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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
VВсероссийская научно-практическая конференция с международным участием «ГЕНЕТИКА ОПУХОЛЕЙ КРОВЕТВОРНОЙ СИСТЕМЫ -ОТ ДИАГНОСТИКИ К ТЕРАПИИ»
listed myeloma defining events (actualized CRAB criteria)): Hypercalcemia: serum calcium 0.25 mmol/L (1 mg/dL) higher than the upper limit of normal or 2.75 mmol/L (11 mg/dL); renal insufficiency: creatinine clearance 40 mL/min and/or serum creatinine 173 mmol/L (2 mg/dL); Anemia: hemoglobin value of .2.0 g/dL below the lower limit of normal, or a hemoglobin value 10.0 g/dL; Bone lesions: 1 or more osteolytic lesions on skeletal radiography (ie, X-ray), low-dose CT, or PET-CT; clonal bone marrow plasma cell percentage 60 %; Involved/uninvolved serum free light chain ratio 100, and the involved serum free light chain concentration 10 mg/dL or higher; two or more focal lesions based on MRI studies of the skeleton.
With the introduction of the 2014 IMWG criteria for multiple myeloma, a proportion of patients previously considered to have smoldering multiple myeloma now fulfill the criteria of multiple myeloma requiring therapy. Ironically, with the change of the multiple myeloma criteria, the patients sometimes referred to as "ultra high risk smoldering multiple myeloma" (ie, very high risk of developing multiple myeloma) have become "ultra low risk multiple myeloma" because they now represent the earliest stage of multiple myeloma (ie, with a better likelihood of good clinical outcomes). Again, with the change of the definition of multiple myeloma in 2014, multiple myeloma
Санкт-Петербург 26-27 апреля 2019 г.
no longer is a disease that requires symptoms. The old terminology "asymptomatic multiple myeloma" has become irrelevant (because it includes both smoldering multiple myeloma and some patients with multiple myeloma) and the currently correct terminologies are smoldering multiple myeloma and multiple myeloma requiring therapy.
In 2015, A. Palumbo published in Blood the revised international scoring system (R-ISS), included LDH and cytogenetic aberrations (interphase FISH) to level of albumin and beta2 microglobulin. This new risk stratification led to our recent understanding, based on genetic determined course of disease in individual patient. Following this new definition of different myelomas, clinicians started first time treatment programs last year, based on this high risk criterias. This should be the future of myeloma treatment going on in direction to cure this disease.
Here we review and dissect data and models on the topics of clinical features, underlying biology, and early treatment trials in smoldering multiple myeloma, and first trials based on cytogenetic aberrations. The presentation highlights assumptions, facts, and gaps in the literature. As indicated in the title of the paper, the recurrent theme of the text is this: shall we treat smoldering multiple myeloma in the near future and could we cure myeloma patients by differential therapy.
Olga Blau
Charité University Berlin, Clinic for Hematology, Oncology and Tumorimmunology, Berlin Germany
DNMT3A MUTATION IN AML
Acute myeloid leukemia (AML) is caused by the accumulation of genetic mutations in undifferentiated myeloid precursors, resulting in impaired hematopoiesis and bone marrow failure. One of the common aberration in AML is mutation in the epigenetic modifying gene, DNA methyltransferase 3A (DNMT3A). DNMT3A is a de novo DNA methyltransferase that has recently gained relevance because of its frequent mutation in a large variety of immature and mature hematologic neoplasms. DNMT3A mutations are early events during cancer development and seem to confer poor prognosis to AML patients making this gene an attractive target for new therapies.
The occurrence of DNMT3A mutation in pre-leukemic cells (pre-LSCs) explains a particular attention to DNMT3A. Much evidence confirmed
that early mutations transform stem cells into pre-LSCs. Later, cooperating mutations would arise in cells that already contain the initiating mutations, resulting that pre-LSCs undergo clonal evolution leading to AML. Last studies have exposed a complex architecture of leukemia, where several genetically diverse subclones coexist with the dominant primary clone. We and other groups have shown that clonal genetic diversity, complex structure of gene crosstalk, multiple mutations, and extensive sub-clonal changes are common for AML.
DNMT3A mutation is a specific alteration with distinct biological properties. It was shown that DNMT3A mutations are present in T-cells and B-cells in diagnostic samples of AML and in T-cells several years later. The evidence from our study confirmed this data. The presence of DNMT3A in
