MDS 101. What is bone marrow? Myelodysplastic Syndrome: Let s build a definition. Dysplastic? Syndrome? 5/22/2014. What does bone marrow do?

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1 101 May 17, 2014 Myelodysplastic Syndrome: Let s build a definition Myelo bone marrow Gail J. Roboz, M.D. Director, Leukemia Program Associate Professor of Medicine What is bone marrow? What does bone marrow do? Dysplastic? Dysplasia abnormal appearance of cells when viewed under the microscope Difference shapes, sizes, granules (particles within cells) Can be caused by many medical conditions, not only Syndrome? Collection of signs and symptoms associated together 1

2 Myelodysplastic Syndrome Heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, progressive pancytopenia, morphologic abnormalities and propensity to transform to AML Dysplastic hematopoiesis Impaired differentiation Accumulation of blasts Hypercellular bone marrow in ~90% Peripheral cytopenias Risk of progression to AML in 25-35% Abnormal bone marrow cytogenetics in ~50% 1. Cazzola M, Malcovati L. N Engl J Med. 2005;352: Heaney ML, Golde DW. N Engl J Med. 1999;340: Hofmann W-K, et al. Hematol J. 2004;5: Foundation Resource Center. Available at: Risk Factors Cause is unknown in >80% of patients Prior exposure to chemotherapy and/or radiation Advancing age Congenital diseases (Fanconi anemia, congenital neutropenia, rare familial )? Environmental toxins (organic solvents, benzene,?agent Orange,? WTC) Pathogenesis of Epidemiology Overall incidence: 3.4 per 100,000 Cytogenetic abnormalities Gene mutations (ras, P53) * Medullary angiogenesis Stromal dysregulation Immune system abnormalities Epigenetic DNA modification Accelerated apoptosis Proliferation Overall Males Females < *P for trend <.05 Age at Diagnosis (Yrs) Rollison DE, et al. Blood. 2008;112: Bone Marrow Failure A low number of normal circulating blood cells (white cells, red cells and/or platelets) caused by a low number or failure of bloodforming stem cells in the bone marrow Keep in mind: depending on the disease, the bone marrow itself can be very full of cells (hypercellular) or very empty (hypocellular or aplastic) and the total WBC doesn t necessarily have to be low to be called bone marrow failure Hallmark of : Ineffective hematopoiesis Why are blood counts low in? Is the bone marrow making too few cells? Are the cells dying too soon? Are the levels of growth factors too low? Are cells less sensitive to the effects of growth factors? 2

3 Anemia Fatigue, pallor Bone Marrow Failure: Signs and Symptoms Shortness of breath, decreased exercise tolerance Exacerbation of heart failure, angina Neutropenia Active infection (bronchitis, sinusitis, pneumonia, etc.) Risk of infections Thrombocytopenia Petechiae, bruising, bleeding Risk of bleeding Required Initial Evaluation H&P CBC with diff, platelet count, & retic Examination of peripheral blood smear BM aspirate with iron stain and cytogenetics BM biopsy Baseline serum EPO level prior to RBC transfusion RBC folate and serum B12 Serum iron/tibc/ferritin Documentation of transfusion history NCCN Practice Guidelines in Oncology: Myelodysplastic Syndrome v Performing a bone marrow aspiration OOOuch!! Other diseases of bone marrow failure Hematologic conditions: congenital (hereditary sideroblastic anemia, congenital dyserythropoietic anemia, Fanconi anemia, etc.) Nutritional: deficiencies of vitamin B12, folate, iron Aplastic anemia (AA) Pure red cell aplasia Paroxysmal nocturnal hemoglobinuria (PNH) Systemic mastocytosis Hairy cell leukemia (HCL) Large granular lymphocyte disease (LGL) Myeloproliferative syndromes (idiopathic myelofibrosis, advanced polycythemia vera or essential thrombocythemia) Toxins (alcohol, medications, etc) Chronic diseases, viral infections, malignancies Diseases of bone marrow failure Paroxysmal Nocturnal Hemoglobinuria Pure Red Cell Aplasia Large Granular Lymphocytosis Aplastic Anemia Hypocellular Myeloproliferative Disease 1. Young NS. Ann Intern Med. 2001;136: Macjewiski JP, et al. Blood. 2001;98: AML Myelodysplastic Syndromes: Optimizing Patient Outcomes clinicaloptions.com/oncology Revised IPSS: Prognostic Score Values and Risk Categories/Scores Prognostic Variable Cytogenetics Greenberg PL, et al. Blood. 2012;120: Score Value Very good BM blast, % 2 Hemoglobin, g/dl 10 Platelets, x 10 9 /L to < 100 ANC, x 10 9 /L 0.8 < 0.8 Good > 2 to < 5 Intermediate Poor 5-10 > 10 Very poor 8 to < 10 Risk <8 Score Very low 1.5 < 50 Low > 1.5 to 3 Intermediate > 3.0 to 4.5 High > 4.5 to 6.0 Very high > 6 3

4 Cummulative Proportion Alive 5/22/2014 IPSS-R Survival Related to Age* IPSS-R Prognostic Risk Categories Ages Very Low Low Intermediate High Very High All yo NR [13.0-NR] 8.8 [ ] >60-70 yo [9.1-NR] [ ] >70-80 yo [ ] [ ] >80 yo [ ] [ ] 5.2 [ ] 3.3 [ ] 2.7 [ ] 1.8 [ ] 2.1 [ ] 1.6 [ ] 1.5 [ ] 1.5 [ ] 60 yo NR >60 yo yo >70 yo *Years, Medians [95% CIs] Yo = years old NR = nor reached 0.9 [ ] 0.8 [ ] 0.7 [ ] 0.7 [ ] Greenberg et al, Blood, 2012, epub ahead of print. What does low risk really mean? Prognostic Model for Low-risk What does high-risk mean? Adverse Factor Unfavorable cytogenetics* Coefficient P Value Assigned Score < Age 60 yrs < Hb < 10 g/dl < Plt < 50 x10 9 /L x 10 9 /L BM blasts 4% < *In this analysis, diploid and 5q were favorable cytogenetics, all others were considered as unfavorable cytogenetics Assigned Total Score (%) Dead (21) (48) (31) MosFrom Referral Survival Median, % 4 Yrs Worsening blood counts Transformation to acute leukemia Bone marrow failure Garcia-Manero G, et al. Leukemia. 2008;22: BLASTS..don t get caught up in the numbers 0...5%...10%...15%...20%+ Molecular genetics ASXL1 EZH2 ETV6 RUNX1 TP53 New ones coming every week

5 Epigenetics: Fine-tuning gene expression Inheritable changes in gene expression patterns that are not due to changes in DNA sequence Changes mediated by covalent attachment of chemical groups (e.g. acetyl, methyl) to DNA and associated proteins (chromatin, histones) Key in modifying differential expression of genes and defining cellular identity Key in transforming normal to malignant cells 5

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