Interaction of cyclosporin A and etoposide. Clinical and in vitro assessment in blast phase of chronic myeloid leukaemia.

Combination chemotherapy has had a low impact on survival of blast crises in chronic myelogeneous leukaemia (CML) which may be due to drug resistance. This work attempted to correlate the clinical response and some experimental evidence for the MDR phenotype. Blast cells were positive for P-glycoprotein using APAAP assay. In vitro tests showed that etoposide was partially toxic to blast cells when used alone but had its toxicity increased by nearly sixfold when combined with cyclosporin A (CSA). The patient responded poorly to treatment with etoposide combined with mitoxantrone and high-dose ara-c. However, when etoposide was associated with CSA, this patient returned to the chronic phase reinforcing our in vitro studies. Because no serious toxicity was seen clinically, we are inclined to consider the circumvention protocol an useful strategy to treat blast crises of CML.

Clinical approach to circumvention of multidrug resistance in refractory leukemic patients: association of cyclosporin A with etoposide.

Alternative therapy for refractory leukemic patients is being increasingly adopted. Circumvention of multidrug resistance represents a strategy that has been taken into account when conventional chemotherapy failed. In this work a group of 15 refractory, heavily pretreated, patients was enrolled in a circumvention protocol including etoposide (ETO) and cyclosporin A (CSA). All patients received etoposide prior to this schedule. Toxicity to circumvention protocol was acceptable and only one serious side-effect was observed. Two hematological clinical responses were seen, both of which were positive to P-glycoprotein immunostaining and exhibited in vitro modulation by CSA in cultures using the thymidine incorporation assay. Three out of four patients negative for P-glycoprotein achieved a minor response. Three out of six clinical failures were also negative for Pgp immunostaining one of which exhibited sinergistic effect between ETO and CSA. Our study suggests that hematological response to ETO and CSA association can be obtained in intensely pretreated leukemic patients. Several factors may affect the response such as clinical status before this therapy. Additionally, it also suggests that not all CSA effects on the combination ETO-CSA can be attributed to Pgp modulation.

T-cell malignancies in Brazil. Clinico-pathological and molecular studies of HTLV-I-positive and -negative cases.

T-cell malignancies in Brazil have a high seroprevalence rate of HTLV-I antibodies. We have analyzed the disease features in 188 Brazilian patients with a T-cell disorder. These included 40 with T-lymphoblastic leukaemia or lymphoma (T-ALL/T-LbLy) and 148 with mature T-cell diseases: 5 T-prolymphocytic leukaemia, 53 adult T-cell leukaemia/lymphoma (ATLL), 54 cutaneous T-cell lymphomas, 29 pleomorphic T-cell lymphomas and 7 large granular lymphocyte leukaemia. The diagnosis was based on clinical, morphological and immunological features and HTLV-I serology. ATLL in Brazil has the same diseases features as in other endemic regions, the only apparent differences being: age, Brazilian patients being younger than Japanese, and ethnic grouping, one third of Brazilians being white Caucasians of European descent. We applied a scoring system based on the presence or absence of typical features associated with ATLL; hypercalcaemia, cell morphology, immunophenotype, histopathology and HTLV-I status, to see whether it may help in diagnosing cases of ATLL. All had high scores, whereas all other T-cell diseases scored low. Only 5 ATLL cases were HTLV-I-negative by serology, but they had otherwise typical features of ATLL, and their cells did not have HTLV-I proviral sequences by DNA analysis. Such cases suggest that ATLL may develop in a minority of individuals living in regions where it is endemic, without evidence of HTLV-I infection, and that other factors may contribute to the pathogenesis of the disease.