Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor.

Abstract

Between October 2007 and July 2013, 183 Mayo Clinic patients (median age 65 years; 58% males) with high/intermediate risk myelofibrosis (MF) were enrolled in consecutive phase 1/2 JAK2 inhibitor (JAKi) clinical trials with momelotinib (n = 79), ruxolitinib (n = 50), fedratinib (n = 23) and BMS-911543 (n = 31). Using conventional criteria, the respective response rates for spleen and "transfusion-dependent anemia" were 47%, 32%, 83%, 62% and 51%, 30%, 10%, 44%, respectively, favoring momelotinib for anemia response (p = 0.02) and fedratinib for spleen response (p < 0.01). All study patients were followed to death or 2022, during which time 177 (97%) drug discontinuations, 27 (15%) leukemic transformations, and 22 (12%) allogeneic stem cell transplants (ASCT) were recorded. 5/10-year survival rate for all 183 patients was 41%/16% and not significantly different across the four drug cohorts (p = 0.33). Multivariable analysis of pre-treatment variables identified age >65 years (HR 3.5), absence of type 1/like CALR mutation (HR 2.8), baseline transfusion need (HR 2.1), and presence of ASXL1/SRSF2 mutation (HR 1.6) as risk factors for overall survival; subsequent HR-based modeling segregated three risk categories with 5/10-year survival rates of 84%/60%, 44%/14%, and 21%/5% (p < 0.01). In addition, spleen (p < 0.01) and anemia (p = 0.01) responses were independently associated with improved short-term survival while long-term survival was secured only by ASCT (5/10-year survival rate 91%/45% vs 47%/19% in non-transplanted patients; p < 0.01). The current retrospective study suggests the value of specific pre-treatment variables in identifying long-lived MF patients receiving JAKi and also confirms recent observations on the favorable impact of treatment response on short-term and of ASCT on long-term survival.

• Authors: Naseema Gangat, Kebede H Begna, Aref Al-Kali, William Hogan, Mark Litzow, Animesh Pardanani, Ayalew Tefferi
• Journal: Blood cancer journal (Blood Cancer J) Vol. 13 Issue 1 Pg. 3 (01 04 2023) ISSN: 2044-5385 [Electronic] United States
• PMID: 36599841 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• JAK2 protein, human
• Janus Kinase 2
• Janus Kinase Inhibitors
• N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo(4,5-d)pyrrolo(2,3b)pyridine-7-carboxamide
• N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
• ruxolitinib
• Sulfonamides

Topics

• Aged
• Female
• Humans
• Male
• Anemia (drug therapy)
• Janus Kinase 2 (genetics, metabolism)
• Janus Kinase Inhibitors (therapeutic use)
• Primary Myelofibrosis (drug therapy, genetics, mortality)
• Retrospective Studies
• Sulfonamides (therapeutic use)
• Survival Rate