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

Supplements And Featured Publications, ASCO 2021: Updates in Myeloproliferative Neoplasms, Volume 1, Issue 1

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.

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.1,2

Additionally, data suggest that a momelotinib-associated, transfusion-independent response at week 24 is associated with a survival advantage in this patient population.1-3

“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.2

“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.3

“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.

References

  1. 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. J Clin Oncol. 2021;39(suppl 15):e19039. doi:10.1200/JCO.2021.39.15_suppl.e19039
  2. 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.
  3. Mesa RA, Hudgens S, Floden L, et al. Longitudinal and individual symptom analyses of momelotinib and ruxolitinib treated myelofibrosis patients from SIMPLIFY-1. J Clin Oncol. 2021;39(suppl 15):e19040. doi:10.1200/JCO.2021.39.15_suppl.e19040
  4. 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. J Clin Oncol. 2021;39:3844-3850. doi:10.1200/JCO.2017.73.4418