KEY TAKEAWAYS
- The phase 2 MANIFEST study aimed to evaluate the efficacy and safety of pelabresib as an add-on therapy to ruxolitinib (RUX) in patients with myelofibrosis (MF) who have suboptimal or lost response to RUX.
- At week 24, 17% of patients achieved a 35% reduction in spleen volume (SVR35), and this response was reported at any time in 31% of cases.
- In patients with suboptimal or lost response to RUX monotherapy, adding PELA resulted in durable and deepening splenic and symptom responses.
Myelofibrosis (MF) is distinguished by fibrosis of the bone marrow (BM), splenomegaly, and cytopenias. Progressive BM fibrosis is caused by abnormal megakaryopoiesis and proinflammatory cytokine expression, regulated by BET protein-mediated gene expression.
Janus kinase inhibitors (JAKIs) like ruxolitinib (RUX) are the current standard of care for myelofibrosis (MF). However, an unmet need persists due to the limited profundity and durability of JAKi monotherapy responses, high discontinuation rates, and toxicity (Tefferi A. Am J Hematol 2021;96(1):145–162). Pelabresib (CPI-0610; PELA) is an investigational, oral, small-molecule BET inhibitor that inhibits NF-B signaling and other genes implicated in MF disease pathways. In the ongoing, open-label Phase 2 MANIFEST study(NCT02158858), PELA is being evaluated as a monotherapy and in combination with RUX in patients with MF. To present updated results from Arm 2 of the MANIFEST study regarding the efficacy and safety of PELA as an ‘add-on’ to ongoing RUX in patients with suboptimal or lost response to RUX.
Patients received oral PELA 125 mg QD in 21-day cycles with continuous oral RUX (at screening dose). Patients in Arm 2 are stratified according to whether they require transfusions. The primary endpoints are conversion from transfusion dependence (TD) to transfusion independence (TI) in the TD cohort and a 35% reduction in spleen volume relative to baseline (BL; SVR35) at week 24 in the non-TD cohort. Secondary endpoints include a 50% reduction in total symptom score from baseline (TSS50) as measured by the MF Symptom Assessment Form v4.0 at week 24. Researchers evaluated the durability of responses, Hb changes, BM biopsies, and safety. At the data cutoff (29 July 2022), 87 pts (TD cohort = 58; non-TD cohort = 29) received PELA as an add-on to RUX (TD cohort = 58; non-TD cohort = 29). Mean (SD) age was 68 (9) years; 8%, 63%, and 29% of patients, respectively, were DIPSS Int-1, Int-2, or high risk. Patients who did not reach Week 24 were considered nonresponders for the SVR35 and TSS50. The median duration of PELA treatment was 13.0 (range: 0.25–65.4) months. About 17% (15/86) of evaluable patients had SVR35 at week 24. SVR35 was reported at any time in 31% (27/86) of cases. At Wk 24, 26% (22/86) of patients had a spleen volume less than 25% of BL. At week 48, 21% (18/86) and at week 60, 19% (16/86) of patients had SVR35 response. At 24, the median spleen volume reduction was -17%. The conversion rate from TD to TI was 36.8% (14/38). The mean duration of TI was 37 weeks (range: 15–192). 7/29 patients in the non-TD cohort had a Hb response (mean Hb increase of 1.5 g/dL from baseline without transfusions over 12 weeks).
At week 24, TSS50 was 38% (32/85) overall. At any point, 55% (47/85) of pts had TSS50. At week 24, the median TSS reduction was 48%. By central pathology review, 26% of patients with BM fibrosis improved by 1 grade after 24 weeks; 54% maintained the improvement at the next available assessment or longer, and 35% had 1-grade improvement at any time (optimal response). The two most prevalent hematologic TEAEs of any grade were thrombocytopenia (54%) and anemia (30%). About 30% of patients reported TEAEs that led to PELA discontinuation. Anemia (7 patients) and pneumonia (6 patients) were the most common serious adverse events (AEs) affecting 3 patients. In patients with a suboptimal or lost response to RUX monotherapy, treatment with PELA as an add-on to RUX resulted in durable and deepening splenic and symptom responses and was generally well tolerated. Transfusion independence was attained in 36.8% of patients, and improvement in BM fibrosis, a marker of disease modification, was noted in 35% of patients.
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02158858
Marina Kremyanskaya, Claire Harrison, Prithviraj Bose, Vikas Gupta, Raajit K Rampal, Jonathan Lambert, Moshe Talpaz, Alessandro Vannucchi, Andrew Kuykendall, Jean-Jacques Kiladjian, Srdan Verstovsek, Ruben Mesa, Gozde Colak, Sandra Klein, Carmelita Alvero, John Mascarenhas/ UPDATED RESULTS FROM MANIFEST ARM 2: EFFICACY AND SAFETY OF PELABRESIB (CPI-0610) AS ADD-ON TO RUXOLITINIB IN MYELOFIBROSIS/Inc, M. G. (n.d.). UPDATED RESULTS FROM MANIFEST ARM 2: EFFICACY AND SAFETY OF… by Marina Kremyanskaya. Library.ehaweb.org. Retrieved July 15, 2023, from https://library.ehaweb.org/eha/2023/eha2023-congress/385468/marina.kremyanskaya.updated.results.from.manifest.arm.2.efficacy.and.safety.of.html?f=menu%3D16%2Abrowseby%3D8%2Asortby%3D2%2Ace_id%3D2489%2Aot_id%3D27888%2Atrend%3D4016%2Amarker%3D4178
