Patients who discontinue ruxolitinib (RUX) have poor prognoses and limited alternative therapeutic options. Evidence suggests abnormal nuclear factor kappa B (NFκB) signaling contributes to myelofibrosis (MF). Pelabresib is a potent oral, first-in-class, selective inhibitor of bromodomain and extraterminal domain proteins that can modify the expression of genes involved in NFκB signaling. MANIFEST is an open-label, phase 2 study currently investigating pelabresib monotherapy in patients with advanced MF who are ineligible for or refractory to treatment with RUX or other JAK inhibitors.
To date, a total of 86 patients have been enrolled as either red blood cell (RBC) transfusion-dependent (TD: n = 36; enrollment ongoing), requiring ≥2 units of RBCs per month over 12 weeks, or non-TD (n = 50, enrollment complete) if TD criteria were not met and spleen volume was ≥450 cc. Median treatment duration in the TD group was 32 weeks (range, 5-78 weeks); in the non-TD group, median treatment duration was 51 weeks (range, 2-147 weeks). The primary end point in the TD cohort is RBC transfusion-independence (no transfusion for ≥12 weeks), and in the non-TD cohort, ≥35% spleen volume reduction (SVR35) at week 24. In the TD cohort, 16% (4/25) of evaluable patients achieved RBC transfusion independence for ≥12 weeks. At week 24, 18% (7/38) of evaluable non-TD patients achieved SVR35 (median change: –29%). Among both TD and non-TD patients (n = 64), 11% reached SVR35.
Secondary end points included safety and number of patients with ≥50% total symptom score reduction (TSS50) as defined by Myelofibrosis Symptom Assessment Form v4.0 at week 24, of which 28% (18/64) of all patients (TD and non-TD) achieved TSS50 (median change: –40%). All patients were evaluated for safety during pelabresib treatment. Patients experienced both treatment-induced hematologic and nonhematologic side effects. The most common hematologic events were thrombocytopenia (33% all grades; grade ≥3, 23%) and anemia (24% all grades; grade ≥3, 15%). The most common (≥20%) nonhematologic events were nausea (33%; no grade ≥3), diarrhea (34%; grade ≥3, 6%), altered taste sensation (23%, no grade ≥3), physical weakness (33%; no grade ≥3), respiratory tract infections (23%; grade ≥3, 5%), cough (26%; no grade ≥3), constipation (21%, grade ≥3, 1%), and weight decrease (22%; grade ≥3, 2%). There were no treatment-related deaths among patients who discontinued pelabresib therapy (19%).
Additional end points of interest included changes in levels of proinflammatory cytokines and bone marrow morphology/fibrosis. Plasma samples were evaluated at baseline and during therapy for cytokines that are known to be elevated in patients with MF, as well as those associated with NFκB signaling. Overall, pelabresib significantly reduced plasma levels of several cytokines in patients treated with or without RUX. Changes in cytokines IL-6, CRP, RANTES, TNF-alpha, and IL-18 with pelabresib treatment are characterized by higher baseline values and greater decreases over time. Cytokines EPO, TARC, ICAM1, and IL-8 are characterized by relatively lower baseline values and less profound decreases over time and were more pronounced in patients who had not been previously treated with RUX.
These analyses demonstrate evidence of safety and clinical activity of pelabresib in a subset of patients who are ineligible for or intolerant to RUX therapy. Clinical benefits observed with pelabresib included achievement of SVR35 and TSS50, improvements in bone marrow fibrosis, and transfusion independence. As clinical development continues, investigators anticipate providing additional 24-week data with a larger cohort and new long-term data at 48 weeks.
Source
- Kremyanskaya M, Mascarenhas J, Palan F, et al. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing MANIFEST trial. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 141.