While ruxolitinib improves outcomes in patients with myelofibrosis (MF), some patients’ disease may have a suboptimal response to JAK inhibition due to persistent PI3K/AKT pathway activation. In a phase II trial of patients with MF who were receiving ruxolitinib, the addition of parsaclisib, a highly selective next-generation PI3K? inhibitor, led to improvements in spleen volume reduction and symptom burden. The combination also appeared to be well tolerated.
Abdulraheem Yacoub, MD, from Kansas University Medical Center, who presented these findings at the 2021 AACR Annual Meeting, noted that the safety and efficacy findings appeared to favor the daily-dosing strategy.
The trial enrolled people with primary/secondary MF, an Eastern Cooperative Oncology Group score of ?2, and suboptimal response after at least 6 months of treatment with ruxolitinib. Suboptimal response was defined as palpable spleen >10 cm below left subcostal margin or palpable spleen 5 to 10 cm below LSM and active symptoms.
Per trial protocol, patients remained on their stable ruxolitinib dose and were randomized to either add-on parsaclisib QD/QW (10 or 20 mg once-daily for 8 weeks/same dose once-weekly thereafter) or parsaclisib QD (5 or 20 mg for eight weeks/5 mg once daily thereafter).
At the time of data cutoff, 33 patients had received parsaclisib QD/QW and 20 received it QD, for a median treatment duration of 197 days. The median average daily doses of each agent were parsaclisib 4.9 mg/day and ruxolitinib, 30.0 mg/day.
At baseline, spleen volumes were 2,333 cm3 in the QD/QW group and 1,890 cm3 in the QD group. The median percent changes in spleen volume by 12 weeks after parsaclisib addition were ?2.3% and ?15.4%, respectively. The reduction was greater at week 24 (?2.5% with QD/QW and ?25.4% with QD). One-third of patients had a spleen volume reduction ?10% at week 12 in the QD/QW group, compared with 59% in the QD group.
Myelofibrosis-Symptoms Assessment Form Total Symptom Scores dropped by a median of –14% in the QD/QW and ?39.6% in the QD group.
Notably, hemoglobin levels in all study subjects remained stable during the study and there were no cases of anemia. Also, in the daily dosing-only group, there was no colitis, grade 2 or higher diarrhea, or rash. One AE of special interest in the all-daily dosing group was varicella-zoster virus infection, which occurred in only 1 patient. AEs of special interest among patients treated daily/weekly were grade 2 or greater diarrhea in 4 patients, elevated liver function tests in 2 patients, grade 2 or greater rash in 1 patient, and varicella-zoster virus infection in 1 patient.
The nonhematologic adverse events (AEs) observed were primarily grade 1/2, Dr. Yacoub reported. Grade 3/4 treatment-related, nonhematologic AEs included disseminated tuberculosis, enteritis, fatigue, hypertension, increased alanine aminotransferase, and increased aspartate aminotransferase with QD/QW dosing and stomatitis with QD dosing. In the QD/QW and QD groups, respectively, 18% and 30% had new-onset grade 3 thrombocytopenia, but hemoglobin levels remained steady during the study in both groups. No colitis or dose-limiting diarrhea/rash occurred.
Approximately half of patients in each dosing group required an interruption of parsaclisib, and 12% in the QD/QW group and 2% in the QD group interrupted ruxolitinib due to AEs.
Based on these results, the authors concluded that add-on parsaclisib was efficacious in the population of patients with MF who experience suboptimal response to ruxolitinib response, with a preference for once-daily dosing.