Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton’s tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)–mediated platelet destruction and reduced production of pathogenic autoantibodies. In an international, adaptive, open-label, dose-finding, phase 1–2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×10³ per cubic millimeter and an increase from baseline of ≥20×10³ per cubic millimeter without the use of rescue medication). Sixty patients were enrolled. At baseline, the median platelet count was 15×10³ per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×10³ per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×10³ per cubic millimeter was 65%. Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.)

Primary immune thrombocytopenia is an autoimmune disease mediated by antiplatelet autoantibodies that cause platelet destruction and suppression of platelet production. In vitro effects of autoantibodies on megakaryocyte production and maturation have been recently reported. However, the impact of these autoantibodies on the crucial megakaryocyte function, proplatelet formation and the subsequent platelet release, has not been evaluated. We examined the effects of serum and IgG from 19 immune thrombocytopenia patients using Day 8 or 9 megakaryocytes (66.3 +/- 10.6% CD41+), derived from cord blood haematopoietic stem cells (CD34+). The number of proplatelet-bearing megakaryocytes, the number of platelets released in the culture, total megakaryocyte numbers, ploidy pattern and caspase activation were measured at various days after treatment. After 5 days of treatment the number of proplatelet-bearing megakaryocytes was significantly decreased by 13 immune thrombocytopenia autoantibodies relative to the control group (P < 0.0001) and this decrease was accompanied by a corresponding reduction of platelet release. Other features including total megakaryocyte numbers, maturation and apoptosis were not affected by immune thrombocytopenia antibodies. Moreover, we show that treatment of megakaryocytes with thrombopoietin receptor agonists romiplostim and eltrombopag reversed the effect of the autoantibodies on megakaryocytes by restoring their proplatelet formation capacity. We concluded that antiplatelet antibodies in immune thrombocytopenia inhibit proplatelet formation by megakaryocytes and hence their ability to release platelets and treatment with either romiplostim or eltrombopag regenerates proplatelet formation from these megakaryocytes.

Key Points: Triple therapy is well tolerated and effective in patients with chronic ITP. Relapse free survival was 92% for responders after 12 months and 76% after 24 months.

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Introduction The absence of high quality evidence for basic clinical dilemmas in immune thrombocytopenic purpura (ITP) underlines the need for contemporary guidelines relevant to the local treatment...