Investigating Tyrosine Kinase Inhibitors for ITP

In two presentations presented at EHA25 Virtual, the 25th European Hematology Association Annual Congress, investigators shared updates on two kinase inhibitors for the treatment of adults with immune thrombocytopenia (ITP): fostamatinib and rilzabrutinib.

Fostamatinib: The Earlier, the Better

Patients with persistent or chronic ITP were more likely to respond to fostamatinib, a tyrosine kinase inhibitor that was approved by the FDA in 2018 for the treatment of chronic ITP, if it was initiated as second-line therapy, rather than as third line or beyond, according to an analysis of three phase III trials.1

In these three trials, which included two randomized trials and one open-label extension study, “the overall population was difficult to treat with long-standing disease and many prior therapies, but also included a subgroup of patients treated in earlier lines of therapy,” the researchers, led by Nichola Cooper, MD, of Hammersmith Hospital in the U.K., explained. With this post hoc analysis, the authors evaluated whether earlier treatment with fostamatinib resulted in better response rates.

Participants had persistent or chronic ITP that had not responded to prior ITP treatment and at least three platelet counts of <30×109/L at screening. Per study protocols, patients received oral fostamatinib 100 mg twice daily, which was escalated to 150 mg twice daily after 4 weeks if platelet counts were <50×109/L.

In the three trials, fostamatinib was given as:

  • second-line therapy in 32 patients
  • third-line therapy in 42 patients
  • fourth-line therapy in 27 patients
  • fifth-line therapy in 14 patients

Patients who received fostamatinib as second-line therapy had a shorter median duration of ITP compared with the total population (2.6 vs. 8.4 years). Those who received fostamatinib as their second-line ITP therapy also had a higher median platelet count (21×109/L vs. 16×109/L).

Overall, the platelet response rate (defined as the achievement of ≥1 platelet count of ≥50×109/L in the absence of rescue therapy) was 54%, the authors reported. In participants who received fostamatinib as second-line therapy, the platelet response rate was 78%, which was proportionally higher than patients who received fostamatinib as third- (64%), fourth- (52%), and fifth-line therapy (36%).

The durability of response, defined as the median percentage of time on therapy when responders continued to experience a response, was 86% among all fostamatinib-treated patients. Earlier treatment did not appear to affect duration of response, the authors reported, with durability of response at 83% for second-line, 86% for third-line, 81% for fourth-line, and 95% for fifth-line therapy.

Looking at the safety profile according to line of therapy, the researchers noted that the type and frequency of adverse events (AEs) in the second-line patients were consistent with those of the overall population. All AEs were generally mild or moderate in severity, they added, and were resolved or managed with dose modifications, with or without the addition of a secondary therapy.

Rilzabrutinib: An Investigational BTK Inhibitor

In a small phase I/II trial of the investigational Bruton tyrosine kinase (BTK) inhibitor rilzabrutinib, half of patients were able to achieve ≥2 consecutive platelet counts of ≥50×109/L. The treatment also was associated with significant increases in platelet count from baseline, without the use of rescue therapy.2

“BTK inhibition targets both adaptive and innate drivers of immune-mediated disease,” explained David J. Kuter, MD, DPhil, from Massachusetts General Hospital, during his EHA25 Virtual presentation. But, unlike the BTK inhibitor ibrutinib, he added, the reversible, small molecule inhibitor rilzabrutinib does not alter platelet aggregation.

As of April 22, 2020, investigators enrolled 42 patients with relapsed or refractory ITP (primary or secondary) whose disease had previously responded to prior ITP therapy but who have no available treatment options. Eligible participants had two platelet counts <30×109/L. Patients were heavily pretreated, Dr. Kuter noted, with a median of 6 prior therapies and a median ITP duration of 7.8 years at baseline. Median platelet count at baseline was 14×109/L.

Oral rilzabrutinib was administered at starting doses of 200 mg once daily, 400 mg once daily, 300 mg twice daily, or 400 mg twice daily. Intra-patient dose escalation was permitted every 4 weeks, as were stable doses of concomitant corticosteroids and thrombopoietin receptor agonists.

Of the 36 patients who had been treated with rilzabrutinib for at least 12 weeks by the time of data presentation, 18 (50%) achieved the study’s primary endpoint. Thirteen of the 26 patients who received the highest dose of rilzabrutinib (400 mg twice daily) achieved the primary endpoint.

Responses were achieved early, with more than half of patients reaching the primary endpoint by week 4 of treatment and maintained it over time, the authors reported. The benefit appeared to be consistent across subgroups, including in heavily pretreated patients (≥4 prior therapies), in those who received rilzabrutinib as a monotherapy, and in those who received concomitant therapy.

Twenty-one patients (45%) experienced treatment-related AEs, all of which were grade 1/2 and transient. These included diarrhea (34%), nausea (28%), and fatigue (13%). No dose-limiting toxicities, treatment-related bleeding events, or thrombotic events were reported.

The findings are limited by the small patient population and short follow-up. Dr. Kuter said that enrollment in the 400-mg twice-daily group is continuing to further characterize the magnitude and durability of clinical benefit.

Study authors report relationships with Rigel Pharmaceuticals, the manufacturer of fostamatinib, and Principal Bio, the manufacturer of rilzabrutinib.


  1. Cooper N, Ghanima W, Hill Q, et al. Second-line therapy for immune thrombocytopenia with the spleen tyrosine kinase inhibitor fostamatinib. Abstract EP1625. Presented as part of EHA25 Virtual, June 12, 2020.
  2. Kuter DJ, Boccia RV, Lee E-J, et al. Safety and efficacy of rilzabrutinib (PRN1008), an oral Bruton tyrosine kinase inhibitor, in relapsed/refractory patients with primary or secondary immune thrombocytopenia: phase I/II adaptive study. Abstract EPS316. Presented as part of EHA25 Virtual, June 12, 2020.