All-Trans Retinoic Acid Plus Low-Dose Rituximab Vs Low-Dose Rituximab in Corticosteroid-Resistant or Relapsed ITP
Authors: Wu Ye-Jun , Liu Hui , Zeng Qiao-Zhu , Liu Yi , Wang Jing-Wen , Wang Wen-Sheng , Feng Jia , Zhou He-Bing , Huang Qiu-Sha , Fu Hai-Xia , Zhu Xiao-Lu , He Yun , Jiang Hao , Chang Ying-Jun , Xu Lan-Ping , Huang Xiao-Jun , Zhang Xiao-Hui 
Published: November 2021

Abstract
Introduction
Approximately one-third of immune thrombocytopenia (ITP) patients fail to achieve a response with first-line treatments, and most patients who respond to first-line treatment relapse and require further second-line therapies. Rituximab (RTX) has been frequently used in ITP treatment, and proposed schedules include the standard dose (SD) and low dose (LD). Previous studies on LD-RTX in ITP revealed a comparable overall response (OR) and reduced incidences of short- and long-term complications (e.g., infections) compared with SD-RTX (Blood, 2012; Platelets, 2019). However, LD-RTX does not achieve a rapid and long-lasting response in the treatment of ITP. Our preliminary studies demonstrated the efficacy of all-trans retinoic acid (ATRA) in the ITP model due to its effects on inducing megakaryocyte maturation and its immunomodulatory effects (Stem Cells Dev, 2017; J Thromb Haemost, 2017; Br J Haematol, 2018; Haematologica, 2019). Since RTX and ATRA share disparate mechanisms in treating ITP, a combination of RTX and ATRA may work synergistically based on a "double-hit" mechanism targeting both platelet production and destruction, which may overcome the long TTR and improve the SR rate of LD-RTX. Therefore, our study aimed to determine the efficacy and safety of ATRA plus LD-RTX compared to LD-RTX monotherapy in patients with corticosteroid-resistant or relapsed ITP (NCT03304288).
Methods
Eligible corticosteroid-resistant or relapsed ITP patients with a platelet count &lt; 30 × 10 9/L or bleeding symptoms at enrolment were randomly allocated in a 2:1 ratio to receive 100 mg of RTX weekly for 6 weeks plus ATRA orally at 20 mg/m 2 daily for 12 weeks or 100 mg of RTX weekly for 6 weeks. Stable doses of concomitant corticosteroids, danazol, and cyclosporin were permitted. Treatment was discontinued if platelet counts in two consecutive tests at least 2 weeks apart were more than 300 × 10 9/L and resumed when the platelet count fell to less than 150 × 10 9/L. Assessments were performed at baseline, weekly during the first 4 weeks, every 2 weeks until week 24, and every 4 weeks thereafter. The primary outcome was OR, defined as a platelet count ≥ 30 × 10 9/L, a doubling of the baseline platelet count and the absence of bleeding. Secondary endpoints included sustained response (SR), initial response, complete response, time to response, duration of response and adverse events. SR was defined as maintenance of a platelet count &gt; 30 × 10 9/L, the absence of bleeding, and no requirement for other ITP-specific treatment for 6 consecutive months.
Results
One hundred sixty-eight patients from 7 tertiary medical centres in China were included between 2017 and 2020, 112 patients received combination treatment of LD-RTX and ATRA, and 56 patients received LD-RTX monotherapy. All the baseline characteristics were comparable between the two groups. The median ages of patients in the LD-RTX plus ATRA group and LD-RTX monotherapy group were 46.0 years and 44.5 years, respectively. For patients in the combination and monotherapy groups, the median number of previous therapies was 2.0. The median baseline platelet count was 17.0 × 10 9/L in the combination group and 19.0 × 10 9/L in the monotherapy group. All the patients were followed up for more than 11 months. OR was observed in 90 (80.4%) patients in the combination group and 33 (58.9%) in the LD-RTX monotherapy group (between-group difference, 0.22; 95% CI, 0.07 to 0.36), indicating that the combination treatment increased the response rate. SR was achieved by 68 (60.7%) patients in the combination group and 23 (41.1%) patients in the monotherapy group at the 6-month follow-up (between-group difference, 0.20; 95% CI, 0.04 to 0.35). Additionally, 56 (50%) subjects in the combination group and 19 (34%) in the monotherapy group were still in sustained remission at 12 months (between-group difference: 0.16; 95% CI, -0.01 to 0.33). No significant difference was found between the 2 treatment groups in terms of the time to a response. The severity of AEs was primarily of grade 1-2. The 2 most common AEs for the combination group were dry skin and headache or dizziness, with incidences of 40.2% (45/112) and 18.8% (21/112), respectively.
Conclusions
In conclusion, ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a novel promising treatment option for corticosteroid-resistant or relapsed adult ITP patients.

Disclosures
No relevant conflicts of interest to declare.