Myelodysplastic Myelodysplastic SyndromesSyndromes

Terrance Comeau, M.D., F.R.C.P.Terrance Comeau, M.D., F.R.C.P.3-25-20023-25-2002

MDSMDS

Heterogeneous group of clonal Heterogeneous group of clonal hematopoietic stem cell disordershematopoietic stem cell disorders

Characterized by:Characterized by:– ineffective hematopoiesis and ineffective hematopoiesis and – peripheral cytopeniasperipheral cytopenias

MDS is best considered a preleukemic MDS is best considered a preleukemic disorder in which the neoplastic clone that disorder in which the neoplastic clone that has been established may or may not fully has been established may or may not fully progress to acute leukemia.progress to acute leukemia.

Usually affects patients > 65 years of Usually affects patients > 65 years of ageage

More prominent in menMore prominent in men

PathophysiologyPathophysiology

Initiating lesion in stem cell:Initiating lesion in stem cell:– Inherited or acquired:Inherited or acquired:

Somatic DNA damageSomatic DNA damage Genomic instabilityGenomic instability Defective DNA repairDefective DNA repair Perturbation in signal transduction pathwaysPerturbation in signal transduction pathways

Gives rise to clones with growth advantageGives rise to clones with growth advantage Accompanied by mutations in p53, FLT3, Accompanied by mutations in p53, FLT3,

RASRAS Promotes acquisition of secondary genetic Promotes acquisition of secondary genetic

events (e.g. -5, -7, etc.)events (e.g. -5, -7, etc.)

PathophysiologyPathophysiology

Transforming event in stem cellTransforming event in stem cell Results in antigenic changes in stem cellResults in antigenic changes in stem cell Autoimmune response directed at marrow:Autoimmune response directed at marrow:

– CD8+ CTL:CD8+ CTL: Inhibit normal stem cells more than MDS cellsInhibit normal stem cells more than MDS cells

– Increase in TNF-a levels:Increase in TNF-a levels: Increased apoptosisIncreased apoptosis

End result:End result:– Ineffective hematopoiesisIneffective hematopoiesis

PathophysiologyPathophysiology

Aberrant cytokine production:Aberrant cytokine production:– MDS mononuclear cells secrete:MDS mononuclear cells secrete:

TNFa:TNFa:– Inhibits normal hematopoiesisInhibits normal hematopoiesis– Increases apoptosisIncreases apoptosis

TGFb: increases apoptosisTGFb: increases apoptosis Il-1b: supports clonal expansion of aberrant stem cellsIl-1b: supports clonal expansion of aberrant stem cells

Altered stem cell adhesion to stroma/endothelium: Altered stem cell adhesion to stroma/endothelium: results in increased apoptosisresults in increased apoptosis

Abnormal marrow microenvironment:Abnormal marrow microenvironment:– Mega’s produced increased VEGF which leads to increased Mega’s produced increased VEGF which leads to increased

marrow vascularity which is associated with leukemic marrow vascularity which is associated with leukemic transformationtransformation

Early in the disease process:Early in the disease process:– Ineffective hematopoiesis and marrow Ineffective hematopoiesis and marrow

failurefailure With progression in acute leukemia:With progression in acute leukemia:

– Decrease in apoptosisDecrease in apoptosis

Clinical FeaturesClinical Features

May be asymptomaticMay be asymptomatic Symptoms of anemiaSymptoms of anemia

DyserythropoiesisDyserythropoiesis

Peripheral blood:Peripheral blood:– AnemiaAnemia– ReticulocytopeniaReticulocytopenia– AnisocytosisAnisocytosis– PoikilocytosisPoikilocytosis– Basophilic stipplingBasophilic stippling– MacrocytosisMacrocytosis

DyserythropoiesisDyserythropoiesis

Bone Marrow:Bone Marrow:– Ineffective erythropoiesisIneffective erythropoiesis– Erythroid hyperplasiaErythroid hyperplasia– Ringed sideroblastsRinged sideroblasts– Megaloblastoid maturation:Megaloblastoid maturation:

MultinuclearityMultinuclearity Nuclear fragmentsNuclear fragments Cytoplasmic abnormalitiesCytoplasmic abnormalities

Bizarre erythroid precursors.

Bizarre erythroid precursors (clover-leaf nuclei).

Ringed Sideroblasts

DysgranulopoiesisDysgranulopoiesis

Peripheral blood:Peripheral blood:– NeutropeniaNeutropenia– Abnormal neutrophil functionAbnormal neutrophil function– Decreased or abnormal neutrophil granulesDecreased or abnormal neutrophil granules– Neutrophil nuclear changes with:Neutrophil nuclear changes with:

Hyposegmentation (pseudo-Pelger-Huet anomaly)Hyposegmentation (pseudo-Pelger-Huet anomaly) HypersegmentationHypersegmentation Bizarre shapesBizarre shapes

Hyposegmented/hypogranular neutrophi

Pelger-Huethyposegmentation

Abnormal ring nucleus withabnormal granulation pattern.

DysgranulopoiesisDysgranulopoiesis

Bone Marrow:Bone Marrow:– Granulocytic hyperplasiaGranulocytic hyperplasia– Abnormal or decreased granules in Abnormal or decreased granules in

neutrophil precursorsneutrophil precursors– Increased numbers of blast cellsIncreased numbers of blast cells

DysmegakaryocytopoiesisDysmegakaryocytopoiesis

Peripheral Blood:Peripheral Blood:– ThrombocytopeniaThrombocytopenia– Large platelets with abnormal or Large platelets with abnormal or

decreased granularitydecreased granularity– Abnormal platelet functionAbnormal platelet function

DysmegakaryocytopoiesisDysmegakaryocytopoiesis

Bone Marrow:Bone Marrow:– Reduced numbers of megakaryocytesReduced numbers of megakaryocytes– MicromegakaryocytesMicromegakaryocytes– Megakaryocytes with large, single nuclei Megakaryocytes with large, single nuclei

or multiple small nucleior multiple small nuclei

FAB ClassificationFAB Classification

Refractory Anemia (RA)Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts Refractory Anemia with Ringed Sideroblasts

(RARS)(RARS) Refractory Anemia with Excess Blasts Refractory Anemia with Excess Blasts

(RAEB)(RAEB) Refractory Anemia with Excess Blasts in Refractory Anemia with Excess Blasts in

Transformation (RAEB-T)Transformation (RAEB-T) Chronic Myelomonocytic Leukemia (CMML)Chronic Myelomonocytic Leukemia (CMML)

Refractory Anemia (RA)Refractory Anemia (RA)

Cytopenia of one peripheral blood Cytopenia of one peripheral blood lineagelineage

Normo- or hypercellular marrow with Normo- or hypercellular marrow with dysplasiasdysplasias

< 1% blasts in peripheral blood< 1% blasts in peripheral blood < 5% blasts in bone marrow< 5% blasts in bone marrow

Refractory Anemia with Refractory Anemia with Ringed Sideroblasts (RARS)Ringed Sideroblasts (RARS)

Cytopenia of one peripheral blood Cytopenia of one peripheral blood lineagelineage

Normo- or hypercellular marrow with Normo- or hypercellular marrow with dysplasiasdysplasias

< 1% blasts in peripheral blood< 1% blasts in peripheral blood < 5% blasts in bone marrow< 5% blasts in bone marrow Ringed sideroblasts account for > 15% Ringed sideroblasts account for > 15%

of nucleated cells in the marrowof nucleated cells in the marrow

Refractory Anemia with Refractory Anemia with Excess Blasts (RAEB)Excess Blasts (RAEB) Cytopenia of two or more peripheral Cytopenia of two or more peripheral

blood lineagesblood lineages Dysplasia involving all 3 lineagesDysplasia involving all 3 lineages < 5% blasts in peripheral blood< 5% blasts in peripheral blood 5%-20% blasts in bone marrow5%-20% blasts in bone marrow

Refractory Anemia with Excess Refractory Anemia with Excess Blasts in Transformation (RAEB-T)Blasts in Transformation (RAEB-T)

Cytopenia of two or more peripheral Cytopenia of two or more peripheral blood lineagesblood lineages

Dysplasia involving all 3 lineagesDysplasia involving all 3 lineages > 5% blasts in peripheral blood or> 5% blasts in peripheral blood or 21%-30% blasts in bone marrow or21%-30% blasts in bone marrow or Auer rods in the blastsAuer rods in the blasts

Chronic Myelomonocytic Chronic Myelomonocytic Leukemia (CMML)Leukemia (CMML) Monocytosis in Peripheral Blood:Monocytosis in Peripheral Blood:

– > 1 X 10> 1 X 1099 per liter per liter < 5% blasts in peripheral blood< 5% blasts in peripheral blood ≤ ≤ 20% blasts in bone marrow20% blasts in bone marrow

FAB ClassificationFAB Classification

> 1 X 109 /L≤ 20%< 5%CMML

21-30%> 5%RAEB-T

5-20%< 5%RAEB

< 5%< 1%> 15%RARS

< 5%< 1%RA

PB Monocytes

BM BlastsPB Blasts% Ringed Sideroblasts

WHO Classification SystemWHO Classification System

Myelodysplastic Syndromes:Myelodysplastic Syndromes:– Refractory Anemia (RA):Refractory Anemia (RA):

With ringed sideroblasts (RARS)With ringed sideroblasts (RARS) Without ringed siderblastsWithout ringed siderblasts

– Refractory Cytopenia (MDS) with Multilineage Refractory Cytopenia (MDS) with Multilineage Dysplasia (RCMD)Dysplasia (RCMD)

– Refractory Anemia with Excess Blasts (RAEB)Refractory Anemia with Excess Blasts (RAEB)– 5q- syndrome5q- syndrome– Myelodysplastic syndrome, unclassifiableMyelodysplastic syndrome, unclassifiable

WHO Classification SystemWHO Classification System

Myelodysplastic/Myeloproliferative Myelodysplastic/Myeloproliferative Diseases:Diseases:– Chronic Myelomonocytic Leukemia Chronic Myelomonocytic Leukemia

(CMML)(CMML)– Atypical Chronic Myelogenous Leukemia Atypical Chronic Myelogenous Leukemia

(aCML)(aCML)– Leukemia (JMML)Leukemia (JMML)

IPSS Risk-Based Classification SystemIPSS Risk-Based Classification System

Overall IPSS Risk Score is Based on:Overall IPSS Risk Score is Based on:– Marrow Blast PercentageMarrow Blast Percentage– Cytogenetic Features:Cytogenetic Features:

Good Prognosis Good Prognosis – -Y, 5q-, 20q-, normal-Y, 5q-, 20q-, normal

Intermediate PrognosisIntermediate Prognosis– +8, single misc. abnormality, double abnormalities+8, single misc. abnormality, double abnormalities

Poor PrognosisPoor Prognosis– any chrom. 7 abn, complex (≥3)any chrom. 7 abn, complex (≥3)

– Cytopenias:Cytopenias: Hgb < 10 g/dl ANC < 1500 /mm3

PLT < 100,000 /mm3

Marrow Blast %Marrow Blast %

221-30

1.511-20

0.55-10

0< 5

IPSS ScoreBlast %

Cytogenetic FeaturesCytogenetic Features

1.0Poor Prognosis

0.5Intermediate Prognosis

0Good Prognosis

IPSS ScoreKaryotype

CytopeniasCytopenias

0.52 or 3 Types

0None or 1 Type

IPSS ScoreCytopenia

Overall IPSS Score and SurvivalOverall IPSS Score and Survival

0.4 yearsHigh (≥ 2.5)

3.5 years1.2 years

Intermediate1 (0.5 or 1.0)2 (1.5 or 2.0)

5.7 yearsLow (0)

Median SurvivalOverall Score

TherapyTherapy

Supportive care:Supportive care:– Despite supportive care, 50% of patients Despite supportive care, 50% of patients

die of infection or bleeding even before die of infection or bleeding even before transformation to acute leukemiatransformation to acute leukemia

Only curative therapy:Only curative therapy:– Allogeneic Stem Cell TransplantAllogeneic Stem Cell Transplant– Autologous Stem Cell Transplant (if no Autologous Stem Cell Transplant (if no

suitable allogeneic donor)suitable allogeneic donor)

TherapyTherapy

Cytokine support:Cytokine support:– G-CSF + ErythropoietinG-CSF + Erythropoietin

Cytokine inhibition: (block TNFa)Cytokine inhibition: (block TNFa)– AmifostineAmifostine– PentoxifyllinePentoxifylline– EnbrelEnbrel

TherapyTherapy

Immunosuppressive therapy:Immunosuppressive therapy:– Antithymocyte globulin (ATG)Antithymocyte globulin (ATG)– CyclosporinCyclosporin– ThalidomideThalidomide

Intensive Chemotherapy:Intensive Chemotherapy:– High Dose AraCHigh Dose AraC– Topotecan + AraCTopotecan + AraC

TherapyTherapy

Low Dose Chemotherapy:Low Dose Chemotherapy:– Low dose AraCLow dose AraC– MelphalanMelphalan– 5-azacytidine5-azacytidine– 5-aza-2’-deoxycytidine5-aza-2’-deoxycytidine

TherapyTherapy

Supportive Care:Supportive Care:– Transfusion support:Transfusion support:

pRBC’spRBC’s PlateletsPlatelets

– Management of infectionsManagement of infections

Questions?Questions?