Adding vitamin A compound boosts outcomes in hard-to-treat ITP
Combo treatment in trial led to fewer relapses, with no added side effects
Written by |
In a clinical trial involving adults with hard-to-treat immune thrombocytopenia (ITP), adding a 12-week course of a vitamin A-derived compound called all-trans retinoic acid (ATRA) to eltrombopag — the active ingredient in two approved ITP treatments — significantly improved long-term outcomes.
New data from the late-stage trial demonstrate that the combination therapy worked better than eltrombopag alone, and without increasing side effects. Specifically, adding ATRA led to more sustained treatment responses, fewer disease relapses, and a reduced need for additional therapies among participants.
Importantly, the researchers noted that all adults in the Phase 3 trial had ITP that had returned or failed to respond to standard corticosteroid therapy.
According to the team, the greatest responses to the added vitamin A compound were observed among those individuals with the poorest prognosis at the trial’s start. Those results suggest that, if confirmed in future studies, the prognostic score used in this trial to evaluate the combo therapy may help “identify patients who derive substantial benefit from ATRA addition,” the researchers wrote.
The study, “All-Trans Retinoic Acid plus Eltrombopag for Refractory/Relapsed Immune Thrombocytopenia,” was published in the journal NEJM Evidence by researchers in China.
A rare autoimmune disease, ITP occurs when the immune system mistakenly attacks and destroys platelets, the blood cell fragments that help stop bleeding. This leads to abnormally easy and prolonged bleeding.
Growing evidence suggests the disease also impairs platelet production within the bone marrow, where blood cells are made.
Combo tested in ITP patient for whom steroids didn’t work
First-line treatment for ITP usually involves corticosteroids, which are medicines that suppress the immune system. While many patients initially respond, more than 30% fail to achieve an adequate response, and as many as 85% eventually relapse, leaving them with persistent or recurrent disease that requires second-line treatment.
One such treatment is eltrombopag — the active ingredient in Alvaiz and Promacta — which stimulates the body to produce new platelets. Although eltrombopag helps increase platelet counts in many patients, long-term disease control remains challenging, with more than half of treated individuals eventually experiencing treatment failure or disease relapse.
In previous work, the research team, from institutions in Beijing, showed that ATRA could boost platelet counts by restoring the function of platelet-producing cells in the bone marrow.
Because ATRA appears to target underlying disease mechanisms distinct from those affected by eltrombopag, the team now hypothesized that combining the two therapies might yield more lasting responses than eltrombopag alone.
To test this idea, the researchers conducted a Phase 3 clinical trial (NCT05438875) that enrolled 96 adults with primary ITP between October 2022 and May 2024 at five hospitals in the country. Eligible participants had platelet counts below 30 billion per liter of blood and had either not responded adequately to, or relapsed after, at least one full course of corticosteroid therapy.
All participants were given 50 mg of eltrombopag, with half also receiving a 12-week course of ATRA, given at a dose of 10 mg twice daily. After 12 weeks, or about three months, ATRA was discontinued; eltrombopag could be tapered or stopped in either group if patients maintained platelet counts of at least 30 billion per liter without bleeding.
A total of 91 participants (95%) completed the full 18-month follow-up.
The study’s main goal was to determine how many patients achieved a sustained response at 1.5 years, defined as maintaining a platelet count of at least 30 billion per liter — double their baseline count, or the number at the trial’s start — without bleeding or requiring rescue therapy.
Vitamin A combo worked best in those with poor prognosis
At the 18-month mark, 60% of participants given the combination therapy achieved a sustained response, compared with 35% of those treated with eltrombopag alone. The effect of the combination therapy on the primary endpoint appeared to be greatest among patients who had the poorest prognosis, or a low prognostic score, at the start of the study, the researchers noted.
Among these patients, 57% of those given ATRA plus eltrombopag achieved a sustained response, compared with 4% of those treated with eltrombopag alone. In contrast, sustained response rates were similar between the two treatments in patients who entered the trial with a more favorable prognosis.
Complete responses, defined as platelet counts of at least 100 billion per liter, were also more common with the combination (79% vs. 58%), the data showed.
Also, the benefits lasted longer: The data showed that those receiving ATRA maintained their responses for a median of 75 weeks, or about 1.4 years, compared with 37 weeks, or about nine months, for those given eltrombopag alone. Those given the combo with the vitamin A compound also were less likely to relapse (31% vs. 58%) and less likely to require rescue treatment (27% vs. 52%), the data showed
Bleeding outcomes improved as well, according to the researchers. After 12 weeks, or about three months, the overall bleeding rate dropped from 58% to 10% in the combination group and from 54% to 25% with eltrombopag alone. Clinically significant bleeding disappeared entirely in the combination group (21% to 0%) but declined just slightly in the eltrombopag-only group (10% to 8%).
Side effects occurred at similar rates in the two groups (27% vs. 25%) and were mostly mild or moderate, the data showed. Dry skin was more common among patients receiving ATRA, affecting 13% of the participants.
“Our trial showed that in patients with [corticosteroid]-resistant or relapsed ITP a 12-week ATRA course combined with eltrombopag significantly enhanced the sustained response rate at 18 months compared to eltrombopag alone,” the researchers wrote.
The team also noted that their prognostic score, if validated in future trials, may help to distinguish patients who may benefit from adding ATRA. That score, the researchers wrote, “represents a
potential step toward a personalized treatment approach” for those with hard-to-treat ITP.
Leave a comment
Fill in the required fields to post. Your email address will not be published.