Ruxolitinib Combinations in MPNs: Updates From ASH

Following its approval in 2011 for myelofibrosis (MF), ruxolitinib (Jakafi, Incyte) became the backbone of treatment for MF and later for polycythemia vera (PV), 2 of the 3 common myeloproliferative neoplasms (MPNs).

But although ruxolitinib improves survival outcomes and quality of life, some patients may not respond to therapy, while others may stop due to genetic mutations, disease progression, or other factors. For years now, investigators have been studying the Janus kinase (JAK) inhibitor in combination with other drugs, both in first-line treatment and refractory disease. Abstracts and oral presentations at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, offered updates on several combinations in the pipeline:

MANIFEST-2. Previous results from this phase 3 study (NCT04603495) of pelabresib, a selective bromodoman and extraterminal domain (BET) inhibitor, with ruxolitinib show it met its primary end point; in patients with MF

Jakafi packaging | Image credit: Incyte

not treated with a JAK inhibitor, a statistically significant higher proportion showed at least 35% reduction in spleen volume from baseline at week 24 with the combination vs ruxolitinib and placebo. Results presented at ASH showed those results were maintained after a median follow-up of 72 weeks, with a 48-week response rate of 57.0% for the combination vs 37.5% for ruxolitinib and placebo. An improvement in the Myelofibrosis Symptom Assessment Form total symptom score (TSS) by at least 50% was seen in 45.3% of patients receiving the combination vs 39.4% in the placebo group.¹

Bomedemstat. An abstract at ASH reported on an ongoing phase 2 study (NCT05569538) involving bomedemstat combined with ruxolitinib in patients with advanced MF.² Bomedemstat is an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), which plays a role in gene regulation; blocking this enzyme alters cell differentiation and growth. In August 2024, Merck announced the second phase 3 trial of bomedemastat in another MPN, essential thrombocythemia (ET).

The abstract authors noted that about 50% of patients with MF stop ruxolitinib after 3 years, mostly due to disease progression or cytopenia; median OS after discontinuation is 14 months.² LSD1, they write, is “critical for self-renewal” of cancerous stem cells, and has shown promise as a single agent. This study reported on 2 cohorts: Cohort A had a suboptimal response to ruxolitinib, and cohort B patients had MF and were treatment naive. Patients in cohort A remained on the entry dose of ruxolitinib while cohort B started 10 mg twice per day; all patients received a starting dose of 0.4 mg/kg/day of bomedemstat. Dose adjustments were permitted every 4 weeks to achieve an optimal platelet count; downward titrations were done at any time for safety reasons. After a median of 61.7 weeks, in 40 evaluable patients, at week 24, 11 patients had at least a 50% improvement in TSS, with 25.9% in cohort A and 30.7% in cohort B; 17.5% had at least 35% spleen volume reduction, with 7.4% in cohort A and 38.5% in cohort B; and 50% of patients had stable or improved hemoglobin (51.9% in cohort A and 46.3% in cohort B). There were no safety signals or deaths related to the drug, the authors said.²

RESTORE. Data from the ongoing phase 2 RESTORE trial involving elritercept (NCT05037760), with and without ruxolitinib, continued to demonstrate that the investigational therapy showed benefits in spleen volume reduction, improved TSS, and “can potentially ameliorate ineffective hematopoiesis and address cytopenias” in patients with MF, according to a statement from Keros Therapeutics, which is developing the drug.

Elritercept, which is also being studied in myelodysplastic syndromes (MDS), is described by Keros as “an engineered ligand trap” featuring “a modified ligand-binding domain of the [transforming growth factor]-ß receptor known as activin receptor type IIA that is fused to the portion of the human antibody known as the Fc domain.” A recent study in Blood stated that in preclinical studies, a research form of elritercept increased red blood cells and platelet production in healthy and diseased mouse models, supporting additional studies.

According to Keros, this ongoing, open-label, 2-part trial is evaluating elritercept administered with or without ruxolitinib in patients with MF who have anemia and were either already receiving, failed, or ineligible for ruxolitinib at baseline. Study authors presented safety data for 73 patients who received at least 1 dose of elritercept as of the August 30, 2024, data cutoff date, and efficacy data for evaluable patients.^3,4 Data presented included evaluations of markers of hematopoiesis and anemia over 12 weeks, along with measurements of spleen volume and TSS scores over 24 weeks for dose levels 1 through 4, which ranged from 0.75 mg/kg to 5.0 mg/kg. A second part, the dose expansion portion, is now enrolling.

Increases in hemoglobin were seen in 82.8% of evaluable non–transfusion-dependent patients in both arms over a 12-week period in the first 24 weeks, which Keros officials said suggested the potential of a new option to address anemia. Spleen volume was reduced in 40% with 3 having reductions of at least 35%. Five patients had a reduction of at least 50% in their TSS score; 3 in the monotherapy arm and 2 in the combination arm. There were 6 cases of treatment-emergent adverse events deemed unrelated to treatment; the most common adverse events were thrombocytopenia and diarrhea.

Just before ASH 2024, Keros Therapeutics announced a licensing agreement with Takeda.

References

1. Mascaraenhas JO, Grosicki S, Chraniuk D, et al. Updated results from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for Janus kinase inhibitor–naïve patients with myelofibrosis. Presented at: 66th American Society of Hematology Meeting and Exhibition, December 7-10, 2024; San Diego, CA. Abstract 3178.
2. Gill H, Au L, Tsai D, et al. Bomedemstat (MK3543) in combination with ruxolitinib in patients with advanced myelofibrosis. Presented at: 66th American Society of Hematology Meeting and Exhibition, December 7-10, 2024; San Diego, CA. Abstract 1796
3. Keros Therapeutics presents clinical data from its elritercept program at the 66th American Society of Hematology Annual Meeting and Exposition. News release. Keros Therapeutics. December 10, 2024. Accessed January 8, 2024. https://www.globenewswire.com/news-release/2024/12/10/2994148/0/en/Keros-Therapeutics-Presents-Clinical-Data-from-its-Elritercept-Program-at-the-66th-American-Society-of-Hematology-Annual-Meeting-and-Exposition.html
4. Harrison C, Chee LCY, Devos T, et al. Hematological improvement and other clinical benefits of elritercept as monotherapy and in combination with ruxolitinib in participants with myelofibrosis from the ongoing phase 2 RESTORE trial. Presented at: 66th American Society of Hematology Meeting and Exhibition, December 7-10, 2024; San Diego, CA. Abstract 997.