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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?