ADDITION OF ETOPOSIDE TO INITIAL THERAPY OF ADULT ACUTE LYMPHOBLASTIC-LEUKEMIA - A COMBINED CLINICAL AND LABORATORY STUDY

The role of high-dose etoposide in the initial treatment of newly diag nosed adult ALL was assessed in a combined clinical and laboratory stu dy. Therapy on protocol JH8802 consisted of two induction modules, mod ule 1 containing prednisone, vincristine, high-dose etoposide and L-as paraginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance t herapy. Results were compared to the preceding protocol (JH8302), whic h was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH830 2 (p < 0.0002). Nonetheless, the two protocols had similar CR rates fo llowing module 2 (69% on protocol JH8302; 77% on JH8802) and indisting uishable survivals. Laboratory investigations performed on blasts harv ested prior to chemotherapy revealed two factors that could potentiall y contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected smal l P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a qu arter of the samples. Western blotting demonstrated that topoi someras e II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affin ity-purified antibodies revealed that topo II alpha, the target for et oposide, was detectable in only a minority of the blasts (median 7.5%, range <1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme lev els might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.