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Several adverse effects have been reported to occur after clinical application of all-trans retinoic acid (RA) in acute promyelocytic leukemia (APL). Except for severe side effects including retinoic acid syndrome, the mechanism of action of RA on adverse effects remains unclear. Here we describe some rare adverse effects and their management. We reviewed the English literature, and we added our cases of endocrine and metabolic adverse effects, such as hypercalcemia, male infertility, bone marrow necrosis, fibrosis and acute pancreatitis. We also described our cases of thromboembolic events, RA-dependent growth of pathologic cells including Sweet's syndrome, erythema nodosum, hyperhistaminemia, granulomatous proliferation, and mild cases of pulmonary complications. In addition, we reviewed the efficacy of RA administration for other types of leukemia or myelodysplastic syndrome. RA and chemotherapeutic agents might induce complete remission, but we obtained a response in only one case of M2 in the third relapse. During RA administration the patient should be monitored for these adverse effects, and early diagnosis and appropriate treatment are important.

In 11/13 acute promyelocytic leukaemia (APL) cases treated with tretinoin (RA) we observed RA-induced inaspirable collagenous fibrosis of the bone marrow. To study the mechanism of RA on collagen production, we cultured a human bone marrow derived stromal cell line and an osteoblastic cell line with RA in vitro. 10(-7) and 10(-6)M of RA stimulated collagen production. Clinical and experimental observation may be important to understand this adverse effect of RA as it is useful in cancer chemoprevention as well as treatment for APL. This adverse effect is spontaneously reversible after stopping RA or following chemotherapy.