Genetic determinants of response and survival in momelotinib-treated patients with myelofibrosis.
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ABSTRACT:
SUBMITTER: Pardanani A
PROVIDER: S-EPMC4360208 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
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Genetic determinants of response and survival in momelotinib-treated patients with myelofibrosis.
Pardanani A A Abdelrahman R A RA Finke C C Lasho T T TT Begna K H KH Al-Kali A A Hogan W J WJ Litzow M R MR Hanson C A CA Ketterling R P RP Tefferi A A
Leukemia 20141111 3
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Project description:Between October 2007 and July 2013, 183 Mayo Clinic patients (median age 65 years; 58% males) with high/intermediate risk myelofibrosis (MF) were enrolled in consecutive phase 1/2 JAK2 inhibitor (JAKi) clinical trials with momelotinib (n = 79), ruxolitinib (n = 50), fedratinib (n = 23) and BMS-911543 (n = 31). Using conventional criteria, the respective response rates for spleen and "transfusion-dependent anemia" were 47%, 32%, 83%, 62% and 51%, 30%, 10%, 44%, respectively, favoring momelotinib for anemia response (p = 0.02) and fedratinib for spleen response (p < 0.01). All study patients were followed to death or 2022, during which time 177 (97%) drug discontinuations, 27 (15%) leukemic transformations, and 22 (12%) allogeneic stem cell transplants (ASCT) were recorded. 5/10-year survival rate for all 183 patients was 41%/16% and not significantly different across the four drug cohorts (p = 0.33). Multivariable analysis of pre-treatment variables identified age >65 years (HR 3.5), absence of type 1/like CALR mutation (HR 2.8), baseline transfusion need (HR 2.1), and presence of ASXL1/SRSF2 mutation (HR 1.6) as risk factors for overall survival; subsequent HR-based modeling segregated three risk categories with 5/10-year survival rates of 84%/60%, 44%/14%, and 21%/5% (p < 0.01). In addition, spleen (p < 0.01) and anemia (p = 0.01) responses were independently associated with improved short-term survival while long-term survival was secured only by ASCT (5/10-year survival rate 91%/45% vs 47%/19% in non-transplanted patients; p < 0.01). The current retrospective study suggests the value of specific pre-treatment variables in identifying long-lived MF patients receiving JAKi and also confirms recent observations on the favorable impact of treatment response on short-term and of ASCT on long-term survival.
| S-EPMC9813003 | biostudies-literature
Project description:The suite of marked anemia benefits that momelotinib has consistently conferred on myelofibrosis (MF) patients stem from its unique inhibitory activity on the BMP6/ACVR1/SMAD and IL-6/JAK/STAT3 pathways, resulting in decreased hepcidin (master iron regulator) expression, higher serum iron and hemoglobin levels, and restored erythropoiesis. Clinical data on momelotinib from the phase 2 and the two phase 3 SIMPLIFY trials consistently demonstrated high rates of sustained transfusion-independence. In a recent phase 2 translational study, 41% of the patients achieved transfusion independence for ≥ 12 weeks. In the phase 3 trials SIMPLIFY-1 and SIMPLIFY-2, 17% more JAK inhibitor-naïve patients and two-fold more JAK inhibitor-treated patients achieved or maintained transfusion independence with momelotinib versus ruxolitinib and best available therapy (89% ruxolitinib), respectively. Anemia is present in approximately a third of MF patients at diagnosis, eventually developing in nearly all patients. The need for red blood cell transfusions is an independent adverse risk factor for both overall survival and leukemic transformation. Presently, FDA-approved medications to address anemia are lacking. Momelotinib is one of the prime candidates to durably address the critical unmet needs of MF patients with moderate/severe anemia. Importantly, momelotinib may have overall survival benefits in frontline and second-line MF patients. MOMENTUM is an international registration-track phase 3 trial further assessing momelotinib's unique constellation of anemia and other benefits in second-line MF patients; the results of the MOMENTUM trial are keenly awaited and may lead to regulatory approval of momelotinib.
| S-EPMC8772195 | biostudies-literature
Project description:Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib's pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.
| S-EPMC9417985 | biostudies-literature
Project description:Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis (MF). This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), representing MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM, ruxolitinib in SIMPLIFY-1, and best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol (XAP). Across these studies, 725 patients with MF received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27% and grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% discontinuation rate). The incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, and hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in MF demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity. These trials were registered at www.clinicaltrials.gov as: MOMENTUM (#NCT04173494), SIMPLIFY-1 (#NCT01969838), SIMPLIFY-2 (#NCT02101268), and XAP (#NCT03441113).
| S-EPMC10368854 | biostudies-literature
Project description:One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%. Clinical improvement (CI) occurred in 57% of patients, including 44% anemia and 43% spleen response. CI was more likely to occur in ASXL1-unmutated patients (66% vs 44%) and in those with <2% circulating blasts (66% vs 42%). Response was more durable in the presence of CALR type 1/like and absence of very high-risk karyotype. In multivariable analysis, absence of CALR type 1/like (HR 3.0; 95% CI 1.2-7.6) and presence of ASXL1 (HR 1.9; 95% CI 1.1-3.2) or SRSF2 (HR 2.4, 95% CI 1.3-4.5) mutations adversely affected survival. SRSF2 mutations (HR 4.7, 95% CI 1.3-16.9), very high-risk karyotype (HR 7.9, 95% CI 1.9-32.1), and circulating blasts ≥2% (HR 3.9, 95% CI 1.4-11.0) predicted leukemic transformation. Post-MMB survival (median 3.2 years) was not significantly different than that of a risk-matched MF cohort not receiving MMB.
| S-EPMC5841331 | biostudies-literature
Project description:Background/Objectives: Red blood cell transfusions for anemia impose high financial and healthcare resource utilization burdens on patients with myelofibrosis (MF). This study estimates projected differences in medical costs and transfusion-related cost and time burdens with momelotinib vs. ruxolitinib or best available therapy (BAT) in Janus kinase (JAK) inhibitor-naive and -experienced patients. Methods: Analyses used 24-week transfusion data from the phase 3 SIMPLIFY-1 and SIMPLIFY-2 trials and cost estimates from a study of adult patients with MF using the US IBM MarketScan Commercial database. The analyses were stratified by transfusion status at baseline (transfusion dependent [TD], transfusion independent/requiring [TI/TR]). Subgroup analyses were conducted among patients with anemia (moderate anemia, hemoglobin ≥ 8 to <10 g/dL; moderate-to-severe anemia, hemoglobin < 10 g/dL) and for patients aged ≥65 years. Cost estimates for patients aged ≥65 years were extracted from a study using the Medicare Fee-for-Service database. Results: In JAK inhibitor-naive patients, momelotinib was projected to result in cost and time savings vs. ruxolitinib in both TD and TI/TR patients across all populations evaluated. Projected cost and time savings were also observed with momelotinib vs. BAT in JAK inhibitor-experienced patients across all populations evaluated, primarily in TD patients. Conclusions: These results suggest that momelotinib may provide medical and transfusion-related cost and time burden offsets for both JAK inhibitor-naive and -experienced patients with MF.
| S-EPMC11640613 | biostudies-literature
Project description:BackgroundMyelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy.MethodsLongitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data.ResultsMomelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as "improved" or "stable" compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm.ConclusionsThese findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings.
| S-EPMC10225216 | biostudies-literature
Project description: Not available
| S-EPMC10948874 | biostudies-literature
Project description:Aim: To estimate projected US-based cost and time burden for patients with myelofibrosis and anemia treated with momelotinib compared with danazol.Methods: Cost and time burden were calculated based on the transfusion status of patients in the MOMENTUM trial and estimates extracted from previous studies.Results: Reductions in transfusion associated with momelotinib are projected to result in cost and time savings compared with danazol in transfusion-dependent and transfusion-independent/requiring patients with myelofibrosis, respectively: annual medical costs ($53,143 and $46,455 per person), outpatient transfusion costs ($42,021 and $8,370 per person) and annual time savings (173 and 35 h per person).Conclusion: Fewer transfusions with momelotinib are projected to result in cost and time savings in patients with myelofibrosis and anemia compared with danazol.
| S-EPMC11508939 | biostudies-literature
Project description:BackgroundMyelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.MethodsThis was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.ResultsA total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23-0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36-0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.ConclusionsThese findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.Trial registrationClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .
| S-EPMC5622445 | biostudies-literature