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. 2023 Oct 27;7(11):e963.
doi: 10.1097/HS9.0000000000000963. eCollection 2023 Nov.

Momelotinib in Myelofibrosis Patients With Thrombocytopenia: Post Hoc Analysis From Three Randomized Phase 3 Trials

Jean-Jacques Kiladjian  1 , Alessandro M Vannucchi  2 , Aaron T Gerds  3 , Vikas Gupta  4 , Srdan Verstovsek  5 , Miklos Egyed  6 , Uwe Platzbecker  7 , Jiří Mayer  8   9 , Sebastian Grosicki  10 , Árpád Illés  11 , Tomasz Woźny  12 , Stephen T Oh  13 , Donal McLornan  14 , Ilya Kirgner  15   16 , Sung-Soo Yoon  17   18   19 , Claire N Harrison  20 , Barbara Klencke  21 , Mei Huang  21 , Jun Kawashima  21 , Ruben Mesa  22
Affiliations

Momelotinib in Myelofibrosis Patients With Thrombocytopenia: Post Hoc Analysis From Three Randomized Phase 3 Trials

Jean-Jacques Kiladjian et al. Hemasphere. .

Abstract

The oral activin A receptor type I, Janus kinase 1 (JAK1), and JAK2 inhibitor momelotinib demonstrated symptom, spleen, and anemia benefits in intermediate- and high-risk myelofibrosis (MF). Post hoc analyses herein evaluated the efficacy and safety of momelotinib in patients with MF and thrombocytopenia (platelet counts <100 × 109/L) from randomized phase 3 studies: MOMENTUM (momelotinib versus danazol; JAK inhibitor experienced); SIMPLIFY-1 (momelotinib versus ruxolitinib; JAK inhibitor naïve); and SIMPLIFY-2 (momelotinib versus best available therapy; JAK inhibitor experienced); these studies were not statistically powered to assess differences in thrombocytopenic subgroups, and these analyses are descriptive. The treatment effect of momelotinib versus ruxolitinib on week 24 response rates (spleen volume reduction ≥35%/Total Symptom Score reduction ≥50%/transfusion independence) was numerically comparable or better in thrombocytopenic patients versus the overall JAK inhibitor naive population; rates were preserved with momelotinib in thrombocytopenic patients but attenuated with ruxolitinib (momelotinib: 27%/28%/67% overall versus 39%/35%/61% in thrombocytopenic group; ruxolitinib: 29%/42%/49% overall versus 0%/22%/39% in thrombocytopenic group, respectively). In contrast to ruxolitinib, momelotinib maintained high dose intensity throughout the treatment. In the JAK inhibitor experienced population, thrombocytopenic patients had the following: (1) numerically higher symptom and transfusion independence response rates with momelotinib than in control arms; and (2) preserved spleen, symptom, and transfusion independence response rates with momelotinib relative to the overall study populations. The safety profile of momelotinib in thrombocytopenic patients was also consistent with the overall study population. In summary, momelotinib represents a safe and effective treatment option for patients with MF and moderate-to-severe thrombocytopenia.

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Conflict of interest statement

J-JK reports honoraria from Novartis, and participation on a data safety monitoring board or advisory board for AbbVie, AOP Orphan, Bristol Myers Squibb, Incyte, and Novartis. AMV reports honoraria from AbbVie, Blueprint Medicines, Bristol Myers Squibb, GSK, Incyte, and Novartis, and participation on a data safety monitoring board or advisory board for AbbVie, Blueprint Medicines, Bristol Myers Squibb, GSK, Incyte, MorphoSys, Novartis, and Roche. ATG reports consulting fees from AbbVie, Bristol Myers Squibb, Constellation/MorphoSys, CTI Biopharma, Novartis, PharmaEssentia, and Sierra Oncology. VG reports consulting fees from AbbVie, Bristol Myers Squibb/Celgene, Constellation Biopharma, Novartis, Pfizer, and Sierra Oncology; honoraria from Bristol Myers Squibb/Celgene, Constellation Biopharma, and Novartis; and participation on data safety monitoring board or advisory board for AbbVie, Bristol Myers Squibb/Celgene, Pfizer, and Roche. SV reports consulting fees from Bristol Myers Squibb/Celgene, Incyte, Novartis, and Sierra Oncology, and research funding from AstraZeneca, Blueprint Medicines, Bristol Myers Squibb/Celgene, CTI BioPharma, Genentech, Gilead, Incyte, Italfarmaco, Novartis, NS Pharma, PharmaEssentia, and Promedior. UP reports consulting fees from AbbVie, Bristol Myers Squibb/Celgene, Janssen, and Novartis; honoraria from Amgen, Jazz Pharmaceuticals, and Takeda; and participation on data safety monitoring board or advisor board for AbbVie and Novartis. JM reports research support from Sierra Oncology. AI reports consulting fees from Celgene, Janssen, Novartis, Pfizer, Roche, and Takeda; and meeting/travel support from Janssen, Novartis, Pfizer, and Roche. TW reports meeting/travel support from Novartis and Roche. STO reports consulting fees from AbbVie, Blueprint Medicines, Bristol Myers Squibb/Celgene, Constellation Pharmaceuticals, CTI Biopharma, Disc Medicine, Incyte, Kartos Therapeutics, PharmaEssentia, and Sierra Oncology. DML reports grant support from CPI; speaker fees from AbbVie, Celgene, Jazz, and Novartis. S-SY reports grant support from Roche-Genentech and Yuhan Pharmaceuticals; consulting fees from Amgen and Novartis; honoraria for lectures from Novartis; and participation in data safety monitoring board or advisory board for Hanmi and Pharos iBio. CH reports grant support from Bristol Myers Squibb/Celgene, Constellation Pharmaceuticals, and Novartis; consulting fees from AOP, Galecto, Keros, and Roche; honoraria from AbbVie, Celgene, Constellation Pharmaceuticals, CTI Biopharma, Janssen, and Novartis; participation in data safety monitoring board or advisory board for AbbVie, AOP, CTI Biopharma, Geron, Promedior, Roche, and Sierra Oncology; and leadership or fiduciary role in the European Hematology Association and MPN Voice. BK, MH, and JK report employment and stock or stock options at Sierra Oncology, a GSK company. RM reports grants or contracts from AbbVie, Celgene, CTI Biopharma, Constellation Biopharma, Genotech, Incyte, Promedior, Samus Therapeutics, and the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174), and consulting fees from Constellation Biopharma, LaJolla, Novartis, and Sierra Oncology. All the other authors have no conflicts of interest to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Week 24 response rates by treatment arm among patients with baseline platelet counts <100 × 109/L, 50–100 × 109/L, and <50 × 109/L in MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2. (A) SVR35 response rate, (B) red blood cell transfusion independence rate, and (C) TSS response rate. Horizontal lines indicate response rates achieved in the overall study population with momelotinib (solid line) and controls (dotted line). BAT = best available therapy; JAKi = JAK inhibitor; SVR35, spleen volume reduction of ≥35% from baseline; TSS = Total Symptom Score ≥50%.
Figure 2.
Figure 2.
Kaplan-Meier estimates of overall survival. Shown is overall survival by treatment arm in patients with baseline platelet counts <100 × 109/L in (A) MOMENTUM, (B) SIMPLIFY-1, and (C) SIMPLIFY-2. Vertical dashed line indicates the end of the randomized period and the beginning of the open-label period, when patients randomized to the control arms were allowed to cross over to momelotinib therapy. BAT = best available therapy; HR = hazard ratio; NE = not estimable; OS = overall survival.
Figure 3.
Figure 3.
Mean platelet counts in phase 3 studies of momelotinib (up to week 48) in patients with baseline platelet counts <100 × 109/L. (A) Mean platelet counts in the randomized and open-label phases of (A) MOMENTUM (anemic patients with prior JAKi exposure), (B) SIMPLIFY-1 (patients naïve to previous JAKi therapy), and (C) SIMPLIFY-2 (patients with prior JAKi exposure). Vertical dashed line indicates the end of the randomized period and the beginning of the open-label period, when patients randomized to the control arms were allowed to cross over to momelotinib therapy. BAT = best available therapy; JAKi = Janus kinase inhibitor.
Figure 4.
Figure 4.
(Continued on next page) Dose intensity over time among patients with baseline platelet count <100 × 109/L. Mean daily dose intensity in (A) the momelotinib arm of MOMENTUM, (B) the danazol to momelotinib crossover arm of MOMENTUM (weeks 24–48 of therapy), (C) the momelotinib arm of SIMPLIFY-1, (D) the ruxolitinib to momelotinib crossover arm of SIMPLIFY-1, (E) the momelotinib arm of SIMPLIFY-2, and (F) the BAT to momelotinib crossover arm of SIMPLIFY-2. Vertical dashed line indicates the end of the randomized period and the beginning of the open-label period, when patients randomized to the control arms were allowed to cross over to momelotinib therapy. BAT = best available therapy.
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