Recombinant Human Thrombopoietin (rh-TPO) in Combination with Rituximab As a Novel Therapy in Corticosteroid-Resistant Primary Immune Thrombocytopenia (ITP)
Authors: Guo Li , Dong Xiaoyuan , Li Jie , Ji Danyan , Qin Ping , Peng Jun , Xu Ruirong , Wang Xin , Zhou Yuhong , Hou Ming 
Published: October 2019

Abstract
Abstract 2223

Background:
Both thrombopoietin (TPO) receptor agonist and rituximab were recommended as second-line options for adult primary immune thrombocytopenia (ITP) according to the 2010 International Consensus Guideline. The mechanism of rituximab therapy mainly refers to inhibition of accelerated platelet destruction mediated by autoantibody, while the latter, TPO receptor agonist, is reported to be effective in the salvage of impaired platelet production in patients. Despite the considerable response rate (about 50–70%) and sustained response (about 20–40%), the median time to response (TTR) was about 5.5 weeks for patients undergoing rituximab therapy, indicating high bleeding risk in the early stage of the treatment (Arnold, et al. Ann Intern Med. 2007;146:25–33.). On the other hand, novel TPO receptor agonists could initiate fast but unenduring responses. We hereby report a novel therapy which combines low-dose rituximab with short-term application of a TPO receptor agonist, the recombinant human thrombopoietin (rh-TPO), based on the preliminary results of an ongoing multi-centered, non-randomized clinical study in corticosteroid-resistant adult ITP patients.

Patients:
Twenty-one adult ITP patients were enrolled since December, 2009. All the subjects had a baseline platelet count (PC) of <30×109/L or bleeding, were refractory to, or had relapsed after, at least one prior corticosteroids therapy and splenectomy, or acquired corticosteroid-resistance but were excluded from splenectomy, without application of other second-line therapies recommended in the Guideline in the previous 3 weeks.

Methods:
Rituximab was given intravenously at a dose of 100 mg weekly for 4 consecutive weeks (Day 1, 8, 15, 22). Rh-TPO (TPIAO™, a product of Sunshine Pharmaceutical Co Ltd, China, approved by China State Food and Drug Administration) was given subcutaneously at a dose of 1.0 μg/kg daily for 14 days (Day 1–14). PC was monitored every three or four days until day 22, followed by tests every week. Responses were required to be independent of measures and supportive platelet transfusion. The criteria for response were defined as follows: (1) complete response (CR): platelet count >100×109/L and; (2) response (R): platelet count>30×109/L and at least 2-fold increase the baseline count and absence of bleeding; (3) No response (NR): platelet counts <30×109/L or less than 2-fold increase of baseline platelet count or bleeding. TTR: times from starting treatment to time of achievement of CR or R. Patients were followed for 3 months, and any adverse effects were recorded during the period of treatment and during the follow-up.

Results:
All the patients received the therapy, but 4 were lost during follow-up. The efficacy of treatment is outlined in Table 1. Compared with rituximab alone, the combination therapy resulted in a rapid response (TTR 9 vs. 21–44 days) with similar response rate (CR 57% vs. 30–60%, OR 76% vs. 50–70%). Moreover, the rh-TPO seemed to not only shorten the TTR but also significantly increase the sustained response (69% vs. 20–40%), indicating a synergistic effect with rituximab. In addition, there was no toxicity overlap observed. Adverse events recorded were mild (WHO grades 1–2), including fever (2), fatigue (2), myalgia (2), secondary infection (2), chills (1),and insomnia (1). No serious adverse events occurred during the course of treatment and the period of follow-up.

Conclusions:
The efficacy of this novel combination therapy are very satisfactory, considering the higher overall and complete response, shorter TTR as well as higher sustained response, in comparison with administrating rituximab alone. However, the combination should be used with caution and needs further and larger scale observation, especially to monitor for serious adverse effects such as thrombosis, bone marrow fibrosis and infection.

Disclosures:
No relevant conflicts of interest to declare.