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Reply to C.S. Hourigan et al.

The information provided by Hourigan et al, similar to the work of Araki et al, underlines the value of achieving a minimal residual disease (MRD) –negative complete remission, which improves significantly the chance for cure after hematopoietic cell transplantation (HCT) in adult acute myeloid leukemia (AML). The importance of being MRD negative must be considered under a precise clinical and diagnostic context given the relevance of this assay in acute leukemia therapy. MRD is measurable through multiparameter flow cytometry (MFC) in which MRD negativity refers to an undetectable leukemia-associated immunophenotype or, by means of realtime quantitative reverse transcriptase polymerase chain reaction (RQ-PCR), confirms the disappearance of any genetic lesion detectable at diagnosis. With a sensitivity of approximately 10 to 10 for MFC and 10 to 10 for RQ-PCR, the current definition of MRD negativity is far from proving a complete eradication of residual AML cells. Although this possibility cannot be formally excluded, there is no way to check simply because to assess a dismantling of approximately 10 leukemic cells would require a much greater sensitivity in terms of log reduction than that reached by MFC or RQ-PCR. At present, MRD negativity means that undetectable MRD signals exist below the higher sensitivity threshold provided by the two methods. Despite technical limitations, we have been more fortunate on the clinical side because this type of MRD negativity retains a high predictive value for complete remission duration in individual patients. A striking prognostic difference was consistently ascertained in favor of patients with MRD-negative remission in these and many other studies. This discrepancy explains why MRD analysis is increasingly used in association with modern treatment programs for both AML and acute lymphoblastic leukemia (ALL) to refine the individual risk profile and sometimes orient treatments. Although MRD-based experience in AML is relatively abundant and growing, it was in ALL that the smarter outcome of pediatric and adult patients with MRD-negativity was first confirmed independently of risk class, disease subset, and/or HCT choice and even in very-high-risk patients with Philadelphia-positive ALL treated without HCT in the age of tyrosine kinase inhibitors. If separating the MRD negative from the positive is so important, two big questions arise about the exact place of HCT according to MRD risk class and the optimal management of patients with MRD positivity who fared bad in the two AML studies. The HCT issue inMRD-negative AMLwas openly posed by the Fred Hutchinson Cancer Research Center group and can only be addressed by ad hoc phase II/III trials, with risk stratification and analysis of results by MRD cohort in accordance with the view expressed by the National Institutes of Health group. In adult ALL, three independent prospective phase II trials did not confirm the usefulness of HCT in patients with high-risk ALL who were MRD negative. On the contrary, salvage HCT proved relatively effective in patients with MRD-positive ALL and yielded survival rates of 25% to 55% because of a high risk of relapse. An urgent need now exists for clinicians to dispose of new agents active against measurable MRD to avert clinical relapse, which is the worst therapeutic scenario, and to improve HCT outcome in patients withMRD-positive AML. In AML, for example, the FLT3 inhibitor midostaurin, successfully tested in a phase III trial, could be developed to target MRD before HCT in patients with FLT3-positive AML. For MRD-positive B-lineage ALL, new compounds of interest include monoclonal antibodies, such as anti-CD20 rituximab and ofatumumab, anti-CD22 calicheamicinconjugated inotuzumab ozogamicin, anti-CD19/CD3 bispecific T-cell engager blinatumomab, anti-CD19 chimeric antigen receptor– modified T cells, ponatinib in Philadelphia-positive ALL, and combinations thereof. A large international study of blinatumomab monotherapy reported a very high response rate in patients with MRD-positive ALL, with many of the patients proceeding to a successful HCT. We should really focus on how to optimize MRD negativity rates, which would make it possible to bring more patients to HCT with a greater chance of success or, alternatively, to exclude fromHCT subsets of patients with persistent MRD negativity, an objective that should be exclusively pursued within prospective clinical trials. In addition, when economic constraints are imposed, the indication for costly, novel treatments could bemore rationally based on priorMRD response. The measurement of MRD is a cornerstone of modern treatment strategy for acute leukemia and represents a sound investment for innovative clinical studies and the testing of new drugs.