In an ongoing study, we treated 79 patients with a molecular diagnosis of
acute promyelocytic leukemia (APL) using
all-trans retinoic acid (RA) for
remission induction. Newly diagnosed patients received cytotoxic
chemotherapy for consolidation, and previously treated patients received extended all-trans RA
therapy, or a
radionuclide-conjugated
monoclonal antibody as post-remission treatment. Unlike studies in Europe, full-dose
chemotherapy was not given during induction for patients who developed
leukocytosis. Overall, 43 of 49 newly diagnosed patients (88%) and 25 of 30 previously treated patients (83%) achieved complete remission. We did not encounter de novo resistance to all-trans RA in any patient who was positive for PML/RAR-alpha rearrangements by reverse transcription polymerase chain reaction analysis. Ten patients died during induction from intracranial or pulmonary
hemorrhage (six patients) or the '
retinoic acid syndrome' (four patients). The use of leukapheresis or low-dose
chemotherapy (
hydroxyurea or
cytosine arabinoside) for
drug-induced
leukocytosis did not decrease early mortality. Compared to historical controls, early mortality was not affected by treatment with all-trans RA; however, both relapse-free and overall survival were significantly increased. Maintenance
therapy with all-trans RA was associated with short remission duration, and relapses while taking the
drug were universally associated with resistance to further
retinoid treatment. We conclude that the use of all-trans RA for
remission induction, with or without full-dose
chemotherapy, has significantly increased the survival of patients with APL. While early mortality has not yet been reduced, the avoidance of full-dose
chemotherapy during induction has significantly reduced early morbidity. The major outstanding clinical issue is the development of strategies that maximize safety in high-risk patients for whom
intracranial hemorrhage remains the major cause of death.