Pelabresib-ruxolitinib combination reduces spleen volume, symptom score in myelofibrosis
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Pelabresib plus ruxolitinib conferred benefit to Janus kinase inhibitor-naive patients with myelofibrosis, according to study results presented at ASH Annual Meeting and Exhibition.
The combination of pelabresib (CPI-0610, MorphoSys) and ruxolitinib (Jakafi, Incyte) led to durable improvements in spleen volume, bone marrow fibrosis and total symptom score, findings of the phase 2 MANIFEST study showed.
The regimen also appeared generally well-tolerated, according to investigators.
Background
The JAK inhibitor ruxolitinib is standard treatment for myelofibrosis.
However, the depth and durability of responses are limited. In addition, a considerable percentage of patients do not achieve two key efficacy thresholds — at least 35% reduction in spleen volume and at least 50% reduction in total symptom score from baseline — with ruxolitinib monotherapy, according to study background.
Pelabresib — an oral investigational bromodomain and extraterminal domain (BET) inhibitor — downregulates nuclear factor-kappa B signaling and other relevant genes involved in myelofibrosis disease pathways.
The ongoing phase 2 MANIFEST study is evaluating pelabresib as monotherapy and in combination with ruxolitinib for treatment of myelofibrosis.
At ASH, John O. Mascarenhas, MD — professor of medicine at Icahn School of Medicine at Mount Sinai, as well as director of the institution’s Center of Excellence for Blood Cancers and Myeloid Disorders — presented results from Arm 3 of the study, which assessed pelabresib and ruxolitinib for JAK inhibitor-naive patients with myelofibrosis.
Methodology
Eighty-four patients (median age, 67 years) received at least one dose of pelabresib (125 mg daily on days 1-14 of each 21-day cycle) and ruxolitinib dosed by baseline platelet count (median, 10 mg twice daily; range, 5-25).
About one-quarter (23%) had Dynamic International Prognostic Scoring System intermediate-1 disease, 62% had intermediate-2 disease and 16% had high-risk disease.
A 35% or greater spleen volume reduction after 24 weeks served as the primary endpoint. Secondary endpoints included a 50% or greater reduction in total symptom score, duration of splenic response, pharmacokinetics and safety. Transfusion independence and changes in bone marrow fibrosis from baseline served as exploratory endpoints.
Investigators used CT or MRI to assess spleen volume every 12 weeks. They used Myelofibrosis Symptom Assessment Form v4.0 to assess total symptom score, and they performed biopsies at week 24 and week 28 to evaluate bone marrow fibrosis.
Results
At data cutoff, 35 patients remained on treatment and 49 had discontinued. The most common reasons for discontinuation included adverse events or lab abnormality (8%), consent withdraw (8%), primary investigator decision (8%) or progressive disease (7%).
More than two-thirds (68%) of patients achieved at least a 35% reduction in spleen volume by week 24 (median change at week 24, – 50%; range, – 84.4 to 27.9).
More than half (61%) maintained that outcome by week 48 and 54% maintained that outcome at week 60.
Median time to 35% reduction in spleen volume was 12 weeks (range, 10-51).
More than half (56%) of patients achieved at least a 50% reduction in total symptom score by week 24 (median change at week 24, – 59%; range, – 100 to 225), 44% maintained this outcome by week 48, and 43% maintained this outcome at week 60.
Analyses of total symptom score change over time indicated sustained reduction in symptom burden, according to investigators.
More than one-quarter (27%) of evaluable patients achieved at least a one-grade improvement in bone marrow fibrosis by week 24 per central pathology review, and more than half (59%) maintained the improvement at the next available assessment, performed at week 48 or beyond. Forty percent achieved at least a one-grade improvement in bone marrow fibrosis at any time.
Thirty-eight percent of patients achieved at least 20% reduction in JAK2 V617F variant allele frequency (median reduction, – 14%).
Thrombocytopenia represented the most common hematologic treatment-emergent adverse event (any grade, 55%; grade 3, 18%). Anemia occurred among 43% of patients (grade 3, 34%).
Researchers reported three cases each of pyrexia and COVID-19, as well as two cases each of gastrointestinal hemorrhage, multiple organ dysfunction syndrome, COVID-19 pneumonia, pneumonia, respiratory tract infection, urinary tract infection, fall and respiratory failure.
Seven patients experienced a combined eight grade 5 treatment-emergent adverse events. These included acute respiratory distress syndrome due to ruxolitinib withdrawal, multiorgan failure due to COVID-19, multiorgan failure due to sepsis secondary to pneumonia, and respiratory failure due to COVID-19, bacterial endocarditis and urinary tract infection. Researchers determined all grade 5 events to be unrelated to pelabresib with the exception of the case of multiorgan failure due to sepsis secondary to pneumonia.
Twelve patients (14%) reported treatment-emergent adverse events that led to pelabresib discontinuation.
The randomized phase 3 MANIFEST-2 study will further evaluate the efficacy and safety of the pelabresib-ruxolitinib combination for JAK inhibitor-naive patients with myelofibrosis. Enrollment is underway for the double-blind, active-controlled study.
Perspective
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Myeloproliferative diseases are difficult to control, particularly when they reach an advanced stage like myelofibrosis. At that point, data show 50% of patients will survive somewhere in the 1- to 4-year window. That's an emergency, so getting better therapies for myelofibrosis is important.
Ruxolitinib is widely used to control the disease, but it's really for relief of symptoms and reduction in spleen size. That has been the basis of approval.
That said, it still does not clear the disease, so pelabresib is an important contribution to further control myelofibrosis with a second targeted approach. This particular abstract using it in combination with ruxolitinib looks promising. We're already seeing the percentage of patients who have reduction in spleen size greater than 35% appears to be higher when ruxolitinib and pelabresib are combined.
Learning how to use these drugs in combination to achieve further reduction in spleen size and hopefully symptom relief will be important on the road to hopefully better control of myelofibrosis.
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Mascarenhas J, et al. Abstract 238. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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