Aplastic Anemia & MDS International Foundation Talk. Definition. Introduction 4/20/2012. April 2012 H. Phillip Koeffler, M.D.

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1 Aplastic Anemia & MDS International Foundation Talk April 2012 H. Phillip Koeffler, M.D. Definition Myelo Greek prefix; marrow Dysplasia abnormal morphology Can affect: RBCs WBCs Plts Introduction 1949: subacute form of AML recognized 1953: Block et al. studied 12 pts with evidence of marrow failure 1982: French American British (FAB) cooperative group developed consensus guidelines for classification/diagnosis of MDS Myelodysplastic syndromes (MDS): represent a heterogenous spectrum of stem cell malignancies No biological marker exists for diagnosing MDS Morphology essential for diagnosing 1

2 Pluripotent Stem Cell Hematopoietic Differentiation Myeloid Stem Cell Lymphoid Stem Cell CFU-E CFU-MK Myeloblast Monoblast Myeloblast Myeloblast B Lymphoblast T Lymphoblast Proerythroblast Megakaryocyte Neutrophilic Promonocyte Myelocyte Eosinophilic Basophilic Myelocyte Myelocyte Erythrocyte Platelets Neutrophil Monocyte Eosinophil Basinophil B Cell T cell Macrophage Myeloid Related Plasma Cell Dendritic Cell Blood Cell Life Span Function Erythrocyte 120 Days xygen Transport Monocyte 3 Days Host Defense, Immune Surveillance (Precursor of Tissue Macrophage) Neutrophil 7 Hours Host Defense Eosinophil? Host Defense against parasites, Allergies Basophil? Inflammation and allergy Platelets 7 8 Days Blood Clotting T Lymphocytes? Cellular Immunity B Lymphocytes? Antibody defenses (precursor of plasma cell) MDS morphological features Megaloblastic erythroid precursors Pseudo Pelger- Huet neutrophil (PB) Multinucleated erythroid precursor (BM) Micromegakaryocyte (BM) Ringed sideroblast (BM) Misshapen nuclei in erythroid precursors (BM) 2

3 Clinical Presentation MDS affects 5/ , >70y 22 45/ Median age of onset: 7 th decade of life Affects more than (60:40) Risk factors: exposure to radiation, chemotherapy (alkylating agents), benzene, organic compounds Clinical picture: may be asymptomatic Impaired hematopoiesis Cytopenias Bleeding/bruising Infection Fatigue Short of breath Cytopenia suspect MDS? H&P Diagnosing MDS CBC, differential and reticulocyte counts BM aspirate/biopsy (Fe stain, cytogenetics) RBC folate, vit B12, serum erythropoietin, serum iron/tibc/ferritin Cytogenetics Selected gene sequencing The Myelodysplastic Syndromes Clonal Bone Marrow Disorders PNH RAEB RARS AML RA CML RAEB-T Myelodysplastic CLL Leukemias Syndromes CMML ALL MMM Myeloproliferative Syndromes P.V. E.T. FAB Classification of Myelodysplastic Syndromes Classification % Blasts Bone Marrow % Blasts Peripheral Monocytes Blood 1000/ul Ringed Sideroblasts >15% In Bone Marrow RA RARS RAEB CMML RAEB-Tr AML <5% <5% 5-20% <20% >20-30% >30% <1% 1% <5% <5% >5% -/+ + -/ /+ -/+ -/+ 3

4 Classification of Myelodysplastic Syndrome (MDS) FAB RA RARS RAEB RAEB-T CMML WH RA (unilineage) 5q- syndrome RCMD: refractory cytopenia with multilineage dysplasia RARS (unilineage) RCMD (with RS) RAEB-1 (5% - 10% blasts) RAEB-II (> 10% - 20% blasts) AML (> 20% blasts) MDS/MPD ( 13,000 WBC/ 13,000 WBC) - Unclassified MDS: International Prognostic Scoring System (IPSS) Prognostic Survival and AML Evolution Score Value Variable Marrow blasts (%) < Karyotype+ Good Intermediate Poor Cytopenias (all lineages) Risk Category Combined Score Low 0 Int Int High >2.5 International MDS Risk Classification + Kayrotype: Good = normal, -Y, del(5q), del(20q); Poor = complex ( 3 abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities. 4

5 Gene Expression Profiling of Hematopoietic Stem Cells ligonucleotide Microarray RT IVT Biotin Biotin Hybridize Biotin Biotin Biotin Scan CD34+ Total RNA cdna crna Microarray Expression Image Risk Prediction (11 Genes) in Preleukemia Training set Test set TACSTD2 UQCC1 TNNC1 KDELR2 CLC H-PLK RGS19 ATF3 FARP1 GNG7 TPD52L2 TACSTD2 H-PLK FARP1 ATF3 TNNC1 TPD52L2 KDELR UQCRC1 RGS19 CLC GNG Low-risk High-risk Control Low-risk High-risk Genetic analysis of human cancers by SNP-CHIP Single nucleotide polymorphism (SNP) ligonucleotide SNP probes TGCAT GCATGCA : Allele A TGCAA GCATGCA : Allele B Chr. 1 cmpl Chr. 2 DNA CHIP Distribution of CN neutral LH (UPD) in MDS Chr. 3 N-Ras trysomy 8 (4/6), normal karyotype (2/6) Chr. 4 Chr. 5 Chr. 6 Chr. 7 Chr. 8 Chr. 9 Chr. 11 normal karyotype (7/9) Chr. 10 Chr. 12 Jak2 Chr. 13 FLT3 Chr. 14 Chr. 15 Chr. 16 Chr. 17 Chr. 18 Chr. 19 Chr. 20 Chr. 21 Chr. 22 p53 all complex karyptypes (7/7) Runx1 Candidate gene and large scale sequencing Molecular defects in MDS Frequency (%) NRAS Point mutations 15 FLT3 Tandem duplications 5 TP53 Mutation, deletion 5 RUNX1 Mutation 5 MLL Amplification 5 TET2 Mutation 20 CSF1R Mutation Rare KIT Mutation Rare ASXL Mutation Rare CDKN2B Promoter methylation 40 EVI1 Ectopic expression 30 IRF1 Exon skipping 20 5

6 Spliceosome Machiney: mutated 45 90% of MDS cases Cancer Cell 20(4) pp , 2011 Close bservation Treatments Transfusions Trials B12 and Folate Pyridoxine Androgens Corticosteroids 6

7 Mutagen-Related MDS Alkylating Agents Chlorambucil Busulphan Melphalan Cyclophosphamide Long-Term Latency ccupational Genotoxins Chemical solvents Insecticides Petroleum products 80% with 5/del(5q) Probable multistep and/or 7/del(7q) process with an extended MDS phase Poor prognosis Agents Targeting Topoisomerase II Epipodophyllotoxins Anthracyclines Actinomycin Short-Term Latency t(8;21) t(15;17) t(3,21)(q26;q22) t(11,variable)(q23;v) ne or several steps to MDS/AML Prognosis same as AML subtype MDS clinical syndromes MDS with fibrosis: Reticulin fibrosis in bone marrow Difficult to distinguish from myelofibrosis Trilineage dysplasia and absence of hepatomegaly favor diagnosis of MDS Hypoplastic MDS: Difficult to distinguish from aplastic anemia Cytogenetic analysis required for diagnosis NEJM, 1999, 240(41):

8 Therapies of MDS Erythropoietin: Red cells Granulocyte colony stimulating factor: Neutrophils [Romiplostim (Nplate)] Lenolidomide: Less severe disease Antithymocyte globulin: Immune attack? 5 Azacytidine (Vidaza) (Severe disease) 2 deoxy 5 Azacytidine (Decitabine) (Severe disease) Aggressive chemotherapy: Severe disease Stem cell transplant: Severe disease Anemia Associated With MDS Common, >85% ften macrocytic Chronic Frequent transfusion dependence Erythropoietin (EP) and MDS 16% have significant stimulation of erythropoiesis. Response to EP or Darbepoetin: similar response Patients with the greatest need for RBC transfusions have least likely chance to respond Combination of G-CSF and EP: improvement of RBC in RARS (40% response rate), other subgroups unclear Neutropenia/Thrombocytopenia and MDS Neutropenias Management of infections Recombinant growth factors Thrombocytopenias Platelet transfusions Transfusion Risks: Iron verload Each unit of prbc adds 250 mg of iron RBC transfusions = 5 10 g iron Elevated serum ferritin ( ) Iron accumulation results in progressive organ dysfunction Heart Liver Endocrine glands Bone marrow Exjade: ral Iron Chelator H ral, dispersible tablet Administered once daily Highly specific for iron Chelated iron excreted mainly in feces (<10% in urine) H N N N * * * Fe H 8

9 Thalidomide Less severe disease but transfusion dependence. Thalidomide is poorly tolerated by many patients, particularly elderly. 1. Somnolence 2. Neurotoxicity 3. Skin Rash Lenalidomide (Revlimid) N H N N H N NH 2 Thalidomide Lenalidomide times more potent than Thalidomide Safety profile: non neurotoxic, non sedating, non teratogenic Erythroid Response to Lenalidomide % 65% % Patients % Transfusion independence HI E Minor HI E Total mg/day) 10 mg/day 10 mg/day, 21 days Lenalidomide Treatment 5q- Low risk (non-5q-) Transfusion independence 65% 25% Duration of Transfusion Independence 115 weeks 41 weeks Median Hgb increase 3.9 g/dl 2.3 g/dl Erythroid Response to Lenalidomide by MDS Classification MDS Classification (n) Erythroid Response FAB Class RA 75% RARS 46% RAEB, RAEB-t 33% CMML 0% IPSS Risk Category Low 68% Int-1 50% Int-2, High 20% Correlation Between Karyotype and Erythroid Response to Lenalidomide Erythroid Response Karyotype del(5)(q31.1) 83% Normal 57% ther 12% 9

10 Cytogenetic Response to Lenalidomide Chromosomal Abnormality >50% Decrease in Abnormal Cells in Metaphase Complete Cytogenetic Response del(5)(q31.1) 83% 75% Bad prognosis, complex karyotypes 0 0 Lenalidomide Associated Adverse Events Neutropenia 65% Thrombocytopenia 74% Pruritus 23% Diarrhea 21% Urticaria 14% 1. Toxic cytopenias occur usually within first 8 weeks of therapy. 2. Consider alternative therapies in non-responders after 4 months thearpy. 3. Use only if favorable or intermediate karyotype. 4. Clonal suppression of malignant clone uncommon with poor karyotype. bservation Therapies of MDS Erythropoietin: Red cells Granulocyte colony stimulating factor: Neutrophils Lenolidomide: Less severe disease Antithymocyte globulin: Immune attack? 5 Azacytidine (Vidaza) (Severe disease) 2 deoxy 5 Azacytidine (Decitabine) (Severe disease) Aggressive chemotherapy: Severe disease Stem cell transplant: Severe disease 10