A combination regimen comprising all-trans retinoic acid (ATRA) plus low-dose rituximab was associated with an 80% overall response rate and a 61% sustained response rate in patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia (ITP). These results, published in Blood, suggest the combination could offer a promising management approach for this challenging patient population.
Given that rituximab and ATRA have different mechanisms as they relate to ITP treatment, a combination of the therapies “may work synergistically based on a ‘double-hit’ mechanism targeting both platelet production and destruction, which may overcome the long time to response and improve the rate of sustained response with low-dose rituximab,” wrote lead author Ye-Jun Wu, MD, of Peking University People’s Hospital in Beijing, China, and colleagues.
In their open-label, multicenter study, the researchers sought to gauge the efficacy and safety of the ATRA and low-dose rituximab combination versus low-dose rituximab alone in 168 patients with corticosteroid-resistant or relapsed ITP. Patients across seven tertiary medical centers in China were randomly assigned to either the ATRA plus low-dose rituximab combination (n=112) or low-dose rituximab monotherapy (n=56).
Rituximab was administered at a fixed 100 mg weekly dose for six weeks. In the combination arm, oral ATRA was administered at a dose of 20 mg/m2 per day for a total of 12 weeks. The combination treatment lasted for 12 weeks, while patients in the monotherapy arm received treatment for six weeks. The investigators made allowances for treatment discontinuation, including patient withdrawals due to severe side effects, loss to follow-up, or other interventions. Treatment was also discontinued for cases in which platelet counts were >300×109/L in two consecutive tests at least two weeks apart, but treatment was then resumed if platelet counts decreased to <150×109/L.
The primary endpoint included overall response (OR), which was defined as a platelet count of ≥30×109/L, and at least a doubling of the platelet count from baseline without other ITP-specific therapy, as well as absence of bleeding for one year after enrolment. Researchers looked for the primary endpoint at any time during the one-year period following enrollment. Assessments were conducted at baseline, weekly during the first month, every two weeks until week 24, and every four weeks thereafter.
Additionally, the investigators examined sustained response, which was defined as a sustained platelet count of >30 x 109/L, an absence of bleeding, and no need for any other ITP-specific therapy for six consecutive months after achieving an overall response during the year after enrollment.
At the time of enrollment, approximately 14% of patients in the combination therapy arm and 18% of patients in the monotherapy arm were on maintenance therapy. The median ages were 46.0 years in the combination arm and 44.5 years in the monotherapy arm, while the median duration from ITP diagnosis was 20.0 and 20.5 months, respectively. There were more males in the combination arm (53%) versus the monotherapy arm (43%).
All patients enrolled in the study had disease that was not controlled by first-line corticosteroid treatment. Each group of patients had received a median of two prior therapies. The median baseline platelet counts were 17.0×109/L and 19.0×109/L in the combination group and in the monotherapy group, respectively.
The OR primary endpoint was reported in a significantly greater proportion of patients assigned to low-dose rituximab plus ATRA compared with those assigned to low-dose rituximab monotherapy (80% vs. 59%, respectively; between-group difference = 0.22; 95% CI 0.07-0.36). In addition, the sustained response was observed in 61% of patients treated with the combination regimen versus 41% of patients treated with low-dose rituximab alone (between-group difference = 0.20; 95% CI 0.04-0.35).
In terms of safety, the most frequently reported adverse events (AEs) in the combination arm included dry skin (40.2%) and headache or dizziness (18.8%). In the monotherapy arm, the most frequently reported AEs included fever (21.4%) and upper respiratory infection (14.3%).
The study protocol did not mandate patients and clinicians be blind to assigned treatments, which the researchers suggest may have affected the results. Despite this limitation, the investigators note that masked experts collected and analyzed all study data to help minimize bias.
The researchers reported no relevant conflicts of interest.
Wu Y, Liu H, Zeng QZ, et al. All-trans retinoic acid plus low-dose rituximab vs low-dose rituximab in corticosteroid-resistant or relapsed ITP [published online ahead of print, 2021 Oct 19]. Blood. doi: 10.1182/blood.2021013393.