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Clinical Trial
. 2024 Sep;41(9):3722-3735.
doi: 10.1007/s12325-024-02928-4. Epub 2024 Jul 11.

Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2

Claire N Harrison  1 , Alessandro M Vannucchi  2 , Christian Recher  3 , Francesco Passamonti  4 , Aaron T Gerds  5 , Juan Carlos Hernandez-Boluda  6 , Abdulraheem Yacoub  7 , Shireen Sirhan  8 , Catherine Ellis  9 , Bharat Patel  9 , Bryan Strouse  9 , Uwe Platzbecker  10
Affiliations
Clinical Trial

Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2

Claire N Harrison et al. Adv Ther. 2024 Sep.

Abstract

Introduction: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration.

Methods: SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively.

Results: In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower.

Conclusion: In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies.

Trial registration: ClinicalTrials.gov: NCT02101268.

Keywords: Anemia; Anemia supportive therapy; Erythropoiesis-stimulating agents; Hemoglobin; Momelotinib; Myelofibrosis; Red blood cell transfusions; Ruxolitinib; Transfusion independence.

Plain language summary

Patients with the rare blood cancer myelofibrosis often experience symptoms such as tiredness, an increase in the size of their spleens (an organ involved in filtering the blood), and anemia (too few red blood cells). One type of treatment for myelofibrosis, called a Janus kinase (JAK) inhibitor, can help patients to feel better and reduce the size of their spleens, but some JAK inhibitors do not help with anemia and may make it worse. In those situations, patients may continue to take their JAK inhibitor but also receive another type of treatment, called an anemia supportive therapy, and may also receive red blood cell transfusions. This study compared 2 treatment approaches, continuing the JAK inhibitor ruxolitinib and adding an anemia supportive therapy and/or transfusions versus switching to another treatment called momelotinib, in 2 groups of patients from a clinical trial: (1) patients with levels of hemoglobin (a red blood cell protein) at the start of the trial that indicated that they had anemia, and (2) patients who were already receiving red blood cell transfusions at the start of the trial. In both groups, more patients did not need red blood cell transfusions anymore at week 24 with momelotinib, and their hemoglobin levels on average became higher over time. More patients also had improvements in spleen size and symptoms with momelotinib. Overall, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using supportive therapies and/or red blood cell transfusions to treat anemia.

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Conflict of interest statement

Claire N. Harrison reports consultancy with Novartis, MorphoSys, Sierra, Constellation, AOP, Galecto, Keros, AbbVie, Geron, Janssen, Promedior, Sumitomo, GSK, and CTI; participation in a company-sponsored speakers’ bureau for AbbVie, BMS, Celgene, CTI, and Novartis; research funding from Constellation, Novartis, Celgene (BMS), and Imago Biosciences, Inc., a subsidiary of Merck & Co.; sole ownership and directorship of Chakana Medical Limited; advisory roles with Galecto and Keros; patents and royalties from Blood Cancer UK, BMS, Chakana Medical, Constellation, EHA, MPN Voice, and Novartis; and honoraria from BMS, Novartis, CTI, GSK, AOP, Galecto, AbbVie, and MorphoSys. Alessandro M. Vannucchi reports honoraria from Incyte, Novartis, BMS, GSK, AbbVie, Roche, and AOP. Christian Recher reports honoraria from and an advisory role with AbbVie, Astellas, Amgen, BMS, Jazz Pharmaceuticals, Novartis, and Servier and research funding from AbbVie, Astellas, Amgen, BMS, Jazz Pharmaceuticals, and Servier. Francesco Passamonti reports honoraria from AbbVie, AOP Orphan, and Bristol Myers Squibb/Celgene and consultancy with AbbVie, AOP Orphan, Celgene, Bristol Myers Squibb, Janssen, Kartos, Karyopharm, Kyowa Kirin, MEI, Novartis, Roche, Sierra Oncology, and Sumitomo. Aaron T. Gerds reports consultancy with AbbVie, Bristol Myers Squibb, Celgene, Constellation Pharmaceuticals, GSK, Kartos, Novartis, PharmaEssentia, and Sierra Oncology; consultancy with and research funding from CTI BioPharma, Imago BioSciences/Merck, and Constellation Pharmaceuticals/MorphoSys; research funding from Accurate Pharmaceuticals, Constellation Pharmaceuticals, CTI BioPharma, Imago BioSciences, Incyte Corporation, and Kartos Pharmaceuticals; and an advisory role with AbbVie, Bristol Myers Squibb, CTI BioPharma, GSK, Imago, Kartos, MorphoSys, PharmaEssentia, and Rain Oncology. Juan Carlos Hernandez-Boluda reports an advisory role with Incyte, Pfizer, Novartis, and BMS. Abdulraheem Yacoub reports consultancy with Incyte, CTI Pharma, PharmaEssentia, Pfizer, Novartis, and Acceleron Pharma. Shireen Sirhan reports honoraria from Constellation and consultancy with and honoraria from GSK, Novartis, and Constellation. Catherine Ellis, Bharat Patel, and Bryan Strouse are employees of GSK. Uwe Platzbecker reports consultancy with AbbVie, Curis, and Geron and an advisory role with MDS Foundation. All authors acknowledge editorial support in the preparation of this manuscript, funded by GSK.

Figures

Fig. 1
Fig. 1
Week 24 transfusion independence in the baseline Hb < 100 g/L and non-TI subgroups. Transfusion independence at week 24 (terminal 12-week definition; defined as no RBC transfusions and no Hb of < 80 g/L in the last 12 weeks before week 24) or by week 24 (rolling 12-week definition; defined as no RBC transfusions and no Hb of < 80 g/L during any 12-week period through week 24). BAT best available therapy, Hb hemoglobin, RBC red blood cell, TI transfusion independent
Fig. 2
Fig. 2
Mean Hb levels over time in the baseline Hb < 100 g/L (A) and non-TI (B) subgroups. Results through week 84 are shown for illustrative purposes, although the study continued beyond this time point. BAT best available therapy, BL baseline, Hb hemoglobin, TI transfusion independent
Fig. 3
Fig. 3
SVR35 and TSS50 at week 24 in the baseline Hb < 100 g/L and non-TI subgroups. For TSS50, response rates are based on the number of patients evaluable for TSS at week 24. BAT best available therapy, Hb hemoglobin, SVR35 spleen volume reduction ≥ 35%, TI transfusion independent, TSS50 total symptom score reduction ≥ 50%. aIn the Hb < 100 g/L subgroup, n = 65 for the momelotinib arm and n = 38 for the BAT/ruxolitinib arm
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