Robust Overall Survival and Sustained Efficacy Outcomes during Long Term Exposure to Momelotinib in JAK Inhibitor Naïve and Previously JAK Inhibitor Treated Intermediate/High Risk Myelofibrosis Patients (original) (raw)
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Annals of Hematology
Ruxolitinib (RUX) is a Janus kinase 1/2 inhibitor (JAKi) approved in the EU for treating disease‑related splenomegaly or symptoms in adults patients with myelofibrosis (MF). This is an interim analysis of JAKoMo, a prospective, non‑interventional, phase IV study in MF. Between 2012–2019 (cutoff March 2021), 928 patients (JAKi-naïve and -pretreated) enrolled from 122 German centers. This analysis focuses on JAKi-naïve patients. RUX was administered according to the Summary of Product Characteristics. Compared to the COMFORT-I, -II, and JUMP trials, patients in JAKoMo were older (median 73 years), had poorer Eastern Cooperative Oncology Group (ECOG) performance statuses (16.5% had ECOG ≥ 2), and were more transfusion dependent (48.5%). JAKoMo represents the more challenging patients with MF encountered outside of interventional studies. However, patients with low-risk International Prognostic Scoring System (IPSS) scores or without palpable splenomegaly were also included. Following ...
Journal of Clinical Oncology
Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2%...
Future Oncology
Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.
Haematologica, 2016
Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis (MF) but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase 2 study, we evaluated the efficacy and safety of 3 dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk MF and a platelet count ≥50x10(9)/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score (TSS) was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, 2 patients (20%) in the 100 mg twice-daily cohort had ≥50% TSS reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts...
Leukemia, 2014
Current estimates of response to JAK inhibitor therapy, in patients with myelofibrosis (MF), are based on the 2006 response criteria published by the International Working Group for Myeloproliferative Neoplasms (MPN) Research and Treatment (IWG-MRT). 1 These criteria were recently revised by the IWG-MRT and the European LeukemiaNet (ELN), with the intent to include stricter definitions of red cell transfusion dependency and independency, objective measurement of spleen size and formal assessment of response in disease-related symptoms. 2 In addition, the 2013 revised criteria require at least 12 weeks of response duration and a clinical improvement (CI) response category that accounts for the absence of concomitant deterioration in severity of cytopenias. 2 The latter is particularly relevant to JAK inhibitor therapy, because their value in reducing spleen size is often antagonized by their adverse effect on hemoglobin level and platelet count. 3-6 The currently available drugs are incapable of inducing complete (CR) or partial (PR) remission in MF. CR or PR in MF requires a hemoglobin level ⩾ 10 g/dl without transfusion, platelet count ⩾ 100 × 10 9 /l, neutrophil count ⩾ 1 × 10 9 /l and resolution of disease-related symptoms, palpable hepatosplenomegaly and leukoerythroblastosis; in addition, reversal of bone marrow fibrosis and normalization of bone marrow cellularity is required for CR or 'PR with incomplete recovery of blood counts'. 2 In other words, 'CI' is currently the maximum benefit that one derives from drug treatment in MF, including JAK inhibitor therapy. 3-6 Furthermore, as discussed above, previously reported CI rates associated with JAK inhibitor therapy might not be valid in the context of the 2013 revised criteria. In the current study, we provide a retrospective estimation of response, taking into consideration elements of the 2013 IWG-MRT-ELN criteria, wherever possible, for 111 patients with MF treated with either momelotinib (n = 60) or ruxolitinib (n = 51), in the context of phase-1/2 studies at our institution. 5,7,8 The core study with ruxolitinib included a total of 153 patients, including 51 patients from our institution. 7 Using the 2006 IWG-MRT criteria, response rates in the 51 patients treated at our institution were 0% for CR, 0% for PR and 22% for CI. Anemia and spleen responses were 11% and 20%, respectively. Anemia response in transfusion-dependent patients was 17%. The magnetic resonance imaging-based spleen response rate in a subsequent phase-3 study that compared ruxolitinib with the best available therapy (BAT) was 28.5%. 4 In the latter study, the benefit of ruxolitinib therapy, in terms of spleen response, was undermined by the occurrence of treatmentassociated anemia (40.4% vs 12.3% for BAT) and thrombocytopenia (44.5% vs 9.6% for BAT). Among the 51 ruxolitinib-treated patients at our institution, grade 2 or higher thrombocytopenia was documented in 26% of the patients and anemia in 33%. 8 The first formal publication of the study with momelotinib included 60 patients, all of whom were treated at our institution. 5 Using the 2006 IWG-MRT criteria, response rates were 0% for CR, 1.7% for PR and 67% for CI. Spleen and anemia responses based on the 2006 IWG-MRT criteria were 51% and 52%, respectively. Anemia response in transfusion-dependent patients was 59%.
Future Oncology
Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 ( ClinicalTrials.gov )
Leukemia
is an acquired clonal hematopoietic stem cell disorder associated with debilitating constitutional symptoms, extramedullary hematopoiesis resulting in splenomegaly, and a propensity to transform to a blast phase/acute myeloid leukemia (AML). The discovery of JAK inhibitors (JAKi) has been pivotal in the treatment of symptomatic MF by reducing spleen size, and alleviating cytokine-related symptom burden [1]. Despite this, up to 50% of MF patients discontinue JAKi by 2-3 years and only one quarter of patients remain on treatment at 5 years [2, 3]. Prospective trials of JAKi therapy provide little information after patients discontinue therapy and safety specific follow up is completed. Although survival following ruxolitinib cessation is poor, in the range 13-16 months, the clinical course and reasons for JAKi failure in MF patients are not well characterized [4-7]. Criteria for JAKi failure are variably defined in retrospective studies and second-line JAKi therapy trials [8-10]. JAKi therapy may fail for a variety of reasons including sub-optimal/loss of spleen response, severe cytopenias, progression to an accelerated or blast phase (AP/BP) of disease, secondary malignancies other than AML, recurrent severe infections, or other non-hematological toxicities. Recognition of patterns of failure is important to accurately characterize, and plan treatment strategies in these patients. We conducted a retrospective study analyzing a molecularly annotated, mature dataset of MF patients treated with JAKi followed in a prospective MPN registry (NCT02760238) at Princess Margaret Cancer Centre. We evaluated the impact of baseline clinical and molecular factors on clinical outcomes and therapy failure. We characterized different patterns of JAKi failure according to consensus criteria of the Canadian MPN Group (Supp. Table S1) [11] and its impact on survival. In a subset of patients with paired samples we evaluated the impact of clonal evolution on outcomes following JAKi failure. Cohort selection, study definitions, molecular, and statistical analysis are summarized in Appendix.
Blood, 2015
Pacritinib (SB1518) is a JAK2, JAK2(V617F) and FLT3 kinase inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies, or were newly diagnosed with intermediate- or high-risk Lille Score. Patients with any degree of thrombocytopenia, anemia or neutropenia were eligible. Thirty-five patients were enrolled and treated with pacritinib. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100,000/µL. Up to week 24, 8/26 (31%) evaluable patients achieved ≥ 35% decrease in MRI-determined spleen volume and 14/33 (42%) attained ≥ 50% reduction in spleen size by physical examination. Median MF symptom improvement was ≥50% for all symptoms except...
Beyond JAK2 Inhibitors: A Systematic Review of Management Strategies for Myelofibrosis
Blood, 2018
Introduction Drugs that target activating mutations of Janus Kinase 2 (JAK2) have been the backbone of myelofibrosis (MF) management. With recent advancements in our understanding of the underlying molecular mechanisms involved in myelofibrosis (MF) pathogenesis, numerous novel agents have been developed in the last decade. We have systematically reviewed the mechanisms of actions, efficacy and safety of these drugs. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade were screened for relevant studies. Of these, 212 articles were finalized for our final analyses. Results Hedgehog inhibitors (saridegib, glasdegib and sonidegib) targets signaling membrane protein, smoothened. The combination of sonidegib + ruxulotinib (RUX) elic...