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Proposed Diagnostic Criteria for Classical Chronic Myelomonocytic Leukemia (CMML), Ferrata Storti Foundation CMML Variants and Pre-CMML Conditions

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Proposed Diagnostic Criteria for Classical Chronic Myelomonocytic Leukemia (CMML), Ferrata Storti Foundation CMML Variants and Pre-CMML Conditions GUIDELINE ARTICLE Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), Ferrata Storti Foundation CMML variants and pre-CMML conditions Peter Valent, 1,2 Attilio Orazi, 3 Michael R. Savona, 4 Mrinal M. Patnaik, 5 Francesco Onida, 6 Arjan A. van de Loosdrecht, 7 Detlef Haase, 8 Torsten Haferlach, 9 Chiara Elena, 10 Lisa Pleyer, 11 Wolfgang Kern, 9 Tea Pemovska, 12 Gregory I. Vladimer, 12 Julie Schanz, 8 Alexandra Keller, 1 Michael Lübbert, 13 Thomas Lion, 14 Karl Sotlar, 15 Andreas Reiter, 16 Theo De Witte, 17 Michael Pfeilstöcker, 2,18 Klaus Geissler, 19 Eric Padron, 20 Michael Deininger, 21 Alberto Haematologica 2019 Orfao, 22 Hans-Peter Horny, 23 Peter L. Greenberg, 24 Daniel A. Arber, 25 Luca Volume 104(10):1935-1949 Malcovati 10 and John M. Bennett 26 1Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria; 2Ludwig Boltzmann Institute for Hematology & Oncology, Vienna, Austria; 3Department of Pathology, Texas Tech University Health Sciences Center, El Paso, TX, USA; 4Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 5Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA; 6Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; 7Department of Hematology, Amsterdam UMC, location VU University Medical Center, Cancer Center Amsterdam, the Netherlands; 8Clinic of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany; 9MLL Munich Leukemia Laboratory, Munich, Germany; 10 Department of Molecular Medicine, University of Pavia, Pavia, Italy; 11 3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Paracelsus Medical University, Salzburg, Austria; 12 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; 13 Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 14 Children's Cancer Research Institute and Department of Pediatrics, Medical University of Vienna, Vienna, Austria; 15 Institute of Pathology, Paracelsus Medical University, Salzburg, Austria; 16 Department of Hematology and Oncology, University Hospital Mannheim, 17 University of Heidelberg, Mannheim, Germany; Department of Tumor Immunology- Correspondence: Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; 18 3rd Medical Department, Hanusch Hospital, Vienna, PETER VALENT Vienna, Austria; 19 Sigmund Freud University, Vienna, Austria; 20 Malignant Hematology [email protected] Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; 21 Huntsman Cancer Institute & Division of Hematology and Hematologic Malignancies, 22 Received: March 14, 2019. University of Utah, Salt Lake City, UT, USA; Servicio Central de Citometría, Centro de Investigación del Cáncer (IBMCC, CSIC-USAL), CIBERONC and IBSAL, Universidad de Accepted: April 29, 2019. Salamanca, Salamanca, Spain; 23 Institute of Pathology, Ludwig-Maximilians University, 24 Pre-published: May 2, 2019. Munich, Germany; Stanford University Cancer Institute, Stanford, CA, USA; 25 Department of Pathology, University of Chicago, Chicago, IL, USA and 26 Department of Pathology, Hematopathology Unit and James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA doi:10.3324/ haematol.2019.222059 Check the online version for the most updated information on this article, online supplements, ABSTRACT and information on authorship & disclosures: www.haematologica.org/content/104/10/1935 hronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumula - ©2019 Ferrata Storti Foundation tion of monocytic cells and an elevated risk of transforming into C Material published in Haematologica is covered by copyright. acute leukemia. Over the past two decades, our knowledge about the All rights are reserved to the Ferrata Storti Foundation. Use of pathogenesis and molecular mechanisms in CMML has increased sub - published material is allowed under the following terms and stantially. In parallel, better diagnostic criteria and therapeutic strategies conditions: have been developed. However, many questions remain regarding prog - https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter - nostication and optimal therapy. In addition, there is a need to define nal use. Sharing published material for non-commercial pur - potential pre-phases of CMML and special CMML variants, and to sepa - poses is subject to the following conditions: rate these entities from each other and from conditions mimicking https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com - CMML. To address these unmet needs, an international consensus group mercial purposes is not allowed without permission in writing met in a Working Conference in August 2018 and discussed open ques - from the publisher. tions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag - haematologica | 2019; 104(10) 1935 P. Valent et al. nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distin - guish between normal , pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and p´rognosti´c evaluations in daily practice and clinical studies in applied hematology. Introduction tions remain concerning basic diagnostic standards, prog - nostication, optimal management and therapeutic Chronic myelomonocytic leukemia (CMML) is a options. Furthermore, there is a need to define clinically myeloid stem cell disease characterized by an abnormal relevant pre-phases of CMML and distinct CMML vari - production and accumulation of monocytic cells, often in ants by clinical variables, histomorphological features, association with other signs of myeloproliferation, sub - flow cytometric phenotypes, molecular markers and cyto - stantial dysplasia in one or more hematopoietic cell line - genetic findings. It is also important to separate CMML ages, and an increased risk of transformation into second - and pre-CMML conditions from diverse mimickers. To ary acute myeloid leukemia (AML). 1-5 As per definition, address these unmet needs, an international consensus the Philadelphia chromosome and its related BCR-ABL1 group discussed open questions and issues around fusion gene are absent in CMML. Other disease-related CMML, its variants and pre-CMML entities in a Working drivers, such as the JAK2 mutation V617F or the KIT Conference held in August 2018. The outcomes of this mutation D816V, may be detected and may indicate a spe - meeting are summarized in this article and include pro - cial variant of CMML, such as CMML associated with posed diagnostic criteria and a classification of pre-CMML systemic mastocytosis (SM-CMML). 6-8 However, most conditions as well as updated minimal diagnostic criteria somatic mutations identified in CMML patients, such as for CMML and its variants. In addition, diagnostic stan - mutations in SRSF2 , TET2 , or RAS , are not disease-specif - dards and diagnostic algorithms are proposed. Details con - ic, but are also detected in myelodysplastic syndromes cerning the conference format, pre- and post-conference (MDS), myeloproliferative neoplasms (MPN), or AML. 8-11 discussion and consensus-finding are described in the For many years, CMML was listed as a separate variant Online Supplement . among the MDS in the classification of the French- American-British (FAB) working group. 2,12 However, in Definition of CMML and minimal diagnostic criteria 2001, the World Health Organization (WHO) reclassified The diagnostic criteria of CMML, as defined by the CMML into a newly created MDS/MPN overlap group, WHO, 15,16 are depicted in Online Supplementary Table S1 . defined by the presence of both MDS-related and MPN- Our faculty is of the opinion that these criteria are valid in related morphological and clinical features. 13 Depending general for the classical form of CMML, but need adjust - on the leukocyte count, CMML can be divided into a ‘dys - ments for special variants of CMML. Based on consensus 9 plastic’ variant (leukocyte count ≤13x10 /L) and a ‘prolif - discussion, the following concept is proposed. erative’ variant (leukocyte count >13x10 9/L). 2 In 2001 and The classical form of CMML is defined by the following 2008, the WHO also proposed a split into CMML-1 and pre-requisite criteria: (i) persistent (at least 3 months) 9 CMML-2, based on the percentage of blast cells in the absolute PB monocytosis ( ≥1×10 /L) and relative monocy - 13,14 + blood and bone marrow (BM). In the most recent tosis ( ≥10% of PB leukocytes); (ii) exclusion of BCR-ABL1 updates of the WHO 2016 classification, CMML is again leukemia, classical MPN and all other hematologic neo - listed amongst the MDS/MPN overlap disorders. 15,16 Based plasms that may serve as a primary source of monocyto - on the percentage of blasts, CMML is now divided into sis; and (iii) a
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