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Myelodysplastic Syndromes: Disease Overview, New Therapies, and Treatment Options

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Myelodysplastic Syndromes: Disease Overview, New Therapies, and Treatment Options Myelodysplastic Syndromes: Disease Overview, New Therapies, and Treatment Options Rafael Bejar MD, PhD MDS Foundation Patients & Caregivers LIVING with MDS Forums February 3, 2018 Overview • Introduction to MDS • Clinical Practice - Making the diagnosis - Classification - Risk stratification • Treatment Goals and Options • Novel Therapies • Questions and Answers Low Blood Counts 65 year-old woman with mild anemia and a platelet count that fell slowly from 230 to 97 over the past 3 years. Normal Range Myelodysplastic Syndromes • Shared features: – Low blood counts – Clonal overgrowth of bone marrow cells – Risk of transformation to acute leukemia ASH Image Bank • Afflicts 15,000 – 45,000 people annually • Incidence rises with age (mean age 71) MDS Incidence Rates 2000-2008 US SEER Cancer Registry Data 60 50 40 30 20 10 Incidence Rate per 100,000 per Rate Incidence 0 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 >85 Age http://seer.cancer.gov. Accessed May 1, 2013. Age and Sex in MDS . Overall incidence in this analysis: 3.4 per 100,000 36.4* 50 Overall Males Females 40 20.9 30 20 7.5 10 0.7 2.0 0.1 0 < 40 40- 49 50-59 60-69 70-79 ≥ 80 *P for trend < .05 Age at MDS diagnosis (years) Slide borrowed from Dr. David Steensma Rollison DE et al Blood 2008;112:45-52. Etiology of MDS <5% 10-15% 85% Topoisomerase II inhibitors “De novo” Familial or Congenital Ionizing radiation (idiopathic, primary) DNA alkylating agents Often early onset and part of Peaks 1-3 or 5-7 years Median age ~71 years; a larger syndrome following exposure increased risk with aging Slide adapted from Dr. David Steensma Differentiation Normal Transformation Early MDS Advanced MDS Secondary AML Making the Diagnosis Minimal Diagnostic Criteria Cytopenia(s): MDS “decisive” criteria: • Low hemoglobin, or • >10% dysplastic cells in 1 or more lineages, • Low neutrophil count, or or • Low platelet count • 5-19% blasts, or • Abnormal karyotype typical for MDS, or • Specific mutation typical of MDS Other causes of cytopenias and morphological changes EXCLUDED: • Vitamin B12/folate deficiency • HIV or other viral infection • Copper deficiency • Alcohol abuse • Medications (esp. methotrexate, azathioprine, recent chemotherapy) • Autoimmune conditions (ITP, Felty syndrome, SLE etc.) • Congenital syndromes (Fanconi anemia etc.) • Other hematological disorders (aplastic anemia, LGL disorders, MPN etc.) Valent P, et al. Leuk Res. 2007;31:727-736. Slide borrowed from Dr. David Steensma Valent P et al Leuk Res 2007;31:727-736. Diagnostic Overlap HIV EBV Fanconi Hepatitis Medications Anemia Acute Myeloid Leukemia (AML) Aplastic Anemia Autoimmune Disorders Vitamin Deficiency Clonal Copper Deficiency Iron Deficiency Myelodysplastic Myeloproliferative Paroxysmal Syndromes (MDS) Neoplasms Nocturnal AlcoholHematuria Abuse T-LGL Non-Clonal Looking for Answers 65 year-old woman with mild anemia and a platelet count that fell slowly from 230 to 97 over the past 3 years. B12 level - Normal Normal Folate - Normal Range Thyroid - Normal No toxic medications No alcohol use No chronic illness Bone Marrow Biopsy From: NCCN Guidelines for Patients: MDS The Bone Marrow From: NCCN Guidelines for Patients: MDS Bone Marrow Dysplasia Chromosomes and Mutation Testing Bone Marrow Biopsy 65 year-old woman with mild anemia and a platelet count that fell slowly from 230 to 97 over the past 3 years. Too many cells in the bone marrow Developing cells are dysplastic (abnormal) No extra ‘blasts’ seen Chromosomes are NORMAL Classification of MDS Subtypes World Health Organization MDS categories (2008) Name Abbreviation Blood findings Bone Marrow findings Refractory anemia (RA) • Unilineage dysplasia (≥10% of cells in one Refractory cytopenia with • Unicytopenia; occasionally myeloid lineage) unilineage dysplasia Refractory neutropenia (RN) bicytopenia • <5% blasts (RCUD) • No or rare blasts (<1%) • <15% of erythroid precursors are ring Refractory thrombocytopenia (RT) sideroblasts • ≥15% of erythroid precursors are ring Refractory anemia with • Anemia sideroblasts ring sideroblasts RARS • No blasts • Erythroid dysplasia only • <5% blasts • Isolated 5q31 deletion • Anemia • Normal to increased megakaryocytes with MDS associated with • Usually normal or increased hypolobated nuclei Del(5q) platelet count isolated del(5q) • <5% blasts • No or rare blasts (<1%) • No Auer rods • Cytopenia(s) • ≥10% of cells in ≥2 myeloid lineages dysplastic Refractory cytopenia with • No or rare blasts (<1%) • <5% blasts multilineage dysplasia RCMD • No Auer rods • No Auer rods • <1 x 109/L monocytes • ±15% ring sideroblasts • Cytopenia(s) • Unilineage or multilineage dysplasia Refractory anemia with • <5% blasts • 5-9% blasts RAEB-1 • No Auer rods excess blasts, type 1 • No Auer rods • <1 x 109/L monocytes • Cytopenia(s) • Unilineage or multilineage dysplasia Refractory anemia with • 5-19% blasts • 10-19% blasts RAEB-2 • ±Auer rods excess blasts, type 2 • ±Auer rods • <1 x 109/L monocytes • Minimal dysplasia but clonal cytogenetic • Cytopenia(s) abnormality considered presumptive evidence of MDS - unclassified MDS-U • ≤1% blasts MDS • <5% blasts Swerdlow SH, Campo E, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Lyon: IARC Press, 2008, page 89 (Section: Brunning RD et al, “Myelodysplastic syndromes/neoplasms, overview)”. World Health Organization MDS/MPN categories (2008) Name Abbreviation Blood findings Bone Marrow findings • ≥15% of erythroid precursors are ring Refractory anemia with • Anemia sideroblasts ring sideroblasts and RARS-T • No blasts • Erythroid dysplasia only • ≥450 x 109/L platelets • <5% blasts thrombocytosis • proliferation of large megakaryocytes Chronic myelomonocytic • >1 x 109/L monocytes • Unilineage or multilineage dysplasia leukemia, type 1 CMML-1 • <5% blasts • <10% blasts Chronic myelomonocytic • >1 x 109/L monocytes • Unilineage or multilineage dysplasia leukemia, type 2 CMML-2 • 5%-19% blasts or Auer rods • 10%-19% blasts or Auer rods Atypical chronic myeloid • WBC > 13 x 109/L • Hypercellular aCML • Neutrophil precursors >10% • <20% blasts leukemia • <20% blasts • BCR-ABL1 negative • Unilineage or multilineage dysplasia Juvenile myelomonocytic • >1 x 109/L monocytes • <20% blasts JMML • <20% blasts leukemia • BCR-ABL1 negative MDS/MPN – unclassified • Dysplasia with myeloproliferative MDS/MPN-U features • Dysplasia with myeloproliferative features (‘Overlap Syndrome’) • No prior MDS or MPN Swerdlow SH, Campo E, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Lyon: IARC Press, 2008, page 89 (Section: Brunning RD et al, “Myelodysplastic syndromes/neoplasms, overview)”. World Health Organization MDS categories (2016) Prognosis & Risk Assessment MDS Risk Assessment 65 year-old woman with mild anemia and a platelet count that fell slowly from 230 to 97 over the past 3 years. Diagnosis: Normal Range MDS with single lineage dysplasia - MDS-SLD International Prognostic Scoring System Greenberg et al. Blood. 1997;89:2079-88. International Prognostic Scoring System LOWER Risk HIGHER Risk Low Int-1 Int-2 High 100 100 80 80 n = 235 60 60 40 40 n = 171 n = 295 Patients, % Patients, Patients, % Patients, n = 267 20 n = 314 20 n = 179 n = 56 n = 58 0 0 0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18 Overall Survival, Years Time to AML Evolution, Years IPSS-Revised (IPSS-R) ipss-r.com Greenberg et al. Blood. 2012:120:2454-65. Limitations of the IPSS-R Very low 100 Low Int 80 High Very high 60 40 Patients, % Patients, 20 0 0 2 4 6 8 10 12 Overall Survival, years •Considers only UNTREATED patients •IPSS-R does not consider somatic mutations •Somatic mutations are common in MDS •Several mutated genes have prognostic significance independent of the IPSS-R MDS Risk Assessment 65 year-old woman with mild anemia and a platelet count that fell slowly from 230 to 97 over the past 3 years. Diagnosis: Normal Range MDS with single lineage dysplasia - MDS-SLD WPSS - Very Low Risk IPSS - Low Risk IPSS-R - Very Low Risk Mutations? Gene Mutations in MDS Tyrosine Kinase Pathway Transcription Factors Others JAK2 KRAS BRAF RUNX1 TP53 GATA2 NPM1 ETV6 NRAS NOTCH? RTK’s MAML? PHF6 PTPN11 CBL WT1 ZSWIM4? BCOR UMODL1? Epigenetic Dysregulation Splicing Factors ZRSF2 IDH EZH2 U2AF1 1 & 2 DNMT3A SF3B1 PRPF40B SETBP1 U2AF2 UTX TET2 SRSF2 ASXL1 PRPF8 SF1 ATRX SF3A1 MDS Mutation Profiles ASXL1 EZH2 RUNX1 ETV6 TP53 30% of MDS patients have a mutation in one of these genes These mutations indicate more severe disease! Bejar et al. NEJM. 2011;364:2496-506. Bejar et al. JCO. 2012;30:3376-82. Impact of Mutations by IPSS Group 1.0 1.0 0.9 IPSS Low (n=110) 0.9 IPSSIPSS Low Low Mut (n=110) Absent (n=87) IPSS Int1 (n=185) IPSS Low Mut Present (n=23) TP53 0.8 0.8 IPSS Int2 (n=101) p < 0.001 0.7 0.7 IPSS High (n=32) IPSS Int1 (n=185) 0.6 0.6 0.5 0.5 ETV6 0.4 0.4 Overall Survival Overall 0.3 Overall Survival Overall 0.3 Overall Survival Overall 0.3 0.2 0.2 0.1 0.1 0.0 0.0 ASXL1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years Years 1.0 1.0 0.9 IPSS Int1 Mut Absent (n=128) 0.9 IPSS Int2 Mut Absent (n=61) IPSS Int1 Mut Present (n=57) IPSS Int2 Mut Present (n=40) 0.8 0.8 p < 0.001 p = 0.02 0.7 IPSS Int2 (n=101) 0.7 IPSS High (n=32) EZH2 0.6 0.6 0.5 0.5 0.4 0.4 Overall Survival Overall 0.3 Survival Overall 0.3 0.2 0.2 RUNX1 0.1 0.1 0.0 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Bejar et al.
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