Pelabresib/Ruxolitinib Efficacious in JAK Inhibitor–Naïve Myelofibrosis


Overall, 65.9% of patients who received the combination of pelabresib and ruxolitinib demonstrated a 35% or greater reduction in spleen volume by week 24.

Raajit Rampal, MD

Raajit Rampal, MD

More patients with JAK inhibitor–naive myelofibrosis achieved a 35% or greater reduction in spleen volume (SVR35) with pelabresib (CPI-0610) plus ruxolitinib (Jakafi) than with placebo plus ruxolitinib, according to findings from the phase 3 MANIFEST-2 trial (NCT04603495).

Patients in the experimental arm also appeared to experience a better mean absolute total symptom score (TSS), with more patients achieving a TSS reduction by 50% (TSS50) at 24 weeks. The data were presented during the 2023 American Society of Hematology Annual Meeting and Exposition.1

At a median follow-up of 45.4 weeks, the SVR35 response at week 24 was seen in 65.9% of patients who received the combination of pelabresib and ruxolitinib (n = 214) vs 35.2% in those who received placebo/ruxolitinib (n = 216), leading to a 30.4 difference (95% CI, 21.6-39.3; P < .001) in the intention-to-treat (ITT) population, which was statistically significant. The mean percentage change in spleen volume at week 24 was –50.6% (n = 171; 95% CI, –53.2% to –48%) and –30.6% (n = 183; 95% CI, –33.7 to –27.5) with the pelabresib and placebo groups, respectively.

“There were fewer anemia adverse events, a higher rate of hemoglobin response, and fewer patients with transfusion requirements on combination therapy,” lead study author Raajit Rampal, MD, a leukemia specialist of the Leukemia Service at Memorial Sloan Kettering Cancer Center, said in a presentation during the meeting. “Pelabresib in combination with ruxolitinib showed reduction of pro-inflammatory cytokines, and improvement in bone marrow fibrosis and anemia response. As such, we believe these results support a potential paradigm shift in the treatment of patients with myelofibrosis.”

JAK inhibitors are the current standard of care in patients with intermediate- and high-risk myelofibrosis. However, there is an unmet need to improve the depth and durability of responses with therapy, as well as treatment-emergent adverse effects (TEAEs).

Pelabresib is an investigational, oral, small-molecule BET inhibitor that can also decrease BET-mediated gene expression involved in myelofibrosis pathogenesis.

In the international, double-blind, active-control, phase 3 MANIFEST-2 study, investigators evaluated the efficacy and safety of pelabresib in combination with ruxolitinib in 430 JAK inhibitor-naive patients with myelofibrosis.

To be eligible for enrollment, patients needed to have either primary myelofibrosis or post-essential thrombocytopenia/polycythemia vera myelofibrosis and must have not received prior treatment with a JAK inhibitor. They also needed to have a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1 or higher, splenomegaly of at least 450 cm3, and a TSS of 10 or greater (≥3 for 2 symptoms, Myelofibrosis Symptom Assessment Form version 4.0).

Patients were randomized 1:1 to receive oral pelabresib at 125 mg daily on days 1 to 14 plus ruxolitinib at a starting dose of 10 mg or 15 mg twice daily on days 1 to 21 (n = 214) or placebo plus ruxolitinib (n = 216) in 21-day cycles.

“Now, importantly, this is 5 mg [twice daily] below the label’s starting dose,” Rampal noted. “However, dose escalation of ruxolitinib was required for protocol after cycle 1, provided patients met certain hematologic parameters.”

Stratification factors included DIPSS risk category (intermediate-1 vs intermediate-2 vs high), platelet count (>200 x 109/L vs 100-200 x 109/L), and spleen volume (≥1800 cm3 vs <1800 cm3).

The primary end point was SVR35 at week 24. Key secondary end points were TSS absolute change from baseline at week 24, TSS50 at week 24, and all-grade and serious adverse effects (AEs).

The data cutoff date was August 31, 2023. A total 27.1% and 25.0% of patients on pelabresib/ruxolitinib vs ruxolitinib alone discontinued double-blind treatment due to AEs (10.7% vs 6.5%, respectively), physician decision (4.2% vs 9.3%), disease progression (2.3% vs 2.3%), eligibility for transplant (3.7% vs 4.2%), and other (6.0% vs 2.8%). Double-blind treatment was ongoing in 72.0% and 74.1% of patients, respectively.

The mean daily dose of pelabresib was 108 mg and was 29.3 mg for ruxolitinib.

Regarding baseline characteristics, the median age across both arms was 66 years (range, 19-88), and more than half of patients were male (58.4%); most patients were White (75.2%), and half (50.5%) had primary myelofibrosis. Nearly 60% (59.3%) had intermediate-1 DIPSS disease, followed by intermediate-2 (34.7%), and high-risk (6.0%). The median hemoglobin was 11.0 g/dL (5.8-18.0), and 34.0% of patients had a hemoglobin 10 g/dL or lower.

Additionally, the median platelet count was 286 x 109/L (66 x 109/L to 1303 x 109/L) and 72.4% of patients had platelet counts above 200 x 109/L. Sixteen percent of patients on pelabresib required red blood cell (RBC) transfusions at baseline vs 12% of those on the ruxolitinib/placebo arm. The median spleen volume was 1308.89 (range, 200.24-7117.03) with pelabresib/ruxolitinib compared with 1382.97 (range, 277.87-5540.45); the median TSS was 26.6 (range, 7.3-66.4) and 24.7 (range, 9.0-68.4), respectively.

Further efficacy data showed that the absolute TSS at week 24 was numerically improved with pelabresib/ruxolitinib at –15.99 compared with –14.05 with placebo/ruxolitinib, with a mean difference of –1.94 (95% CI, –3.92 to 0.04; P = .0545). Pelabresib/ruxolitinib also showed a numerically greater TSS50 response at week 24 at 52.3% compared with 46.3% with placebo/ruxolitinib, translating to a 6.0 difference (95% CI, –3.5 to 15.5; P = .0216). Symptoms included were fullness after eating (–47.46% with pelabresib vs –31.05% with placebo), bone pain (–39.51% vs –35.20%), pain under left rib (–53.27% vs –45.18%), abdominal discomfort (–43.19% vs –36.31%), itching (–56.48% vs –41.37%), night sweats (–52.27% vs –50.45%), and fatigue (–38.55% vs –34.90%).

There was a two-fold increase in patients achieving both SVR35 and TSS50 with pelabresib/ruxolitinib at 40.2% compared with 18.5% with placebo/ruxolitinib.

SVR35 response at week 24 was also consistently higher with pelabresib/ruxolitinib vs placebo/ruxolitinib across all predefined subgroups, including DIPSS intermediate-1 risk (72.7% vs 37.8%), DIPSS intermediate-2 risk (54.7% vs 33.8%), DIPSS high risk (63.6% vs 20.0%), primary myelofibrosis (65.4% vs 32.7%), post-polycythemia vera myelofibrosis (77.8% vs 41.5%), post-essential thrombocytopenia myelofibrosis (58.1% vs 34.0%), and baseline spleen volume (≥1800 cm3, 71.7% vs 32.2%; <1800 cm3, 64.0% vs 36.3%).

There was a similar improvement in regard to TSS across most subgroups with pelabresib/ruxolitinib vs placebo/ruxolitinib. TSS changes from baseline were reported with DIPSS intermediate-1 risk (15.44 vs 13.44), DIPSS intermediate-2 risk (17.53 vs 11.91), DIPSS high risk (12.50 vs 16.96), primary myelofibrosis (15.79 vs 12.99), post-polycythemia vera myelofibrosis (18.88 vs 15.68), post-essential thrombocytopenia myelofibrosis (13.98 vs 10.75), and baseline spleen volume (≥1800 cm3, 15.65 vs 16.13; <1800 cm3, 16.09 vs 12.13).

Across baseline hematologic subgroups, the SVR response was also improved with pelabresib/ruxolitinib, as seen with hemoglobin greater than 10 g/dL (70.1%) vs placebo/ruxolitinib (34.3%), hemoglobin 10 g/dL or lower (57.1% vs 36.8%, respectively), platelet count greater than 200 x 109/L (70.8% vs 40.1%), and platelet count between 100 and 200 x 109/L (53.3% vs 22.0%).

Absolute change in TSS was also improved with pelabresib/ruxolitinib vs placebo/ruxolitinib in these hematologic subgroups, with hemoglobin greater than 10 g/dL (16.04 vs 13.57), hemoglobin 10 g/dL or lower (15.86 vs 12.40), platelet counts greater than 200 x 109/L (15.40 vs 13.42), and platelet count between 100 and 200 x 109/L (17.77 vs 12.44).

Rampal noted that at approximately 9 weeks, there was a separation in curves regarding hemoglobin response. In the pelabresib/ruxolitinib arm, the hemoglobin response at 1.5 g/dL or greater mean increase was 9.3% (95% CI, 5.45%-13.25%) compared with 5.6% (95% CI, 2.50%-8.61%) with placebo/ruxolitinib. A total 16.4% and 11.6% of patients in each arm, respectively, required RBC transfusions during screening; 30.8% and 41.2% of patients, respectively, required RBC transfusions during the first 24 weeks of study therapy.

Investigators also explored the impact of treatment on bone marrow fibrosis and inflammatory cytokines. Reticulin fibrosis was worsened by 1 grade or more in 16.3% of patients on pelabresib vs 28.3% of those on placebo (OR, 0.47; 95% CI, 0.23-0.92); moreover, it was improved by at least 1 grade in 38.5% and 24.2% of patients, respectively (OR, 2.09; 95% CI, 1.14-3.93). By week 24, inflammatory cytokines were reduced in NFkB – set in 33.1% and 19.1% of pelabresib- and placebo-treated patients, respectively; in interleukin (IL-6), IL-8, and TNF alpha, these mean reduction rates were 35.5% vs 10.9%, 8.8% vs –35.3%, and 42.4% vs 23.6%, respectively.

Regarding safety, the pelabresib/ruxolitinib combination was consistent with observations from prior clinical studies. Any-grade and grade 3 or higher TEAEs occurred in 96.7% and 49.1% of pelabresib-treated patients compared with 97.2% and 57.5% of placebo-treated patients. The incidence of serious AEs was similar in both arms at 29.7% and 29.4%, respectively. Discontinuation rates from TEAEs with pelabresib/placebo were 12.3% and 7.9%; these were 9.9% and 6.5% for discontinuations associated with ruxolitinib.

TEAE dose reductions linked with pelabresib occurred in 32.5% of patients compared with 29% for those on placebo; dose reductions with ruxolitinib occurred in 47.6% and 41.6% of patients, respectively. Pelabresib or placebo interruptions were reported in 32.1% and 22.9% of patients, respectively. Ruxolitinib interruptions took place in 23.1% and 16.4% of those on pelabresib and placebo, respectively. There were 2.4% deaths from TEAEs on the pelabresib arm vs 2.8% deaths on the placebo arm.

Any-grade TEAEs that occurred in at least 10% of patients with pelabresib/ruxolitinib and placebo/ruxolitinib, respectively, were anemia (43.9% vs 55.6%), thrombocytopenia (32.1% vs 23.4%), decreased platelet count (20.8% vs 15.9%), diarrhea (23.1% vs 18.7%), dysgeusia (18.4% vs 3.7%), constipation (18.4% vs 24.3%), nausea (14.2% vs 15.0%), cough (12.7% vs 11.2%), asthenia (11.8% vs 13.6%), fatigue (11.8% vs 16.8%), dizziness (11.3% vs 8.3%), headache (11.3% vs 10.7%), COVID-19 (11.3% vs 15.9%), and dyspnea (0.5% vs 13.1%).

Grade 3 or higher TEAEs reported in the pelabresib arm were anemia (23.1%), thrombocytopenia (9.0%), decreased platelet count (4.2%), and diarrhea, dysgeusia, nausea, asthenia, fatigue, headache, and dyspnea (0.5% each). In the placebo/ruxolitinib arm, grade 3 or higher TEAEs included anemia (36.4%), thrombocytopenia (5.6%), COVID-19 (1.9%), diarrhea (1.4%), and decreased platelet count, fatigue, and dyspnea (0.9% each).

Editor’s Note: Dr Rampal cited the following disclosures: research funding from Zentalis, Constellation, Ryvu, Incyte, and Stemline; consultancy from Celgene-BMS, Kartos, Dainippon, Karyopharm, CTI BioPharm Corp, Galecto, Morphosys, Sumitomo, Pharmaessentia, Servier, GSK-Sierra, Zentalis, Incyte


Rampal R, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus Kinase Inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141

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