A Randomized Study with or without Intensified Maintenance Chemotherapy in Patients with Acute Promyelocytic Leukemia Who Had Become Negative for PML-RARα Transcript after Consolidation Therapy: The Japan Adult Leukemia Study Group (JALSG) APL97 Study.

The use of all-trans retinoic acid (ATRA) has markedly improved therapeutic outcome in patients with acute promyelocytic leukemia (APL). Non-cross resistance between ATRA and chemotherapeutic drugs has contributed to not only a high complete remission (CR) rate but also a decrease in the relapse rate, leading to the significant improvement in disease-free survival (DFS) and overall survival (OS) rates. However, it is not clear whether maintenance chemotherapy actually prevents relapse in APL patients treated with ATRA and chemotherapy. If short-term therapy without maintenance shows identical DFS rates as compared to long-term therapy with maintenance, it would be beneficial for quality of life of patients as well as to medical costs. In these aspects, to determine an efficacy of maintenance/intensification chemotherapy, this study was designed to compare the DFS and OS rates in previously untreated adult patients with APL who showed absence of PML-RARα fusion transcript at the end of consolidation therapy and were randomly allocated to either maintenance therapy or observation. Of 302 registered, 283 patients were assessable and 267 (94%) achieved a CR. Predicted 6-year OS and DFS rates were 83.7% and 69.2%, respectively. The PML-RARα fusion gene was amplified using bone marrow samples at the diagnosis and after consolidation therapy by the reverse transcriptase-polymerase chain reaction analysis. The detection limit of PML-RARα fusion transcript in this assay was 10^-4. Among 235 patients who completed 3 courses of consolidation chemotherapy, five (2.1%) were positive for the PML-RARα fusion transcript. Three of them subsequently relapsed and another one patient received allogeneic hematopoietic stem cell transplantation. On the other hand, 230 patients (97.9%) showed no PML-RARα transcript in the bone marrow cells at the end of consolidation. Of these, 175 patients were randomly assigned to receive moderately intensive and intermittent maintenance chemotherapy (n=89) or to observation (n=86). Predicted 6-year DFS was 63.2% for the chemotherapy group and 81.8% for the observation group, showing no statistically significant difference (p=0.102). Predicted 6-year OS in patients assigned to observation was 98.7% and was significantly higher than 85.9% in those allocated to maintenance therapy (p=0.013). These results indicate no benefit from adding maintenance chemotherapy in APL patients who are negative for PML-RARα fusion transcript after 3 courses of intensive consolidation.