Momelotinib therapy for myelofibrosis: a 7-year follow-up

Ayalew Tefferi, Daniela Barraco, Terra L Lasho, Sahrish Shah, Kebede H Begna, Aref Al-Kali, William J Hogan, Mark R Litzow, Curtis A Hanson, Rhett P Ketterling, Naseema Gangat, Animesh Pardanani, Ayalew Tefferi, Daniela Barraco, Terra L Lasho, Sahrish Shah, Kebede H Begna, Aref Al-Kali, William J Hogan, Mark R Litzow, Curtis A Hanson, Rhett P Ketterling, Naseema Gangat, Animesh Pardanani

Abstract

One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%. Clinical improvement (CI) occurred in 57% of patients, including 44% anemia and 43% spleen response. CI was more likely to occur in ASXL1-unmutated patients (66% vs 44%) and in those with <2% circulating blasts (66% vs 42%). Response was more durable in the presence of CALR type 1/like and absence of very high-risk karyotype. In multivariable analysis, absence of CALR type 1/like (HR 3.0; 95% CI 1.2-7.6) and presence of ASXL1 (HR 1.9; 95% CI 1.1-3.2) or SRSF2 (HR 2.4, 95% CI 1.3-4.5) mutations adversely affected survival. SRSF2 mutations (HR 4.7, 95% CI 1.3-16.9), very high-risk karyotype (HR 7.9, 95% CI 1.9-32.1), and circulating blasts ≥2% (HR 3.9, 95% CI 1.4-11.0) predicted leukemic transformation. Post-MMB survival (median 3.2 years) was not significantly different than that of a risk-matched MF cohort not receiving MMB.

Conflict of interest statement

The clinical trial was sponsored by Gilead Sciences. Inc., Foster City, CA, USA.

Figures

Fig. 1
Fig. 1
Survival of 83 molecularly annotated patients with myelofibrosis from the time of momelotinib study entry to the last follow-up or death, and stratified by age and mutation profile
Fig. 2
Fig. 2
Comparison of survival data between 100 patients receiving and 442 patients not receiving momelotinib treatment; the two populations consisted of DIPSS-plus high or intermediate-2 risk patients only with the exception of a single momelotinib-treated patient who was intermediate-one risk

References

    1. Pardanani A, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;27:1322–1327. doi: 10.1038/leu.2013.71.
    1. Pardanani A, et al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009;23:1441–1445. doi: 10.1038/leu.2009.50.
    1. Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 2016;91:1262–1271. doi: 10.1002/ajh.24592.
    1. Tyner JW, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115:5232–5240. doi: 10.1182/blood-2009-05-223727.
    1. Pardanani, A. et al. Long-term efficacy and safety of momelotinib, a JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis. Leukemia 2017 .
    1. Tefferi A, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122:1395–1398. doi: 10.1182/blood-2013-03-488098.
    1. Caramazza D, et al. Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients. Leukemia. 2011;25:82–88. doi: 10.1038/leu.2010.234.
    1. Guglielmelli P., et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J. Clin. Oncol. 2017. doi: 10.1200/JCO.2017.76.4886.
    1. Tefferi A, et al. Targeted next-generation sequencing in myelodysplastic syndromes and prognostic interaction between mutations and IPSS-R. Am. J. Hematol. 2017;92:1311–1317. doi: 10.1002/ajh.24901.
    1. Gangat N, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J. Clin. Oncol. 2011;29:392–397. doi: 10.1200/JCO.2010.32.2446.
    1. Asshoff M, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood. 2017;129:1823–1830. doi: 10.1182/blood-2016-09-740092.
    1. Abdelrahman RA, et al. Momelotinib treatment-emergent neuropathy: prevalence, risk factors and outcome in 100 patients with myelofibrosis. Br. J. Haematol. 2015;169:77–80. doi: 10.1111/bjh.13262.
    1. Gotlib JR, et al. Phase 3 randomized trial of Momelotinib versus Ruxolitinib in Jak inhibitor naive patients with myelofibrosis: results of the Simplify-1 study. Haematologica. 2017;102:320–320. doi: 10.3324/haematol.2016.147843.
    1. Verstovsek S, et al. Phase 3 randomized trial of Momelotinib versus best available therapy in patients with myelofibrosis previously treated with Ruxolitinib: results of the Simplify-2 study. Haematologica. 2017;102:320–321. doi: 10.3324/haematol.2016.147843.
    1. Coltro G, et al. A life-threatening ruxolitinib discontinuation syndrome. Am. J. Hematol. 2017;92:833–838. doi: 10.1002/ajh.24775.
    1. Lussana F, Cattaneo M, Rambaldi A, Squizzato A. Ruxolitinib-associated infections: a systematic review and meta-analysis. Am. J. Hematol. 2018;93:339–347. doi: 10.1002/ajh.24976.
    1. Eyal O, Flaschner M, Ben Yehuda A, Rund D. Varicella-zoster virus meningoencephalitis in a patient treated with ruxolitinib. Am. J. Hematol. 2017;92:E74–E75. doi: 10.1002/ajh.24688.
    1. Slostad J, et al. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: a single patient experience. Am. J. Hematol. 2018;93:E47–E49. doi: 10.1002/ajh.24971.
    1. Pieri L, Guglielmelli P, Vannucchi AM. Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia. Am. J. Hematol. 2015;90:82–83. doi: 10.1002/ajh.23871.
    1. Tefferi A, et al. Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1A095 patients. Am. J. Hematol. 2017;93:348–355. doi: 10.1002/ajh.24978.
    1. Pardanani A, et al. Genetic determinants of response and survival in momelotinib-treated patients with myelofibrosis. Leukemia. 2015;29:741–744. doi: 10.1038/leu.2014.306.

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