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ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.

Publication ,  Journal Article
Oh, ST; Talpaz, M; Gerds, AT; Gupta, V; Verstovsek, S; Mesa, R; Miller, CB; Rivera, CE; Fleischman, AG; Goel, S; Heaney, ML; O'Connell, C ...
Published in: Blood Adv
September 22, 2020

Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.

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Published In

Blood Adv

DOI

EISSN

2473-9537

Publication Date

September 22, 2020

Volume

4

Issue

18

Start / End Page

4282 / 4291

Location

United States

Related Subject Headings

  • Pyrimidines
  • Primary Myelofibrosis
  • Janus Kinase 2
  • Janus Kinase 1
  • Humans
  • Hepcidins
  • Benzamides
  • Activin Receptors, Type I
  • 3201 Cardiovascular medicine and haematology
 

Citation

APA
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Oh, S. T., Talpaz, M., Gerds, A. T., Gupta, V., Verstovsek, S., Mesa, R., … Brachmann, C. B. (2020). ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv, 4(18), 4282–4291. https://doi.org/10.1182/bloodadvances.2020002662
Oh, Stephen T., Moshe Talpaz, Aaron T. Gerds, Vikas Gupta, Srdan Verstovsek, Ruben Mesa, Carole B. Miller, et al. “ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.Blood Adv 4, no. 18 (September 22, 2020): 4282–91. https://doi.org/10.1182/bloodadvances.2020002662.
Oh ST, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020 Sep 22;4(18):4282–91.
Oh, Stephen T., et al. “ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.Blood Adv, vol. 4, no. 18, Sept. 2020, pp. 4282–91. Pubmed, doi:10.1182/bloodadvances.2020002662.
Oh ST, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, Miller CB, Rivera CE, Fleischman AG, Goel S, Heaney ML, O’Connell C, Arcasoy MO, Zhang Y, Kawashima J, Ganz T, Kowalski M, Brachmann CB. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020 Sep 22;4(18):4282–4291.

Published In

Blood Adv

DOI

EISSN

2473-9537

Publication Date

September 22, 2020

Volume

4

Issue

18

Start / End Page

4282 / 4291

Location

United States

Related Subject Headings

  • Pyrimidines
  • Primary Myelofibrosis
  • Janus Kinase 2
  • Janus Kinase 1
  • Humans
  • Hepcidins
  • Benzamides
  • Activin Receptors, Type I
  • 3201 Cardiovascular medicine and haematology