[Current and new therapeutic strategies in acute myeloid leukemia]

Abstract

Seventy to 80% of patients with acute myeloid leukemia (AML) achieve complete remission (CR) by chemotherapy, but more than 50% of them then relapse. Phase III clinical trials in the treatment of patients with previously untreated AML and acute promyelocytic leukemia (APL) are ongoing in Japan (JALSG AML 201, APL 204). And continuous efforts are being made to improve the efficacy of chemotherapy. We discussed six topics in the treatment of AML. (1) To determine whether adding the MDR-1 modulator to chemotherapy provided clinical benefits to patients with AML and high-risk myelodysplastic syndrome (MDS), a phase III randomized study was performed using PSC 833. CR rates and overall survival (OS) were not improved by using PSC 833 compared to chemotherapy alone. (2) A large randomized study selectively focused on the G-CSF priming was performed. Among patients in this study attaining CR, the probability of relapse was reduced when they had been assigned to treatment with G-CSF along with induction chemotherapy. The benefit of chemotherapy-sensitization by G-CSF was particularly evident among the intermediate-risk. (3) Fludarabine in addition to Ara-C increases the accumulation of Ara-CTP, which is responsible for the cytotoxic effect in leukemic blasts. In a randomized phase III trial, patients with high-risk MDS or patients with AML were randomized to receive 2 induction courses consisting of Ara-C and G-CSF during and after chemotherapy with or without fludarabine (FLAG versus AG). Although Ara-CTP accumulation in leukemic cells after FLAG was enhanced, the clinical outcome in terms of CR rate, OS, event-free survival, and disease-free survival was not significantly improved by combining fludarabine with Ara-C. (4) Calicheamicin-conjugated humanized anti-CD 33 mouse monoclonal antibody, mylotarg, has recently been introduced. In combined phase II studies of 277 patients with CD 33-positive AML in their first relapse, the overall response rate was 26%. (5) Arsenic trioxide (ATO) has been established as a highly effective therapy for patients with APL, even for those with disease refractory to ATRA. ATO was recently approved in Japan. (6) There has been great interest in developing FLT 3 inhibitors because of the high frequency and poor prognosis of AML patients with mutant FLT 3. Some compounds are currently under development.