Investigating the Effectiveness and Safety of Combining Thrombopoietin Receptor Agonist and Immunosuppressant Drugs for Patients with Multirefractory Immune Thrombocytopenia after Second-Line Monotherapy Treatments
Authors: Mingot-Castellano Maria Eva , Alcalde Mellado Patricia , Entrena Ureña Laura , Pascual Izquierdo Maria Cristina , Zafra Denis , Canaro Hinryk Mariana , Bastida Jose Maria , Bernat Silvia Bernat , Martinez Carballeira Daniel , Caparros Miranda Isabel , Cuesta Garcia Amalia , Lakhwani Sunil , Sanchez Gonzalez Blanca , Canet Maldonado Marta , Gómez del Castillo Solano Maria Carmen , García Culebra Marta , Chiclana Rodriguez Beatriz , Fernanadez-Villalobos Manuel , Sanchez Llorca Paula , Piquer Monsonis Lola , Puerta Vazquez Carlos , Perez Montes Rocio , Garcia-Pallarols Francesc , Valcarcel David , Pedrote Amador Begoña 
Published: December 2024

Introduction
Combining thrombopoietin receptor agonists (TPO-RAs) with immunosuppressant drugs (ISTs) may be beneficial for patients with multi-refractory immune thrombocytopenia (mrITP). There is limited evidence based on small series and clinical cases, with the longest series involving 39 patients from the French ITP registry. Our objective is to describe the types of combinations used, the rate and type of response, and the safety profile of combined TPO-RA and IST treatment in mrITP in our setting.
Material and Methods
This is a multicenter, observational and retrospective study endorsed by the Spanish ITP group (GEPTI). Patients with ITP older than 18 years old, refractory to three or more lines of treatment in monotherapy, who received combined TPO-RA and IST therapy between January 2021 and December 2023 were included. The response criteria used were The International Working Group standards. Statistical analysis was applied with 95% confidence interval, 5% significance level, using chi-square or ANOVA for group comparisons.
Results
A total of 113 patients were included in this study, with 130 different combinations treatments indicated. The median age was 53 years (IQR: 34-65), 47.6% were male and 35.4% had two or more vascular risk factors. Regarding the phase of ITP, 65% of cases were chronic ITP (cITP). The median number of previous treatment lines was 4 (IQR, 3-7). The TPO-RAs used included eltrombopag (ELT) in 44% of cases, romiplostim (ROM) in 36%, and avatrombopag (AVA) in 20%. The most commonly used ISTs were prednisone (41%), azathioprine/mycophenolate (20.3%), and dexamethasone (19%). The median time from ITP diagnosis to combination therapy was 31 months (IQR: 6.8-103). The overall response rate was 75.4% (62.3% complete responses), which was higher in those treated with ROM (84.1% vs. 69.2%, p = 0.012), with no differences according to IST. The median time to response was 15 days (IQR: 7-60). The response time was shorter in those treated with dexamethasone (median 6 days vs. 15 days, p = 0.048), with no difference according to TPO-RA. The median weekly dose of TPO-RA at the time of response was ELT 525mg (IQR:350-525), ROM 531mcg (IQR: 352.5-772.5), and AVA 280mg (IQR: 280-280).
With a median follow-up of 120 weeks (IQR: 69.5-170), 22.4% of subjects required rescue treatment on at least two occasions, with 14% needing hospitalization. 73% of patients maintained response, and 60% of responses were complete. Treatment was discontinued in 12 patients while maintaining the response (responsible use of medications in 7 patients and eltrombopag in 5, combined with prednisone or azathioprine). In terms of safety, 14% of the people treated with corticosteroids needed antidiabetic treatment. There were three thrombotic events reported (1 venous sinus thrombosis and 2 ischemic events. Three patients were hospitalized for SARS-CoV-2 pneumonia. Additionally, 16% of the subjects received antibiotic prevention, and 19% were given osteopenia prevention. Five patients experienced digestive issues with ELT treatment. Among those treated with fostamatinib, one case of hypertension and two cases of grade 2 digestive issues were reported.
Conclusion
The combination of TPO-RAs and immunosuppressants has been effective and safe in treating multi-refractory ITP in our experience. However, more clinical trials are needed to validate its use.