Parsaclisib Added to Ruxolitinib Decreases Spleen Volume and Improves Symptom Scores in Myelofibrosis


Add-on parsaclisib with ruxolitinib resulted in decreased spleen volume and improved symptom assessment scores in patients with myelofibrosis.

Abdulraheem Yacoub, MD

Abdulraheem Yacoub, MD

The PI3Kδ inhibitor parsaclisib added to a stable dose of ruxolitinib (Jakafi) reduced spleen volume and improved symptom scores for patients with myelofibrosis who experienced a suboptimal response to ruxolitinib, according to findings from a phase 2 study (NCT02718300) published in Blood Adv.

Final results of the study revealed that patients who received daily-to-weekly dosing of parsaclisib (n = 32) and those who received all-daily dosing of parsaclisib (n = 42) achieved a decrease in spleen volume of at least 10% at 12 weeks at rates of 28.0% and 59.5%, respectively. Moreover, patients achieved a 50% decrease or more at week 12 in Myelofibrosis Symptom Assessment Form symptom scores at rates of 14% and 28%, respectively; the rates of at least a 50% decrease at week 12 in Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 18% and 32%, respectively.

“Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the PI3K/protein kinase B pathway,” Abdulraheem Yacoub, MD, professor of Hematologic Malignancies and Cellular Therapeutics at KU Medical Center in Kansas City, Kansas, and coauthors wrote. “The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib.”

The study authors added that parsaclisib was designed with a different molecular structure than earlier-generation PI3K inhibitors—the orally bioavailable, potent, and highly selective next-generation inhibitor may in turn be able to limit both on- and off-target toxicities that were previously seen.

Additional findings from the study demonstrated that in the overall population evaluable for the primary end point (n = 65), the median change in spleen volume was −163.6 cm3 (range, −735.6 to 10173 cm3), with a median percentage change of −11% (range, −47% to 444%). At week 24, these figures were −192.0 cm3 (range, −2040 to 761.4 cm3) and −10% (range, −89% to 34%) among 49 evaluable patients. The median percentage change was greater among patients who received all-daily dosing compared with those who received daily-to-weekly dosing both at 12 weeks (−15.0% vs −2.0%) and 24 weeks (−19.0% vs −2.5%, respectively).

Examining Dosing and Study Design

The open-label study enrolled adult patients with primary or secondary myelofibrosis who received ruxolitinib for at least 6 months and via a stable dose of 5 to 25 mg twice daily for at least 8 weeks before study initiation—patients previously experienced a suboptimal response to the agent. Patients also needed to have an ECOG performance status of 2 or less. Those who received drugs for myelofibrosis besides ruxolitinib, underwent splenic irradiation within 6 months, received prior PI3K inhibitor treatment, and had inadequate bone marrow reserve, inadequate liver or renal function, uncontrolled cardiac disease, active infections requiring therapy, HIV infection, or history of grade 3 or 4 immune-related adverse effects (AEs) or any-grade ocular immune-related AEs were excluded from the study.

The part 1 safety run-in assessed the safety and tolerability of parsaclisib added-on to ruxolitinib, and determined the dose—the highest tested dose was 20 mg daily and no dose-limiting toxicities were reported. In part 2, investigators had planned for patients to receive parsaclisib at either 10 or 20 mg daily for the first 8 weeks, then the same dose once weekly through the end of study (daily-to-weekly regimen) continued with a stable ruxolitinib dose. In part 3, investigators planned for patients to receive parsaclisib 20 mg daily plus ruxolitinib then, after 8 weeks, 1 group would switch to once-weekly dosing of parsaclisib 20 mg plus ruxolitinib (daily-to-weekly regimen) and another group would continue with once-daily dosing but at a reduced dose of parsaclisib 5 mg with ruxolitinib (all-daily dosing regimen). However, after parts 2 and 3 were suspended based on investigator feedback, part 4 proceeded and randomly assigned patients to receive 2 all-daily dosing regimens: parsaclisib 5 mg daily for the duration of the study, or an initial parsaclisib induction phase of 20 mg daily, with a transition to 5 mg daily after 8 weeks.

The coprimary end points of parts 2, 3, and 4 were absolute and percentage change in spleen volume from baseline to week 12. Key secondary end points included absolute and percentage change in spleen volume from baseline to week 24, changes in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form total symptom score from baseline to week 12 or 24, number of patients with response, Patient Global Impression of Change score, and safety. Change and percentage change in palpable spleen length from baseline to each study visit and change in bone marrow fibrosis grade from baseline to week 24 represented exploratory end points.

Patients Enrolled in the Phase 2 Trial and Safety Findings

The baseline patient characteristics between the cumulative daily-to-weekly and all-daily dosing groups were generally well balanced; the median age was 67 years (range, 41-89) vs 69 years (range, 51-84), respectively. Most patients in both groups were White (78% vs 83%, respectively), had primary myelofibrosis (53% vs 55%), and were female (53% vs 52%). The respective median time since first myelofibrosis diagnosis was 30.5 months (range, 6.7-268.9) compared with 37.5 months (range, 4.9-251.5).

Further, the median palpable spleen length in the cumulative daily-to-weekly group was 14 cm (range, 8-30) vs 11 cm (range, 5-30) in the all-daily dosing group. The median spleen volume was 2414.5 cm3 (range, 327.1-5323.7) compared with 1877.5 cm3 (range, 434.2-3904.1), respectively. Additionally, the median daily dose of ruxolitinib was 28.9 mg (range, 13.8-50.0) vs 29.3 mg (range, 8.7-44.8), respectively.

In terms of safety, no dose-limiting toxicities were observed during the safety run-in. In the overall safety population (n = 74), 96% of patients experienced an any-grade treatment-related AE (TRAE); 40 patients experienced a TRAE of grade 3 or greater severity. The most common nonhematologic any-grade AEs included nausea (23%), diarrhea (22%), abdominal pain (19%), fatigue (19%), cough (18%), and dyspnea (18%). Serious AEs, AEs leading to discontinuation, and fatal AEs occurred at rates of 35%, 18%, and 8%, respectively.

“Further studies are needed to fully evaluate individual symptom effects because [of] the number of patients with data decreased beyond 24 weeks in our study, but data presented support a preliminary conclusion that symptom improvement was related to effects from both spleen volume and cytokines,” study authors wrote in conclusion. “In summary, our phase 2 study suggests that the addition of parsaclisib to stable ruxolitinib therapy can reduce splenomegaly and meaningfully improve clinical symptoms without significantly affecting hemoglobin levels, and with manageable thrombocytopenia, in patients with myelofibrosis with suboptimal response to ruxolitinib monotherapy. Safety and tolerability of the combination was acceptable for all dosing regimens tested, and daily dosing may provide the greatest benefit.”


Yacoub A, Borate U, Rampal RK, et al. Phase 2 study of add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: final results. Blood Adv. 2024;8(6):1515-1528. doi:10.1182/bloodadvances.2023011620

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