Parsaclisib Plus Ruxolitinib Demonstrates Splenic Volume Reduction in Myelofibrosis Irrespective of Platelet Count

Add-on parsaclisib and ruxolitinib (Jakafi) elicited promising spleen volume reduction in patients with myelofibrosis who experienced suboptimal response to ruxolitinib alone, regardless of baseline platelet count, according to findings from a subgroup analysis of a phase 2 study (NCT02718300) that were presented at the 2022 EHA Congress.

By week 12, 85.7% (n = 18) of patients with low platelet counts had achieved spleen volume reduction compared with 82.6% (n = 38) of patients with higher platelet counts. Of these patients, 50% (n = 9) achieved at least a 10% reduction in the low platelet count group vs 39% (n = 15) in the higher platelet count group. Additionally, 1 patient (6%) in the low platelet count group achieved at least a 25% reduction compared with 4 patients (11%) in the higher platelet count group. No patients in the low platelet count group achieved at least a 35% reduction compared with 1 patient (3%) in the higher platelet count group.

“In patients with myelofibrosis [who received] a stable dose of ruxolitinib, the addition of parsaclisib resulted in splenic volume reduction and occasional deep responses in both groups with low platelet counts and higher platelet counts,” said lead study author Abdulraheem Yacoub, MBBS, associate professor, hematologic malignances and cellular therapeutics at the University of Kansas Medical Center, in a presentation of the data.

Ruxolitinib, a potent JAK1 and JAK2 inhibitor, has shown efficacy in patients with myelofibrosis. However, some patients may display suboptimal responses or no responses to this therapy. Parsaclisib is a highly selective next-generation PI3Kδ inhibitor that, when combined with a stable dose of ruxolitinib, showed preliminary efficacy in a phase 2 trial in patients with myelofibrosis who had suboptimal responses to ruxolitinib alone.

However, JAK inhibitors such as ruxolitinib can cause thrombocytopenia, a particular issue in patients with low platelet counts. A subgroup analysis of the ongoing phase 2 trial evaluated the effect of baseline platelet count on the efficacy and safety of parsaclisib when added to ruxolitinib.

Patients 18 years of age or older were eligible for enrollment in this study if they had primary or secondary myelofibrosis, including post–polycythemia vera myelofibrosis or post–essential thrombocythemia myelofibrosis. Eligible patients also needed to have suboptimal response to ruxolitinib monotherapy after being treated with ruxolitinib at a dose of 5 to 25 mg twice daily for at least 6 months with a stable dose for at least 8 weeks immediately before enrollment. Patients also needed to have a platelet count of at least 50 x 10⁹/L in the 4 weeks prior to screening.

Additional enrollment criteria included a palpable spleen of over 10 cm below the left subcostal margin, or a palpable spleen of 5 to 10 cm below the left subcostal margin and active symptoms of myelofibrosis. Active symptoms were defined as 1 symptom score of at least 5 or 2 symptom scores of at least 3 each, using the 10-point scale on the trial’s Screening Symptom Form.

Patients enrolled in the trial received a stable ruxolitinib dose and add-on parsaclisib at either 10 mg or 20 mg once a day (QD) for 8 weeks and then once a week thereafter, or 5 mg or 20 mg QD for 8 weeks and 5 mg QD thereafter.

For the purposes of this subgroup analysis, patients were grouped into low vs high platelet count groups, with low being defined as platelet counts of 50 to less than 100 x 10⁹/L, and high being defined as platelet counts of at least 100 x 10⁹/L.

Baseline characteristics collected from both subgroups showed the patients with low platelet counts to have a longer median time since initial diagnosis, 52.6 months (range, 10.1-268.9) vs 30.5 months (range, 4.9-212.6) in patients with higher platelet counts. Additionally, patients with low platelet counts had experienced longer durations of prior ruxolitinib therapy, at a median of 34.7 months (range, 8.7-93.9) vs 14.9 months (range, 5.1-78.2) in patients with higher platelet counts. A larger median spleen volume was also observed in the low platelet count group, at 2119 cm3 (range, 574-5324) compared with 1934 cm3 (range, 327-4793) in the higher platelet count group. Patients with lower platelet counts also reported higher symptom burdens at a median of 21.4 (range, 0.6-47.0) compared with 10.0 (range, 0-43.0) in patients with higher platelet counts. Symptom burdens were measured using the Myelofibrosis Symptom Assessment Form (MFSAF) v3.0, which measured total symptom score (TSS).

At a data cutoff of August 27, 2020, out of the 67 enrolled patients, 32 had received parsaclisib at daily then weekly dosing, and 35 had received parsaclisib at all daily dosing. When analyzed for baseline platelet count, 21 patients were found to have low platelet counts, and 46 were found to have high platelet counts.

The median duration of treatment was 30.4 weeks (range, 0.6-147.6). The median average daily dose was 30.0 mg per day for ruxolitinib and 5.0 mg per day for parsaclisib.

The primary end point of this study was a change in spleen volume from the start of treatment to week 12, measured by magnetic resonance imaging or computed tomography scan. Secondary end points included a change in spleen volume from the start of treatment to week 24, a change in spleen length from the start of treatment to the time of each study visit, a change in TSS from the start of treatment to weeks 12 and 24, and safety.

Additional efficacy results showed that by week 24, 81% (n = 17) of patients with low platelet counts had achieved spleen volume reduction compared with 76.1% (n = 35) of patients with higher platelet counts. Of these patients, 35% (n = 6) in the low platelet count group achieved at least a 10% reduction vs 37% (n = 13) in the higher platelet count group. Of these patients, 4 with low platelet counts and 9 with higher platelet counts were receiving all daily dose regimens of parsaclisib. Additionally, 18% (n = 3) of the lower platelet count group achieved at least a 25% reduction compared with 23% (n = 8) of the higher platelet count group. A total of 2 patients (12%) in the low platelet count group achieved at least a 35% reduction vs 1 patient (3%) in the higher platelet count group.

“The reduction in splenic length by examination was [observed to be] similar between the 2 subgroups [over 24 weeks],” Yacoub noted.

The addition of parsaclisib to a stable dose of ruxolitinib resulted in similar TSS improvements and median percentage change in TSS in both subgroups. At 12 weeks, 11 patients in the low platelet count group experienced a –20.5% change (range, –56.6-17.1) in TSS compared with 27 patients in the higher platelet count group who experienced a –22.2% change (range, –100.0-500). At 24 weeks, 10 patients in the low platelet count group experienced a –26.1% change (range, –54.7-2.4) in TSS compared with 18 patients in the higher platelet count group who experienced a –23.3% change (range, –91.3-222.5).

In terms of safety, the nonhematologic treatment-emergent adverse effects (TEAEs) were primarily grade 1 or 2. The most common TEAEs in the low platelet count group were diarrhea (any grade, 19%), nausea (any grade, 19%; grade 3 or higher, 5%), fall (any grade, 33%; grade 3 or higher, 10%), abdominal pain (any grade, 10%), cough (any grade, 19%), fatigue (any grade, 14%; grade 3 or higher, 5%), dyspnea (any grade, 33%; grade 3 or higher, 10%), peripheral edema (any grade, 29%; grade 3 or higher, 5%), and nasal congestion (any grade, 24%).

The most common TEAEs in the higher platelet count group were diarrhea (any grade, 28%; grade 3 or higher, 2%), nausea (any grade, 24%), fall (any grade, 13%), abdominal pain (any grade, 24%; grade 3 or higher, 2%), cough (any grade, 20%), fatigue (any grade, 20%; grade 3 or higher, 2%), dyspnea (any grade, 7%), peripheral edema (any grade, 2%), and nasal congestion (any grade, 4%).

In total, 43% (n = 9) pf patients in the low platelet count group experienced interruption of parsaclisib treatment due to thrombocytopenia compared with 7% (n = 3) of patients in the higher platelet count group. One patient in the low platelet count group experienced thrombocytopenia that led to ruxolitinib treatment interruption. All dose interruptions of both parsaclisib and ruxolitinib were temporary, and patients were able to resume treatment.

A total of 71% (n = 15) of patients in the low platelet count group discontinued treatment. Reasons for discontinuation included progressive disease or lack of efficacy (14%, n = 3), physician decision (33%, n = 7), AEs (14%, n = 3), subject withdrawal (5%, n = 1), and other reasons (5%, n = 1). Of the patients in the higher platelet count group, 61% (n = 28) discontinued treatment. Reasons for discontinuation included progressive disease or lack of efficacy (20%, n = 9), physician decision (9%, n = 4), AEs (11%, n = 5), subject withdrawal (11%, n = 5), death (4%, n = 2), and other reasons (6.5%, n = 3).

These AE profiles demonstrate that this combination is tolerable in patients with both low and higher platelet counts.

In total, 29% (n = 6) of patients in the low platelet count group are still receiving treatment, as well as 39% (n = 18) of patients in the higher platelet count group.

“These results suggest that patients can benefit from treatment with add-on parsaclisib to a stable dose of ruxolitinib, irrespective of their platelet counts,” Yacoub concluded.

Phase 3 studies of parsaclisib added to ruxolitinib (NCT04551053) and frontline parsaclisib plus ruxolitinib (NCT04551066) are being conducted to further investigate the effects of combining JAK and PI3K inhibitors in this setting. Both studies include patients with low platelet counts.

Reference

Yacoub A, Borate U, Rampal R, et al. Efficacy and safety of parsaclisib-ruxolitinib combination therapy in myelofibrosis patients with low vs higher baseline platelet count: a subgroup analysis of data from a phase 2 study. Presented at: 2022 EHA Congress; June 9-12, 2022. Vienna, Austria. Abstract P1063.