The combination of all-trans retinoic acid and high-dose dexamethasone was found to be a safe and active first-line therapy for patients with newly diagnosed immune thrombocytopenia. With few and mild side-effects at 6 months, all-trans retinoic acid plus high-dose dexamethasone resulted in a higher sustained response rate, a lower risk of clinically significant bleeding, and improved health-related quality of life, compared with high-dose dexamethasone alone.
To date, prednisolone and high-dose dexamethasone are considered the standard of care first-line treatments for adult patients with newly diagnosed immune thrombocytopenia (ITP). Unfortunately, only 40-50% of patients have a sustained response within six months after drug discontinuation. All-trans retinoic acid is an active natural metabolite of vitamin A that regulates various biological processes, including the innate and adaptive immune systems. This metabolite has been used for the treatment of several autoimmune disorders, including ITP, with encouraging results. All-trans retinoic acid and high-dose dexamethasone might work synergistically by targeting both the increased platelet destruction and the decreased platelet production found in patients with ITP.
A multicentre, open-label, randomised, controlled, phase II trial was conducted at six different tertiary medical centres in China. The trial enrolled 132 adult patients (aged >18 years) with newly diagnosed (≤3 months), treatment-naive primary ITP who had either a platelet count of less than 30 × 10⁹ platelets per L or a platelet count of less than 50 × 10⁹ platelets per L and clinically significant bleeding symptoms. Patients were randomly allocated in a 1:1 ratio to receive either all-trans retinoic acid plus high-dose dexamethasone or high-dose dexamethasone alone. In both treatment groups, participants received 40 mg/day of intravenous dexamethasone for 4 consecutive days, starting on day 0. If patients did not respond by day 14, the 4-day course of dexamethasone was repeated (beginning on day 14). Starting on day 0, participants in the combination group concomitantly received 10 mg of oral all-trans retinoic acid twice daily for 12 weeks. Other co-medications to treat ITP were not permitted.
Baseline characteristics were well balanced between the groups, but the study population comprised more women than men (62% vs. 38%). At six months of follow-up, a significantly higher proportion of participants in the all-trans retinoic acid plus high-dose dexamethasone group (68%) than in the high-dose dexamethasone monotherapy group (41%) had a sustained response (OR[95%CI]: 3.095[1.516–6.318]; p= 0.0017). Significantly less patients in the all-trans retinoic acid plus high-dose dexamethasone then patients in the high-dose dexamethasone monotherapy group relapsed during six months of follow-up (25% vs. 53%). The proportion of patients who had an initial response or an initial complete response, as well as the time to response and time to complete response did not differ between the treatment groups. After a median follow-up of 26 weeks, the duration of response and the duration of complete response were longer in the all-trans retinoic acid plus high-dose dexamethasone group than in the high-dose dexamethasone monotherapy group. Rescue therapy was administered to 12% of patients in the combination arm and to 30% of patients in the monotherapy arm (OR[95%CI]: 0.317[0.128-0.785], p= 0.011). A lower proportion of patients in the all-trans retinoic acid plus high-dose dexamethasone group (39%) than in the high-dose dexamethasone monotherapy group (64%) had clinically significant bleeding (OR[95%CI]: 0.371[0.184–0.751], p= 0.0053). Finally, with regard to health-related quality of life, participants in the combination group showed significantly greater improvements in the scores of symptoms (p< 0.0001), fatigue (p< 0.0001), fear (p< 0.0001), work (p= 0.0014), social activity (p= 0.0047), and overall quality of life (p< 0.0001).
The most common adverse events were dry skin (48%), headaches (19%), and insomnia (19%) in the combination group, and insomnia (15%) and anxiety or mood disorders (12%) in the monotherapy group. Both treatments were well tolerated and no grade 4 or worse adverse events occurred. There were no treatment-related deaths.
The combination of all-trans retinoic acid and high-dose dexamethasone was safe and active in newly diagnosed patients with primary immune thrombocytopenia, providing a sustained response. This regimen represents a potential first-line treatment in this setting, but further studies are needed to validate its efficacy and safety.
Huang QS, Liu Y, Wang JB, et al. All-trans retinoic acid plus high-dose dexamethasone as first-line treatment for patients with newly diagnosed immune thrombocytopenia: a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Haematol. 2021;8:e688-99.