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.

Myeloid Disease with the CSF3R T618I Mutation after CLL

“…TKI therapy was experimented successfully in a CNL patient for the first time in 2004, for the CSF3R mutation [ 12 ]. Treatment with the SRC kinase inhibitor dasatinib and the JAK1/2 kinase inhibitor ruxolitinib also have shown efficacy for CNL with membrane proximal mutations and truncation mutations, respectively [ 3 , 12 , 13 ]. Most of the agents proposed for CNL treatment are palliative, not achieving remission of the disease.…”

Therapeutic targeting of JAKs: from hematology to rheumatology and from the first to the second generation of JAK inhibitors

“…Trials are underway to determine the efficacy of ruxolitinib in other myeloproliferative diseases, including chronic neutrophilic leukaemia and atypical CML (both often associated with mutations in colony-stimulating factor-3 receptor), as well as AML and T-cell lymphoproliferative disorders. 30 , 31 …”

Clinicopathologic Correlates and Natural History of Atypical Chronic Myeloid Leukemia

“…Furthermore, aCML is characterized by a short median overall survival of 25 months and high risk of transformation to acute myeloid leukemia (AML) compared to other MDS/MPNs (3,11), however there is scarce data evaluating the potential factors associated with aCML prognosis (3). To date, therapeutic options for patients with aCML are limited and, although therapy with ruxolitnib can be associated with responses in patients with CSF3R mutations (5,12,13), particularly in the absence of SETBP1 mutations, there is insufficient evidence on the optimal therapeutic strategies for these patients. Although several reports including small patient cohorts have described the potential use of hypomethylating agents, such as decitabine or azacitidine, for the treatment of aCML (3,(14)(15)(16)(17)(18), evaluation of the survival benefit or clinical activity of these compounds a lager cohort and comparison to other therapeutic approaches is needed.…”

“…Atypical chronic myeloid leukemia (aCML) is a rare hematopoietic stem cell disorder with dismal prognosis and a high rate of transformation to acute leukemia (11). Although prior reports have described activity of ruxolitinib (12), hydroxyurea, low-dose cytarabine, or HMAs (15,16,26) in this disease, data on the optimal clinical management of these patients remains unclear. In addition, given the rarity of this disorder, there is a lack of validated clinical risk models to effectively stratify patients based on predicted outcomes (3,26).…”