Ruben Mesa,1 Aaron Gerds,2 Alessandro Vannucchi,3 Haifa Kathrin Al-Ali,4 David Lavie,5 Andrew Kuykendall,6 Sebastian Grosicki,7 Alessandra Iurlo,8 Yeow Tee Goh,9 Mihaela Lazaroiu,10 Miklos Egyed,11 Maria Laura Fox,12 Donal McLornan,13 Andrew Perkins,14 Sung-Soo Yoon,15 Vikas Gupta,16 Jean-Jacques Kiladjian,17 Rafe Donahue,18 Jun Kawashima,18 Srdan Verstovsek19
1Mays Cancer Center at UT Health San Antonio MD Anderson, San Antonio, TX, USA; 2Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 3University of Florence and AOU Careggi, Florence, Italy; 4University Hospital of Halle, Halle, Germany; 5Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 6Moffitt Cancer Center, Tampa, FL, USA; 7Medical University of Silesia, Katowice, Poland; 8Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; 9Singapore General Hospital, Singapore; 10Policlinica de Diagnostic Rapid Brasov, Romania; 11Somogy County Mór Kaposi General Hospital, Kaposvár, Hungary; 12Vall d’Hebron Institute of Oncology, University Hospital Vall d’Hebron, Barcelona, Spain; 13Guy's and St Thomas' NHS Foundation Trust, London, UK; 14Monash University, Melbourne, Australia; 15Seoul National University Hospital, Seoul, South Korea; 16Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 17Université de Paris, AP-HP, Hôpital Saint-Louis, Centre d’Investigations Cliniques, INSERM, CIC1427, Paris, France; 18Sierra Oncology Inc., San Mateo, CA, USA; 19The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Background: MF is a rare bone marrow cancer characterized by fibrosis, abnormal blood cell production, and dysregulated JAK/STAT signaling.1,2 Clinical manifestations include anemia, constitutional symptoms, and splenomegaly, which can negatively impact patient quality of life.3-5 Although approved JAK inhibitors (JAKi) may improve symptoms and splenomegaly, none actively treat anemia and some may exacerbate it; the efficacy of other agents currently used to manage anemia in MF (eg, DAN) is short-lived.6-8 MF-associated anemia is driven by chronic inflammation and due in part to resultant hyperactive ACVR1 signaling and elevated hepcidin levels.6 MMB is unique among JAKi in that it inhibits not only JAK1 and JAK2 to drive symptom and spleen improvements but also ACVR1 to drive anemia benefits, including increased serum iron and hemoglobin levels.9 In the SIMPLIFY trials, MMB was associated with improvements in symptoms, splenomegaly, and transfusion burden in both JAKi-naive and JAKi-experienced patients with MF.10,11 The pivotal phase 3 MOMENTUM study of MF patients previously treated with a JAKi tested MMB versus DAN on key symptom, anemia, and splenic end points.
Methods: Eligibility: Primary or post-ET/PV MF; DIPSS High/Int-2/Int-1; MF Symptom Assessment Form total symptom score (TSS) ≥10; hemoglobin <10 g/dL; prior JAKi ≥90 days, or ≥28 days if red blood cell (RBC) transfusions ≥4 units in 8 weeks or grade 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm. Stratification: TSS, palpable spleen, and RBC units transfused. JAKi taper/washout ≥21 days. Randomization: 2:1 MMB 200 mg qd + DAN placebo or DAN 600 mg qd + MMB placebo for 24 weeks. Primary end point: TSS response (≥50% reduction from baseline) rate at week 24. Secondary end points, assessed sequentially at week 24: transfusion independence (TI) rate, splenic response rate (SRR; ≥25% volume reduction from baseline), TSS change from baseline, SRR (≥35% reduction) and rate of zero transfusions since baseline.
Results: Ninety-four of 130 (72%) MMB and 38/65 (58%) DAN patients completed randomized treatment (RT). Mean baseline TSS were 28 (MMB) and 26 (DAN), hemoglobin were 8.1 (MMB) and 7.9 (DAN) g/dL, and median platelets were 97 (MMB) and 94 (DAN) × 109/L. Baseline TI was 13% (MMB) and 15% (DAN). Prior JAKi was ruxolitinib in 195 (100%) and fedratinib in 9 (5%) patients. All primary and key secondary end points were met: TSS response (24.6% vs 9.2%), TI (30.8% vs 20.0%), SRR25 (40.0% vs 6.2%), TSS change (-9.36 vs -3.13), SRR35 (23.1% vs 3.1%), and zero transfusions (35.4% vs 16.9%). Most common grade ≥3 treatment-emergent adverse events (TEAEs) in RT were thrombocytopenia (MMB, 22%; DAN, 12%) and anemia (MMB, 8%; DAN, 11%). TEAEs led to study drug discontinuation in 18% of MMB and 23% of DAN patients in RT. A trend toward improved survival up to week 24 was seen with MMB versus DAN (hazard ratio, 0.506; P = .0719).
Conclusions: In symptomatic and anemic MF patients, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may improve MF patient care and quality of life by addressing a critical unmet need, particularly in patients with anemia.
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- Verstovsek S, Chen CC, Egyed M, et al. MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic. Future Oncol. 2021;17:1449-1458.
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- Elena C, Passamonti F, Rumi E, et al. Red blood cell transfusion-dependency implies a poor survival in primary myelofibrosis irrespective of IPSS and DIPSS. Haematologica. 2011;96:167-170.
- Chifotides H, Bose P, Verstovsek S. Momelotinib: an emerging treatment for myelofibrosis patients with anemia. J Hematol Oncol. 2022;15:7.
- Scherber RM, Mesa RA. Management of challenging myelofibrosis after JAK inhibitor failure and/or progression. Blood Rev. 2020;42:100716.
- Bose P, Verstovsek S. Management of myelofibrosis-related cytopenias. Curr Hematol Malig Rep. 2018;13:164-172.
- Oh ST, Talpaz M, Gerds AT, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4:4282-4291.
- Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5:e73-e81.
- Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35:3844-3850.