Real-time consensus on relapse risk in acute promyelocytic leukemia

Abstract

In acute promyelocytic leukemia (APL), there are two main purposes for minimal residual disease (MRD) monitoring by reverse transcription-polymerase chain reaction (RT-PCR) methods: to assess the risk of hematological relapse (HR) in patients in clinical remission after the completion of consolidation therapy and to identify patients at high risk of HR as a basis for initiating salvage therapy on the premise that this will provide a more favorable outcome while persistent or recurrent disease is still sub-clinical. The primary evidence affirmatively supporting both of these purposes was provided by non-quantitative, conventional RT-PCR (C-PCR), principally in association with Italian GIMEMA clinical trials, using all-trans retinoic acid (ATRA) in combination with anthracycline-based chemotherapy (ABCT) [1, 2]. Subsequently, an optimized, standardized version of the C-PCR assay was incorporated into Spanish PETHEMA ATRA/ABCT trials, in which molecular relapse (MR) was regarded as uncensored, i.e., considered in common with HR, for trial outcome evaluation and was prospectively used for treatment modification in some cases [3, 4]. Confident use of these C-PCR assays by GIMEMA/PETHEMA investigators was based on the utilization of the standardized C-PCR assay in multi-institutional protocol trial sites and, critically, the confirmation of all positive initial results using a second sample in two central reference laboratories. Confident use was also enhanced by the clear definition of terms: molecular remission, the disappearance of a gel electrophoretic band generated from PML-RARα mRNA present in a pretreatment patient sample in a post-treatment bone marrow (BM) sample using an assay with a sensitivity of ~10−4 established by appropriate positive dilution controls; molecular persistence, the detection of the PML-RARα gel band after the termination of consolidation therapy and confirmation of this signal in a second specimen; MR, the reappearance of the confirmed gel signal from documented molecular remission during maintenance therapy or follow-up [3].