PROBLEMS EXISTING IN DIFFERENTIATION THERAPY OF ACUTE PROMYELOCYTIC LEUKEMIA (APL) WITH ALL-TRANS-RETINOIC ACID (ATRA)

A large number of acute promyelocytic leukemia (APL) patients, treated with all-trans retinoic acid (ATRA) and chemotherapy, were studied. T he results of the studies are as follows: (1) Among 65 patients invest igated for the postremissional therapy, the 5-year survival probabilit ies were 0.20 +/- 0.13 (X +/- SE) in the group treated with ATRA alone , 0.47 +/- 0.10 (X +/- SE) in the group using chemotherapy alone and 0 .42 +/- 0.09 (X +/- SE) in the group treated with chemotherapy and ATR A. (2) The main severe adverse effects in the ATRA treatment include r etinoic acid syndrome, renal failure, and thrombosis. These sequelae w ere observed more frequently in cases with persistent, marked elevatio n of white blood cell count without significant maturation of leukemic promyelocytes. (3) APL is not a homogeneous disease in that among 50 patients studied at the molecular level, although a PML-RARA fusion ge ne was detected in 45 cases, one had a variant translocation t(11;17) bearing fusion gene PLZF-RARA, one presented no obvious structural alt eration of the PML gene while the RARA gene was rearranged, and three patients had no rearrangement of either PML or RARA genes. (4) Using R T/PCR to detect minimal residual disease, we found positive rates of 2 2%, 18.4%, and 11.5%, respectively, 12, 24, and 36 months after CR. Th is observation justifies the use of chemotherapy for at least 3 years after CR induced by ATRA. (5) It seems likely that the fusion gene PML -RARA plays an important role in APL leukemogenesis and in its respons e to the ATRA treatment.