Pelabresib Provides Clinical Benefit in Patients with Myelofibrosis Ineligible or Intolerant to Ruxolitinib Therapy

As a result of suboptimal response after chronic therapy with JAK inhibitors, a large proportion of patients with myelofibrosis (MF) terminate ruxolitinib (RUX) therapy. Nuclear factor kappa B (NFκB) signaling contributes to development and progression of MF. Pelabresib, a first-in-class, selective inhibitor of bromodomain and extraterminal domain proteins, directly impacts the function of NFκB. The primary goal of the MANIFEST phase 2 clinical study is to evaluate pelabresib monotherapy in patients with advanced MF who are ineligible for or refractory to treatment with JAK inhibitors.

To date, a total of 86 patients have been enrolled in arm 1 of MANIFEST as red blood cell (RBC) transfusion-dependent (TD; n = 36, defined as requiring ≥2 units of RBCs per month over 12 weeks; enrollment ongoing). If patients did not meet TD criteria and spleen volume was ≥450 mL, they were assigned to the non-TD (n = 50, enrollment complete) group. Median treatment duration in the TD group was 32 (range, 5-78) weeks and 51 (range, 2-147) weeks. The primary end point in the TD cohort is RBC transfusion-independence (TI), defined as 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 TI for ≥12 weeks with median time to conversion to TI status of 31 weeks and median duration of 41 weeks (range, 31-53 weeks). At week 24, 18% (7/38) of evaluable non-TD patients achieved SVR35 (median change, –29%). Together, 11% of TD plus non-TD patients (n = 64) reached SVR35. Secondary end points included safety and number of patients with at least 50% total symptom score reduction (TSS50) as defined by Myelofibrosis Symptom Assessment Form v4.0 at week 24, of which 28% (18/64) of TD plus non-TD patients 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 effects were nausea (33%; no grade ≥3), diarrhea (34%; grade ≥3, 6%), constipation (21%; grade ≥3, 1%), 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), and constipation (21%; grade ≥3, 1%). Although 19% of patients discontinued pelabresib, there were no treatment-related deaths.

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 the serum levels of 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 had relatively lower baseline values and less profound decreases over time and were more pronounced in patients who had not been previously treated with RUX due to ineligibility.

Clinical benefits observed with pelabresib included achievement of SVR35 and TSS50, improvements in bone marrow fibrosis, and TI. Pelabresib monotherapy was observed to be safe and effective with clinical improvement in patients ineligible for or intolerant to RUX therapy.

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.

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