Over the past 15 years, JAK2 inhibitors have been the only FDA-approved therapy for myelofibrosis. Initially, patients have experienced symptom relief and improved quality of life, but after a year or two, efficacy greatly diminishes. Then, another JAK2 therapy has been prescribed, which again would fail until all options were depleted. After that, patient survival has hovered around one year.
“This vicious cycle was terrible for patients and their doctors,” said Peter Abdelmessieh, DO, MSc, Assistant Professor, Department of Bone Marrow Transplant and Cellular Therapies, prompting Abdelmessieh to explore new treatment territory with Tomasz Skorski, MD, PhD, DSc, Director, Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine (LKSOM). Together, these scientist-clinicians sought solutions to transform treatment for these rare neoplasms.
Dr. Skorski explained, “The current standard of care for myeloproliferative neoplasms is JAK2 inhibitors designed to hit one target—the JAK2 V617F kinase—the most common mutation in myelofibrosis.”
In the lab, researchers discovered that when JAK2 was inhibited, it produced another cellular effect causing the malignant cell to become functionally deficient in BRCA1 and BRCA2, mimicking mutations found in breast, ovarian, and prostate cancers. Skorski reasoned that perhaps by adding a PARP inhibitor, a targeted drug for breast cancer, to the JAK2-directed standard of care inhibitor, the combination could produce a more durable response. Lab testing backed up his theory and showed increased cell death of malignant cells carrying JAK2 V617F mutation and became the basis for a Phase 1 trial.
“Most patients who fail first-line JAK2 therapy are not candidates for an allogenic stem cell transplant and have an unfavorable prognosis,” said Dr. Abdelmessieh. “The trial drugs we’re using in this phase one study are already FDA approved and well tolerated and include talazoparib, a PARP inhibitor that is standard treatment for BRCA-mutated cancers—combined with pacritinib, a JAK inhibitor standard-care therapy for myelofibrosis, essential thrombocythemia, and polycythemia vera.
“So far, we’ve enrolled two patients, and both have shown substantial clinical benefit with measured disease severity for symptoms and spleen size dropping from a high of 50 to single digits by month three. Transformative results,” said Dr. Abdelmessieh.
This data supports Dr. Skorski’s hypothesis, now in a clinical study, that combining these drugs increases DNA damage in malignant cells more than standard therapy alone—doubling the DNA damage and cell death when the PARP inhibitor was added to the JAK inhibitor. When the PARP inhibitor was paused, the effect decreased, confirming the mechanism. Next steps for the trial are to enroll a total of 24 patients over the next few years.
“Our goal is to deeply understand what happens at the cellular level during treatment by using advanced single-cell DNA sequencing to identify malignant clones and determine which ones disappear and which ones may persist and drive a relapse,” said Dr. Skorski. With the help of Amy Goldberg, MD, The Marjorie Joy Katz Dean, Lewis Katz School of Medicine, we established a core facility that allows us to pursue this patient-oriented, high-tech goal. “The mission is to keep learning from the patients’ success stories and expand knowledge to move the field forward and save lives.”
Dr. Abdelmessieh said, “Fox Chase is the first to explore this combination of drugs and the only study in Philadelphia looking at myelofibrosis. We believe this approach is special and clearly addresses an unmet need.”
Because of our elite standing as an NCI-designated Cancer Center, our research is led by extraordinarily talented scientists who work in an ideal environment for fundamentally important discoveries. With additional support from our partnership with Temple University Health System’s oncology research, treatment, and prevention programs, Fox Chase research makes a world of difference in Philadelphia and all other communities that we serve.
Study Title: Talazoparib in Combination with Pacritinib for the Treatment of Patients with Myeloproliferative Neoplasms Unresponsive to Frontline JAK2 Inhibition https://physicianresources.foxchase.org/news/pacritinib-w/talazoparib-in-pts-w/myeloproliferative-neoplasms-unresponsive-to-jak2-inhibition-clinical-trial
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