Risk-Adapted Maintenance Therapy for Acute Promyelocytic Leukemia

Abstract

TO THE EDITOR: We read with great interest the article by Kelaidi et al concerning clinical trials for acute promyelocytic leukemia (APL) performed by the European APL group. This article is meaningful because the efficacy of maintenance therapy was separately analyzed in patients with high-risk APL who were defined as APL with presenting WBC count higher than 10 10/L and patients with low/intermediate-risk APL presenting WBC count lower than 10 10/L. We would like to make comments regarding risk-adapted maintenance therapy for APL. Maintenance therapy consisting of all-trans retinoic acid, 6mercaptopurine, and methotrexate has been adopted in some trials since the European APL group proved its efficacy. Kelaidi et al updated this data, and the benefit of this combination maintenance therapy in patients with high-risk APL was confirmed. In contrast, this therapy had a marginal benefit to preventing relapse to patients with low/intermediate-risk APL. This knowledge has been described for the first time. Risk-adapted strategies have been performed mainly concerning consolidation therapy and induction therapy in clinical trials for APL all over the world. There are no other reports in which it was mentioned that the benefit of this maintenance therapy was correlated with presenting WBC count. The European LeukemiaNet APL guidelines commented that the relative benefit of maintenance therapy depends on the prior induction and consolidation therapy and promyelocytic leukemia/ retinoic acid receptor-alpha (PML/RAR) mRNA status after consolidation therapy. In fact, combination maintenance therapy did not confer disease-free survival advantage for patients with negative PML/ RARA mRNA after three courses of consolidation therapy in the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) group, although the European APL group has performed maintenance therapy for patients with unknown PML/RARA mRNA status after two courses of consolidation therapy. Taking these into consideration, we should pay attention to the fact that the combination maintenance therapy has never been proven to be effective for patients with low/intermediate-risk APL. Moreover, the introduction of arsenic trioxide and gemtuzumab ozogamicin into first-line treatment for APL may reduce significance of maintenance therapy. In addition, this combination therapy often causes serious adverse events such as pancytopenia and liver dysfunction. Therefore, it is probable that the combination maintenance therapy should be omitted or amended in patients with low/intermediate-risk APL although many clinical study groups including the European APL group have continued to adopt this therapy for all patients with APL. The Southwest Oncology Group now examines whether this omission is beneficial for patients with low/intermediate-risk APL (ClinicalTrials.gov number, NCT00492856). Because the efficacy of maintenance therapy is dependent on the prior therapy as described above, the other study groups should prospectively and separately examine whether maintenance therapy has a clinical benefit for patients with low/ intermediate-risk and high-risk APL who have received the induction and consolidation therapy of their own. We believe that the answer to this topic would be of great significance in guiding therapy for patients with APL.