Pelabresib Monotherapy Shows Benefits in JAK Inhibitor-Naïve Advanced Myelofibrosis

Marina Kremyanskaya, MD, PhD, discusses the safety and efficacy of pelabresib in patients with myelofibrosis, additional data from the MANIFEST trial, and other efforts to study the agent in this disease.

Use of pelabresib (CPI-0610) monotherapy has demonstrated evidence of clinical activity in the form of reduction in spleen volume, reduction in symptoms and benefit in hemoglobin in patients with JAK inhibitor naïve advanced myelofibrosis in the Phase 1/2 MANIFEST trial (NCT02158858), according to Marina Kremyanskaya, MD, PhD.1

The results, which were presented at the ASH 2021 Annual Meeting and Expoalso showed improvement in bone marrow fibrosis in a subset of patients, as well as a reduction in plasma cytokines implicated in the pathogenesis of myelofibrosis.

“This trial is exciting because we’re seeing some responses in patients who are heavily pretreated and don’t have many treatment options,” Kremyanskaya said. “Usually, once these patients stop taking ruxolitinib, their life expectancy is short. For a small number of patients, becoming transfusion independent at this point is really important.

The Phase 3 MANIFEST-2 trial (NCT04603495), examining ruxolitinib (Jakafi) plus pelabresib versus ruxolitinib plus placebo, is open to recruit to collect additional data. “[In the future]I hope that combining these 2 drugs together, whether second-line or first-line, will lead to even more significant responses and allow patients to have better treatment, better outcome and longer survival” , Kremyanskaya added.

In an interview with Live®Kremyanskaya, Assistant Professor of Medicine, Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai, Medical Director, Inpatient Oncology Unit, The Mount Sinai Hospital, discussed the safety and efficacy of pelabresib in patients with myelofibrosis, additional data from the MANIFEST trial and other efforts to investigate the agent of this disease.

Live®: What was the purpose of the MANIFEST trial in myelofibrosis?

Kremenskya: This is a very interesting ongoing trial. We use a bromodomain inhibitor CPI-0610, now called pelabresib, which is believed to affect the NF-κB pathway. This is important in the pathogenesis of myelofibrosis and the inflammatory process seen with myelofibrosis.

The trial has 3 different arms. Two of them last longer and are [examining the agent as] second-line treatment in patients with myelofibrosis. The first arm is for patients who stopped ruxolitinib because they could not tolerate it or because they had progressed. The second arm was for patients who were doing well on ruxolitinib, but not as well as we wanted, so [pelabresib] was added as a second drug.

Then there is arm 3, which is for JAK inhibitor naïve patients. The 2 drugs are combined upstream. [The presentation at the 2021 ASH Annual Meeting] focused on arm 1 as monotherapy: patients who did not tolerate ruxolitinib, progressed on ruxolitinib treatment, or were deemed ineligible for ruxolitinib treatment by the investigator.

What was the trial design and methods used?

This [trial] is for patients who have fairly advanced disease and who have stopped ruxolitinib, which is the standard treatment for patients with myelofibrosis. These patients were often on other therapies, so they saw a lot of medications. Eligibility criteria [included patients who] progressed on ruxolitinib or did not tolerate it…or those deemed ineligible for ruxolitinib treatment by the investigator, and usually this was because of anemia or thrombocytopenia.

They must have had myelofibrosis which was [Dynamic International Prognostic Scoring System] at intermediate to high risk, and they had to have a platelet count of at least 75,000 to be eligible for the study. This arm of the study consisted of 2 cohorts. One was a transfusion-dependent cohort and the other was a transfusion-independent cohort. The endpoint for the transfusion-dependent cohort is achieving transfusion independence, which is defined as not requiring transfusion support for at least 12 weeks. For the second cohort, which is independent of transfusion, the primary endpoint is reduction of the spleen by 35% by imaging. Secondary endpoints in both trial cohorts were a 50% reduction in symptom score.

What were the main conclusions presented during the meeting?

As mentioned previously, in the transfusion-dependent cohort, the primary endpoint was transfusion independence. It is important to keep in mind that these are heavily pretreated patients with fairly advanced disease and [most] had a hemoglobin level below 10 [g/dL], whether they are in the transfusion-dependent or transfusion-independent cohort. Most patients had large spleens and high symptom scores. Approximately 20% of patients in the transfusion-dependent cohort achieved transfusion independence; it’s not a huge number, but for patients who are able to reach that endpoint, it’s a huge improvement in their disease, quality of life, and overall symptoms.

Looking at [at the study] overall, most patients had hemoglobin responses, and this was defined as an increase of 1.5 g/dL or more over a 12-week period. We observe hemoglobin responses in these patients, whether they were transfusion dependent or independent, and approximately 20% of the patients became transfusion independent in the study.

Then we can examine the responses of the spleen. Again, [it is very important to note that] this patient population has very advanced disease and most had already [received] ruxolitinib. In this population, for the transfusion-independent cohort, for which the responses in the spleen [reduction] was the primary endpoint, nearly about 20% [of patients experienced] a 35% reduction in spleen volume by imaging, and most had some spleen response. Nearly 30% had a 25% reduction in their spleen volume, which is significant in this population.

Most patients achieved a reduction in their symptom score. Most patients felt better [after having received] this medicine. Looking specifically at the 50% [or higher] total symptom score [reduction], this was achieved by approximately 40% of patients in the two cohorts combined. These are the clinical parameters.

We have also begun to examine bone marrow fibrosis in study patients by central examination. [Specifically], 7% of patients improved by a grade of 2 or more and 17% improved by a grade of bone marrow fibrosis. About 43% of patients did not feel any change. Interestingly, 71% of patients with improvement in bone marrow fibrosis were also hemoglobin responders.

Next, we examined cytokine profiles associated with general inflammation and the pathogenesis of myelofibrosis. Different cytokines were grouped together to see if there was a response in this cytokine profile. What we see is that the cytokines have been grouped into 6 groups based on their baseline overexpression patterns.

Specifically, we saw changes in interleukin [IL]-10, IL-4, IL-13 and IL-18; these were rapidly down-regulated, as early as day 14 of treatment. The response was maintained for a total of 24 weeks.

How was the drug tolerated? What adverse effects (AEs) have been observed?

The drug is fairly well tolerated. The most common treatment-emergent haematological AEs were anemia and thrombocytopenia, and these were mostly low grade. In terms of non-haematological toxicities, the drug is relatively well tolerated. A small number of patients experienced gastrointestinal AEs, and again most of these were low grade.

Are there any next steps for this research?

The trial is ongoing. This arm of the trial is still recruiting patients, so we may get more data as more patients reach different times when their responses will be assessed. More bone marrow samples will be examined by central review to give us a better idea of ​​what is happening with fibrosis and bone marrow pathology.

This trial led to the opening of phase 3 [MANIFEST 2] trial for this drug, and it is currently recruiting patients. Here, JAK inhibitor treatment naïve patients were randomized to receive ruxolitinib plus pelabresib versus ruxolitinib plus placebo. It will be very exciting to see the added benefit of combining these 2 drugs from the start, with perhaps longer responses and deeper responses in patients with myelofibrosis.


Kremyanskaya, M, Mascarenhas J, Palandri F, et al. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – clinical and translational data update from the ongoing overt trial. Blood. 2021;138(supplement 1):141. doi:10.1182/sang-2021-150172

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