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BECTHMKrEMATOnOMM, tomXV, №2, 2019
Anna Dolnik1,6 Sibylle Cocciardi1, Silke Kapp-Schwoerer1, Frank G. Rücker1, Susanne Hirsch1, Tamara J. Blätte1, Sabrina Skambraks1, Jan Krönke1, Andrea Corbacioalu1, Verena I. Gaidzik1, Peter Paschka1, Veronica Teleanu1, Gudrun Göhrina3, Felicitas Thol4, Michael Heuser4, Arnold Ganser4, Daniela Weber1, Eric Sträng5, Hans A. Kestler5, Karlheinz Holzmann2, Hartmut Döhner1, Lars Butlmger1-6*", Konstanze Döhner1*"
1 Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
2 Genomics Core Facility, University of Ulm, Ulm, Germany
3 Institute of Cell & Molecular Pathology, Hannover Medical School, Hannover, Germany
4 Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
5 Institute of Medical Systems Biology, Ulm University, 89081 Ulm, Germany
6 Department of Hematology, Oncology and Tumorimmunology, Charité University Medicine, Berlin, Germany * these authors contributed equally
CLONAL EVOLUTION PATTERNS IN ACUTE MYELOID LEUKEMIA (AML)
WITH NPM1 MUTATION
Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To further characterize the genetic composition of NPM1 mutated (NPM1mut) AML, we comprehensively assessed 129 paired samples obtained at diagnosis and relapse. We found a significant shift in the genetic pattern from diagnosis to relapse in 77 (60 %) patients (pts) with the highest instability seen for FLT3-ITD, while DNMT3Amut proved to be the most stable aberration (95 %). NPM1mut was lost at relapse in 11 pts (9 %) of which 10 revealed a stable preleukemic mutation (i.e. DNMT3Amut and IDH2mut). To gain further insight into these NPM1mut loss cases, we performed whole exome sequencing (WES), which confirmed persistence of mutations known to be involved in clonal hematopoiesis. Moreover, at the time of relapse NPM1mut loss pts
featured distinct mutational patterns that shared almost no somatic mutation with the corresponding diagnosis sample and impacted different signaling pathways. In contrast, mutational profiles of pts with persistent NPM1mut at relapse were more stable which was reflected by a high overlap of mutations being present at diagnosis and relapse. RNA-Seq of NPM1mut loss diagnosis/relapse pairs further supported a switch in signaling cascades at relapse. This includes the loss of characteristic NPM1mut associated gene expression patterns, thereby supporting the hypothesis that loss of NPM1mut at relapse is a distinct disease. Thus, our findings confirm that relapse often originates from persistent leukemic clones, although NPM1mut loss cases more closely resemble a second "de novo" or treatment-associated AML (tAML).
Igor Wolfgang Blau
Charité University Berlin, Clinic for Hematology, Oncology and Tumorimmunology, Berlin, Germany
RISK STRATIFICATION IN MYLTIPLE MYELOMA
In recent years, several new drugs have been approved for the treatment of multiple myeloma. Many of these newer drugs are highly efficacious and less toxic than older chemotherapy drugs. In 2014, the diagnostic criteria for multiple myeloma were revised. The intent with the new criteria was to identify patients who require therapy at an earlier stage than at manifestation of organ complications. A subset of patients who were previously defined as having high-risk smoldering multiple myeloma was redefined as having multiple myeloma. In this context, it is logical to raise questions regarding the optimal clinical
management of patients who are diagnosed with smoldering multiple myeloma in the current era. When is the optimal time to start therapy?
New diagnostics standards published by V. Rajkumar in Lancet Oncology in 2014 summarized results of previous studies and represented the mind of the International Myeloma Working Group (IMW). Multiple Myeloma as plasmacell proliferative disease is defined by clonal bone marrow (by BM cytology or histology) plasma cells >10 % or biopsy-proven or extramedullary plasmacytoma. The new criterias for treatment indication are (2 any 1 or more of the below
