Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib’s pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.

Related collections

Most cited references 31

Record: found
Abstract: found
Article: not found

A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.

Srdan Verstovsek, Ruben Mesa, Jason Gotlib … (2012)

Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

0 comments Cited 312 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.

Claire Harrison, Jean-Jacques Kiladjian, Haifa Al-Ali … (2012)

Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy. Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).

0 comments Cited 251 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.

Francisco Javier Cervantes, Brigitte Dupriez, Arturo Pereira … (2009)

Therapeutic decision-making in primary myelofibrosis (PMF) is becoming more challenging because of the increasing use of allogeneic stem cell transplantation and new investigational drugs. To enhance this process by developing a highly discriminative prognostic system, 1054 patients consecutively diagnosed with PMF at 7 centers were studied. Overall median survival was 69 months (95% confidence interval [CI]: 61-76). Multivariate analysis of parameters obtained at disease diagnosis identified age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 x 10(9)/L, and circulating blast cells 1% or greater as predictors of shortened survival. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of these variables, 4 risk groups with no overlapping in their survival curves were delineated; respective median survivals were 135, 95, 48, and 27 months (P< .001). Compared with prior prognostic models, the new risk stratification system displayed higher predictive accuracy, replicability, and discriminating power. In 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups. JAK2V617F did not cluster with a specific risk group or affect survival.

0 comments Cited 131 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Ruben Mesa:

ORCID: http://orcid.org/0000-0001-5880-7972

mesar@uthscsa.edu

Journal

Journal ID (nlm-ta): Leukemia

Journal ID (iso-abbrev): Leukemia

Title: Leukemia

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0887-6924

ISSN (Electronic): 1476-5551

Publication date (Electronic): 22 July 2022

Publication date PMC-release: 22 July 2022

Publication date (Print): 2022

Volume: 36

Issue: 9

Pages: 2261-2268

Affiliations

[1 ]GRID grid.267309.9, ISNI 0000 0001 0629 5880, UT Health San Antonio Cancer Center, ; San Antonio, TX USA

[2 ]GRID grid.420545.2, ISNI 0000 0004 0489 3985, Guy’s and St Thomas’ NHS Foundation Trust, ; London, United Kingdom

[3 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Washington University School of Medicine, ; St. Louis, MO USA

[4 ]GRID grid.239578.2, ISNI 0000 0001 0675 4725, Cleveland Clinic Taussig Cancer Institute, ; Cleveland, OH USA

[5 ]GRID grid.415224.4, ISNI 0000 0001 2150 066X, Princess Margaret Cancer Centre, ; Toronto, ON Canada

[6 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Monash University & Frankston Hospital, ; Frankston, Australia

[7 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Hospital Clinic, IDIBAPS, , University of Barcelona, ; Barcelona, Spain

[8 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Department of Hematology, , University Hospitals Leuven and Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, ; Leuven, Belgium

[9 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Medical University of Lublin, ; Lublin, Poland

[10 ]Université de Paris, AP-HP, Hôpital Saint-Louis, Centre d’Investigations Cliniques, INSERM, CIC1427 Paris, France

[11 ]GRID grid.419032.d, ISNI 0000 0001 1339 8589, Institute of Hematology and Transfusion Medicine, ; Warsaw, Poland

[12 ]GRID grid.8404.8, ISNI 0000 0004 1757 2304, University of Florence and AOU Careggi, ; Florence, Italy

[13 ]GRID grid.411339.d, ISNI 0000 0000 8517 9062, Leipzig University Hospital, ; Leipzig, Germany

[14 ]Sierra Oncology Inc, San Mateo, CA USA

[15 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

Author information

Ruben Mesa http://orcid.org/0000-0001-5880-7972

Stephen T. Oh http://orcid.org/0000-0002-8564-5400

Aaron T. Gerds http://orcid.org/0000-0002-3422-1309

Vikas Gupta http://orcid.org/0000-0002-1419-8607

Jean-Jacques Kiladjian http://orcid.org/0000-0002-8121-438X

Donal McLornan http://orcid.org/0000-0003-1224-091X

Uwe Platzbecker http://orcid.org/0000-0003-1863-3239

Barbara Klencke http://orcid.org/0000-0002-9518-2526

Srdan Verstovsek http://orcid.org/0000-0002-6912-8569

Article

Publisher ID: 1637

DOI: 10.1038/s41375-022-01637-7

PMC ID: 9417985

PubMed ID: 35869266

SO-VID: 711459ee-bcd1-4d2c-b32d-23d4e179a020

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 8 April 2022

Date revision received : 17 June 2022

Date accepted : 23 June 2022

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: targeted therapies,myeloproliferative disease

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: targeted therapies, myeloproliferative disease

Comments

Comment on this article

scite_

Cited by 18

See all cited by

Most referenced authors 656

See all reference authors

- Version 1

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis

Read this article at

Abstract

Related collections

Karger: Oncology

Most cited references 31

A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.

New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 1,077

Cited by 18

Most referenced authors 656