Pelabresib Monotherapy Shows Benefit 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 investigating the agent in this disease.

Marina Kremyanskaya, MD, PhD

Marina Kremyanskaya, MD, PhD

The utilization of pelabresib (CPI-0610) monotherapy demonstrated signals of clinical activity in the form of spleen volume reduction, symptom reduction, and hemoglobin benefit in patients with JAK inhibitor–naïve advanced myelofibrosis during the phase 1/2 MANIFEST trial (NCT02158858), according to Marina Kremyanskaya, MD, PhD.1

The results, which were presented at the 2021 ASH Annual Meeting and Exposition, also showed bone marrow fibrosis improvement in a subset of patients, plus reduction of plasma cytokines involved in myelofibrosis pathogenesis.

“This trial is exciting because we are seeing some responses in patients who are heavily pretreated and do not have many treatment options,” Kremyanskaya said. “Typically, once these patients come off ruxolitinib, they have a short life expectancy. For a small number of patients to become transfusion independent at that point is really significant.”

The phase 3 MANIFEST-2 trial (NCT04603495), examining ruxolitinib (Jakafi) plus pelabresib vs ruxolitinib plus placebo, is open for enrollment to gather additional data. “[In the future], hopefully the combination of these 2 drugs together, whether as a second line or up front, will lead to even more significant responses and allow patients to have a better, treatment, a better outcome, and longer survival,” Kremyanskaya added.

In an interview with OncLive®, 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 investigating the agent in this disease.

OncLive®: What was the rationale for the MANIFEST trial in myelofibrosis?

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

The trial has 3 different arms. Two of them have been going on for longer, and are [examining the agent as] second-line therapy in patients with myelofibrosis. The first arm is for patients who came off ruxolitinib because they did not tolerate it or because they progressed on it. The second arm was for patients who were doing OK on ruxolitinib, but not as good we wished, so [pelabresib] was added on as a second drug.

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

What was the design of the trial, and the methods utilized?

This [trial] is for patients who have fairly advanced disease and who have come off ruxolitinib, which is the standard therapy for patients with myelofibrosis. These patients often have been through other therapies, as well, so they have seen many drugs. The eligibility criteria [included patients who] progressed on ruxolitinib or did not tolerate it…or those deemed ineligible for ruxolitinib therapy by the investigator, and typically, that was because of anemia or thrombocytopenia.

They had to have myelofibrosis that was [Dynamic International Prognostic Scoring System] 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 was comprised of 2 cohorts. One was a transfusion-dependent cohort and the other was a transfusion-independent cohort. The end point for the transfusion-dependent cohort is achievement of transfusion independence, which is defined as not requiring transfusion support for at least 12 weeks. For the second cohort, which is transfusion independent, the primary end point is reduction in spleen by 35% by imaging. Secondary end points in both cohorts of the trial were a 50% reduction in symptom score.

What were the key findings presented during the meeting?

As mentioned earlier, in the transfusion-dependent cohort, the primary end point 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 of less than 10 [g/dL], whether they were in the transfusion-dependent or -independent cohort. Most patients had large spleens and high symptom-score assessments. About 20% of patients in the transfusion-dependent cohort achieved transfusion independence; it is not a large number, but for those patients who are able to achieve that end point, that is a huge improvement in their disease, in their quality of life, and in their overall symptoms.

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

Next, we can look at spleen responses. 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 responses in spleen [reduction] was the primary end point, close to about 20% [of patients experienced] a 35% reduction in spleen volume by imaging, and most had some spleen response. Close to 30% had a 25% reduction in their spleen volume, which is significant in this population.

Most patients achieved reduction in their symptom score. Most patients felt better [after having received] this drug. Looking specifically at the 50% [or higher] total symptom score [reduction], this was achieved by about 40% of patients in both cohorts combined. These are the clinical end points.

We also started looking at bone marrow fibrosis in patients on the study by central review. [Specifically], 7% of patients improved by grade 2 or more and 17% improved by 1 grade of bone marrow fibrosis. About 43% of patients did not experience a change. What is interesting is that 71% of patients with bone marrow fibrosis improvement were also hemoglobin responders.

Next, we looked at cytokine profiles associated with general inflammation and myelofibrosis pathogenesis. Different cytokines were clustered together to see whether there was a response in that profile of cytokines. What we are seeing is that cytokines were clustered into 6 groups based on their overexpression patterns at baseline.

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

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

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

Are there any next steps for this research?

The trial is ongoing. This arm of the trial is still enrolling patients, so we will be able to get more data as more patients reach different time points where their responses are being evaluated. More of the bone marrow samples will be reviewed by central review to provide us with a better idea of what is going on with fibrosis and with the bone-marrow pathology.

This trial led to the opening of the phase 3 [MANIFEST 2] trial for this drug, and it is currently enrolling patients. Here, patients who were naïve to JAK-inhibitor therapy were randomized to receive ruxolitinib plus pelabresib vs ruxolitinib plus placebo. It will be very exciting to see the additional benefit in combining these 2 drugs together up front, 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 – update of clinical and translational data from the ongoing manifest trial. Blood. 2021;138(suppl 1):141. doi:10.1182/blood-2021-150172

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