Pelabresib and Rituxan Combo Improves Outcomes in Myelofibrosis

Pelabresib plus Rituxan improved spleen size and symptoms in untreated myelofibrosis, meeting the main goal of the MANIFEST-2 trial.

Pelabresib (CPI-0610) treatment in combination with Rituxan (ruxolitinib) was found to be safe, well tolerated, and improved signs of underlying myelofibrosis pathobiology, as well as provided substantial clinical benefit over standard-of-care therapy with a JAK inhibitor among patients with myelofibrosis. Specifically, these patients were naive to JAK inhibitor treatment.

These findings showed that the treatment combination met the primary end point of the phase 3 MANIFEST-2 trial, data from which were published in the journal, Nature Medicine.

“This is one of the largest myelofibrosis clinical trials to date,” lead study author, Dr. Raajit Rampal, stated in a news release from Memorial Sloan Kettering Cancer Center. “There is a real unmet need for patients with this disease, and the findings from this trial represent an exciting advance.”

Rampal is a hematologist-oncologist specializing in the treatment of myeloproliferative neoplasms, and serves as the director of both the Center for Hematologic Malignancies, as well as the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, located in New York.

Diving into the MANIFEST-2 Data

Study findings, as reported in Nature Medicine, showed that out of 214 patients, a spleen volume reduction of 35% or greater at 24 weeks was seen in 65.9% of patients treated with the investigative combination. Comparatively, of the 216 patients who were treated with placebo plus Rituxan, 35.2% experienced a spleen volume reduction of 35% or greater at 24 weeks. Additionally, in the pelabresib and Rituxan treatment group, the mean percentage change in spleen volume at 24 weeks was -30.6% compared with a mean percentage change of -50.6% in the pelabresib and Rituxan group.

At week 24, the absolute change in total symptom score was -15.99 in the pelabresib plus RItuxan group compared with -14.05 in the placebo plus Rituxan group. Additionally, a reduction of at least 50% in total symptom score from baseline was achieved in 52.3% of patients receiving the pelabresib combination versus 46.3% of those receiving placebo.

Regarding safety, thrombocytopenia and anemia were the most common treatment-emergent side effects. In the pelabresib treatment group, thrombocytopenia occurred in 52.8% of patients, with 13.2% of occurrences being a grade 3 (serious) event or higher compared with 37.4% of patients who were treated with placebo, with 6.1% being grade 3 or higher. When looking to anemia, the rates of occurrence were 44.8% (grade ≥3, 23.1%) with pelabresib plus Rituxan and 55.1% (grade ≥3, 36.5%) with placebo plus Rituxan.

“The MANIFEST-2 study of pelabresib plus Rituxan in JAK inhibitor-naive patients with myelofibrosis met its primary endpoint, with 65.9% of patients experiencing spleen response [at least 35% volume reduction] at week 24 with the combination,” Rampal and study authors wrote in the Nature Medicine article. “Indeed, the spleen response rate in patients treated with pelabresib plus Rituxan was approximately double that seen with placebo plus Rituxan in the MANIFEST-2 study [35.2%], and in previous studies of JAK inhibitor monotherapy [ranging from 18% to 42%]. Furthermore, symptom improvements were also observed with placebo plus Rituxan and pelabresib plus Rituxan, with trends towards further benefit with the combination.”

All patients enrolled on the trial were newly diagnosed and had not undergone prior treatment for myelofibrosis. Approximately half of patients received the combination of pelabresib and Rituxan, while the remaining patients were treated with a placebo and Rituxan. Both medications were administered orally.

A Patient Shares His Experience Being Treated With the Investigative Doublet

In the news release from Memorial Sloan Kettering Cancer Center, now 53-year-old-patient, Jason Weiner — an attorney, husband and father of three — shares his story after being treated with the pelabresib and Rituxan combination

Following a diagnosis of polycythemia vera in his mid-20's, Jason's disease went on to progress into myelofibrosis in 2021, which was diagnosed following regular blood work. It was this shift in disease that led Jason, who was living in Alaska at the time, to be treated at Memorial Sloan Kettering Cancer Center.

“My biggest concern was that the myelofibrosis would convert to leukemia,” Jason explained in the news release. “I wasn’t even feeling sick, but I wanted to stop it right away.”

Since 2011, Rituxan has been the standard treatment for myelofibrosis and can alleviate symptoms in some patients; however, its effectiveness typically diminishes over time due to disease progression or resistance, according to the news release.

“Myelofibrosis is considered a progressive disease, which means it continues to worsen over time,” Dr. Rampal explained. “In many people, it eventually transforms into full-blown leukemia.”

With this in mind, once Dr. Rampal explained the treatment options to Jason, he welcomed the opportunity to enroll onto the MANIFEST-2 trial, making Jason one of the 430 patients who participated in the double-blind, placebo-controlled trial. Now living in Maine with his family, Jason traveled to New York once every three weeks for tests ahead of the study.

When considering side effects that Jason experienced while being enrolled on the trial, the main adverse reaction to treatment that he recalled was a change in his sense of taste, according to the news release from Memorial Sloan Kettering Cancer Center.

Jason recalls that managing the unpleasant taste in his mouth was challenging at first, but he discovered strategies that helped, including frequently sipping water with electrolytes and cranberry juice. Now, he no longer experiences taste-related issues and has since noticed positive effects from the drug combination.

He continues to take the daily combination of pelabresib and Rituxan, the release notes

“I really have no limitations on what I can do,” Jason explained, in reference to his active lifestyle. “I feel better now than I did all the years I was getting interferon.”

“I was one of the younger people in this trial, and because I wasn’t yet very sick when I started, I really gained a lot,” he continued. “I hope this drug will be available to more people earlier in the course of disease, when they have the greatest likelihood for improvements.”

Dr. Rampal concludes the news release by saying that the development of the treatment combination would not have been possible without years of research within the myelofibrosis landscape.

“This is such a clear example of the importance of bench-to-bedside research,” He concludes. “Our discoveries in the lab have really guided this work, which has already helped so many and will continue to benefit more patients in the future.”

Overall, these findings align with the proposed mechanism of action, as well as current understanding of the role of proinflammatory cytokines for the treatment of myelofibrosis. Consistent with preclinical data, treatment with pelabresib and Rituxan in the MANIFEST-2 study resulted in greater and more frequent reductions in proinflammatory cytokine levels compared with Rituxan alone.

Reference:

“Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial” by Dr. Raajit K. Rampal, et al., Nature Medicine.

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