A phase 2 study of the combination of the PI3K inhibitor parsaclisib and the JAK1/2 inhibitor ruxolitinib (Jakafi™) in patients with myelofibrosis showed improvements beyond what would be expected with ruxolitinib alone, according to research findings presented at the 2022 European Hematology Association meeting. Additionally, researchers found the combination showed no unexpected increase in toxicity.
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“Ruxolitinib has been revolutionary in the way we treat myelofibrosis, but the challenge is that it doesn’t work for everyone and it doesn’t work forever,” says study co-author Aaron T. Gerds, MD, a staff physician with Cleveland Clinic Taussig Cancer Institute and Associate Professor of Medicine. (Hematology and Medical Oncology) with the Cleveland Clinic Lerner College of Medicine. “Roughly 40% of patients achieve a strong response in terms of symptom burden and spleen volume reduction, therefore 60% have a suboptimal response. Our goal is to focus on that unmet need.”
While the original COMFORT studies showed a median duration of treatment with ruxolitinib of 3.2 years, real-world analysis revealed the timeframe to be closer to 18 months. Researchers are seeking ways to improve upon this.
Knowing that the PI3K pathway is important in pathogenesis and promoting the survival of myelofibrosis cells and is dysregulated in myelofibrosis cells, researchers at Cleveland Clinic and their collaborators postulated that adding a PI3K inhibitor to ruxolitinib could help regain response in patients who either never achieved an optimal response or are seeing a waning response from their current therapy.
Patients in the study had previously been treated with ruxolitinib alone. The study showed indications of improvements in symptom burden as well as spleen size reduction in patients receiving the combination therapy.
These proportional improvements in symptoms were achieved without excess toxicity. Phase 3 trials will continue to assess the durability of these responses.
Dr. Gerds notes that reconsideration of standard metrics may be warranted in gauging patients’ response to therapy. “In the past, the field of myelofibrosis has been beholden to a threshold of 35% spleen reduction and 50% symptom burden improvement because the original ruxolitinib trials used those as the endpoints. However, using tools like patient global impression of change may better quantify actual improvements. If, for example, a patient had a 34% reduction in spleen volume, they are likely to experience virtually the same benefit as someone who had a spleen reduction of 35%, yet standard metrics wouldn’t quantify the first patient as having a response. We need to rethink this.”
Numerous large prospective randomized phase 3 trials are now underway for treating myelofibrosis. “As we move forward in the next two or three years, we’ll see more of these trials read out, and I think combination therapy for this disease is in the not-so-distant future,” says Dr. Gerds. “I look forward to seeing a larger proportion of patients having a better functional status and potentially improving overall survival. That may not necessarily mean directly reversing scar tissue in the bone marrow or killing off myelofibrosis cells, but it can result in dramatic improvements in people’s quality of life.”
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