Pelabresib/Ruxolitinib Combo Betters Splenomegaly, TSS in JAK Inhibitor-Naive MF


Pelabresib plus ruxolitinib demonstrated a 35% or greater reduction in spleen volume and trended toward reducing mean absolute total symptom score (TSS) as well as improving TSS reduction by 50% at 24 weeks in patients with JAK inhibitor-naive myelofibrosis.

Red blood cells flowing realistic 3d rendering: © Kodjovi -

Red blood cells flowing realistic 3d rendering: © Kodjovi -

Pelabresib (CPI-0610) combined with ruxolitinib (Jakafi) showed a 35% or greater reduction in spleen volume (SVR35) and trended toward lowering mean absolute total symptom score (TSS) as well as improving TSS reduction by 50% (TSS50) at 24 weeks in patients with JAK inhibitor-naive myelofibrosis, meeting the primary end point of the phase 3 MANIFEST-2 trial (NCT04603495). The data were presented during the 2023 ASH Annual Meeting.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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