, Michael M N Deininger, Stephen T Oh, Jorge E Cortes, Robert H Collins Jr, Elliot F Winton, Dana R Parker, Hyunjung Lee, Anna Reister, Schultz, Samantha Savage, Stevens, Chase Brockett, Nan Subbiah, Richard D Press, Philipp W Raess, Michael Cascio, Jennifer Dunlap, Yiyi Chen, Catherine Degnin, Julia E Maxson, Cristina E Tognon, Tara Macey, Brian J Druker, Jeffrey W Tyner
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 38 Issue 10 Pg. 1006-1018 (04 01 2020) ISSN: 1527-7755 [Electronic] United States
• PMID: 31880950 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CSF3R protein, human
• Nitriles
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Receptors, Colony-Stimulating Factor
• ruxolitinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Alleles
• Antineoplastic Agents (therapeutic use)
• Female
• Gene Frequency
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics)
• Leukemia, Neutrophilic, Chronic (drug therapy, genetics)
• Male
• Middle Aged
• Nitriles
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Pyrazoles (adverse effects, therapeutic use)
• Pyrimidines
• Receptors, Colony-Stimulating Factor (genetics)
• Survival Rate