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Information about MDS

Published on January 9, 2010

Author: gaiech


Myelodysplastic syndromes : Myelodysplastic syndromes Speaker : Dr. Govindaraj.T Moderator : Dr. Hemalatha.A.L Prof & HOD Myelodysplastic syndrome (MDS) : Myelodysplastic syndrome (MDS) It is a term for a heterogeneous collection of haemopoietic stem cell disorders affecting older adults. There is underlying ineffectiveness of haemopoiesis that results in dysplasia of bone marrow precursors and peripheral cytopenias. MDS (other names) : MDS (other names) Dysmyelopoietic syndrome Preleukemic syndrome Smoldering acute leukemia Oligoblastic leukemia Myelodysplastic syndrome : Myelodysplastic syndrome A disease of the elderly Incidence : 3 – 20 /100,000 Increasing number of therapy related MDS Clinical features: related to cytopenia MDS: Etiology : MDS: Etiology Primary Not known Secondary Possible etiologies: Virus, Benzene, cigarette (2 fold risk), Fanconi anemia. -therapy-related Chemotherapy (alkylating agents) Radiation Therapy Slide 6: Moderate anaemia is the most common clinical problem in MDS patients complete myeloid bone marrow failure also occurs leading to death from bleeding or infection. Approximately half of the patients transform to AML. MDS : MDS Pathology The cardinal features of MDS are Increased marrow proliferation Failure of stem cells to differentiate And increased marrow apoptosis. The disease is of clonal origin Chromosomal abnormalities are detectable in 30-70% of patients. The no. of chromosomal abn. may correlate with the risk of progression to AML. Dysplasia, apoptosis and cytokines in MDS : Dysplasia, apoptosis and cytokines in MDS Despite increased proliferation of the marrow, there is an increased rate of prgrammed cell deathkinetically the apoptosis prevails over the increased proliferation, causing the peripheral cytopenia Cytokines derived from unselected marrow mononuclear cells are belived to be extrinsic factors predisposing to apoptosis (TNF - inhibit normal and MDS colony growth; INF, IL1, TGF - have also be implicated in causing apoptosis) Evidence for an immune – mediated suppression of the marrow in MDS : Evidence for an immune – mediated suppression of the marrow in MDS T cells inhibit MDS CFU-E CD8+ cells inhibit CFU-GM Immunosuppressive agents improve cytopenia in MDS and eliminate autosuppressive T cells T cells are activated in MDS &T cell show a skewed T cell receptor V- repertoire HLA-DR 15 over representation in MDS and aplastic anemia Slide 10: Transformation to acute leukaemia occurs in up to 40% of patients. Although progression to frank AML is a primary concern, 20-40 % or more of patients die of infections and/or haemorrhagic complications. Known molecular abnormalities in MDS : Known molecular abnormalities in MDS Classification : Classification FAB -1982 WHO- 2001 FAB classification : FAB classification In 1982 The FAB group classified MDS according to Morphology and the % of myeloblasts in the BM and PB These included Refractory anaemia (RA) Refractory anaemia with ringed sideroblasts (RARS) Refractory anaemia with excess blast in marrow (RAEB) Refractory anaemia with excess blast in transformation (RAEB-t) - CMML WHO classification : WHO classification The WHO proposed changes including reclassification of RAEB-t to AML and adding a subgroup called refractory cytopenias with dysplasia (RCD) WHO classification : WHO classification Myelodysplastic Syndromes RA RARS RCMD & RCMD-RS RAEB-1 & RAEB-2 MDS Unclassified MDS del(5q) Myelodysplastic/Myeloproliferative Diseases CMML Atypical CML Juvenile CMML MDS/MPD, unclassified MAJOR CHANGES IN WHOCLASSIFICATION OF MDS : MAJOR CHANGES IN WHOCLASSIFICATION OF MDS • Blast count for a diagnosis of AML is reduced from 30% to 20% • RAEB-T is eliminated • Refractory cytopenia with multilineage dysplasia (RCMD) is added • 5q- syndrome is added • CMML is incorporated into a bridging MDS-MPS classification International Prognostic Scoring System (IPSS) : International Prognostic Scoring System (IPSS) The most practical and validated MDS classification system currently available to clinicians is the IPSS which predicts both survival and risk of transformation to AML based on: Marrow blast % Cytogenetics And number of cytopenias. MDS: Score predicts survival : MDS: Score predicts survival Low = 0 INT-1 = 0.5-1.0 INT-2 = 1.5-2.0 High >= 2.5 Lab features : Lab features RBC Anaemia (80%) Oval macrocytosis (typical) Reticulocyte count low Basophilic stippling Hypochromia Dimorphic red cells Megaloblastoid erythroblasts WBC : WBC Neutropenia (60%) Hypogranular & hypolobated neutrophils(psedo pelger-Huet abnormality) Type 1( non granular) Type 2 ( granular) blasts Platelets : Platelets Thrombocytopenia (50%) BT (due to platelet function defect) Agranular platelets Giant platelets Micromegakaryocytes Megakaryocyte fragments Bone marrow Aspiration : Bone marrow Aspiration Dyserythropoiesis Dysgranulopoiesis dysmegakaryopoiesis Dyserythropoiesis : Dyserythropoiesis Nuclear budding Inter-nuclear bridging Karyorrhexis Multinuclearity Megaloblastoid maturation Ringed sideroblast Vacuolation PAS +ve Myelodysplastic features in MDS : Myelodysplastic features in MDS Dyserythropoiesis : Dyserythropoiesis Dyserythropoiesis : Dyserythropoiesis Perinuclear siderotic granules : Perinuclear siderotic granules Prussian blue reaction of erythroid precursors. : Prussian blue reaction of erythroid precursors. Dysgranulopoiesis : Dysgranulopoiesis Small size Nuclear hypolobulation (pseudo-Pelger Heut) Hypersegmentation Hypogranularity Pseudo-Chediak Higashi granules Dysgranulopoiesis : Dysgranulopoiesis Dysgranulopoiesis : Dysgranulopoiesis Dysmegakaryocytopoiesis : Dysmegakaryocytopoiesis Hypolobulated micro-megakaryocyte Non-lobulated nuclei in megakaryocyte of all sizes Multiple, widely separated nuclei Megakaryocyte dysplasia : Megakaryocyte dysplasia Megakaryocyte dysplasia : Megakaryocyte dysplasia Bone marrow Biopsy : Bone marrow Biopsy Assessment of cellularity Hyper/hypo cellular Hypocellular( sec MDS ) ALIP (immature cells present in centre of marrow) - F/o high-grade lesion(RAEB) - risk to AML BM fibrosis (sec MDS) Abnormal localization of immature precursors : Abnormal localization of immature precursors Genetics : Genetics 5q- syndrome del (17p), small hypolobulated or vacuolated neutrophils, p53 mutations, poor prognosis -5/5q- -7/7q- del(20q) 3q21q26 abnormality Cytogenetics and prognosis : Cytogenetics and prognosis Good risk Normal, isoloted 5q-, isolated 20q-, -Y Poor risk Complex changes (> 3 abnormalities) Chromosome 7 abnormalities Intermediate risk All other changes Myelodysplastic syndromes : Marrow blast percentage: < 5 0 5-10 0.5 11-20 1.5 21-30 2.0 Cytogentic fetures Good prognosis 0 (–Y, 5q- , 20q-) Intermediate prognosis 0.5 (+8, miscellaneous singleabnormality, double abnormalities) Poor prognosis 1.0 (abnor. 7, complex- >3 abnor.) Cytopenias None or one type 0 2 or 3 type 0.5 Myelodysplastic syndromes IPSS risk-based classification system Refractory Anemia (RA) : Refractory Anemia (RA) Unilineage Dysplasia (Erythroid) Anemia refractory to therapy Unequivocal dyserythropoiesis Exclude all other possibilities i.e: Drugs, toxins, virus, immunologic, congenital and vitamin deficiencies Refractory Anemia (RA) : Refractory Anemia (RA) PB: Normochromic, Normocytic RBCs Anisocytosis Poikilocytosis Blasts <1% Normal neutrophils and platelets Refractory Anemia (RA) : Refractory Anemia (RA) BM: Hypercellular, normocellular or hypocellular Dyserythropoiesis Nuclear budding, internuclear bridging, karyorrhexis, multinuclearity, megaloblastoid features Cytoplasmic vacuolization, PAS positivity Ringed Sideroblasts <15% erythroid precursors Myeloblasts < 5% all marrow cells Auer rods absent Refractory anaemia : Refractory anaemia Exclusion of known secondary causes of dyserythropoiesis If no cytogenetic abnormality present, reassess after 6 months Protracted clinical course median survival is 66 months, leukaemic transformation 6% Refractory Anemia (RA) : Refractory Anemia (RA) Observe for 6 months and re-evaluate Myeloblasts: <1% PB and <5% BM DD: Other MDS with multilineage dysplasia or Ringed Sideroblasts Refractory Anemia with Ringed Sideroblasts (RARS) : Refractory Anemia with Ringed Sideroblasts (RARS) 10-12% of MDS cases Older patients Males > females Moderate anemia (Normo or Macro) Dysplasia restricted to erythroid lineage Genetic abnormalities in <10% of cases 1-2% evolve to AML Median survival: 6 years Refractory cytopenia with multilineage dysplasia : Refractory cytopenia with multilineage dysplasia PB Bicytopenia or pancytopenia No or rare blasts No Auer rod < 1 X 109/L monocytes MB Dysplasia in  10% of cells in two or more myeloid cell lines < 5% blasts No Auer rod < 15% ringed sideroblasts Refractory Cytopenia with Multilineage Dysplasia (RCMD) : Refractory Cytopenia with Multilineage Dysplasia (RCMD) RCMD 24% cases of MDS RCMD-RS 15% cases of MDS Older patients BM failure, cytopenia 2 or more myeloid lineage Dysplasia >10% of marrow cells Refractory cytopenia with multilineage dysplasia : Refractory cytopenia with multilineage dysplasia Cytogenetic abnormality seen in 50% +8 Monosomy 7 del(7q) Monosomy 5 del (5q) del (20q) Complex karyotype Refractory cytopenia with multilineage dysplasia : Refractory cytopenia with multilineage dysplasia Refractory cytopenia with multilineage dysplasia : Refractory cytopenia with multilineage dysplasia Refractory cytopenia with multilineage dysplasia : Refractory cytopenia with multilineage dysplasia Leukaemic transformation 11% Overall median survival 33 months RCMD and RCMD-RS are similar in clinical course Patients with complex karyotype have similar clinical course to RAEB Refractory Anemia with Excess Blasts (RAEB) : Refractory Anemia with Excess Blasts (RAEB) 40% of all patients with MDS 50 yrs and older Anemia, thrombocytopenia or neutropenia Abnormalities in all three lines (PB) Anisopoikilocytosis Atypical plts Pseudo Pelger Huet anomaly Blasts (0-19%) Refractory anaemia with excess blasts-1 : Refractory anaemia with excess blasts-1 PB Cytopenia <5% blasts No Auer rod <1% monocytes MB Unilineage or multilineage dysplasia 5-9% blasts No Auer rod Refractory Anemia with Excess Blasts (RAEB) : Refractory Anemia with Excess Blasts (RAEB) BM: Mostly Hypercellular + ALIPs Neutrophil Hyperplasia with dysplasia Small, nuclear hypolobation, hypersegmentation, hypogranularity Erythroid dyserythropoiesis Megakaryocytes hypolobated, micromegas, widely separated nucleii Refractory Anemia with Excess blasts (RAEB) : Refractory Anemia with Excess blasts (RAEB) 5-19% myeloblasts in BM RAEB-1 5-9% blasts (BM) <5% blasts (PB) RAEB-2 10-19% blasts (BM) or 5-19% blasts (PB) & <10% blasts (BM) or Presence of Aur Rods Refractory anaemia with excess blasts-2 : Refractory anaemia with excess blasts-2 Refractory anaemia with excess blasts : Refractory anaemia with excess blasts Blast cells show myeloid phenotype Leukaemic transformation RAEB-1 25% RAEB-2 33% Median survival RAEB-1 18 months RAEB-2 10 months Refractory Anemia with Excess Blasts (RAEB) : Refractory Anemia with Excess Blasts (RAEB) 30%-50% clonal cytogenetic abnormalities +8, -5, del(5q), -7, del(7q) and del(20q) Immunophemotype: Blasts express CD13, CD33, CD117 25% RAEB-1 and 33% RAEB-2 progress to AML Median survival: 18 mo (RAEB-1), 10 mo (RAEB-2) Myelodysplastic syndrome, unclassifiable : Myelodysplastic syndrome, unclassifiable PB Cytopenias No or rare blasts No Auer rods MB Unilineage dysplasia, one myeloid cell line (non-erythroid) <5% blasts No Auer rod MDS, unclassified : MDS, unclassified No specific morphologic findings Neutropenia and thrombocytopenia Dysplasia restricted to myeloid or megas Hyper/normo or hypocellular marrow No specific cytogenetic findings Older or younger patients, even children No increase in blasts 5q- syndrome : 5q- syndrome Myelodysplastic syndrome associated with isolated del (5q) chromosome < 5% Blasts in marrow and blood Predominantly middle-aged to older women Severe Refractory Anemia (Macrocytic) Hypercellular marrow with abnormal megas 5q- syndrome : 5q- syndrome PB Anaemia Usually normal or increased platelet count <5% blasts MB Normal or increased megakaryocytes with hypolobulated nuclei <5% blasts Isolated 5q- abnormality No Auer rod 5q- syndrome : 5q- syndrome 5q- syndrome : 5q- syndrome SUMMARY OF FEATURES OF WHOCATEGORIES : SUMMARY OF FEATURES OF WHOCATEGORIES Type PB Blasts BM Blasts RS Mono Dysplasia (%) (%) RA 0 <5 <15 <1x109/L E only RARS 0 <5 >15 <1x109/L E only RCMD <5 <5 <15 <1x109/L >10% in >2 lineages RCMD-RS <5 <5 >15 <1x109/L >10% in >2 lineages RAEB 1 <5 5-9 var. <1x109/L E, G, Mega RAEB 2 5-19 10-19 var. <1x109/L E, G, Meg DIFFERENTIAL DIAGNOSIS OF MDS : DIFFERENTIAL DIAGNOSIS OF MDS • Non-neoplastic causes of myelodysplasia • Megaloblastic changes • Toxic agents, i.e., heavy metals, acute alcohol intoxication • Drug effects - primarily anti-neoplastic • Congenital dyserythropoietic anemia • Chronic infectious disease • Acquired immunodeficiency syndrome (AIDS) • Neoplastic Diseases • Chronic myeloproliferative disease • Acute myeloid leukemia MDS: Differential Diagnosis : MDS: Differential Diagnosis B12/folate deficiency Heavy metals (Arsenic) Congenital dyserythropoietic anemia Parvovirus B19 GCSF therapy (increased blasts) DISTINCTION OF MDS FROMCHRONIC MYELOPROLIFERATIVEDISORDERS : DISTINCTION OF MDS FROMCHRONIC MYELOPROLIFERATIVEDISORDERS MDS CMPD Cytopenias Normal or elevated Blood counts Ineffective hematopoiesis Effective hematopoiesis Dysplasia No dysplasia No splenomegaly Splenomegaly PROBLEM AREAS IN THEDISTINCTION OF MDS AND AML : PROBLEM AREAS IN THEDISTINCTION OF MDS AND AML • Borderline blast counts • Cases with >50% erythroid precursors • Cases with criteria of MDS with a cytogenetic abn. specific for AML (Rosati S, Anastasi J, Vardiman J. Sem Hematol 23:111-26, 1996) Giant pronormoblast is parvovirus infection : Giant pronormoblast is parvovirus infection Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) : Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Chronic Myelomonocytic Leukemia (CMML) Atypical Chronic Myeloid Leukemia (CML) Juvenile CMML MDS/MPD, unclassified Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) : Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Clonal hematopoietic neoplasms Clinical/lab/morph supporting MDS Positive finding c/w Chronic myeloproliferative diseases, No Ph’chromosome Hypercellular marrow, spleno & hepatomegaly Dysplasia Blasts <20% Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) : Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) t(5;12) (q31:p12) and t(5;10)(q33;q22), enhances the tyrosine kinase of PDGF-R, leading to abnormal RAS activation. JMML associated with neurofibromatosis type-1 (NF-1) Survival ranges from months to years Complications of cytopenias, leukemia Chronic Myelomonocytic Leukemia (CMML) : Chronic Myelomonocytic Leukemia (CMML) Clonal disorder of marrow stem cell Persistent Monocytosis >1x109/L (PB) (-) Philadelphic chr and BCR/ABL fusion gene <20% blasts (PB & BM), including myeloblasts, monoblasts and promonocytes +/- Dysplasia in 1 or more BM lineages. Chronic Myelomonocytic Leukemia (CMML) : Chronic Myelomonocytic Leukemia (CMML) WBC normal (50% of cases), or increased Monocytosis with neutropenia Fatigue, wt loss, fever, night sweat, infection, bleeding Hepatomegaly & splenomegaly if WBC high Carcinogens, radiation, cytotoxic agents…. Chronic Myelomonocytic Leukemia (CMML) : Chronic Myelomonocytic Leukemia (CMML) 31% of cases of MDS Median age at Dx: 65-75 yrs Male predominance 1.5-3.1:1 Blood & BM involvement +/- spleen, liver, skin, LN extramedullary leukemic infiltrate Atypical Chronic Myeloid Leukemia (aCML) : Atypical Chronic Myeloid Leukemia (aCML) MDS and MPD changes NO Philadelphia Chromosome or BCR-ABL fusion gene Elderly patient (60-70s) M:F ratio 1:1-2.5:1 Blood, BM, spleen and liver Neutrophil precursors >10% PB aCML : aCML Hypercellular marrow M:E ratio 10:1 <20% blasts Dysmyelopoiesis (trilineage) Poor prognosis +8, +13, del(20q), i(17q), del (12p) Juvenile Myelomonocytic leukemia (JMML) : Juvenile Myelomonocytic leukemia (JMML) Childhood disorder Clonal hematopoietic disorder Proliferation of granulocytes and monocytes +/- erythroid and megakaryocytic abnormalities 1.3/million children 0-14 yrs of age (75% of cases less than 3 yrs of age) 2-3% of all leukemias JMML : JMML Malaise, pallor, fever, bronchitis, tonsilitis, skin rash, café-au-lait spots, bleeding, hepatosplenomegaly PB: Monocytosis >1x109/L (PB) (-) Philadelphia ch or BCR/ABL fusion gene <20% blasts (PB & BM), including myeloblasts, monoblasts and promonocytes + two or more of the following: Hb F (high for age) Immature granulocytes in PB Clonal chromosomal abnormality (CH 7) GM-CSF hypersensitivity of myeloid precursors (in vitro) JMML (etiology) : JMML (etiology) ? Genetic predisposition Cases reported in twins JMML & Neurofibromatosis (NF-1) Children with NF-1 have 200-500 x risk to develop JMML JMML (prognosis) : JMML (prognosis) Variable Poor with death within 1 year (30% of cases) Median survival 5 mo-4 yrs Better prognosis in children < 1yr of age Poor prognosis if plts< 33 k or HbF>15% MDS/MPD, unclassified : MDS/MPD, unclassified Lab and Morphologic features of MDS AND Prominent myeloprolifetarive features No h/o underlying CMPD or MDS, no toxins, no Ph ch, no del (5q), no t(3;3)(q21;q26), no inv (3)(q21q26) Mixed MPD and MDS cannot be assigned any other category HYPOCELLULAR MDS : HYPOCELLULAR MDS Cellularity of marrow <30% (<20% in patients over 60 yrs) • ~ 10% of cases • More common in therapy related MDS and in children with MDS • RA, RCMD, and RAEB most common MONOSOMY 7 SYNDROME : MONOSOMY 7 SYNDROME • Anemia and leukocytosis • Thrombocytopenia in 50% • Monocytosis • Defective neutrophil function with recurrent infections • Hypercellular BM with ↑ reticulin • Dysplasia • Hepatosplenomegaly • Neurofibromatosis The scope of MDS : The scope of MDS MDS is primarily a disease of the elderly, with a median age at diagnosis of between 60-80 years. The incidence is approximately double that of AML. The recent increase in MDS incidence may be related to growing awareness, better diagnosis, and an aging population. Slide 100: Low intensity chemotherapy with cytarabine induces response in approximately 30% of MDS patients. However , the relapse rate is high, and there is no improvement in overall survival. Recent studies show that using low dose cytarabine in conjunction with M-CSF, GM-CSF, or ATRA may improve overall response and survival. Slide 101: Farnesyltransferase inhibitors- modulate multiple proteins and /or cell signaling pathways that have been implicated in MDS pathophysiology or progression, including Ras, p53.. Antiproliferative, antiangiogeneic and proapoptotic activity Slide 102: Bone marrow transplantation is currently the only potentially curative therapy for MDS patients. Overall disease-free survival at 3 years with allogenic procedures ranges approximately from 35-60% depending on IPSS score and other patient’s risk factor especially age. Patients older than 50 years having an approximately 50% chance of dying from the transplant itself. Slide 103: Most attempts to induce haemopoietic cell differentiation have failed. For example, interferon alfa-2 transiently improves platelet counts in some MDS patients. However progression is also possible. Clinical studies with differentiation promoters such as retinoids, Vit D3, butyrates have been disappointing. In contrast, the hypomethylating agent 5-azacytidine has produced significant clinical benefit in patients with MDS Conventional therapies : Conventional therapies Supportive care including blood products with deferoxamine, haemopoietic growth factors and antibiotics. EPO increases red blood cells in some patients, GM-CSF may limit infections. Hormone suppressive therapy with danazol has been used to help resolve anaemia and reduce transfusion requirements. Conclusion : Conclusion In the majority of patients with MDS who are not eligible for allogenic transplantation, the disease is fatal. Approximately 2/3 of patients die within 3-4 years of diagnosis. Patients with high risk MDS generally survive approximately one year. Slide 107: Except for a recent trial of azacytidine, none of the other currently available drugs for MDS extends survival, and many are highly toxic. The FTIs are an example of targeted therapy with potential clinical applicability in MDS-modulating an array of tumour signaling cascades via inhibition of farnesyitransferase. Anti-MDS agents in development : Anti-MDS agents in development ATRA Amifostine –cytoprotective agent Melphalan Azacytidine- blocks DNA methylation and may initiate transcription and differentiation. Thalidomide-antiangiogenic, anti-TNF alpha and immunosuppressive. Immunosuppressive therapy-ATG, cyclosporine A Slide 109: THANK YOU

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