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Relapse of acute myeloid leukemia (AML) remains a major determinant of outcome. A number of molecularly directed treatment options have recently emerged making comprehensive diagnostics an important pillar of clinical decision making at relapse. Acknowledging the high degree of individual genetic variability at AML relapse, next-generation sequencing (NGS) has opened the opportunity for assessing the unique clonal hierarchy of individual AML patients. Knowledge on the genetic makeup of AML is reflected in patient customized treatment strategies thereby providing improved outcomes. For example, the emergence of druggable mutations at relapse enable the use of novel targeted therapies, including FLT3 inhibitors or the recently approved IDH1/2 inhibitors ivosidenib and enasidenib, respectively. Consequently, some patients may undergo novel bridging approaches for reinduction before allogeneic stem cell transplantation, or the identification of an adverse prognostic marker may initiate early donor search. In this review, we summarize the current knowledge of NGS in identifying clonal stability, clonal evolution, and clonal devolution in the context of AML relapse. In light of recent improvements in AML treatment options, NGS-based molecular diagnostics emerges as the basis for molecularly directed treatment decisions in patients at relapse., (© 2020 John Wiley & Sons Ltd.)

At present, hemato-oncologic diagnostics is facing dynamic changes. This applies to the exploration and introduction of novel technologies such as next-generation sequencing or digital droplet PCR for myeloid and lymphatic malignancies in laboratory routine, or liquid biopsy for patients with lymphoid malignancies. Targeted therapies such as FLT3 or IDH1/IDH2 inhibitors for acute myeloid leukemia are entering clinical practice. Thus, the demand for hematologic precision diagnostics both at initial diagnosis and during the course of the disease are equally increasing, and a short turn-around time becomes crucial. NGS expands the armamentarium for minimal residual disease diagnostics, but novel questions arise relating to sensitivity, the appropriate time points of this analysis, or the thresholds triggering therapeutic interventions. In this review article, we summarize some of the most relevant current changes and subsequent challenges for diagnostics in various myeloid and lymphatic malignancies. Future directions of hemato-oncologic diagnostics in the next 5-10 years are highlighted., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Reciprocal RUNX1 fusions are traditionally found in up to 10% of acute myeloid leukemia (AML) patients, usually associated with a translocation (8;21)(q22;q22) corresponding to the RUNX1-RUNX1T1 fusion gene. So far, alternative RUNX1 rearrangements have been reported only rarely in AML, and the few reports so far have focused on results based on cytogenetics, fluorescence in situ hybridization, and polymerase chain reaction. Acknowledging the inherent limitations of these diagnostic techniques, the true incidence of rare RUNX1 rearrangements may be underestimated. In this report, we present two cases of adult AML, in which we detected rare RUNX1 rearrangements not by conventional cytogenetics but rather by next-generation panel sequencing. These include t(16;21)(q24;q22)/RUNX1-CBFA2T3 and t(7;21)(p22;q22)/RUNX1-USP42, respectively. In both patients the AML was therapy-related and associated with additional structural and numerical alterations thereby conferring bad prognosis. This is in line with previous reports on rare RUNX1 fusions in AML and emphasizes the clinical importance of their detection. In summary, our report not only confirms the clinical utility of NGS for diagnostics of rare reciprocal rearrangements in AML in a real-life scenario but also sheds light on the variety and complexity within AML. It further emphasizes the need for collection of additional cases for deepening insights on their clinical meaning as well as their frequency., (© 2019 Wiley Periodicals, Inc.)