All-Trance Retinoid Acid (ATRA) Makes Refractory Immune Thrombocytopenia (RITP) Less Refractory: A Retrospective Study of Ritp Patients Treated with Combination Therapies Including ATRA

Refractory immune thrombocytopenia (RITP) is a severe bleeding disorder with a high mortality rate of 10% to 30%, which is resulted from the toxicities associated with therapies, as well as from life-threatening bleedings. Up to now, treatments for RITP patients are still limited and no consensus has been reached about the standard treatment protocol, therefore, it remains a great problem and challenge for hematologists to think out ways to treat RITP, that is to say, new therapies should be explored to maintain a relatively stable and safe platelet counts with minimum toxicities, so as to improve patients' quality of life and reduce mortalities related to severe bleedings and therapies. ITP is an autoimmune disorder ascribed not only to increased PLT destruction, but also to reduced PLT production, which appears to be related to impaired megakaryocytes (MKs) maturation. ATRA belongs to a class of retinoids, which exerts immunomodulatory and differentiation inducing capacities, and has been included in clinical trails about autoimmune diseases and has been successfully applied in clinic to cure APL by inducing the differentiation of cancer cells.

In this study, we retrospectively reviewed the medical charts of 35 RITP patients who took ATRA as part of the combination therapy from February 2008 to August 2012. We made phone calls for some other detailed medically relevant information not recorded, including previous ITP history, bleeding episodes and etc. All the patients fulfilled the primary ITP criteria as described. They had a median ITP duration of 29 months (range, 6–129 months), with a diagnosed RITP duration of 11months (range, 2–79 months). All the patients have received a median of 6 therapies (range, 3–8) prior to taking ATRA, including steroids, IVIG, CSA, azathioprine, danazol and etc. The median lowest PLT number in the course of their disease was 12×109/L (range, 1–27×109/L), and the median PLT count before starting take ATRA was 11×109/L (range, 1–23×109/L). Patients were treated with ATRA (10mg 3times/day), in combination with any one of methylprednisolone, danazol and CSA or nothing not randomly. When patients were severely thrombocytopenia or present with bleeding sings or symptoms, transfusion of PLT or injection of thrombopoietin were applied. Patients were monitored every 1 to 3 days at the first two weeks and every 1to 4 weeks afterwards for PLT counts, and were monitored every 1 month for transaminitis and other side effects.

Of the 35 patients, 25 responded to our treatments in a median of 8 weeks (range, 3–16 weeks), with PLT increased to greater than 30*109/L, and remained in remission in a median of 24 months, after which, 10 patients relapsed and 8 patients regained remission with the addition of other drugs. The other 15 patients remained in remission after 24 months during the maintenance therapy process and the following drugs decrement process. 5 patients had a relatively stable and safe PLT count (median 58×109/L, rang 38–225×109/L) after discontinuation of all the medications and the other 10 continued the therapy with a low dose for relapsing after the medicine discontinuation. The median peak PLT count after starting the ATRA therapy was 94×109/L (rang 57–225×109/L), and it is after a median of 3 month (range, 1.5–8 months) before the median PLT count reached to peak level. During the treatment process, no severe adverse events and bleedings happened. Patients refractory to previous conventional first-line therapies and combined therapies responded to the combination of ATRA with any one of methylprednisolone, danazol or CSA, which implies that ATRA has the potential of making RITP less refractory and even curing RITP. Given to the limited samples size and nonrandomization of our study, no prognostic factors were found in our study, including sex, age, ITP duration, the lowest PLT count, previous therapy numbers, previous bleeding episodes, the combined drug and etc.

ATRA may have the potential to help RITP patients gain remission and maintain remission combined with one of the conventional first-line therapies, which requires to be verified by more large-sized, prospective, randomized, and controlled clinical trials, and the mechanism of ATRA in treating RITP also needs to be further investigated.

No relevant conflicts of interest to declare.