Pelabresib/Ruxolitinib Combo Demonstrates Promising Clinical Efficacy in Myelofibrosis

The combination of pelabresib and ruxolitinib produced responses that proved to be durable beyond week 24 in patients with myelofibrosis who experienced a suboptimal response to ruxolitinib and in those who were JAK inhibitor naïve.

The combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) produced responses that proved to be durable beyond week 24 in patients with myelofibrosis who experienced a suboptimal response to ruxolitinib and in those who were JAK inhibitor naïve, according to preliminary data from arms 2 and 3 of the phase 2 MANIFEST trial (NCT02158858).

Findings, which were presented during the 2022 EHA Congress, showed that 68% (95% CI, 57%-78%) of patients with JAK inhibitor–naïve myelofibrosis (n = 84; arm 3) experienced a reduction in spleen volume of at least 35% (SVR35) at week 24 with the combination. Eighty percent of patients achieved this at any point in the study (range, 10-51), and 69% of those with SVR35 maintained response at the time of data cutoff, which was September 10, 2021.

Moreover, 56% (95% CI, 45%-67%) of patients in this arm experienced a 50% or greater reduction in total symptom score (TSS) from baseline at week 24, resulting in a median TSS change of -59% at this time point.

In patients with myelofibrosis who had previously experienced a suboptimal response to ruxolitinib (n = 81; arm 2), 20% experienced SVR35 at week 24; this was observed in 17% of those who were transfusion dependent (TD) and 26% of those who were non–transfusion dependent (NTD). Additionally, 30% of patients achieved SVR35 at any time point. A 25% or higher reduction in spleen volume from baseline by week 24 was noted in 27% of patients. The median SVR was -18%.

The addition of pelabresib to ruxolitinib positively impacted symptoms in these patients, as well. The TSS50 at week 24 was 37%; this rate was 36% in TD patients and 39% in NTD patients, with a median symptom burden reduction of -47%.

“The combination of pelabresib and ruxolitinib was generally well tolerated, and preliminary results showed durable improvements in splenomegaly and symptom burden, with associated biomarker results suggesting potential disease-modifying activity,” Claire Harrison, MD, FRCP, FRCPath, lead study author and professor of myeloproliferative neoplasms at Guy’s and St. Thomas’ NHS Foundation Trust, said in a presentation of the data.

The JAK inhibitor ruxolitinib serves as the current standard of care for patients with myelofibrosis who are not candidates for hematopoietic stem cell transplant. However, JAK inhibitors are associated with limited efficacy and high discontinuation rates due to toxicities. As such, a large unmet need remains for the treatment of these patients with this disease.

The BET inhibitor pelabresib downregulates the expression of genes that contribute to the heterogenous features of the pathology of myelofibrosis, including aberrant erythroid and megakaryocytic differentiation, according to Harrison. Preclinical data have suggested that the combination of BET and JAK inhibitors could have synergistic activity in this disease.

In the ongoing, global, open-label, phase 2 MANIFEST study, investigators sought to further evaluate pelabresib in patients with myelofibrosis and essential thrombocythemia. The trial was comprised of 4 arms.

Arm 1 included patients with myelofibrosis who were no longer on ruxolitinib and who would receive pelabresib monotherapy in the second-line setting. Those in arm 4 had high-risk, essential thrombocythemia and were resistant or intolerant to hydroxyurea (Hydrea).

During the meeting, Harrison reported findings specifically from arms 2 and 3.

Those in arm 2 were given pelabresib as an “add on” to ruxolitinib; these patients had achieved a suboptimal response with ruxolitinib or experienced disease progression. Those in this arm were further divided into 2 cohorts: those who were TD (n = 59; cohort 2A) and those who were NTD (n = 27; cohort 2B). The primary end point in cohort 2A was conversion of TD to transfusion independence (TI), and key secondary end points included SVR35 and TSS50. For cohort 2B, the primary end point was SVR35, and a key secondary end point was TSS50.

Patients enrolled to arm 3 did not previously receive a JAK inhibitor and were considered to have intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System (DIPSS). These patients received the combination of pelabresib and ruxolitinib in the first-line setting. Here, the primary end point was SVR35, and the secondary end point was TSS50.

“Both of these patients have over 80 patients in them, and I just want to highlight that the vast majority were intermediate-2 or high-risk by DIPSS,” Harrison explained. “They represent a high-risk cohort, with more than 50% of patients—two-thirds on arm 3 and nearly 80% on arm 2—being anemic already. Spleen volumes were large and concerning and over half of patients in both arms had high molecular risk mutations.”

Additional data showed that within arm 2, 16% of 38 patients in cohort 2A converted from TD to TI. Moreover, 22% of 27 patients in cohort 2B were found to experience a hemoglobin response, which was defined as a post-baseline mean increase of at least 1.5 g/dL, which is required for any 12 weeks red blood cell transfusion-free period.

Notably, durable spleen volume reduction was observed over time in both arms 3 and 2. “In the JAK inhibitor–naïve patients, [we saw] progressive reduction in spleen volume,” Harrison noted. “Spleen volume reduction over time [was also observed] in the second-line [patients].”

For arm 3, the median treatment duration of pelabresib plus ruxolitinib was not yet reached (95% CI, 19.2–not reached), and the median follow-up time was 21.8 months (95% CI, 21.2-22.5). In arm 2, the median treatment duration with pelabresib add-on to ruxolitinib was 14.0 months (95% CI, 8.4-20.6), and the median follow-up time was 24.4 months (95% CI, 23.0-30.7).

Additional analyses revealed improvements in bone marrow fibrosis grade following 24 weeks of treatment by central pathology review. Specifically, 28% of those in arm 3 (n = 57) and 26% of those in arm 2 (n = 47) experienced an improvement of at least 1 grade at this time point.

Notably, these responses proved to be durable, with 56% and 50% of patients, respectively, maintaining their bone marrow fibrosis improvement at the next available assessment or beyond. Overall, at any time in the study, 40% and 39% of patients, respectively, achieved at least a 1-grade improvement in bone marrow fibrosis.

Utilizing digital pathology, investigators further evaluated features of the bone marrow biopsy. Again, improvements in bone marrow fibrosis were observed, with an increase in erythrocytes and a decrease in megakaryocyte clusters.

“Clustering of megakaryocytes is a key pathological feature in this disease. We saw that over 40% of patients in arm 2 and over 50% of patients in arm 3 experienced a 15% reduction in clustering of megakaryocytes,” Harrison said. “Megakaryocyte ‘de-clustering’ in the bone marrow was correlated with SVR35 response.”

Additionally, a cytokine analysis was performed on paired plasma samples, and investigators noted that there were decreased plasma levels of myelofibrosis-associated or inflammation-related cytokines in patients enrolled to arms 2 and 3.

A reduction in JAK2 variant allele frequency (VAF) and bone marrow fibrosis observed with pelabresib plus ruxolitinib was observed in patients within arm 3. “[With regard to] JAK2V617F VAF reduction, a 20% reduction was attained by over one-third of patients, at only week 24 in the study,” Harrison said. “Regardless of the baseline VAF, there was a reduction in JAK allele burden. [Bone marrow fibrosis grade change] occurred in patients regardless of whether they had a spleen volume response or not, but there seems to be a nice correlation across all these different dimensions of this disease.”

Regarding safety, in the JAK inhibitor–naïve patients, the most common hematologic treatment-emergent adverse effects (TEAEs) experienced with the combination were anemia (all grade, 42%; grade 3, 33%; grade 4, 1%) and thrombocytopenia (all grade, 52%; grade 3, 8%; grade 4, 4%).

Gastrointestinal (GI) events were noted to be mostly low grade; they included diarrhea (all grade, 35%; grade 3, 1%), constipation (all grade, 25%), nausea (all grade, 24%), and abdominal pain (23%). The median time to these events was 16 weeks. “GI events were easily managed with standard prophylaxis,” Harrison noted.

A total of 5 grade 5 TEAEs were reported, and they included COVID-19 (n = 1), multiorgan failure (MOF) due to sepsis secondary to infections (n = 2), and acute respiratory distress syndrome because of ruxolitinib withdrawal (n = 2). All were determined by the investigators to not be related to pelabresib except for the patient who experienced MOF due to sepsis secondary to pneumonia.

Among those in arm 2 who had previously experienced a suboptimal response to ruxolitinib, serious AEs reported in 3 or more patients included anemia (n = 6), respiratory tract infections (n = 4), and urinary tract infections (n = 3). “Similar data were observed in this tougher cohort of patients in the second-line setting with thrombocytopenia and anemia representing grade 3 and 4 events,” Harrison said.

Twenty patients experienced TEAEs that resulted in the discontinuation of pelabresib. “Grade 3 GI events are not common causes for discontinuation and are easily managed,” Harrison added.

A total of 7 grade 5 TEAEs occurred in those within this arm, and they included acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage, disease progression, transformation to acute myeloid leukemia, congestive heart failure, and suspected lung cancer. All TEAEs, except for acute kidney injury, were determined to not be associated with pelabresib.

The double-blind, phase 3 MANIFEST-2 trial (NCT04603495), which is evaluating pelabresib plus ruxolitinib compared with placebo and ruxolitinib in JAK inhibitor–naïve patients with myelofibrosis, has been initiated and is open for enrollment.


Mascarenhas J, Kremyanskaya M, Patriarca A, et al. BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis – JAK inhibitor-naïve or with suboptimal response to ruxolitinib – preliminary data from the MANIFEST study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S198.