Ruxolitinib (RUX), a JAK1/2 inhibitor, has demonstrated ability to improve clinical outcomes in patients with myelofibrosis (MF); however, unmet needs remain in this patient population. Most patients eventually discontinue RUX treatment due to loss of or insufficient response after long-term therapy. RUX treatment is associated with low platelet count. Therefore, patients with an already low platelet count can be challenging to treat. Evidence indicates this effect may be mediated by persistent activation of the PI3K pathway. Therefore, inhibition of PI3K may restore response to RUX treatment. Preliminary research demonstrated parsaclisib, a highly selective PI3K inhibitor, is effective in patients with substandard response to ≥6 months of RUX therapy.
The current study enrolled 67 patients with a median age of 68 years to assess the effect of platelet count on spleen volume response and total symptom score. The cohort was divided according to platelet count (21 low and 46 higher platelet count). Those in the low platelet group received RUX for a median of 34.7 months; the higher platelet group received RUX for 14.9 months. During the study, participants continued RUX treatment at their last stable dose and received add-on parsaclisib. In the daily to weekly group, parsaclisib was administered at 10 mg/day or 20 mg/day for 8 weeks and then once per week. The daily group received 5 mg/day or 20 mg/day for 8 weeks and then 5 mg/day.
The group with a low platelet count achieved slightly higher spleen volume reduction (>10%) by week 12 and were approximately the same by week 24 compared with the higher platelet count cohort. Most of the patients in both groups were on a daily-dose regimen of parsaclisib. Interruptions in parsaclisib therapy were primarily observed due to thrombocytopenia (43% in the group with low platelet count vs 7% in the group with higher platelet count). Adverse events were mostly grade 1 or 2 (low platelet count: shortness of breath, falling, peripheral edema, nasal congestion; high platelet count: diarrhea, nausea, abdominal pain, cough, fatigue).
The data suggest add-on parsaclisib in combination with RUX is an effective treatment in patients with MF with a higher or low platelet count. Both groups demonstrated only mild nonhematologic adverse events and similar reductions in spleen volume response and total symptom score in response to parsaclisib. Traditionally hard-to-treat patients with low platelet counts and suboptimal response to RUX may benefit from add-on parsaclisib.
Source:
Yacoub A, Borate U, Rampal R, et al. Subgroup analysis from a phase 2 study of the efficacy and safety of parsaclisib, a selective PI3Kδ inhibitor, in combination with ruxolitinib in patients with myelofibrosis (MF). American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 3647.