ALL-TRANS-RETINOIC ACID (ATRA) IN PATIENTS WITH CHRONIC MYELOID-LEUKEMIA IN THE CHRONIC PHASE

Since in vitro observations indicated that all-trans retinoic acid (AT RA), especially in combination with IFN alpha, can exert significant s uppressive effects on Ph+ cells, we investigated the effects and the p harmacokinetic profile of ATRA in a selected cohort of patients with P h; chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m(2)/day (p.o.), divided int o two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Ph armacokinetic profiles of ATRA were evaluated during intermittent ther apy on days I and 7 of course 1; on day 1 of course 2; on day 1 of cou rse 6. Out of the 18 patients treated with ATRA, 11 (61%) went off stu dy before the sixth course of treatment because of progressive hyperle ukocytosis (seven cases), or thrombocytosis tone case), or refusal (th ree cases). Seven (39%) patients completed the first six courses (12 w eeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10(9)/l which was induced by the pretreatment w ith hydroxyurea, One patient completed the 12th course of ATRA maintai ning WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpab le. The treatment with ATRA was well tolerated and only one patient di scontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P < 0.001) during the first week of therapy. By adopting an intermitt ent dosing regimen, I week on/ I week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achi eved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML p atients in chronic phase. Moreover, it did not induce any remarkable c ytoreductive effects on the platelet count and on the hemoglobin level . The major interest of ATRA would be in combination with other therap ies. If ATRA was given in combination with IFN alpha or other agents, dose reduction of these would not be planned. On the basis of the phar macokinetic profile, ATRA should be administered intermittently rather than continuously.