Session 5. Pre-malignant clonal hematopoietic proliferations. Chairs: Frank Kuo and Valentina Nardi
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1 Session 5 Pre-malignant clonal hematopoietic proliferations Chairs: Frank Kuo and Valentina Nardi
2 Pre-malignant clonal hematopoietic proliferations Clonal LYMPHOID proliferations: - Monoclonal gammopathy of undetermined significance (MGUS) - Monoclonal B-cell lymphocytosis (MBL) - In Situ Follicular Neoplasia (ISFN) - In Situ Mantle Cell Neoplasia (ISMCN)
3 Pre-malignant clonal hematopoietic proliferations Clonal MYELOID proliferations: - Clonal hematopoiesis of indeterminate potential (CHIP) - Clonal cytopenia of undeterminate significance (CCUS) - Small clones of cells with BCR-ABL1
4 Premalignant clonal LYMPHOID proliferations Monoclonal gammopathy of undetermined significance Post GC B-cell MGUS Most patients do not progress - Non-IgM MGUS (plasma cell) - IgM MGUS (mostly lymphoid/lymphoplasmacytic) - progresses to LPL/WM, other B-cell neoplasms, or primary amyloidosis Adapted from David P. Steensma et al. Blood 2015;126:9-16
5 Premalignant clonal LYMPHOID proliferations Monoclonal B-cell lymphocytosis Post GC B-cell MBL Most patients do not progress - CLL-type, atypical CLL-type, non CLL-type - Low count (<0.5 x10 9 /L) vs High count (> 0.5 x10 9 /L) Adapted from David P. Steensma et al. Blood 2015;126:9-16
6 Premalignant clonal LYMPHOID proliferations In Situ Follicular Neoplasia GC B-cell ISFN Most patients do not progress FL Partial or total colonization of germinal centers by clonal B cells carrying the BCL2 translocation characteristic of FL in an otherwise reactive lymph node. Adapted from David P. Steensma et al. Blood 2015;126:9-16
7 Premalignant clonal LYMPHOID proliferations In Situ Mantle Cell Neoplasia Naïve (pre GC) B-cell ISMCN Most patients do not progress MCL Presence of cyclin D1 positive lymphoid cells with CCND1 rearrangements restricted to the mantle zones of otherwise hyperplastic-appearing lymphoid tissue. Adapted from David P. Steensma et al. Blood 2015;126:9-16
8 Premalignant clonal MYELOID proliferations Clonal hematopoiesis of indeterminate potential CHIP Most patients do not progress myeloid/ lymphoid/ multipotential Progenitor cell Or Stem cell MDS-associated clonal gene mutations identified in haematopoietic cells without significant dysplasia on bone marrow examination and in the absence of cytopenias. Adapted from David P. Steensma et al. Blood 2015;126:9-16
9 Significance of pre-malignant clonal hematopoietic proliferations early involvement by a neoplasm precursor lesion inconsequential finding
10 Somatic mutations in CCUS and risk of progression Risk of evolution (%) * Number of patients >2 Number of mutations/patient * Spliceosome gene mutations * Co-mutation patterns involving DNMT3A, TET2 and ASL1 Malcovati L. et al, Blood 2017
11 Pre-malignant clonal hematopoietic proliferations: cases selected for oral presentation Case Dr. Wood. Clonal cytopenia of undetermined significance. Case 50 - Dr. Thompson-Arildsen. Clonal cytopenia of undetermined significance with progression to myelodysplastic syndrome with excess blasts-2. Case Dr. Shanmugam. Clonal cytopenia of undetermined significance with progression to chronic myelomonocytic leukemia-1. Case 28 - Dr.Rjoop. Occult myeloid sarcoma (in a patient with lymphoplasmacytic lymphoma). Case Dr. Loghavi. 1. Lymphoplasmacytic lymphoma. 2. Chronic myelomonocytic leukemia-1. Case Dr. Stuart. Paroxysmal nocturnal hemoglobinuria.
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14 Clonality assessment for premalignant neoplasms T/B cell clonality, flow cytometric analysis Chromosomal abnormality (karyotype, FISH, acgh) Gene mutations (NGS) same genes and mutations as myeloid /lymphoid neoplasms variable allelic frequency (from low to high) single or multiple some confer higher risk of progression
15 Premalignant (clonal) MYELOID proliferations ICUS Idiopathic Cytopenias of Undeterminate Significance CHIP Clonal Hematopoiesis of Indeterminate Potential CCUS Clonal Cytopenias of Undeterminate Significance Clonality Dysplasia Cytopenias Adapted from David P. Steensma et al. Blood 2015;126:9-16
16 Somatic mutations in CHIP VAF>0.02 VAF>0.05 Jaiswal S., et al. N Engl J Med 2014 Genovese G, et al. N Engl J Med % > age 70, 20%>age 90 DNMT3A, ASXL1 & TET2, most commonly mutated genes
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DISCLOSURE Luca Malcovati, MD. No financial relationships to disclose
ICUS, CCUS and CHIP Luca Malcovati, MD Department of Molecular Medicine, University of Pavia Medical School, & Department of Hematology Oncology, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy DISCLOSURE
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