CLINICAL-STUDY OF 9-CIS RETINOIC ACID (LGD1057) IN ACUTE PROMYELOCYTIC LEUKEMIA

The use of all-trans retinoic acid (RA) for remission induction marked ly increases survival of patients with acute promyelocytic leukemia (A PL) compared to patients treated solely with cytotoxic chemotherapy. H owever, clinical resistance to this agent develops rapidly, which has been associated with a progressive decline in plasma drug concentratio ns. Previous studies suggested that 9-cis RA, a retinoid receptor 'pan agonist' did not induce its own catabolism to the same extent as all- trans RA. Therefore, we conducted a dose-ranging study of this compoun d in patients with both relapsed and newly diagnosed APL. We treated 1 8 patients with morphologically diagnosed APL (13 relapsed, five newly diagnosed). The daily dose of 9-cis RA ranged from 30 to 230 mg/m(2)/ day given as a single oral dose. Four of 12 (33%) relapsed patients (t hree of whom were previously treated with all-trans RA) and four of fi ve (80%) newly diagnosed patients achieved complete remission. The sol e failure in the newly diagnosed group died early from an intracranial hemorrhage. One other patient with t(9;12) translocation had substant ial hematologic improvement. The drug was generally well tolerated; he adache and dry skin were the most common adverse reactions. Three pati ents were treated with corticosteroids for signs of incipient 'RA synd rome.' These preliminary data suggest that g-cis RA is an effective ag ent for remission induction and deserves further investigation in pati ents with retinoid-sensitive APL.