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Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, and cytopenias.1 Despite advances in treating MF-associated splenomegaly and symptoms with the approval of Janus kinase (JAK) inhibitors, disease- and treatment-associated cytopenias remain challenging.2 Thrombocytopenia (platelet counts <100 × 109/L), commonly associated with anemia and transfusion dependence in MF, occurs in ≈21%–25% of patients at diagnosis and in up to 70% of patients at any time during the disease course and is an adverse prognostic factor for leukemia-free survival (LFS) and overall survival (OS).3–7
Ruxolitinib, a JAK1 and JAK2 inhibitor, was the first JAK inhibitor approved for adults with intermediate- or high-risk MF. It reduced spleen size and symptoms but grade ≥3 cytopenias occurred frequently (anemia: 42%–45%; thrombocytopenia: 8%–13%).8–10 Although ruxolitinib remains the most widely prescribed JAK inhibitor for the treatment of MF, reduced starting doses are required for patients with baseline platelet counts <200 × 109/L, and dose-limiting myelosuppression is common.8 Worsening thrombocytopenia commonly results in dose reductions to as little as 25% of the standard dose.11 In the real world, approximately one-third of patients initiate ruxolitinib at a lower dose than recommended12–14 and an estimated 41%–64% of patients discontinue ruxolitinib within 3 years,14,15 most often due to treatment-related cytopenias.12,15 Rapid increases in spleen size and symptoms have been observed with ruxolitinib dose reductions,16 and ruxolitinib discontinuation is associated with poor survival, particularly for patients with thrombocytopenia.12 Grade ≥3 cytopenias were also common with fedratinib (anemia: 38%–43%; thrombocytopenia: 17%–22%), a JAK2 and FMS-like tyrosine kinase 3 inhibitor.17–19 Fedratinib approval came with a boxed warning on the risk of serious and fatal encephalopathy including Wernicke.19 The JAK2 inhibitor pacritinib is the only JAK inhibitor approved by the US Food and Drug Administration (FDA) for use in patients with MF with platelets <50 × 109/L, based on spleen volume reduction ≥35% (SVR35) in 31 patients in PERSIST-2; a confirmatory trial is ongoing.20–22 The most common grade 3/4 adverse events (AEs) with pacritinib were thrombocytopenia (32%) and anemia (22%).22
Treatment of patients with MF and cytopenias remains a high medical need.2,3,5 Momelotinib is the first JAK1 and JAK2 inhibitor demonstrated to also inhibit activin A receptor type I (ACVR1), which downregulates the expression of hepcidin, a key regulator of iron homeostasis.23 Hepcidin is frequently elevated in MF and is associated with poor prognosis.24 Momelotinib suppresses hepcidin production, which leads to increased iron availability and stimulates erythropoiesis, resulting in anemia benefits, in addition to the spleen and symptom benefits provided by JAK inhibition, for patients with MF.23,25 Momelotinib starting dose is fixed for all patients, irrespective of baseline platelet count, and platelet levels are generally maintained on momelotinib therapy without the need for dose adjustments.26 The tolerability and clinical efficacy of momelotinib in improving anemia, symptoms, and splenomegaly were demonstrated in phase 3 trials of patients with MF who were JAK inhibitor naïve (SIMPLIFY-1) and previously exposed to ruxolitinib (SIMPLIFY-2) or any approved JAK inhibitor (MOMENTUM).27–29 In MOMENTUM, which required baseline platelet counts of ≥25 × 109/L, momelotinib showed superior week 24 symptom response and SVR35 rates, and a noninferior transfusion independence rate, when compared with danazol in the overall study population and in patients with baseline platelet counts <100 × 109/L and <50 × 109/L.29 In SIMPLIFY-1, which required baseline platelet counts of ≥50 × 109/L, and in SIMPLIFY-2, which had no restrictions on baseline platelet counts, more patients overall achieved week 24 transfusion independence response with momelotinib than controls (ruxolitinib in SIMPLIFY-1; best available therapy [BAT; 88.5% ruxolitinib] in SIMPLIFY-2).27,28 A systematic review and network meta-analysis of JAK inhibitors in MF reported that momelotinib offered similar SVR35 benefits but was associated with significantly less grade 3/4 anemia compared with ruxolitinib.30
The tolerability of momelotinib and its lower myelosuppressive activity compared with ruxolitinib may enable more prolonged, adequate dose treatment in thrombocytopenic patients.28 This post hoc analysis from MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 evaluates the efficacy and safety of momelotinib in MF patients with thrombocytopenia.
MATERIALS AND METHODS Study design and patientsDetailed study designs for MOMENTUM (NCT04173494),29 SIMPLIFY-1 (NCT01969838),28 and SIMPLIFY-2 (NCT02101268)27 have been published. The phase 3 MOMENTUM study included patients with symptomatic (Myelofibrosis Symptom Assessment Form Total Symptom Score [TSS] ≥10) and anemic (hemoglobin <100 g/L) primary MF (PMF), post-polycythemia vera (post-PV) MF, or post-essential thrombocythemia (post-ET) MF previously treated with JAK inhibitor therapy. Baseline platelet counts ≥25 × 109/L were required for eligibility. Patients (N = 195) were randomized (2:1) to receive momelotinib 200 mg once daily plus danazol placebo or danazol 300 mg twice daily plus momelotinib placebo. Previous JAK inhibitors included ruxolitinib (100%) and fedratinib (5%). For patients with baseline platelet counts ≥100 × 109/L, study treatment doses were reduced if platelet counts fell below 50 × 109/L; if counts fell below 20 × 109/L, treatment was tapered if appropriate, interrupted, and resumed with reduction by 1 dose level if counts recovered to ≥50 × 109/L. For patients with baseline platelet counts <100 × 109/L that fell to <20 × 109/L, treatment was tapered if appropriate, interrupted, and could resume with reduction by 1 dose level if counts recovered to ≥50% of baseline; for those with baseline platelet counts <50 × 109/L, the same protocol was followed with resumption of treatment if counts recovered to ≥25 × 109/L.
SIMPLIFY-1 was a phase 3 noninferiority study of JAK inhibitor-naïve patients with intermediate- or high-risk PMF, post-PV MF, or post-ET MF with baseline platelet counts ≥50 × 109/L. Patients (N = 432) were randomized 1:1 to momelotinib 200 mg once daily plus ruxolitinib placebo or ruxolitinib twice daily plus momelotinib placebo with the ruxolitinib starting dose dependent on baseline platelet counts and other laboratory values (Suppl. Table S1). Doses of momelotinib/momelotinib placebo on study were reduced if platelet counts fell below 50 × 109/L from ≥100 × 109/L at baseline and interrupted if they fell below 25 × 109/L regardless of baseline platelet counts. Ruxolitinib/ruxolitinib placebo dose was reduced to a level dependent on the previous dose if platelet counts fell below 125 × 109/L and with every additional drop of 25 × 109/L, and interrupted if platelet counts fell below 25 × 109/L.
SIMPLIFY-2 was a phase 3 superiority study of patients with intermediate- or high-risk PMF, post-PV MF, or post-ET MF and who experienced hematologic toxicity when previously treated with ruxolitinib. No minimum baseline platelet count was required, and there was no washout period from prior ruxolitinib treatment. Patients (N = 156) were randomized (2:1) to receive momelotinib 200 mg once daily or BAT. BAT included ruxolitinib (88.5%), other standard treatments alone or in combination at a schedule and dose in accordance with the standard of care per investigator, or no treatment. Dose modifications for momelotinib were as described for SIMPLIFY-1. Dose modifications for BAT were as determined by the investigator in accordance with standard of care. One option in the BAT arm of SIMPLIFY-2 was no treatment, and switching and pausing of control arm therapy were permitted per investigator discretion. Risk assessment categories for SIMPLIFY-1 were based on the International Prognostic Scoring System criteria31 and for SIMPLIFY-2 and MOMENTUM were based on Dynamic International Prognostic Scoring System criteria.32
In all 3 studies, patients received randomized treatment for 24 weeks; thereafter, patients randomized to momelotinib could continue receiving momelotinib for an extended treatment period, whereas patients randomized to control arms could cross over to momelotinib without any washout period. Patients receiving momelotinib at study completion were eligible to roll over to an extended access protocol (NCT03441113) if they were tolerating momelotinib therapy and had not experienced disease progression. Data captured during this extension protocol were included in the OS analyses.
End points and statistical analysesIn MOMENTUM, the primary end point was ≥50% reduction in TSS response rate at week 24.29 Key secondary end points were 24-week rates of SVR25, SVR35, transfusion independence, zero transfusions, and change from baseline in mean TSS. Additional secondary end points included OS and anemia-related end points. In SIMPLIFY-1 and SIMPLIFY-2, the primary end point was SVR35 rate at 24 weeks.27,28 Secondary end points included mean TSS response rate and red blood cell (RBC) transfusion independence rate at 24 weeks; exploratory end points included OS and LFS.
Primary efficacy analyses for all 3 studies have been previously reported.27–29 Patients with platelet counts <100 × 109/L at baseline (referred to hereafter as sub-100 group) from MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 were included in the present post hoc, exploratory, efficacy and safety analyses. Patients were further subdivided into those with baseline platelet counts 50 to <100 × 109/L (moderate thrombocytopenia; all 3 studies) and <50 × 109/L (severe thrombocytopenia [sub-50 group]; 31 patients from MOMENTUM only). Zero patients from SIMPLIFY-1 and 16 patients [9 momelotinib and 7 BAT] from SIMPLIFY-2 had platelet counts <50 × 109/L and were not evaluated separately. Efficacy and safety were also evaluated in patients with platelet counts ≤150 × 109/L. Data reported are descriptive and P values were not calculated due to the exploratory nature of this analysis. Major adverse cardiovascular events (MACE) were defined according to the FDA guideline on composite end point determination for cardiovascular and stroke studies.33
All studies were approved by the Institutional Review Boards or independent ethics committees, and all participants provided written informed consent. The present analysis was not prespecified.
Data AvailabilitySierra Oncology, a GSK company, commits to sharing clinical study data with qualified researchers to enable enhancement of public health. As such, Sierra will share anonymized patient-level data on request or if required by law or regulation. Qualified scientific and medical researchers can request patient-level data for studies of Sierra pharmaceutical substances listed on ClinicalTrials.gov and approved by health authorities in the United States and the EU. Patient-level data for studies of newly approved pharmaceutical substances or indications can be requested 9 months after the US FDA and European Medicines Agency approvals. Such requests are assessed at Sierra’s discretion, and the decisions depend on the scientific merit of the proposed request, data availability, and the purpose of the proposal. If Sierra agrees to share clinical data for research purposes, the applicant is required to sign an agreement for data sharing before data release, to ensure that the patient data are deidentified. In case of any risk of reidentification on anonymized data despite measures to protect patient confidentiality, the data will not be shared. The patients’ informed consent will always be respected. If the anonymization process will provide futile data, Sierra will have the right to refuse the request. Sierra will provide access to patient-level clinical trial analysis datasets in a secured environment upon execution of the data sharing agreement. Sierra will also provide the protocol, statistical analysis plan, and the clinical study report synopsis if needed. For additional information or requests for access to Sierra clinical trial data for research purposes, please contact us at [email protected].
RESULTS PatientsIn total, 210 of 783 patients (27%) randomized in MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 had baseline platelet counts <100 × 109/L (sub-100 group) and 47 patients (6%) had baseline platelet counts <50 × 109/L (sub-50 group) including 31 from MOMENTUM (Suppl. Figure S1). Of the 210 patients in the sub-100 group, 126 received momelotinib in the 24-week randomized treatment period (MOMENTUM, n = 66; SIMPLIFY-1, n = 18; and SIMPLIFY-2, n = 42) and 84 received therapy in the control arms (danazol, n = 34; ruxolitinib, n = 23; BAT, n = 27; respectively). Overall, 62 patients crossed over to open-label momelotinib from the control arms after the 24-week randomized treatment period (23/34 patients [68%] from danazol; 17/23 patients [74%] from ruxolitinib; and 22/27 patients [81%] from BAT). In MOMENTUM and SIMPLIFY-2, baseline characteristics were generally comparable between treatment arms (Table 1). In SIMPLIFY-1, baseline demographics were generally comparable between arms except that more patients randomized to momelotinib were older (aged ≥65 years; 61% versus 48%), male (67% versus 48%), and had anemia (hemoglobin levels <100 g/L, 72% versus 57%) compared with those randomized to ruxolitinib.
Table 1 - Baseline Demographics and Characteristics for Patients With Baseline Platelet Count 9/L in MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 Arm MOMENTUM SIMPLIFY-1 SIMPLIFY-2 MomelotinibaMissing or not permitted to be reported. Additionally, in the MOMENTUM study, 4 patients (6%) in the momelotinib arm and 3 patients (9%) in the danazol arm reported Other as their race.
bUnknown, missing, or not permitted to be reported.
cIPSS risk categories based on Cervantes and collaborators (2009) reported in SIMPLIFY-1.31 DIPSS risk categories based on Passamonti and collaborators (2010) reported for the SIMPLIFY-1 and MOMENTUM studies.32dAvailable in 17 patients in the momelotinib arm and 23 patients in the ruxolitinib arm in SIMPLIFY-1.
ePer protocol, patients in MOMENTUM must have had Hb <100 g/L at screening. However, Hb levels increased to >100 g/L without red blood cell transfusions between screening and baseline in 2 patients who were randomized to the momelotinib arm: 1 patient had Hb of 90.7 g/L at screening (study day −30) and 107 g/L at baseline (study day −9), and 1 patient had Hb of 89 g/L at screening (study day −32) and 105 g/L at baseline (study day −7).
fTransfusion dependence at baseline was defined as requiring ≥4 red blood cell/whole blood transfusion units in the 8 wks before the first dose, each associated with hemoglobin levels ≤9.5 g/dL (MOMENTUM), or requiring ≥4 red blood cell/whole blood transfusion units, or a hemoglobin level <8 g/dL, in the 8 wks before the first dose (SIMPLIFY-1 and SIMPLIFY-2).
gTransfusion independence at baseline was defined in all 3 trials as no red blood cell/whole blood units transfused, with all hemoglobin levels ≥8 g/dL, in the 12 wks before the first dose.
hCentrally assessed.
ANC = absolute neutrophil count; BAT = best available therapy; BMI = body mass index; DIPSS = Dynamic International Prognostic Scoring System; ECOG = Eastern Cooperative Oncology Group; Hb = hemoglobin; IPSS = International Prognostic Scoring System; MMB = momelotinib; N/A, not available; Post-ET = post-essential thrombocythemia; Post-PV = post-polycythemia vera; PS = performance status; RBC = red blood cell; RUX = ruxolitinib; TSS = Total Symptom Score.
The SVR35 rate at week 24 was numerically comparable or higher in the sub-100 groups with momelotinib than in the overall study populations in MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 (Figure 1A). In the control arms, the SVR35 rate at week 24 in the sub-100 group was numerically comparable to that in the overall study populations for danazol (MOMENTUM) and BAT (SIMPLIFY-2), but not for ruxolitinib (SIMPLIFY-1), with no patients achieving an SVR35 with ruxolitinib.
Figure 1.: Week 24 response rates by treatment arm among patients with baseline platelet counts <100 × 10 9 /L, 50–100 × 10 9 /L, and <50 × 10 9 /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%.
Transfusion independence rates in the sub-100 group with momelotinib were numerically comparable to the overall study populations across all 3 studies, including when looking specifically in patients with moderate thrombocytopenia (platelet counts 50–100 × 109/L; Figure 1B). The proportion of sub-100 group patients with transfusion independence increased numerically from baseline to week 24 in the momelotinib arms in each study (14% to 27% in MOMENTUM; 28% to 61% in SIMPLIFY-1; and 38% to 48% in SIMPLIFY-2), whereas the rate decreased numerically in the control arms of SIMPLIFY-1 and -2 (47% to 39% and 37% to 30%, respectively). Among patients in the sub-100 group treated with momelotinib, RBC transfusion requirements (median units transfused) during randomized treatment were numerically comparable (MOMENTUM, 5 units; SIMPLIFY-1, 2 units; and SIMPLIFY-2, 1 units) to those observed in the overall momelotinib-treated population of each study.
TSS response rate at week 24 was numerically comparable or higher in the sub-100 groups than the overall study populations with momelotinib in all 3 studies and remained steady in the BAT arm in SIMPLIFY-2 (Figure 1C). In contrast, the TSS response rate in the ruxolitinib arm in the sub-100 group was approximately half the rate observed in ruxolitinib arm of the overall SIMPLIFY-1 population (22% and 42%, respectively).
Efficacy results were generally consistent when evaluating patients in the sub-50 group (Figure 1A–1C) and all patients with platelet counts ≤150 × 109/L, which included patients with mild thrombocytopenia (Suppl. Figure S2).
All patients from MOMENTUM in the sub-100 group were at least moderately anemic (hemoglobin <100 g/L) at screening, per inclusion criteria, and most patients in SIMPLIFY-1 and SIMPLIFY-2 were at least mildly anemic at baseline (Table 1). Among sub-100 group patients with anemia, SVR35, transfusion independence, and TSS response rates were generally numerically higher with momelotinib than controls across all 3 studies with the exception of TSS response in SIMPLIFY-1 (Suppl. Figure S3).
SurvivalOS rates were generally comparable for both the momelotinib and the control arms in the sub-100 groups versus the overall study populations in all 3 studies (Table 2). In the MOMENTUM sub-100 group (median follow-up, momelotinib, 9 months; danazol, 10 months), median OS was not reached in either arm with a hazard ratio (HR; momelotinib versus danazol) of 0.659 (95% confidence interval [CI], 0.268-1.622) when analyzed over the entire follow-up period and 0.616 (95% CI, 0.211-1.802) when assessed over the 24-week randomized treatment period alone (Figure 2A). In the SIMPLIFY-1 sub-100 group (median follow-up, momelotinib, 3.0 years; ruxolitinib, 3.7 years), the estimated 3-year OS rate was 56.7% (95% CI, 29.2-77.0) and 53.3% (95% CI, 28.9-72.7), respectively (HR, 0.848 [95% CI, 0.341-2.2113]) (Figure 2B). In the SIMPLIFY-2 sub-100 group (median follow-up, momelotinib, 3.4 years; BAT, 3.5 years), the estimated 3-year OS rate was 59.8% (95% CI, 41.5-74.0) and 65.5% (95% CI, 44.0-80.4), respectively (HR, 0.984 [95% CI, 0.451-2.147]) (Figure 2C).
Table 2 - Overall Survival in Patients With Thrombocytopenia and in the Overall Populations in MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 SIMPLIFY-1 (JAK Inhibitor Naïve)a
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