Pelabresib Provides Clinical Benefit in Hydroxyurea-Refractory or Intolerant High-Risk Essential Thrombocythemia

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Treatment with pelabresib monotherapy led to a 60% confirmed complete or partial hematologic response at any time without incurring grade 4 or 5 treatment-related adverse effects in patients with high-risk essential thrombocythemia refractory or intolerant to hydroxyurea.

Francesco Passamonti, MD

Francesco Passamonti, MD

Treatment with pelabresib monotherapy led to a 60% confirmed complete or partial hematologic response at any time without incurring grade 4 or 5 treatment-related adverse effects (AEs) in patients with high-risk essential thrombocythemia (ET) refractory or intolerant to hydroxyurea, according to preliminary findings from arm 4 of the phase 2 MANIFEST trial (NCT02158858) presented at the 2023 EHA Congress.

At data cutoff of July 29, 2022, 7 of 20 patients had been treated for at least 6 months, and 14 patients continued to receive treatment with pelabresib. The confirmed complete and partial hematologic response rates were 40% and 20%, respectively.

“Pelabresib monotherapy resulted in hematologic response and symptom improvement in patients with high-risk ET who are resistant/intolerant to hydroxyurea,” Francesco Passamonti, MD, lead study author, professor of hematology at the University of Insubria of Varese, and head of the Division of Hematology at the University Hospital of Varese in Italy, said.

ET is a myeloproliferative neoplasm (MPN) defined by progressive thrombocytosis, thrombohemorrhagic events, and systemic symptoms. Despite first-line cytoreductive therapy with hydroxyurea and interferon alfa-2a, resistance and intolerance remain issues for this population, creating an unmet medical need.

Pelabresib is an oral, small molecule inhibitor of BET, which has the potential to downregulate the expression of genes that reside within the pathogenic pathways that underly MPN progression.

MANIFEST in a 4-arm, ongoing, global, open-label, phase 2 study evaluating pelabresib in patients with myelofibrosis and ET. Arm 1 is evaluating pelabresib alone, and arms 2 and 3 are investigating pelabresib plus ruxolitinib (Jakafi), all in patients with myelofibrosis. Arm 1 is evaluating pelabresib monotherapy as second-line therapy in patients with ruxolitinib-refractory or intolerant disease. Arm 2 is evaluating pelabresib as an add-on to ruxolitinib in the second line following suboptimal response or progression. In arm 3, the combination is being evaluated in the frontline in patients with Dynamic International Prognostic Scoring System intermediate-2/high disease.

The study population in arm 4 consisted of patients with high-risk ET refractory or intolerant to hydroxyurea with at least 2 symptoms of average score of 3 or more, or a total symptom score (TSS) of 15 or more per Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) in the past 7 days, and platelets above 600 x 109/L.

Patients were treated with 225 mg of oral pelabresib monotherapy once daily for 14 days in 21-day cycles (n = 21).

The primary end point of this arm of the study was confirmed complete hematologic response at any time. Secondary end points included confirmed partial hematologic response at any time and symptom improvement. Exploratory end points included translational evaluation of Interleukin-8 (IL-8) expression change, cytokines, and mutation status.

Regarding baseline characteristics (n = 20), the median patient age was 64 years (range, 42-83) and most were older than 60 years (60%) and female (60%). Median hemoglobin, platelet count, white blood cell count, and spleen volume was 13 g/dL (range, 10-16), 722 x 109/L (range, 418-1255), 7.9 x 109/L (range, 4-12.3), and 402 cc (range, 124-907), respectively. Spleen was not palpable in 90% of patients, and median TSS was 32.7 (range, 6.9-123). Median prior hydroxyurea duration was 103 months (range, 0.7-245). Most patients had received at least 2 prior lines of therapy (60%). Fifteen percent of patients had prior thrombosis. Twenty percent of patients had myelofibrosis high-molecular risk, with JAK2, CALR, ASXL1, and MPL mutations residing in 45%, 40%, 15%, and 5% of tumors, respectively.

With respect to blood counts over time, the median platelet, white blood cell, and hemoglobin (n = 13) counts at week 12 were 446 x 109/L, 8.2 x 109/L, and 13.0 g/dL, respectively. Sixty percent of patients had platelets no higher than 400 x 109/L over time. Similarly, most patients (95%) did not experience white blood cell counts above 10 x 109/L over time. The median percentage change in platelet and white blood cell counts at week 12 were –40% and 8.2 x 109/L, respectively. Additionally, by week 24 (n = 7), median hemoglobin remained stable at 13.4 g/dL.

TSS was evaluated in 14 patients, showing 50% reduction in TSS50 in MPN-SAF at any time. By week 12, median TSS had been reduced by 31%.

A NF-κB target cytokine panel linked to bone marrow pathogenesis and inflammation was assayed. Included cytokines were CD40, CD40-L, CRP, IL-6, IL-18, IP-10, MMP-2, TNF-α, thrombospondin-1, RANTES, VCAM-1, and VEGF.

“Pelabresib monotherapy demonstrated a durable reduction in NF-κB–driven cytokines associated with bone marrow abnormalities and inflammation,” Passamonti said, reaching close to 40%.

In addition, IL-8 gene expression was evaluated in whole blood prior to and 4 hours after pelabresib administration. Passamonti stated that “rapid reduction in IL-8 gene expression was observed,” with median expression changes of –67% (95% CI, –79% to –56.9%), –69% (95% CI, –76.5% to –12.2%), and –52% (95% CI, –85% to 106.6%) at cycle 1 day 1 (n = 16), cycle 1 day 14 (n = 11), and cycle 3 day 1 (n = 10), respectively.

Furthermore, investigators explained that although variant allele fraction (VAF) levels were maintained in most patients with 30% or fewer driver mutations, 2 of 6 patients with post baseline JAK2 V617F–mutation assessment showed meaningful reduction in VAF from 60% to 20% and 52% to 40%.

Regarding safety, serious AEs occurred in 3 patients, consisting of leukocytosis, thrombocytosis, and eyelid bleeding in 1 patient, infection in another, and dyspnea and pulmonary embolism in the third. Another 3 patients reported treatment-emergent AEs that led to pelabresib discontinuation. No grade 5 AEs occurred.

“Safety results [were] as expected in the underlying population and consistent with the known safety profile of pelabresib,” Passamonti said.

Leukopenia was the only reported hematologic AE (all-grade, 10%). Non-hematologic AEs included nausea (60%), diarrhea (35%), constipation (30%), vomiting (25%), dyspepsia (10%), dysgeusia (35%), ageusia (30%), abdominal pain (25%), rash (20%), respiratory tract infection (15%), weight decrease (15%), muscle spasms (15%), myalgia (10%), headache (10%), insomnia (10%), pruritus (10%), hypertension (10%), fatigue (10%), and arthralgia (10%).

Hemorrhagic and thromboembolic events included pulmonary embolism (grade 3, 5%), deep vein thrombosis (all-grade, 5%), acute myocardial infarction (all grade, 5%), hemorrhagic diarrhea (grade 3, 5%), eyelid bleeding (grade 3, 5%), hematoma (all grade, 5%), hematuria (all grade, 5%), and petechia (all grade, 5%). All cases of thromboembolic events and eyelid bleeding were unrelated to pelabresib. 

“These preliminary safety and efficacy results in patients with high-risk essential thrombocythemia continue to provide evidence for the potential clinical benefit of pelabresib in myeloid diseases,” Passamonti concluded.


Passamonti F, Patriarca A, Knapper S, et al. Pelabresib (CPI-0610) monotherapy in patients with high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: preliminary results from MANIFEST study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S168.

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