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

Mesa, Ruben A.; Harrison, Claire; Oh, Stephen T.; Gerds, Aaron T.; Gupta, Vikas; Catalano, John; Cervantes, Francisco; Devos, Timothy; Hus, Marek; Kiladjian, Jean‐Jacques; Lech‐Marańda, Ewa; McLornan, Donal P.; Vannucchi, Alessandro M.; Platzbecker, Uwe; Huang, Mei; Strouse, Bryan; Klencke, Barbara; Verstovšek, Srđan

doi:10.1038/s41375-022-01637-7

Cited by 44 publications

(34 citation statements)

References 31 publications

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“…Results were similar in the context of previously ruxolitinib‐exposed patients in SIMPLIFY‐2 assigned to momelotinib or BAT. Baseline transfusion need in both SIMPLIFY trials was associated with inferior survival while momelotinib‐induced transfusion‐independence in SIMPLIFY‐1 was associated with superior survival 116 …”

Section: Symptom‐directed Therapymentioning

confidence: 98%

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Tefferi

2023

American J Hematol

116

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Disease Overview Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell‐derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, risk of leukemic progression, and shortened survival. Diagnosis Bone marrow examination with cytogenetic and mutation studies provides integrated diagnostic information; presence of JAK2, CALR or MPL mutation is expected but not required. New Classification System The International Consensus Classification distinguishes “prefibrotic” from “overtly fibrotic” PMF; the former might mimic essential thrombocythemia (ET) in its presentation. Approximately 15% of patients with ET or polycythemia vera (PV) might progress into post‐ET/PV MF. Mutations SRSF2, ASXL1, and U2AF1‐Q157 mutations predict inferior survival in PMF; RAS/CBL mutations predict resistance to ruxolitinib therapy. Type 1/like CALR mutation is associated with superior survival. Karyotype Very high‐risk abnormalities include −7, inv (3), i(17q), +21, +19, 12p‐ and 11q‐. Favorable risk abnormalities include normal karyotype or isolated +9, 13q‐, 20q‐, 1q abnormalities and loss of Y chromosome. Risk Stratification Contemporary prognostic systems include GIPSS (genetically‐inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation‐and karyotype‐enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype; MIPSSv2 includes, in addition, clinical risk factors. Risk‐Adapted Therapy Observation alone is advised for MIPSSv2 “low” and “very low” risk disease (estimated 10‐year survival 56%–92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment of choice for “very high” and “high” risk disease (estimated 10‐year survival 0–13%), as well as in carefully selected patients with intermediate‐risk disease (estimated 10‐year survival 30%). Drug therapy in MF is currently palliative and targets anemia, splenomegaly, and constitutional symptoms. JAK2 Inhibitors Ruxolitinib, fedratinib, and pacritinib are FDA approved and respectfully utilized in patients failing treatment with hydroxyurea, ruxolitinib, or with platelet count <50 × 10 (9)/L. Momelotinib is another JAK2 inhibitor that is poised for approval sometime in 2023 and has shown erythropoietic benefits, in addition to affecting spleen and symptom responses. Other Treatment Modalities Splenectomy is considered for drug‐refractory splenomegaly and involved field radiotherapy for non‐hepatosplenic EMH and extremity bone pain. New Directions New agents, alone or in combination with ruxolitinib, are currently under clinical trial investigation (ClinicalTrials.gov) and preliminary results were presented at the 2022 ASH annual meeting and highlighted in the current review.

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Section: Symptom‐directed Therapymentioning

confidence: 98%

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Tefferi

2023

American J Hematol

116

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“…Baseline transfusion need in both SIMPLIFY trials was associated with inferior survival while momelotinib-induced transfusion-independence in SIMPLIFY-1 was associated with superior survival. 75 The most recent phase-3 study included 195 JAKi-exposed high/intermediate-risk MF with hemoglobin <10 g/dL, symptoms score of ≥10, and platelets ≥25 x 10 9 /L, assigned to either momelotinib (200 mg daily; N=130) or danazol (600 mg daily; N=65), both in conjunction with placebo pills, for 24 wks, after which pts could receive open-label momelotinib. 76 Transfusion-independence rate "at baseline" vs "at week 24" was 13% vs 31% for momelotinib and 15% vs 20% for danazol (p<0.05; met criteria for non-inferiority); rates of no transfusions to week 24 were 35% for momelotinib and 17% for danazol (met criteria for superiority).…”

Section: Phase-3 Studiesmentioning

confidence: 99%

Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis

2023

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Janus kinase 2 inhibitors (JAKi) are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival and poor quality of life (QoL). Allogeneic stem cell transplant is currently the only treatment modality in MF with the potential to cure the disease or prolong survival. By contrast, current drug therapy in MF targets QoL and does not modify the natural history of the disease. The discovery of JAK2 and other JAK-STAT activating mutations (i.e., CALR and MPL) in myeloproliferative neoplasms, including MF, has facilitated the development of several JAKi that are not necessarily specific to the oncogenic mutations themselves but proved effective in countering JAK-STAT signaling, resulting in suppression of inflammatory cytokines and myeloproliferation. This non-specific activity resulted in clinically favorable effects on constitutional symptoms and splenomegaly and, consequently, FDA approval of three small molecule JAKi: ruxolitinib, fedratinib, and pacritinib. A fourth JAKi, momelotinib, is poised for FDA approval soon and has been shown to provide additional benefit in alleviating transfusiondependent anemia in MF. The salutary effect of momelotinib on anemia has been attributed to inhibition of activin A receptor, type 1 (ACVR1) and recent information suggests similar effect from pacritinib. ACRV1 mediates SMAD2/3 signalling that contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Therapeutic targeting of ACRV1 raises therapeutic prospects in other myeloid neoplasms associated with ineffective erythropoiesis, such as myelodysplastic syndromes with ring sideroblasts or SF3B1 mutation, especially those with co-expression of JAK2 mutation and thrombocytosis.

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“…The corresponding rates in SIMPLIFY‐2, which included patients previously exposed to ruxolitinib, 8 were 49.3% and 21% for patients receiving momelotinib versus best available therapy 8 . Furthermore, in SIMPLIFY‐1, the achievement of transfusion‐independence in patients receiving momelotinib was associated with a higher 3‐year survival rate of 77.2% versus 51.6% in non‐responders 9 . In the MOMENTUM study of patients previously exposed to JAK2 inhibitor therapy, momelotinib proved non‐inferior to danazol in increasing the transfusion‐independence rate from 13% at baseline to 31% at week 24 versus 16% to 20% for danazol 6…”

Section: Introductionmentioning

confidence: 99%

“…non-responders. 9 In the MOMENTUM study of patients previously exposed to JAK2 inhibitor therapy, momelotinib proved non-inferior to danazol in increasing the transfusion-independence rate from 13% at baseline to 31% at week 24 versus 16% to 20% for danazol. 6 In the current study, our primary objective was to (i) identify clinical or molecular predictors of anemia response in momelotinibtreated patients with MF and (ii) examine the impact of anemia response on survival in the context of previously established risk factors.…”

mentioning

confidence: 99%

Predictors of anemia response to momelotinib therapy in myelofibrosis and impact on survival

et al. 2022

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We retrospectively reviewed 72 anemic patients with myelofibrosis (MF; median age 68 years), who were JAK2 inhibitor‐naïve at the time of study entry to a phase‐1/2 momelotinib clinical trial. Driver mutation profile included JAK2 69%, CALR 17%, MPL 8%, and triple‐negative 6%; other mutations included ASXL1 39% and SRSF2 17%. Momelotinib was administered at a median dose of 300 mg daily. Anemia response was assessed by formal criteria and documented in 44% of all patients with hemoglobin levels below the sex‐adjusted reference range (n = 72), 48% of those with hemoglobin <10 g/dl (n = 54), and 46% of those who were transfusion‐dependent at the time of study entry (n = 28). Anemia response was more likely with post‐essential thrombocythemia MF (83% vs 37%; p = .001), lower serum ferritin (p = .003), and shorter time from diagnosis to momelotinib therapy (p = .001); the first two variables were also predictive in transfusion‐dependent patients. Post‐momelotinib median survival was 3.2 years; in univariate analysis, survival was superior in anemia responders (median 3.8 vs. 2.8 years; p = .14) and in the presence of type 1/like CALR mutation and inferior in the presence of age > 65 years, ASXL1/SRSF2 mutation, unfavorable karyotype, DIPSS‐plus high risk, red cell transfusion need and higher serum ferritin. Multivariable analysis confirmed the favorable impact of anemia response on survival (p = .02; HR 0.5, 3/5/10‐year survival; 69%/38%/25%). This survival advantage was also noted in transfusion‐dependent patients (3.7 vs. 1.9 years; p = .01; HR 0.3) and appeared to be restricted to patients with an unfavorable genetic profile. The current study suggests a short‐term survival benefit associated with anemia response in momelotinib‐treated patients with MF.

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

Cited by 44 publications

References 31 publications

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis

Predictors of anemia response to momelotinib therapy in myelofibrosis and impact on survival

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