In a phase II study published in Blood, the oral SYK inhibitor fostamatinib was safe and effective in a cohort of 16 patients with refractory immune thrombocytopenia (ITP). At the 22nd Congress of the European Hematology Association, James Bussel, MD, from the Division of Pediatric Hematology/Oncology at Weill Cornell Medicine in New York, and colleagues presented results from two phase III studies in which fostamatinib improved platelet counts in patients with heavily pretreated severe chronic ITP, appearing to confirm those earlier results.
The two parallel, identical, multicenter, randomized, double-blind trials (S047 and S048) included 150 patients (median age = 54 years; range = 20-88 years) with three documented platelet counts <30,000/µL: 76 patients in S047 and 74 patients in S048.
Patients were randomized 2:1 based on prior splenectomy and baseline platelet count (<15,000/µL vs. ≥15,000/µL) to receive fostamatinib 100 mg or placebo twice-daily for 24 weeks.
Patients had ITP for a median of 8.5 years (range not provided) prior to enrollment and the median baseline platelet count was 16,000/μL (range not provided). The most common prior treatment was steroids (94%), followed by thrombopoietin receptor agonists (TPO-RAs; 47%), splenectomy (35%), and rituximab (32%).
Between the two trials, 29 of 101 patients responded to fostamatinib, compared with one of 49 patients in the placebo groups, for an overall response rate of 29 percent versus 2 percent (p<0.001):
- stable response (SR; defined as platelet count ≥50,000/μL at 4 of 6 biweekly visits over weeks 14-24 without rescue treatment) = 18 vs. 1 (p=0.007)
- intermediate response (IR; defined as at least 2 consecutive biweekly platelet counts ≥50,000/μL without rescue treatment) = 11 vs. 0 (p<0.001)
For fostamatinib-treated patients, median platelet counts at 24 weeks of follow-up were 95,000/μL for those in SR, 49,000/μL for those in IR, and 20,500/μL in non-responders (ranges not provided). In the placebo group, however, median platelet counts only reached 17,500/μL (range not provided).
More than half of fostamatinib-treated patients (54%) had increased platelet levels ≥20,000/μL, compared with 29 percent of patients receiving placebo (n=14/49; p=0.005).
In patients who responded to fostamatinib (SR and IR), the median time to first platelet count ≥50,000/μL was two weeks (range not provided). Rescue medications (including platelet transfusions and intravenous immunoglobulin) were required in 17 percent of patients in SR (n=3/18), nine percent of patients in IR (n=1/11), and 36 percent of non-responders (n=26/72). In the placebo group, 45 percent of patients (n=22/49) required these therapies.
Factors such as age (<65 vs. ≥65 years), sex, baseline platelet count <15,000/µL, and prior treatment with a TPO-RA or splenectomy did not substantially affect response rates, the authors reported.
The researchers also presented data from an open-label study (S049), which included 41 patients who completed or discontinued early from S047 or S048 after receiving fostamatinib. Twenty-two percent of patients (n=9/41) achieved SR, which was consistent with the two identical parallel trials.
In the two trials, serious bleeding occurred in 5.6 percent of non-responders and 10.2 percent of those receiving placebo, but did not occur in any of the 29 patients who achieved a response.
Most patients in both groups experienced one or more adverse events (AEs; 83% with fostamatinib and 75% with placebo), the most common of which were diarrhea (29% vs. 15%), nausea (19% vs. 8%), hypertension (20% vs. 8%), and increased alanine transaminase/aspartate transaminase (10% vs. 0%; p values not provided). Serious AEs were reported in 13 percent receiving fostamatinib and 21 percent receiving placebo.
Based on the safety and efficacy results from the phase III trials, the U.S. Food and Drug Administration (FDA) accepted the new drug application for fostamatinib for the treatment of chronic ITP on June 19, 2017. The drug was previously granted orphan drug designation.
“Given its unique mechanism of action based on inhibition of SYK, fostamatinib could, if approved [by the FDA], be an important alternative as [a] single agent and be a useful component of combination therapy for patients with difficult chronic ITP,” the authors concluded.
However, they wrote, the results will need to be confirmed in larger trials with longer-term follow-up, and fostamatinib should be compared with standard treatments for chronic ITP. Additionally, the open-label design of S049 may have introduced bias in determining treatment efficacy.
Dr. Bussel reports research funding from Rigel Pharmaceuticals.
Bussel J, Mayer J, Cervinek L, et al. Treatment of primary adult chronic immune thrombocytopenia (CITP) with fostamatinib, an oral SYK inhibitor: results of two randomized, placebo-controlled phase 3 studies. Abstract #S435. Presented at the 22nd Congress of the European Hematology Association, June 24, 2017; Madrid, Spain.