{"paper_id":"17deb076-5c9f-40cf-bb01-46bf64c9f728","body_text":"Vol:.(1234567890)\nInternational Journal of Hematology (2025) 122:660–670\nhttps://doi.org/10.1007/s12185-025-04037-6\nORIGINAL ARTICLE\nEfficacy and safety of momelotinib in Janus kinase \ninhibitor‑experienced Asian patients with myelofibrosis and anemia\nSung‑Soo Yoon1  · Chih Cheng Chen2 · Sung‑Eun Lee3 · Hung Chang4 · June‑Won Cheong5 · Hsin‑An Hou6 · \nWon Sik Lee7 · Sung‑Nam Lim8 · Joon Ho Moon9 · Kiat Hoe Ong10 · Yi Dai11 · Chang Liu11 · Jun Kawashima12 · \nYeow Tee Goh13\nReceived: 4 February 2025 / Revised: 2 July 2025 / Accepted: 4 July 2025 / Published online: 21 July 2025 \n© The Author(s) 2025\nAbstract\nIntroduction This post hoc analysis investigated the efficacy and safety of momelotinib in the Asian subpopulation of \nMOMENTUM (NCT04173494).\nMethods Patients were randomized 2:1 to momelotinib 200 mg once daily (QD) plus danazol placebo (momelotinib group) \nor danazol 600 mg QD plus momelotinib placebo (danazol group) for 24 weeks (W), after which they could receive open-\nlabel momelotinib or danazol. Primary endpoint: W24 total symptom score (TSS) response rate (≥ 50% reduction from \nbaseline). W24 key secondary endpoints: transfusion independence rate; mean TSS change from baseline; splenic response \nrate; rate of zero transfusions.\nResults Seventeen Asian patients with myelofibrosis were included (momelotinib: n  = 11; danazol: n = 6). TSS response \nrate at W24 was 36.4% with momelotinib and 0% with danazol. Secondary endpoints favored momelotinib and were con-\nsistent with the intention-to-treat population. Grade ≥ 3 treatment-emergent adverse events were reported in 36.4 and 66.7% \nof the momelotinib and danazol groups, respectively, including one grade ≥ 3 anemia in the momelotinib group. Treatment \ninterruption and/or dose reduction occurred in 18.2 and 16.7% of the momelotinib and danazol groups, respectively. Two \ndanazol-treated patients discontinued study treatment.\nConclusion In the Asian subpopulation of MOMENTUM, momelotinib improved myelofibrosis-associated symptoms, ane-\nmia measures, and spleen response, with generally favorable safety versus danazol.\nKeywords Myelofibrosis · Momelotinib · Danazol · MOMENTUM · Asian\nIntroduction\nMyelofibrosis (MF) is a chronic, progressive myeloprolif-\nerative neoplasm characterized by bone marrow fibrosis, \nextramedullary hematopoiesis, and increased production \nof inflammatory cytokines [1 –3]. Clinical manifestations \ninclude anemia, fatigue, night sweats, fever, cachexia, bone \npain, pruritus, weight loss, abdominal distension, and pain \nassociated with splenomegaly, leading to limited social and \nphysical activity and markedly reduced quality-of-life (QoL) \nin patients with MF [2, 3].\nPatients with MF tend to have poor prognoses. Anemia is \na major risk factor for survival according to prognostic mod-\nels [4, 5], with the refined Dynamic International Prognostic \nScoring System (DIPSS) plus prognostic model considering \nanemia (hemoglobin < 10 g/dL) and transfusion dependency \nas independent prognostic factors [5]. At diagnosis, approxi-\nmately 40% of patients have anemia, and most develop ane-\nmia with disease progression [6]. Other risk factors include \nacute myeloid leukemia, which occurs in 20% of individuals \n[2, 3], infection, hemorrhage, progressive bone marrow fail-\nure, and cardiovascular events [3, 5, 7].\nMF is rare across all ethnicities. The estimated annual \nincidence of MF varies from 0.4 to 3.0 per 100,000 popula-\ntion in North America and Europe [8 –11], compared with \n0.15–0.9 per 100,000 population in Korea [12, 13] and 0.43 \nper 100,000 among the Chinese population in Singapore \n[14].\nDr Kawashima was employed by Sierra Oncology, Inc., a GSK \ncompany, San Mateo, USA, at the time the analysis was conducted. \nThe author is no longer an employee of Sierra Oncology, Inc., a \nGSK company, San Mateo, USA.\nExtended author information available on the last page of the article\n\n661\nEfficacy and safety of momelotinib in Janus kinase inhibitor‑experienced Asian patients with…\nConstitutive activation of the Janus kinase (JAK)-signal \ntransducers and activators of transcription (STAT) signal-\ning pathway, which regulates the cell cycle, cytokines, and \nerythropoiesis, is believed to play a key role in MF patho-\ngenesis [15, 16]. As such, JAK inhibitors have been devel-\noped for the treatment of MF and approved by regulatory \nagencies based on clinical benefits. While approved JAK \ninhibitors have shown benefits on spleen volume and symp-\ntoms, some JAK inhibitors, such as ruxolitinib, may cause \nor worsen anemia in patients with MF, including in Asian \npatients [2 , 17, 18]. The management of MF-associated \nanemia may involve red blood cell (RBC) transfusions, \nprednisolone, and anabolic hormones, such as danazol, as \nsupportive care [17].\nMomelotinib, an oral inhibitor of JAK1/2 and activin \nA receptor type 1 (ACVR1) inhibits the ACVR1 signaling \npathway in addition to the JAK–STAT pathway. As such, \nmomelotinib can improve anemia by decreasing hepatic \nhepcidin expression and increasing the efficiency of iron \nrequired for erythropoiesis [19, 20]. In the phase 3 SIM-\nPLIFY-1 and SIMPLIFY-2 trials, momelotinib was shown \nto reduce spleen size and symptoms, lessen anemia, and \nreduce transfusion dependency [21, 22]. In SIMPLIFY-1, \nJAK inhibitor-naïve patients were treated with momelotinib \ncompared with ruxolitinib and met its primary endpoint \nof non-inferiority in reducing spleen volume by ≥ 35% at \nWeek 24 from baseline. In SIMPLIFY-2, momelotinib was \ncompared with best available therapy, mostly ruxolitinib, \nin JAK inhibitor-experienced patients and did not achieve \nsuperiority in reducing spleen volume by ≥ 35% potentially \ndue to the lack of a post-ruxolitinib washout period [20–22]. \nA third redesigned phase 3 trial, MOMENTUM, was devel-\noped to fully understand the clinical profile of momelotinib \nin patients with MF [20].\nMOMENTUM was an international, double-blind, ran-\ndomized, phase 3 study to evaluate the efficacy and safety \nof momelotinib compared with danazol in patients with \nsymptomatic and anemic MF who were previously treated \nwith JAK inhibitors (funding: Sierra Oncology, Inc., a GSK \ncompany; NCT04173494) [20]. Momelotinib demonstrated \nclinically significant improvements in MF-associated symp-\ntoms, anemia measures, and spleen size, along with favora-\nble safety compared with danazol [20]. This post hoc analy-\nsis investigated the efficacy and safety of momelotinib in the \nAsian subpopulation of the MOMENTUM trial.\nMethods\nStudy design\nThe MOMENTUM study design has been published previ-\nously [20]. Briefly, eligible patients were randomly assigned \n(2:1) to receive momelotinib 200 mg orally once daily plus \ndanazol placebo (momelotinib group) or danazol 300 mg \norally twice daily plus momelotinib placebo (danazol group) \nfor a randomized period of up to 24 weeks, after which \npatients in the danazol treatment group who completed the \nrandomized period could continue to receive open-label \ndanazol or switch to open-label momelotinib.\nEligibility\nThe full eligibility criteria have been reported previously \n[20]. Key inclusion criteria included: aged ≥ 18 years; con-\nfirmed diagnosis of primary MF, post-polycythemia vera \nor post-essential thrombocythemia (post-PV/ET) MF; prior \ntreatment with an approved JAK inhibitor for ≥ 90 days \nor ≥ 28 days if therapy was complicated by ≥ 4 units of RBC \ntransfusion in 8 weeks, or grade 3/4 adverse events of throm-\nbocytopenia, anemia, or hematoma; Myelofibrosis Symp-\ntom Assessment Form (MFSAF) Total Symptom Score \n(TSS) ≥ 10 at screening; anemia (hemoglobin < 10 g/dL); \nplatelets > 25 ×  109 cells/L; DIPSS high, intermediate-2, or \nintermediate-1 risk; palpable splenomegaly ≥ 5 cm below the \nleft costal margin at screening or ≥ 450  cm3 splenomegaly \nvolume as assessed by ultrasonography, MRI, or CT.\nKey exclusion criteria included: prior treatment with \nmomelotinib, JAK inhibitor (within 1 week prior to the first \nday of baseline), CYP3A4 inducers, investigational agents, \ndanazol, splenic irradiation, or current treatment with sim-\nvastatin, atorvastatin, lovastatin, or rosuvastatin; history \nof prostate cancer; prostate specific antigen > 4 ng/mL; \nprior splenectomy; uncontrolled intercurrent illness; active \nor chronic bleeding; unstable angina pectoris; congestive \nheart failure; uncontrolled cardiac arrhythmia; progressive \nthrombosis; QT interval corrected using Fridericia’s For -\nmula interval  > 500 ms; history of porphyria; Child–Pugh \nscore ≥ 10; psychiatric illness; prior or concurrent malig-\nnancy; anemia; HIV; viral hepatitis; unresolved non-hemato-\nlogic toxicities from prior therapies; peripheral neuropathy; \npregnant or lactating.\nEndpoints\nThe primary endpoint of the MOMENTUM trial was TSS \nresponse rate (≥ 50% reduction in TSS from baseline at \nWeek 24 as assessed by MFSAF v4.0). If the primary \nendpoint was met, hierarchical testing of the following \nkey secondary endpoints at Week 24 were performed: \ntransfusion independence (TI) rate (percentage of patients \nwith no RBC transfusions in the 12 weeks prior to com-\npletion of the 24-week randomized-treatment period and \nno hemoglobin < 8 g/dL), splenic response rate (SRR; \npercentage of patients with ≥ 25% or ≥ 35% reduction in \nspleen volume from baseline as measured by MRI or CT), \n\n662 S.-S. Yoon et al.\nmean change in TSS from baseline, percentage of patients \nwho did not receive RBC or whole blood transfusion dur -\ning the randomized-treatment period, TI rate in patients \nwith transfusion dependence (TD) at baseline (≥ 4 RBC \nunits transfused in the 8 weeks prior to the first dose of \nstudy drug), overall survival (OS; the interval from the \nfirst study drug dosing date [or randomization date for \nparticipants who did not receive treatment] to death from \nany cause) and leukemia-free survival (LFS; the interval \nfrom first study drug dosing date [or randomization date \nfor participants who did not receive treatment] to any evi-\ndence of leukemic transformation and/or death from any \ncause).\nSafety\nAdverse events (AEs) were coded using the using the \nMedical Dictionary for Regulatory Activities and graded \naccording to the National Center Institute Common Ter -\nminology Criteria for AEs, including treatment-emergent \nAEs (TEAEs; AEs occurring or worsening on or after the \nfirst dose of study treatment, and up to 30 days after the \nlast dose of study drug received).\nData interpretation\nResults in this sub-analysis are descriptive as this Asian \nsubgroup was defined post hoc and was not powered for \nstatistical comparison.\nResults\nPatient disposition\nFrom April 24, 2020, to December 3, 2021 (data cut-off  \ndate), 10 sites in Asia participated in the MOMENTUM \ntrial [20]; 17 Asian patients with MF were enrolled (from \nKorea, n = 11 [64.7%]; Singapore, n = 4 [23.5%]; Taiwan, \nn = 2 [11.8%]) (Fig.  1), of whom 11 and 6 were randomly \nassigned to the momelotinib and danazol group, respectively, \nand 10 and 3 completed the 24-week randomized phase of \ntreatment. Reasons for treatment discontinuation were AEs \n(0 in the momelotinib group, 2 [33.3%] in the danazol group) \nand subject decision (1 [9.1%] in the momelotinib group and \n1 [16.7%] in the danazol group). Of the momelotinib and \ndanazol groups, 10 and 3 patients, respectively, continued \nto the open-label phase and received open-label momelo-\ntinib. Eight (72.7%) patients in the momelotinib group and \n1 (16.7%) patient in the danazol group completed 24 weeks \nof the open-label phase.\nBaseline and clinical characteristics of participants\nPatient baseline and clinical characteristics are summa-\nrized in Table  1. Six (54.5%) patients were female in the \nmomelotinib group; no patients were female in the dana-\nzol group. At baseline, 54.5% (6/11) and 50.0% (3/6) of \npatients in the momelotinib and danazol groups, respec-\ntively, were diagnosed with primary MF; median plate-\nlet counts were 87.0 ×  109/L and 89.5 ×  109/L, and mean \nhemoglobin levels were 7.9 g/dL and 7.5 g/dL. All 17 \nFig. 1  Patient disposition DAN, danazol; MMB, momelotinib; OL, open-label\n\n663\nEfficacy and safety of momelotinib in Janus kinase inhibitor‑experienced Asian patients with…\npatients received prior ruxolitinib treatment for a mean \n(SD) duration of 134.4 (116.5) and 64.3 (67.0) weeks in \nthe momelotinib and danazol groups, respectively; one \npatient in the momelotinib group also received prior fed-\nratinib for 92.4 weeks. At baseline, 18.2% (2/11) and 9.1% \n(1/11) of patients in the momelotinib group were TD and \nTI, respectively, versus 50.0% (3/6) and 0% in the danazol \ngroup. There were small differences between the treat-\nment groups in sex, age group, MF type, prognostic risk \ncategory, spleen volume, and RBC units transfused, but \nTable 1  Baseline demographics and clinical characteristics\na TSS was assessed using Myelofibrosis Symptom Assessment Form v4.0. bThe percentage of patients with TI in the 12 weeks prior to comple-\ntion of the 24-week randomized-treatment period (84 consecutive days). cDefined as four or more RBC units transfused in the 8 weeks prior \nto the first dose of study drug. dNot meeting definition of TI or TD. eData were from the case report form. DAN, danazol; DIPSS, Dynamic \nInternational Prognostic Scoring System; ECOG, Eastern Cooperative Oncology Group; JAK, Janus kinase; MMB, momelotinib; post-ET, post-\nessential thrombocythemia; post-PV, post-polycythemia vera; RBC, red blood cell; SD, standard deviation; TI, transfusion independent; TSS, \ntotal symptom score\nMMB\n(n = 11)\nDAN\n(n = 6)\nMedian age at baseline, years (range) 65.00\n(38.0, 74.0)\n66.00\n(54.0, 78.0)\nAge group, n (%)\n < 65 years 3 (27.3%) 3 (50.0%)\n ≥ 65 years 8 (72.7%) 3 (50.0%)\nSex, n (%)\n Male 5 (45.5%) 6 (100%)\n Female 6 (54.5%) 0 (0%)\nMyelofibrosis disease type, n (%)\n Primary myelofibrosis 6 (54.5%) 3 (50.0%)\n Post-PV myelofibrosis 3 (27.3%) 0 (0%)\n Post-ET myelofibrosis 2 (18.2%) 3 (50.0%)\nPrior JAK inhibitor therapy\n Median duration, weeks (range) 96.86\n(25.0, 400.6)\n30.00\n(12.1, 165.9)\n Ongoing JAK inhibitor at screening, n (%) 3 (27.3%) 1 (16.7%)\nDIPSS prognostic risk category, n (%)\n Intermediate-1 2 (18.2%) 0 (0%)\n Intermediate-2 7 (63.6%) 6 (100%)\n High 2 (18.2%) 0 (0%)\nECOG performance status, n (%)\n 0 4 (36.4%) 2 (33.3%)\n 1 7 (63.6%) 4 (66.7%)\n 2 0 (0%) 0 (0%)\nTSS at baseline, mean (SD)a 25. 8 (12.98) 27.4 (14.31)\nCentral lab spleen volume  (cm3), mean (SD) 1966.9\n(1047.92)\n1247.3\n(649.76)\nTransfusion dependence\n Transfusion  independentb, n (%) 1 (9.1%) 0 (0%)\n Transfusion  dependentc, n (%) 2 (18.2%) 3 (50.0%)\n Transfusion  requiringd, n (%) 8 (72.7%) 3 (50.0%)\nRBC units transfused ≤ 8 weeks before randomized treatment, n (%) e\n 0 4 (36.4%) 0 (0%)\n 1–4 5 (45.5%) 5 (83.3%)\n ≥ 5 2 (18.2%) 1 (16.7%)\nHemoglobin (g/dL), mean (SD) 7.93 (0.79) 7.52 (0.51)\nPlatelet count (×  109/L), mean (SD) 149.09 (110.36) 111.67\n(94.22)\n\n664 S.-S. Yoon et al.\nthe number of patients was limited and there were no dif-\nferences in other categories.\nEndpoint outcomes\nTSS response rate was 36.4% (4/11) and 0% (0/6) in the \nmomelotinib and danazol groups, respectively (greater pro-\nportion difference, 33.3%; 95% CI, −20.0, 86.68) (Table  2, \nFigs.  2a, 3).\nAt Week 24, the TI rate was 63.6% (7/11; 95% CI, 30.79, \n89.07) and 0% (0/6; 95% CI, 0.00, 45.93) in the momelotinib \nand danazol groups, respectively.  SRR (≥ 25% reduction) \nwas 63.6% (7/11; 95% CI, 30.79, 89.07) and 16.7% (1/6; \n95% CI, 0.42, 64.12) in the momelotinib and danazol group, \nrespectively; SRR (≥  35% reduction) was 36.4% (4/11; 95% \nCI, 10.93, 69.21) in the momelotinib group and 0% (0/6; \n95% CI, 0.00, 45.93) in the danazol group (Table 2, Fig.  2b).\nAt Week 24, the least squares (LS) mean (standard \nerror [SE]) change in TSS from baseline was − 9.52 (2.78) \nand − 9.19 (4.08) in the momelotinib and danazol groups, \nrespectively (difference, − 0.34; 95% CI, − 10.92, 10.25). \nAlthough the difference in LS means was small, the decrease \nin individual item scores was greater in the momelotinib \ngroup than in the danazol group (Table  2, Fig.  3).\nAt Week 24, the proportion of patients who had zero \nRBC transfusions was 72.7% (8/11; 95% CI, 39.03, 93.98) \nand 0.0% (0/6; 95% CI, 0.00, 45.93) in the momelotinib and \ndanazol groups, respectively (Table  2). In the momelotinib \ngroup, 18.2% (2/11) of patients were TD and 9.1% (1/11) of \npatients were TI at baseline; 72.7% (8/11) of patients were \ntransfusion requiring (TR [not meeting the definition of TI \nor TD]). At Week 24, 0.0% (0/11), 63.6% (7/11), and 36.4% \n(4/11) of patients were TD, TI, and TR, respectively. In the \ndanazol group, 50.0% (3/6), 0.0% (0/6), and 50.0% (3/6) \nof patients were TD, TI, and TR at baseline, respectively; \nthere was no change in transfusion status at Week 24. In the \nmomelotinib group, none of the patients with TD at baseline \n(18.2% [2/11]) achieved TI at Week 24, but both became TR \nat Week 24; of the eight patients who were TR at baseline, \nsix converted to TI and two remained TR. The patient in the \nmomelotinib arm who was TI at baseline remained TI at \nWeek 24 (100% [1/1]; 95% CI 2.50, 100.00).\nTen and three patients continued or crossed over to open-\nlabel momelotinib after the randomized-treatment period, \nwith a median follow-up of 49.6 weeks and 37.4 weeks in the \nmomelotinib and danazol groups, respectively. Fatal events \nwere reported in 9.1% (1/11) of patients in the momelotinib \ngroup and 16.7% (1/6) patients in the danazol group, both \ndue to leukemic transformation; median OS and LFS were \nnot reached in either group (Supplementary Fig. S1).\nHemoglobin levels\nAt Week 4, mean hemoglobin levels increased to 9.1 g/dL \nfrom the baseline level of 7.9 g/dL for momelotinib and to \n8.7 g/dL from 7.5 g/dL for danazol (Supplementary Fig. S2), \nwith patients treated with momelotinib consistently having \nhigher mean levels of hemoglobin than those treated with \ndanazol. However, after crossing over to open-label momelo-\ntinib at Week 24, mean hemoglobin levels in the danazol \ngroup increased from 7.7 to 9.5 g/dL after 20 weeks.\nSafety\nNo new safety signals were identified in this sub-analysis \ncompared with the overall intention-to-treat (ITT) cohort of \nthe MOMENTUM trial (Table 3). During the 24-week rand-\nomized period, all patients reported at least one TEAE, most \ncommonly constipation, hyperkalemia, nausea, peripheral \nedema, and pruritis (17.6% [3/17] each across both groups).\nIn the momelotinib group, the most common TEAEs \nwere peripheral edema, diarrhea, dizziness, fluid overload, \nhyperuricemia, and vomiting (18.2% [2/11] each). In the \ndanazol group, constipation, hyperkalemia, nausea, pru-\nritis, and increased alanine aminotransferase, aspartate \nTable 2  Efficacy outcomes at \nWeek 24\na Differences in TSS response rate, SRRs and rate of zero transfusions were based on a stratified Cochran–\nMantel–Haenszel test; bNon-inferiority proportion difference; cLeast squares mean difference. CI, con-\nfidence interval; DAN, danazol; LS, least square; MMB, momelotinib; N/A, not available; SD, standard \ndeviation; SRR, splenic response rate; TI, transfusion independence; TSS, total symptom score\nEfficacy endpoints MMB\nn = 11\nDAN\nn = 6\nDifferencea\n(95% CI)\nTSS response, n (%) 4 (36.4) 0.0 33.3 (− 20.0, 86.7)\nTI rate, n (%) 7 (63.6) 0.0 100.0b (58.4, 141.6)\nSRR (≥ 25% reduction), n (%) 7 (63.6) 1 (16.7) 33.3 (− 20.0, 86.7)\nMean TSS change from baseline (SD) − 11.51 (8.92) − 3.59 (6.26) N/A\nLS mean TSS change from baseline (SD) − 9.52 (2.78) − 9.19 (4.08) − 0.34 c (− 10.9, 10.3)\nSRR (≥ 35% reduction), n (%) 4 (36.4) 0.0 33.3 (− 20.0, 86.7)\nRate of zero transfusions, n (%) 8 (72.7) 0.0 100.0 (100, 100)\n\n665\nEfficacy and safety of momelotinib in Janus kinase inhibitor‑experienced Asian patients with…\naminotransferase, and blood creatinine were the most com-\nmon TEAEs (33.3% [2/6] each).\nGrade ≥ 3 TEAEs were reported in 36.4% (4/11) and \n66.7% (4/6) of the momelotinib and danazol groups, respec-\ntively, including fluid overload in 18.2% (2/11) of patients \nin the momelotinib group; one patient in the momelotinib \ngroup reported grade ≥ 3 anemia. No patients reported \ngrade ≥ 3 thrombocytopenia or peripheral neuropathy.\nTEAEs led to treatment interruption and/or dose reduction \nin 18.2% (2/11) and 16.7% (1/6) of patients in the momelotinib \nand danazol groups, respectively. TEAEs led to discontinua-\ntion of the study treatment in two patients in the danazol group: \none experienced increased alanine aminotransferase and the \nother experienced increased aspartate aminotransferase.\nFig. 2  Percent change in (a) total symptom scores and (b) splenic volume at Week 24 post-dose for individual patients DAN, danazol; MMB, \nmomelotinib\n\n666 S.-S. Yoon et al.\nFig. 3  Median MFSAF symptom-scores at baseline and Week 24 Analysis includes patients with both baseline and Week 24 data available. \nDAN, danazol; MFSAF, Myelofibrosis Symptom Assessment Form; MMB, momelotinib\nTable 3  Summary of TEAEs \nduring the 24-week randomized \nperiod\na TEAE assessed as related to the study treatment by investigator. DAN, danazol; MMB, momelotinib; \nTEAE, treatment-emergent adverse event\nPatients with at least one event, n (%) MMB\nn = 11\nDAN\nn = 6\nTEAE 11 (100) 6 (100)\nGrade ≥ 3 TEAE 4 (36.4) 4 (66.7)\nTEAE related to the study treatment 7 (63.6) 2 (33.3)\nGrade ≥ 3 TEAE related to the study  treatmenta 2 (18.2) 1 (16.7)\nTEAE leading to treatment interruption and/or dose reduction 2 (18.2) 1 (16.7)\nTEAE leading to permanent discontinuation of the study treatment 0 (0.0) 2 (33.3)\nSerious TEAE 3 (27.3) 3 (50.0)\nSerious TEAE related to the study treatment 1 (9.1) 1 (16.7)\nFatal TEAE 1 (9.1) 1 (16.7)\nMost common TEAEs, n (%)\n Peripheral edema 2 (18.2) 1 (16.7)\n Dizziness 2 (18.2) 0 (0)\n Diarrhea 2 (18.2) 0 (0)\n Fluid overload 2 (18.2) 0 (0)\n Hyperuricemia 2 (18.2) 0 (0)\n Vomiting 2 (18.2) 0 (0)\n Constipation 1 (9.1) 2 (33.3)\n Hyperkalemia 1 (9.1) 2 (33.3)\n Nausea 1 (9.1) 2 (33.3)\n Pruritis 1 (9.1) 2 (33.3)\n Increased alanine aminotransferase 0 (0) 2 (33.3)\n Increased aspartate aminotransferase 0 (0) 2 (33.3)\n Increased creatinine 0 (0) 2 (33.3)\n\n667\nEfficacy and safety of momelotinib in Janus kinase inhibitor‑experienced Asian patients with…\nDiscussion\nConsistent with the ITT population of the MOMENTUM \ntrial [20], this sub-analysis showed that, compared with \ndanazol, momelotinib improved splenomegaly, symptoms, \nand anemia associated with primary MF, post-PV/ET MF \nin Asian patients previously treated with JAK inhibitors. \nNotably, efficacy at Week 24 in the momelotinib group \nwas numerically greater in this Asian subpopulation than \nin the overall population, including TSS response rate \n(36.4% and 25%, respectively), reduction in splenic vol-\nume (≥ 25% reduction: 63.6% and 39%; ≥ 35% reduction: \n36.4% and 22%), change in TSS (LS mean − 9.52 and \n− 9.36), and TI rate (63.6% and 30%)[20]. As this is a post \nhoc analysis of the MOMENTUM trial where the num -\nber of Asian patients was small, the sample size should \nbe considered when interpreting these data.\nThe primary endpoint of TSS response rate was higher \nin the momelotinib group than the danazol group in this \nsub-analysis (36.4% [4/11] vs. 0% [0/6]). This trend was \nalso observed in the primary MOMENTUM analysis \nwhere patients in the momelotinib group had a higher \nTSS response rate than those in the danazol group (24.6% \n[32/130] vs. 9.2% [6/65]) [20].\nFor the secondary endpoints, the results of this sub-\nanalysis also aligned with that of the primary MOMEN-\nTUM analysis. SRR (≥ 35% reduction) was greater in the \nmomelotinib group than the danazol group (36.4% [4/11] \nvs. 0% [0/6]), aligning with the primary analysis (22.3% \n[29/130] vs. 3.1% [2/65]) [20].\nIn this sub-analysis, a greater LS mean (SE) change in \nTSS at Week 24 from baseline was observed in the momelo-\ntinib group than in the danazol group (− 9.5 [2.78] vs. − 9.2 \n[4.08]), similar to the primary analyses (LS mean change: \n− 11.5 for momelotinib vs. − 3.9 for danazol; LS mean dif-\nference: − 6.2 [95% CI: − 10.0, − 2.4, p = 0.0014]) [20].\nThe TI rate at Week 24 in this sub-analysis was higher \nin the momelotinib group than the danazol group (63.6% \n[7/11] vs. 0% [0/6]), aligning with the results of the over -\nall cohort (30.0% [39/130] for momelotinib vs. 20.0% \n[13/65] for danazol) [20]. In this analysis, there were fewer \npatients with TD at Week 24 in the momelotinib group (0% \n[0/11]) than the danazol group (50% [3/6]). Together, these \nfindings demonstrate the potential efficacy of momelotinib \nin treating anemia and reducing the transfusion burden on \npatients with MF. TD is associated with lower functioning \nand health-related QoL; reducing TD in patients with MF \ncan improve QoL and prognoses compared with patients \nwho remain transfusion dependent [23, 24]. For patients \nwith MF living in Asia, particularly Southeast Asia and \nChina, reducing TD is important due to the limited blood \nsupply and access to health care [25– 27].\nIn both this sub-analysis and the primary analysis, fewer \ndeaths occurred in the momelotinib group than in the dana-\nzol group (9.1% [1/11] vs. 16.7% [1/6] and 19.2% [25/130] \nvs. 24.6% [16/65], [20], respectively); median OS was not \nreached in either group in this analysis.\nThere was one LFS event in each group, after a median \nfollow-up of 49.6 weeks and 37.4 weeks in the momelotinib \nand danazol groups, respectively; each event was fatal in this \nsub-analysis. In the primary analysis, leukemic transforma-\ntion events occurred in 2% (3/130) and 6% (4/65) in the \nmomelotinib and danazol group, respectively; median LFS \nwas not reached in either group [20].\nThe safety profile was consistent with the overall ITT \npopulation [20], with no unusual or unexpected AEs in \nthis patient population. AEs were primarily gastroin-\ntestinal and hematologic, and manageable; few patients \nrequired dose reductions for safety. Although one patient \nreported grade ≥ 3 anemia in the momelotinib group, the \nrisk of cytopenia was low in the momelotinib and dana-\nzol groups despite the high mean relative dose intensities \nfor both groups (96.2% vs. 94.1%); however, one patient \n(9.1%) treated with momelotinib required dose adjustments \ndue to thrombocytopenia. No patients reported peripheral \nneuropathy.\nIn addition to approvals in the United States [28], Europe \n[29], and the United Kingdom [30 ], momelotinib has \nrecently been approved by the Ministry of Health, Labour \nand Welfare, Japan, for patients with MF and anemia [31] \nbased on the pivotal phase 3 trials SIMPLIFY-1 [21] and \nMOMENTUM [20]. Many therapies, including anticancer \ntherapies, have demonstrated racial and ethnic differences \nin response and safety [32, 33]. In particular, Asian patients \nhave pharmacogenetic variations that may predispose them \nto reduced clinical benefits and increased risk of toxicity \nwith some anticancer therapies, highlighting the importance \nof analyzing the efficacy and safety of new therapies in this \npopulation [32, 33]. Together with the Japanese subgroup \nanalysis of the SIMPLIFY-1 trial [34], this analysis of the \nAsian subpopulation of the MOMENTUM study demon-\nstrated that the efficacy and safety of momelotinib aligned \nwith the overall ITT population [20], supporting its use in \nAsian patients.\nLimitations\nThe primary limitation of this sub-analysis is its small sam-\nple size, so findings must be confirmed by future investi-\ngations. Results may not be geographically representative \nof the Asian continent as the study population only com-\nprised a limited number of countries. As a sub-analysis of \nthe MOMENTUM trial, this study inherits any limitations \nin the original study design. Notably, a lack of long-term \n\n668 S.-S. Yoon et al.\ncomparison of survival between treatment groups due to the \ncrossover study design, and the use of danazol as the com-\nparator drug, which may be a limitation as it is typically only \nused to manage anemia in MF, and not splenomegaly and \nassociated symptoms; however, momelotinib still outper -\nformed danazol in the treatment of MF-associated anemia. \nPatients and investigators may have also tried to predict their \ntreatment assignment based on previous JAK-inhibitor expe-\nrience. Finally, as a post hoc analysis of a larger study, this \nwas designed to be descriptive, with no formal hypothesis \ntesting; results from this sub-analysis should be validated in \nfuture studies.\nConclusion\nAmong the JAK inhibitor-experienced Asian subpopulation \nwith symptomatic and anemic MF from the MOMENTUM \ntrial, momelotinib was associated with clinically significant \nimprovements in MF-associated symptoms, anemia meas-\nures, and spleen size, with favorable safety compared with \ndanazol, which were generally consistent with the over -\nall ITT population. These data support momelotinib as a \npotentially effective treatment option for Asian patients with \nsymptomatic and anemic MF.\nSupplementary Information The online version contains supplemen-\ntary material available at https:// doi. org/ 10. 1007/ s12185- 025- 04037-6.\nAcknowledgements Writing and editorial support, funded by GSK was \nprovided by Rebecca Yao, PhD, and Joyce Lee, PhD, CMPP of Nucleus \nGlobal, an Inizio company.\nAuthor contribution Jun Kawashima contributed to the conception and \ndesign of the study. Acquisition of data were performed by Sung-Soo \nYoon, Sung-Eun Lee, Hung Chang, June-Won Cheong, Hsin-An Hou, \nWon Sik Lee, Sung-Nam Lim, Joon Ho Moon, Kiat Hoe Ong, and \nYeow Tee Goh. Data analyses were performed by Sung-Soo Yoon, \nChih Cheng Chen, Sung-Eun Lee, Yi Dai, Chang Liu, Jun Kawashima, \nand Yeow Tee Goh. All authors reviewed and commented on each \nversion of the manuscript. All authors read and approved the final \nmanuscript.\nFunding Open Access funding enabled and organized by Seoul \nNational University Hospital. The MOMENTUM study and primary \nanalysis was funded by Sierra Oncology, a GSK company. The post \nhoc analysis was funded by GSK.\nData availability For requests for access to anonymized subject level \ndata, please contact corresponding author.\nDeclarations \nCompeting interests S-SY has provided consultancy to Amgen, Jans-\nsen, Novartis, and Sanofi, and research funding from Genentech and \nPharos iBio. CCC  reports no conflicts of interest. S-EL reports no con-\nflicts of interest. HC reports no conflicts of interest. J-WC reports no \nconflicts of interest. H-AH has received research support from Abbvie, \nBMS, Celgene, Kirin and PharmaEssential and honorarium/travel/con-\nsultancy from Abbvie, Astellas, BeiGene, BMS, Celgene, Chugai, CSL \nBehring, Daiichi Sankyo, IQVIA, Johnson & Johnson, Kirin, Lotus, \nMerck Sharp & Dohme, Novartis, Ono, Panco healthcare Co., Pfizer, \nPharmaEssential, Roche, Synmosa, Takeda, TSH Biopharm, TTY \nBiopharm Company and Zuellig Pharma. WSL reports no conflicts of \ninterest. S-NL reports no conflicts of interest. JHM reports no conflicts \nof interest. KHO has served on a Janssen Oncology Advisory Board. \nYD is an employee of GSK.\nEthical approval This study was performed in accordance with the \nDeclaration of Helsinki and the International Council for Harmonisa-\ntion guidelines on Good Clinical Practice. Institutional review boards \nor independent ethics committees at each site approved the protocol, \nincluding the National Health Group Domain Specific Review Board, \nSeoul National University Hospital Institutional Review Board, Insti-\ntutional Review Board of Yonsei University Health System, Severance \nHospital, Institutional Review Board of Inje University Busan Paik \nHospital, Kyungpook National University Hospital Institutional Review \nBoard, Inje University Haeundae Paik Hospital Institutional Review \nBoard, The Catholic University of Korea, Seoul St. Mary’s Hospital \nInstitutional Review Board, Chang Gung Medical Foundation Institu-\ntional Review Board, and the Research Ethics Committee of National \nTaiwan University Hospital. All participants provided written consent. \nA data monitoring committee reviewed study progress, safety data, and \ncritical efficacy endpoints every six months.\nOpen Access This article is licensed under a Creative Commons Attri-\nbution 4.0 International License, which permits use, sharing, adapta-\ntion, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes \nwere made. The images or other third party material in this article are \nincluded in the article’s Creative Commons licence, unless indicated \notherwise in a credit line to the material. If material is not included in \nthe article’s Creative Commons licence and your intended use is not \npermitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. 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Momelotinib versus ruxolitinib in JAK inhibitor-naïve \npatients with myelofibrosis: an efficacy/safety analysis in the \nJapanese subgroup of the phase 3 randomized SIMPLIFY-1 trial. \nInt J Hematol. 2024;120(3):314–24. https:// doi. org/ 10. 1007/ \ns12185- 024- 03822-z.\n\n670 S.-S. Yoon et al.\nAuthors and Affiliations\nSung‑Soo Yoon1  · Chih Cheng Chen2 · Sung‑Eun Lee3 · Hung Chang4 · June‑Won Cheong5 · Hsin‑An Hou6 · \nWon Sik Lee7 · Sung‑Nam Lim8 · Joon Ho Moon9 · Kiat Hoe Ong10 · Yi Dai11 · Chang Liu11 · Jun Kawashima12 · \nYeow Tee Goh13\n * Sung-Soo Yoon \n ssysmc@snu.ac.kr\n1 Division of Hematology/Medical Oncology, Department \nof Internal Medicine, Seoul National University Hospital, \nSeoul National University College of Medicine, Seoul, \nKorea\n2 Department of Internal Medicine - Division of Hematology \nand Oncology Chang Gung Medical Foundation, Chiayi \nChang Gung Memorial Hospital, Puzi City, Taiwan\n3 Department of Hematology, Seoul St. Mary’s Hospital, \nCollege of Medicine, The Catholic University of Korea, \nSeoul, Korea\n4 Department of Internal Medicine - Division of Hematology, \nChang Gung Medical Foundation - Linkou Chang Gung \nMemorial Hospital, Taoyuan City, Taiwan\n5 Department of Medicine - Division of Hematology, \nSeverance Hospital, Seoul, Korea\n6 Divisions of Hematology and General Medicine, Department \nof Internal Medicine, National Taiwan University Hospital, \nTaipei, Taiwan\n7 Department of Internal Medicine, Inje University Busan Paik \nHospital (Cancer Center), Busan, Korea\n8 Department of Internal Medicine, Inje University College \nof Medicine, Haeundae Paik Hospital, Busan, Korea\n9 Department of Hematology -Oncology, Kyungpook National \nUniversity Hospital (KNUH), Daegu, Korea\n10 Haematology Service, National Healthcare Group (NHG) \n- Tan Tock Seng Hospital (TTSH), Singapore, Singapore\n11 GSK Plc, Shanghai, China\n12 Sierra Oncology, a GSK Company, San Mateo, USA\n13 Department of Haematology, Singapore Health Services \n(SingHealth) - Singapore General Hospital (SGH), \nSingapore, Singapore\nPublisher's Note Springer Nature remains neutral with regard to \njurisdictional claims in published maps and institutional affiliations.","source_license":"CC0","license_restricted":false}