Efficacy and Safety of Tyrosine Kinase Inhibitors in the Treatment of Relapsed/Refractory Immune Thrombocytopenia

Introduction:

Immune thrombocytopenia (ITP) is characterized by immune-mediated impairment of platelet production or platelet destruction leading platelet count of <100x10³/mm³. First-line therapy of ITP includes IV immunoglobulin, steroids, and anti-D. However, long-term durable responses to these therapies are uncommon. Fc receptors on splenic phagocytes signal via spleen tyrosine kinases (Syk). Bruton tyrosine kinase (BTK) plays a crucial role in B-cell maturation and Fcy receptor-mediated phagocyte function. Therefore, inhibiting SyK or BTKIs can reduce macrophage activation leading to ITP. In this review, we assessed the efficacy and safety of BTKIs in the treatment of relapsed/refractory ITP.

Methods:

We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Web of Science, Embase (Ovid), and clinicaltrials.gov. with mesh terms, “Immune thrombocytopenia” and “tyrosine kinase” from the inception of data till 07/01/2022. We screened 474 articles and included three randomized clinical trials (RCTs, N=195) and one non-RCT (N=60) in this review. In the included clinical studies, stable response (SR) was platelets ≥50000/ micro L on ≥4 of 6 biweekly visits, modified stable response (MSR) was ≥2 consecutive platelet counts, separated by at least 5 days of ≥50,000 per micro L and the overall response (OR) was ≥1 platelet count of ≥50 000/micro L within the first 12 weeks on treatment.

Results:

In 4 clinical trials (N=255), the range of age of relapsed/refractory TKI participants was 18 to 88. 135 patients were treated with Syk inhibitors, 60 with BTK inhibitors, and 60 with placebo. In two clinical trials (N=135), SR and OR were reported in 18/101 (17.8%) and 43/101 (42.5%) patients, respectively in patients treated with fostamatinib versus SR and OR in 1/49 (2%) and 7/49 (14%), respectively in patients treated with placebo. In a clinical trial by Yang et al. (N=45), SR and OR were reported in 5/16 (31%) and 11/16 (68.8%) patients, respectively treated with HMPL-523 (Syk inhibitor) versus SR and OR in 1/11 (9%) patients treated with placebo. In a clinical trial by Kuter et al. (N=60), SR and MSR were reported in 17/60 (28%) and 24/60 (40%) patients, respectively treated with rilzabrutinib. Table 1.

Diarrhea, hypertension, dizziness, and neutropenia were serious side effects reported with fostamatinib leading to dose reduction in 9% of the patients. There were no dose-limiting adverse events reported with rilzabrutinib and HMPL-523. Table 1.

Conclusion:

Syk inhibitors (fostamatinib and HMPL-523) and oral BTK inhibitor (rilzabrutinib) were effective and well tolerated by most of the patients with relapsed/refractory ITP. Rilzabrutinib and HMPL-523 had no dose-limiting side effects. A randomized phase III clinical trial (NCT04562766) is in progress to assess the efficacy and safety of rilzabrutinib. More trials are in progress to assess the efficacy and safety of novel TKIs like baricitinib, orelabrutinib, and zanubrutinib. Table 2.