Achieving transfusion independence after 24 weeks of treatment with momelotinib is associated with clinical benefit in patients with myelofibrosis irrespective of the degree of anemia, platelet count, or transfusion status at baseline, according to an analysis of the phase 3 SIMPLIFY 1 trial (NCT01969838) that were presented as an abstract during the 2021 ASCO Annual Meeting and expanded upon in a poster presentation during the EHA 2021 Virtual Congress.

Additionally, data suggest that a momelotinib-associated, transfusion-independent response at week 24 is associated with a survival advantage in this patient population.

“Taken together, these data further support the potential benefits of momelotinib’s ACVR1/ALK2 inhibitory activity in addition to inhibiting JAK1 and JAK2, leading to improved transfusion independence rates and improved overall survival [OS],” lead study author Jean-Jacques Kiladjian, MD, PhD, a professor of clinical pharmacologist at Paris Diderot University and a consultant hematologist and head of the Clinical Investigation Center at the Saint-Louis Hospital in Paris, France, and coinvestigators, wrote in the poster presented during the EHA meeting.

“Momelotinib has the potential to become a preferred treatment for patients with myelofibrosis who are anemic or who are at risk of myelosuppression as a result of treatment with currently available JAK inhibitors,” the authors wrote.

Momelotinib is a JAK1/2 and ACVR1/ALK2 inhibitor that has demonstrated clinical utility in improving symptom burden for patients with myelofibrosis. The agent has shown activity against key disease features such as anemia, constitutional symptoms, and splenomegaly in patients with myelofibrosis irrespective of prior JAK inhibitor status.

Decreased survival has been associated with elevated hepcidin that causes iron-restricted anemia of inflammation. Inhibiting ACVR1/ALK2 has been shown to reduce hepcidin and could contribute to improved survival in this patient population.

However, progressive anemia is a common, negative prognostic factor in myelofibrosis and most patients require regular blood transfusions.

The double-blind, randomized SIMPLIFY-1 trial failed to demonstrate noninferiority at 24 weeks with momelotinib vs ruxolitinib (Jakafi) for symptom response, but was noninferior for splenic response, in 432 patients with intermediate- or high-risk JAK inhibitor–naïve myelofibrosis.4 Subgroup analyses from SIMPLIFY 1 and the phase 3 SIMPLIFY 2 trial (NCT02101268), which were presented during the 2021 ASCO Annual Meeting, demonstrated that week-24 transfusion independence was associated with an improvement in OS vs week-24 transfusion dependence in patients with myelofibrosis who were randomized to momelotinib.

“Given the positive impact of transfusion independence on survival in patients receiving [momelotinib]…we explored the week 24 transfusion independence response rates for JAK inhibitor–naïve patients randomized to ruxolitinib or momelotinib in the SIMPLIFY-1 study,” Kiladjian and the authors noted.

Patient subgroups for analysis were defined by baseline hemoglobin level, platelet count, and transfusion status.

Further results showed that the rates of transfusion independence with momelotinib at 24 weeks by baseline hemoglobin levels of less than 8 g/dL (n = 28), less than 10 g/dL (n = 86), less than 12 g/dL (n = 159), 14 or less g/dL (n = 204), and more than 14 g/dL (n = 11) were 29% (n = 8), 47% (n = 40), 62% (n = 99), 67% (n = 136), and 64% (n = 7), respectively.

In patients receiving ruxolitinib, the rates of transfusion independence at 24 weeks by baseline hemoglobin levels of less than 8 g/dL (n = 22), less than 10 g/dL (n = 95), less than 12 g/dL (n = 164), 14 or less g/dL (n = 199), and more than 14 g/dL (n = 18) were 18% (n = 4), 27% (n = 26), 37% (n = 61), 46% (n = 91), and 89% (n = 16), respectively.

By baseline platelet count, patients receiving momelotinib with less than 150 x 109 platelets/L (n = 47) had a transfusion independence rate at 24 weeks of 62% (n = 29). Patients with a baseline platelet count of less than 300 x 109 platelets/L (n = 136) had a 68% (n = 93) transfusion independent rate, whereas the rate in patients with 300 x 109 or more platelets/L (n = 70) was 63% (n = 50).

In ruxolitinib-treated patients, the transfusion independence rates were 43% (n = 24), 48% (n = 62), and 51% (n = 45) for patients with baseline platelet counts of less than 150 x 109 platelets/L (n = 56), less than 300 x 109 platelets/L (n = 128), and 300 x 109 or more platelets/L (n = 89), respectively.

Patients treated with momelotinib who were transfusion independent at baseline (n = 147) had a week 24 transfusion independence rate of 81% (n = 119) compared with 53% (n = 8) in those who were transfusion requiring (n = 15) and 30% (n = 16) in those who were transfusion dependent (n = 53).

In the ruxolitinib-treated cohort, the response rates were 62% (n = 94), 31% (n = 4), and 17% (n = 9) in patients who were transfusion independent (n = 152), transfusion requiring (n = 13), and transfusion dependent (n = 52) at baseline, respectively.

Additionally, patients with baseline hemoglobin levels of 14 g/dL or less accounted for 93% of all patients evaluated in the SIMPLIFY 1 trial, “representing a population where the majority have some degree of anemia,” the authors concluded.

Kiladjian JJ, Platzbecker U, Mayer J, et al. Improved transfusion independence rates for momelotinib versus ruxolitinib in anemic JAKi naïve myelofibrosis patients independent of baseline platelet or transfusion status. 

. 2021;39(suppl 15):e19039. doi:10.1200/JCO.2021.39.15_suppl.e19039

Kiladjian JJ, Platzbecker U, Mayer J, et al. Improved transfusion independence rates for momelotinib vs ruxolitinib in anemic JAKi naïve myelofibrosis patients independent of baseline platelet or transfusion status. Presented at: EHA 2021 Virtual Congress; June 9-17, 2021. Abstract EP1081.

Mesa RA, Hudgens S, Floden L, et al. Longitudinal and individual symptom analyses of momelotinib and ruxolitinib treated myelofibrosis patients from SIMPLIFY-1. 

. 2021;39(suppl 15):e19040. doi:10.1200/JCO.2021.39.15_suppl.e19040

Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase iii randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor–naïve patients with myelofibrosis

. 2021;39:3844-3850. doi:10.1200/JCO.2017.73.4418

Articles

Achieving transfusion independence after 24 weeks of treatment with momelotinib is associated with clinical benefit in patients with myelofibrosis irrespective of the degree of anemia, platelet count, or transfusion status at baseline.

Transfusion Independence With Momelotinib Confers Benefit Regardless of Baseline Factors in Myelofibrosis 

Momelotinib can provide clinically relevant and comparable improvement in overall symptom burden and individual symptom items compared with ruxolitinib (Jakafi) in patients with intermediate- and high-risk JAK inhibitor–naïve myelofibrosis, according to findings from an analysis of the phase 3 SIMPLIFY-1 trial (NCT01969838) that were presented as an abstract during the 2021 ASCO Annual Meeting and further expanded on as a poster during the virtual ISPOR 2021 Meeting.

Meaningful improvements in symptom burden per Anchor-based Meaningful Change Threshold (MCT) Derivation were similar between patients in the overall population of SIMPLIFY-1 treated with momelotinib vs ruxolitinib. Moreover, 39% (n = 69) of patients treated with momelotinib (n = 175) demonstrated an improvement in symptom burden of at least 8 points compared with 41% (n = 77) of patients treated with ruxolitinib (n = 190). In the symptomatic cohort of patients, which were not included in the poster presentation, 56% vs 58% of patients achieved at least an 8-point improvement, respectively.

At week 24 after treatment initiation, the mixed effect models for repeated measures (MMRM) revealed mean within-subject improvements of 6.35 points with momelotinib vs 7.87 points with ruxolitinib, which both nearly reached but were less than the calculated study-specific within-subject 8-point MCT. In the symptomatic cohort, both treatment groups exceeded the MCT at 8.8 points vs 10.5 points, respectively.

“Item analyses and MMRM showed clinically important and comparable improvements in total symptom score [TSS],” Ruben A. Mesa, MD, director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, and co-authors.

Myelofibrosis is characterized by constitutional symptoms that cause significant burden on quality of life for patients. Although tools to evaluate patient-reported outcomes have improved in recent years, analytical methods to quantify symptom benefit with various therapeutic interventions have not improved significantly.

In the clinical trials evaluating JAK1/2 inhibitors, symptom improvement has generally been measured with a landmark analytic tool that requires a minimum 50% reduction in TSS from baseline over the last 28 days of a 24-week treatment cycle. Notably, however, patients with very high or low baseline TSS are required to reach significantly different absolute TSS improvements to be considered responsive to JAK inhibitor therapy.

The SIMPLIFY-1 trial failed to demonstrate noninferiority on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) response rate at week 24 with momelotinib vs ruxolitinib in 432 patients with intermediate- or high-risk JAK inhibitor–naïve myelofibrosis. The response rates were 28% vs 42%, respectively. However, each of the 7 TSS items evaluated—tiredness, early satiety, abdominal discomfort, night sweats, itching, bone pain, and pain under

the ribs on the left side—were similar between the momelotinib and ruxolitinib treatment arms.

“SIMPLIFY-1 is the only head-to-head phase 3 study comparing 2 highly active JAK inhibitors in the [myelofibrosis]-disease setting, yet was impacted by low symptom burden at baseline because of the failure to restrict enrollment to symptomatic subjects. SIMPLIFY-1 was also impacted by the heterogeneity in symptoms across [momelotinib] and [ruxolitinib] arms at baseline,” wrote Mesa and co-authors.

In order to evaluate the discrepancy between MPN-SAF response rates and TSS items, an item analysis and MMRM were applied to the data from SIMPLIFY-1.

The MMRM estimated the treatment effect difference by score change between momelotinib- and ruxolitinib-treated patients with myelofibrosis across the longitudinal 24-week period. Factors analyzed included treatment, time, treatment-by-time interaction, age, race, and baseline TSS. These were included as fixed and random covariates.

The TSS individual item analysis compared baseline measures with health state shift scores at week 24. The 11-point scale measured health states by none (score of 0), mild (1-3), moderate (4-6), severe (7-9), or very severe (10).

Further results revealed that 29 patients in the overall population treated on SIMPLIFY-1 experienced a very much improved symptom burden, followed by much improved (n = 156), minimally improved (n = 108), no change (n = 36), minimally worse (n = 12), and much worse (n = 7).

Treatment effect for the between-treatment group comparison was 1.52 points in the overall population compared with 1.67 points in the symptomatic population based on a 70-point scale.

Additionally, findings from cumulative distribution function curves reported comparable distributions of change from baseline irrespective of treatment in both the overall and symptomatic cohorts. The median numerical change in MPN-SAF TSS from baseline to week 24 was 4.69 points with momelotinib (n = 178) vs 5.36 points with ruxolitinib (n = 196) in the overall population. In the symptomatic population, the median numerical change in MPN-SAF TSS was 8.57 points with momelotinib (n = 123) vs 9.63 points with ruxolitinib (n = 132).

Regarding specific symptoms, no or mild symptoms were reported in 44% to 81% of patients in the overall population. Tiredness was most prevalent and severe at baseline in this patient population, whereas early satiety was mostly mild with a large proportion of patients not reporting baseline itchiness.

“The individual items provide a heterogenous contribution to the baseline TSS value. The distribution of baseline scores in the symptomatic subgroup was consistent with the overall population,” wrote Mesa and co-authors.

Patients receiving momelotinib were more likely to report severe or very severe scores at baseline compared with patients receiving ruxolitinib; however, the proportion of patients who reported severe or very severe symptoms at baseline decreased similarly for both treatment cohorts at week 24. Likewise, the proportion of patients who reported none or mild symptoms increased similarly for both cohorts at week 24.

Specifically, a 20.7% increase was observed in the number of patients receiving momelotinib who reported none/mild tiredness compared with a 17.4% increase in those receiving ruxolitinib. In the symptomatic population, a 31.3% vs 26.4% increase was observed, respectively.

“The magnitude of improvement in [momelotinib] versus [ruxolitinib] was similar for all items in the overall population and symptomatic population,” wrote Mesa and co-authors.

Finally, the likelihood of improvement on individual symptom items appeared to be similar for patients treated with momelotinib vs ruxolitinib in both the overall and symptomatic populations.

“Imbalance in baseline symptom scores in [momelotinib] subjects may have contributed to the inability to demonstrate non inferiority in TSS response rate at week 24. These analyses require further validation in independent data sets on the basis of the modified MPN-SAF,” concluded Mesa and co-authors.

Mesa RA, Hudgens S, Floden L, et al. Beyond a binary endpoint: longitudinal and individual symptom analyses from the SIMPLIFY-1 study demonstrate clinically comparable symptomatic benefit of momelotinib to ruxolitinib in JAK inhibitor naïve myelofibrosis patients. Presented at: Virtual ISPOR 2021; May 17-20, 2021; virtual. Abstract 109778.

Momelotinib can provide clinically relevant and comparable improvement in overall symptom burden and individual symptom items compared with ruxolitinib in patients with intermediate- and high-risk JAK inhibitor–naïve myelofibrosis. 

Symptom Improvement Appears Similar With Momelotinib Vs Ruxolitinib in Myelofibrosis

Week 24 transfusion independence was associated with an improvement in overall survival (OS) vs week 24 transfusion dependence in patients with myelofibrosis who were randomized to momelotinib in the phase 3 SIMPLIFY 1 (NCT01969838) and SIMPLIFY 2 (NCT02101268) trials, according to subgroup analyses from both trials that were presented during the 2021 ASCO Annual Meeting.

In SIMPLIFY 1, week 24 transfusion independent responders randomized to momelotinib had an OS advantage, with a median OS that was not reached and a 3-year OS rate of 80% (HR, 0.30; 

 <.0001) vs a median OS of 3 years and a 3-year OS rate of 50% in momelotinib transfusion independent non-responders.

In SIMPLIFY 2, week 24 transfusion independent responders randomized to momelotinib showed a trend toward improved OS vs momelotinib transfusion independent non-responders (HR, 0.57; 

The comparison between OS from week 24 and OS from randomization demonstrated comparable results.

“In both SIMPLIFY studies, momelotinib transfusion independence in responders showed an advantage in OS,” lead study author Ruben A. Mesa, MD, director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, said in a virtual presentation of the data. “These findings suggest that clinical benefit of transfusion independence may predict for improved OS in myelofibrosis, supporting the clinical relevance of momelotinib’s proerythropoietic inhibition of ACVR1.”

Approximately 60% of patients with myelofibrosis are anemic and 45% require red blood cell transfusions within 1 year of diagnosis, with the majority progressing to transfusion dependency.

Transfusion dependence and anemia are negative prognostic factors in myelofibrosis and confer poor quality of life.

Approved JAK inhibitors provide spleen and symptom improvements but are typically myelosuppressive and do not treat transfusion dependence.

Momelotinib is a potent JAK1/2 and ACVR1/ALK2 inhibitor that is effective against anemia, constitutional symptoms, and splenomegaly in myelofibrosis. Additionally, preclinical and clinical studies support the use of momelotinib as an effective agent against anemia and transfusion dependence through inhibition of ACVR1/ALK2.

Prior data demonstrated that rates of week 24 transfusion independence were higher in the momelotinib arms of SIMPLIFY 1 and SIMPLIFY 2, which compared momelotinib with ruxolitinib (Jakafi) in JAK inhibitor–naïve patients and momelotinib with best available therapy in ruxolitinib pretreated patients, respectively.

Moreover, momelotinib has been shown to provide higher rates of transfusion independence vs ruxolitinib irrespective of the degree of baseline anemia, baseline platelet count, or transfusion status.

To evaluate the relationship between efficacy outcomes and OS, subgroup analyses were performed for patients randomized to momelotinib in SIMPLIFY 1 and SIMPLIFY 2. The subgroups were defined as follows:

Week 24 transfusion independence response: No red blood cell transfusion for at least 12 weeks, with a hemoglobin level of at least 8 g/dL

Week 24 spleen response: At least a 35% reduction in spleen volume vs baseline

Week 24 symptom response: At least a 50% reduction in Myelofibrosis Symptom Assessment Form total symptom score vs baseline

Additional analyses of patients with spleen and symptom response at week 24 in SIMPLIFY 1 indicated that the hazard ratios for spleen and symptoms among responders vs non-responders were 0.59 (

 = .1657), respectively. Although these findings were not statistically significant, they suggest a trend toward improved OS in responders for spleen and symptom response.

Similarly, in SIMPLIFY 2, no statistically significant difference in OS was observed between spleen and symptom responders vs non-responders, with hazard ratios of 2.06 (

“The new subgroup analysis of OS in patients with myelofibrosis randomized to momelotinib suggest patients who are transfusion independent at week 24 have clinically relevant improvement in OS,” concluded Mesa.

Mesa RA, Oh ST, Gerds AT, et al. Association of transfusion independence with improved overall survival in myelofibrosis patients receiving momelotinib. 

. 2021;39(suppl 15):7046. doi:10.1200/JCO.2021.39.15_suppl.7046

Week 24 transfusion independence was associated with an improvement in overall survival vs week 24 transfusion dependence in patients with myelofibrosis who were randomized to momelotinib in the phase 3 SIMPLIFY 1 and SIMPLIFY 2 trials. 

Week 24 Transfusion Independence With Momelotinib Is Associated With Improved OS in Myelofibrosis

Allogeneic hematopoietic cell transplant (allo-HCT) should be considered a standard of care option for patients with high-risk myelofibrosis, according to findings from a systematic review and meta-analysis that were presented during the 

The meta-analysis, which evaluated 8739 patients from 43 studies, demonstrated an overall survival (OS) rate of 66.7% (95% CI, 63.5%-69.8%) at 1 year, 64.4% (95% CI, 57.6%-70.6%) at 2 years, and 55% (95% CI, 51.8%-58.3%) at 5 years among patients who underwent allo-HCT.

The non-relapse mortality (NRM) rate was 25.9% (95% CI, 23.3%-28.7%) at 1 year, 29.7% (95% CI, 24.5%-35.4%) at 2 years, and 30.5% (95% CI, 25.9%-35.5%) at 5 years.

“Given the poor prognosis of patients not receiving transplant and in the absence of curative non-transplant therapies, our results support the consideration of allo-transplant for eligible patients with myelofibrosis,” said lead study author Jan Philipp Bewersdorf, MD, a hospital resident at Yale School of Medicine, in a virtual presentation of the data.

Allo-HCT remains the only curative-intent treatment option available for patients with myelofibrosis. However, many patients are ineligible for transplant or sustain significant transplant-related mortality. As a result, patient selection is critical to minimize the risks associated with allo-HCT, Bewersdorf explained.

Moreover, the efficacy and safety data that surround allo-HCT are mixed and largely attained retrospectively.

The systematic review and meta-analysis was conducted via various databases, including Cochrane Library, Google Scholar, Ovid MEDLINE, Ovid Embase, PubMed, Scopus, and the Web of Science Core Collection from inception to October 11, 2020.

“Databases were searched using a combination of controlled vocabulary and free-text terms for relevant studies on the efficacy and safety of allo-HCT in patients with primary and secondary myelofibrosis,” said Bewersdorf.

Overall, 7595 records were identified through database searching. After removing duplicates, 4247 records were screened. Of these, 3854 records were excluded.

From there, 393 full-text articles were assessed for eligibility. Of these, 350 were excluded for reasons including conference abstracts (n = 217), insufficient reporting of primary outcomes (n = 80), less than 5 myelofibrosis patients included (n = 13), outcomes of myelofibrosis patients not reported (n = 13), no English full-text available (n = 10), outcomes of patients who underwent allo-HCT not reported separately (n = 5), editorials (n = 4), review articles (n = 4), duplicate study analysis (n = 3), and data that were only on post-transplant relapse (n = 1).

As such, 43 studies were included in the quantitative synthesis meta-analysis.

Random-effects models were used to pool response rate data to evaluate the co-primary end points of 1-year, 2-year, and 5-year OS rates. Secondary end points included NRM, relapse-free survival (RFS), and incidence and severity of acute and chronic graft-vs-host disease (GVHD). 

Additionally, the study protocol was registered on PROSPERO (CRD42020188706).

Further results from the analysis revealed that the RFS rate was 65.3% at 1 year, 56.2% at 2 years, and 53.6% at 5 years, Bewersdorf highlighted. 

Additionally, 44% (95% CI, 39.6%-48.4%) of patients who underwent allo-HCT developed some degree of acute GVHD (aGVHD). Grade 3 or 4 aGVHD was observed in 15.2% of patients.

Any-grade chronic GVHD (cGVHD) was observed in 46.5% (95% CI, 42.2%-50.8%) of patients. Extensive or moderate/severe cGVHD was noted in 26.1% of patients.

Notably, no significant difference between conditioning regimen intensity, median patient age, and proportion of Dynamic International Prognostic Scoring System–intermediate-2/high patients with myelofibrosis was observed.

The analysis was limited by the absence of randomized clinical trial data and the retrospective designs in most of the studies included in the review.

“Regarding future research, additional studies are necessary to enhance patient selection—for example, by incorporation of molecular markers to identify high-risk patients that benefit the most from transplant—and to optimize pre- and post-transplant treatment strategies, such as pre-transplant ruxolitinib [Jakafi], conditioning regimens, and donor selection,” concluded Bewersdorf.

Bewersdorf JP, Sheth AH, Vetsa S, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis: a systematic review and meta-analysis. 

. 2021;39(suppl 15):7045. doi:10.1200/JCO.2021.39.15_suppl.7045

Allogeneic hematopoietic cell transplant should be considered a standard of care option for patients with high-risk myelofibrosis, according to findings from a systematic review and meta-analysis.

Allo-Transplant Recommended for Eligible Patients With Myelofibrosis

This publication covers a multitude of presentations in myeloproliferative neoplasms that were presented and discussed during the 2021 ASCO Annual Meeting. 

ASCO 2021: Updates in Myeloproliferative Neoplasms | Supplements and Featured Publications

Transfusion Independence With Momelotinib Confers Benefit Regardless of Baseline Factors in Myelofibrosis

Symptom Improvement Appears Similar With Momelotinib Vs Ruxolitinib in Myelofibrosis

Week 24 Transfusion Independence With Momelotinib Is Associated With Improved OS in Myelofibrosis

Allo-Transplant Recommended for Eligible Patients With Myelofibrosis