MYELODYSPLASTIC SYNDROME MODERATOR-DR SURESH HANAGAVADI PRESENTER- DR ARIJIT ROY “We are put off by the fact that MDS is a heterogenous vaguely defined group ofconditions with seemingly ever changing names Cole.P, Sateren W - Epimediological perspective on MDS &Leukemia Leuk Res 1995 19 361-365
• First described in 1900 by Leube who used the term ―Leukanamie‖• Subsequently it had undergone a trial of jargon 30’s - Refractory anemia 40’s- Preleukemic anemia 50’s- Preleukemia/RARS/ Refractory normoblastic anemia 60’s-Smoldering acute leukemia 70’s –CMML/Refractory anemia with excess myeloblasts• 1982- Myelodysplastic syndrome (Benett et al )
• WHO definition 2008• A group of clonal hematopoietic stem cell diseases characterized by Cytopenia Dysplasia in one or more major myeloid cell lines Ineffective hematopoiesis Increased risk of development of AML
The threshold for cytopenia as recommended by the IPSS forrisk stratification are• Hb < 10 g/dl• Absolute neutrophil count< 1.8x 109 /L• Platelets < 100 x 10 9/L
• PREDISPOSING FACTORS HEREDITARY A) Constitutional genetic disorders Downs Syndrome: 10-30 times more risk Trisomy 8 : Seen in 50% cases of MDS Monosomy 7 : Seen in 50% cases of MDS. B) Neurofibromatosis C) Congenital neutropenia syndrome Kostmann Agranulocytosis Shwachman Diamond syndrome
• D) DNA repair defects Fanconi anemia, Ataxia telangiectasia Bloom syndrome• E) Mutagen detoxification(GSTq1-null) Glutathione-S-Transferase. Studies show that GST- q1null genotype increases risk by 4 times. .
• ACQUIRED These factors play a major role in secondary MDS/ t-MDS a)Mutagen exposure 1.Genotoxic therapy- alkylating agents 2. Beta-emitter phosphorus; Used in the treatment of Polycythemia Vera- 10-15% increased risk. 3. Topoisomerase(Topo-II) interactive agents like anthracycline, etoposide. 4. Autologous stem cell transplantation- long term survivors
b) Environmental /occupational exposures Exposure to benzene-5-20 fold increase in risk. Other agents like solvents, petrochemicals,Insectidec) Tobacco Tobacco smoke contains a number of leukemogens like nitrosamines, benzene and polonium-210 d) Senescence e) Aplastic anemia
• ETIOLOGY a) PRIMARY OR DE-NOVO Benzene exposure Cigarette smoking Agricultural chemicals Family h/o haematopoietic neoplasms Fanconi anemia, Shwachmann diamond, Diamond-Blackfan
• SECONDARY Prior exposure to cytotoxic chemotherapy/radiation Alkylating agents cyclophosphamide, Topoisomerase II inhibitors Etoposide Risk increases with age & prolonged exposure to low - dose chemotherapy Autologous transplantation for lymphoma-MDS seen in 12 % Most cases develop within 5 years—poor outcome
FAB CLASSIFICATION OF MDS SUBTYPE BLOOD BONE MARROW • 1%BLASTREFRACTORY <1%BLASTS DYSPLASIA;ANEMIA(RA) <5%BLASTSREFRACTORY <1%BLASTS DYSPLASIA;ANEMIA WITH <5%BLASTS;RINGED >15%RINGEDSIDEROBLASTS( SIDEROBLASTSRARS)REFRACTORY <5%BLASTS DYSPLASIA;ANEMIA WITH 5-19%BLASTSEXCESSBLASTS(RAEB)
WHO CLASSIFICATION OF MDS (2008) SUBTYPE BLOOD BONE MARROWREFRACTORY ANEMIA; UNILINEAGECYTOPENIA WITH NO OR RARE BLASTS DYSPLASIA > 10%UNILINEAGE UNICYTOPENIA CELLS IN ONEDYSPLASIA (RCUD) BICYTOPENIA MYELOID LINE WITHREFRACTORY < 5% BLASTSANEMIA (RA), <15%RINGEDREFRACTORY SIDEROBLASTSNEUTROPENIA(RN) ,(REFRACTORYTHROMBOCYTOPENIA(RT)REFRACTORY ANEMIA; >15%RINGEDANEMIA WITH NO OR RARE BLASTS SIDEROBLASTS;RINGED ERYTHROIDSIDEROBLASTS DYSPLASIA; <5%BLASTS;
SUBTYPE BLOOD BONE MARROWREFRACTORY BI / PAN CYTOPENIAS; DYSPLASIA IN >10% OFCYTOPENIA WITH NO OR RARE BLASTS; THE CELLS >2MULTILINEAGE NO AUER RODS; MYELOID LINESDYSPLASIA (RCMD) <1X109/L MONOCYTES <5%BLASTS IN BM >15%RINGED SIDEROBLAST NO AUER RODSREFRACTORY ANEMIA BI / PAN CYTOPENIAS; UNI OR MULTILINEAGEWITH EXCESS BLASTS < 5%BLASTS; DYSPLASIA;1 NO AUER RODS; 5-9%BLASTS; <1X109/L MONOCYTES NO AUER RODSREFRACTORY ANEMIA CYTOPENIAS; UNI OR MULTILINEAGEWITH EXCESS BLASTS 5-19%BLASTS; DYSPLASIA;2 AUER RODS PRESENT; 10-19%BLASTS; <1X109/L MONOCYTES AUER RODS PRESENT
SUBTYPE BLOOD BONE MARROWMYELODYSPLASTIC CYTOPENIAS; UNILINEAGE DYSPLASIA;SYNDROME, NO OR RARE BLASTS; <5% BLASTS;UNCLASSIFIED(MDS-u) NO AUER RODS; NO AUER RODS5q-SYNDROME ANEMIA; NORMAL/INCREASED NORMAL/INCREASED MEGAKARYOCYTES; PLATELET COUNT; <5%BLASTS; <5%BLASTS NO AUER RODSCHILDHOOD MDS < 2 % BLASTS DYSPLASTIC CHANGES IN > DYSPLASTIC CHANGES IN 10 % ERYTHROID >10 % NEUTROPHILS PRECURSORS DYSPLASTIC CHANGES IN > 10 % GRANULOCYTE PRECURSORS MICROMEGAKARYOCYTES, DYSPLASTIC CHANGES IN MGKS
SUBTYPE BLOOD BONE MARROWMYELODYSPLASTIC CYTOPENIAS; UNILINEAGESYNDROME, NO OR RARE BLASTS; DYSPLASIA;UNCLASSIFIED(MDS-u) NO AUER RODS; <5% BLASTS; NO AUER RODS5q-SYNDROME ANEMIA; NORMAL/INCREASED NORMAL/INCREASED MEGAKARYOCYTES; PLATELET COUNT; <5%BLASTS; <5%BLASTS NO AUER RODSCHILDHOOD MDS < 2 % BLASTS DYSPLASTIC CHANGES DYSPLASTIC CHANGES IN > 10 % ERYTHROID IN >10 % NEUTROPHILS PRECURSORS DYSPLASTIC CHANGES IN > 10 % GRANULOCYTE PRECURSORS MICROMEGAKARYOCY TES,DYSPLASTIC CHANGES IN MGKS
DIFFERENCES BETWEEN WHO AND FAB The WHO system• Makes use of cytogenetic findings.• The category of RAEB-t was eliminated as it got included within AML(>20%blasts).• CMML was removed and put in a new category of myelodysplastic/myeloproliferative diseases.• Adds the subtypes 5q syndrome and unclassifiable MDS.• Recognizes the prognostic importance of % of bone marrow blasts
INCIDENCE• The mean age of presentation in the western population is 65 yrs, whereas in India it is 45 yrs.• The incidence as reported by Aul et al in United States is 4.1 per 1,00,000.• Rare in childhood, the median age of onset is 6yrs.
PATHOGENESIS MDS : a stem cell disorder• It represents manifestation of the malignant transformation of myeloid stem cell• The abnormal cells in MDS are clones derived from an abnormal stem cell Apoptosis in MDS• Mechanism appears to be one of increased apoptosis of haemopoietic precursors in the marrow,• Presence of cytopenias despite a typically hypercellular bone marrow.• For those patients undergoing leukaemic transformation,the cytopenias arise due to maturation block of the malignant cells• Apoptosis is more prominent in early MDS, such as RA and RARS, than in advanced MDS with excess myeloblasts
Ineffective Hematopoiesis• Colony forming capacities of pleuripotent stem cells and their progeny are low or absent• Lower level of GM-CSF, M-CSF,IL 6 .IL 3,• CFU- GM less responsive to both G-CSF & GM-CSF• More dramatic in pts with RAEB or RAEB –t Immunological abnormalities in MDS• Commonly encountered in MDS, suggesting that they may play a role in the aetiology and pathogenesis of the disease.
• Particularly apparent in cases of hypoplastic MDS that share a number of features in common with aplastic anaemia, notably clinical presentation with macrocytosis and varying levels of dyserythropoiesis• Acquired mutations in the PIG-A gene characteristic of paroxysmal nocturnal haemoglobinuria (PNH) are also encountered Angiogenesis• Autocrine production of angiogenic molecules promotes expansion of leukemic clone• Vascular endothelial growth factor(VEGF) and its receptor VEGFR-1 And VEGFR-2 is overexpressed
Molecular basis of MDS• MDS is a preleukaemic disorder characterized by impaired cellular differentiation that has the potential to transform to AML if this abnormality is coupled to enhanced survival and proliferation.• The common chromosomal abnormalities found in MDS include loss of Y, monosomy 5, monosomy 7,trisomy 8, 20q – , abnormalities of 11q23, and deletions of 17p, 12p, 13q and 11q among others.
Genetic abnormalities in MDS• Mutations of the AML1 gene (also known as RUNX1 ) have recently been recognized to occur in MDS, particularly where it is treatment - related or radiation - induced.• Activating mutations of RAS , usually involving NRAS , are found in up to 20% of cases of MDS• Class 1 mutation-mutation involving Tyrosine kinase GATA1 , PU.1 ( SPI1 ), CEBPA , MLL and TP53 .• Class 2 mutation –mutation involving Transcription factors FMS (now called CSF1R ), KIT , FLT3 , PDGFRB and GCSFR• Association of both Class 1 &2 – highly predisposed to MDS & AML
Epigenetic abnormalities• refers to alteration of gene expression without altering the DNA sequence• Two important epigenetic modifications relevant to MDS, are DNA methylation and histone modification.• Promoter methylation of p15INK4B – t-MDS• methylation of p15INK4B also seen in loss of Chr 7 and in pts who progresses from RA to RAEB
ENVIRON MENTAL MOLECUL AR GAIN EPIGENET OF IC FUNCTIO NIMMUNOL OGICAL MDS APOPTOSI S STEM ANGIOGE CELL NESIS DEFECT GENETIC LOSS OF SIGNAL
Clinical features• Asymptomatic - Many patients are diagnosed on routine laboratory screening• Fatigue, weakness, angina - as a result of anemia.• Infections most commonly bacterial, predominate with skin being the most common site. This is the most common cause of mortality and morbidity in MDS.
• Autoimmune abnormalities (uncommon) - Seen in 14 % of the patients. Most common is cutaneous vasculitis.• Cutaneous manifestations of MDS Sweet syndrome Granulocytic sarcoma
MORPHOLOGY OF BLASTS• The standard criteria for a blast are Cell with a central nucleus Fine nuclear chromatin Prominent nucleoli High nucleocytoplasmic ratio Deeply basophilic and agranular cytoplasm 3 types of blasts have been found in the blood and bone marrow of MDS.
TYPE I• Finely dispersed nuclear chromatin• Prominent nucleoli• Variable N:C ratio , agranular cytoplasm
TYPE IIThey resembletype I blasts buthave primarygranules in thecytoplasm(<20)
TYPE IIIThese are similar to typeII blasts but have morethan 20 granules in theircytoplasm
CYTOCHEMICAL IDENTIFICATION OF BLASTS MYELOPEROXIDASE POSITIVE
• OTHER ERYTHROCYTE CHANGES• Increase in fetal hemoglobin• Altered A,B, antigens on the surface.
• LEUKOCYTESNeutropenia - 2nd most common cytopeniaDysgranulopoiesis is seen by agranular or hypogranularneutrophilsPersistent basophilia of cytoplasmHyposegmentation (pseudo Pelger-Huet) of the nucleusHypersegmentation of the nucleus is seen sometimes
• OTHER DEFECTS Enzyme defects such as Decreased myeloperoxidase, Decreased leukocyte alkaline phosphatase . Causes functional impairment of the neutrophils like defectivebactericidal, phagocytic and chemotactic properties.
PLATELETS• Varying degree of thrombocytopenia• Platelets may show agranular/hypogranular cytoplasm• Giant platelets are seen• Micromegakarocytes are seen. They have a single lobe nucleus with cytoplasmic tags. Nucleus shows densely clumped chromatin.
BONE MARROW ASPIRATE• Well stained BM aspirate smears• At least 500 cells are to be counted• At least 30 megakaryocyte to be evaluated• Dysplastic features should be present in > 10 % cells CELLULARITY In most cases it is hypercellular But is hypocellular in Hypoplastic MDS
Erythropoeisis• Usually megaloblastic erythropoeisis• Feature of dyserthropoiesis• Some precursors may show Howell Jolly bodies• Vacoulization , basophilia and poor hemoglobinisation• Ring sideroblasts• PAS stain – may show granular positivity of normoblasts• Advanced cases – erythroid hypoplasia seen
Granulopoiesis• Usually myeloid hyperplasia• Hypogranulrity and hyposegmentation• Maturation arrest in myelocyte stage may be seen• Abnormal staining of primary granules seen in myelocyte & promyelocytes. Granules may be larger than normal or completely absent.• Irregular cytoplasmic basophilia seen• Diminished staining to MPO and SBB
• Thrombopoiesis• Usually normal or megakaryocytic hyperplasia• Micromegakaryocytes, multinucleated megakaryocytes , & hypolobated megakaryocytes• Presence of > 10 % Micromegakaryocytes in a population suggests MDS• CD 61 staining
TREPHINE BIOPSY IN MDS Useful for determining• Cellularity of marrow• Abnormal localization of immature precursors (ALIP)• Reticulin fibrosis, Megakaryocytic dysplasia, Lymphoid aggregate• Hypoplastic MDS• Increases the diagnostic accuracy & helps in refining the IPSS score
Flowcytometry• Erythroid abnormalities detected by H- ferritin , CD71 ,CD105 in Glycophorin A• Abnormal maturation pattern in Granulocytes• For borderline dysplasia ,FC is highly suggestive for MDS only if aberrant features are present in all three lineages
OTHER INVESTIGATIONS• A) Immunophenotyping- do not play a major role in the diagnosis of MDS and need not be routinely performed• However, various abnormalities are sometimes discernible, Low side scatter, reduced expression of normal myeloid markers, Aberrant patterns of expression of markers like CD34 and to a lesser degree CD117, often correlates with the blast percentage, Coexpression of CD7 is significant for conferring a worse prognosis.
• B) Ferrokinetics- to assess erythropoiesis.• C) Haemoglobin electrophoresis or HPLC, to detect HbH and HbF• D) Granulocyte function tests to demonstrate defective phagocytosis• E) Platelet function tests to demonstrate reduced aggregation and prolonged bleeding time.• F) Serum protein electrophoresis to assess immunoglobulins and detect paraprotein.
EVALUATION OF SUSPECTED MDS• HISTORY Prior exposure to CT/RT Recurrent infections, bleeding gums• EXAMINATION Pallor/ bruising Splenomegaly• BLOOD COUNTS Hb, TLC, platelet count reticulocyte count• BLOOD FILM Macrocytosis, cytopenia, neytrophilia, monocytosis pseudo pelger huet anomaly,hypogranular neutrophils
• BONE MARROW ASPIRATE• BONE MARROW TREPHINE BIOPSY• BONE MARROW CYTOGENETICS ANALYSIS• EXCLUSION OF REACTIVE CAUSES OF DYSPLASIA Megaloblastic anaemia HIV infection Recent cytotoxic therapy Alcoholism Recurrent intercurrent infection
REFRACTORY CYTOPENIA WITH UNILINEAGE DYSPLASIA• Includes Refractory Anaemia (RA), Refractory neutropenia (RN) Refractory Thrombocytopenia (RT)• Majority of RCUD cases are RA. RN and RT are rare• 10-20 % of all cases of MDS
• Older age 65-70 yrs• M:F equal prediliction• C/F due to type of cytopenia• Cytopenia refractory to hematinics , but respond to growth factors
• Refractory Anaemia RBC are normochromic ,normocytic or normochromic microcytic Anisopoilkilocytosis- none / marked Normal neutrophils and platelets BM in RA Erythroid precursors- decreased / markedly increased Dyserythropoiesis – slight/ moderate
• Myeloblasts ≤ 5% of nucleated BM cells• Neutrophils & megakaryocytes – normal or minimal dysplasia• BM- hypercellular due to increased rbc precursors• Ring sideroblasts if present are ≤ 15 % of erythroid precursors
• Genetics RA includes del 20q , +8 , abnormality of 5 and / or 7• Median survival is 66 months and risk for AML transformation at 5 yrs is 2 %• 90-95% of pts with RA have low to intermediate IPSS score
RCUD: Refractory Neutropenia• Most important to exclude secondary causes eg drugs ,toxins• Characteristics of Dysgranulopoiesis• Nuclear: hypolobation (pseudo-Pelger Huet), irregular hypersegmentation• Cytoplasmic: hypogranularity, pseudo-Chediak Higashi granules, Auer rods, small or abnormally large size
REFRACTORY ANAEMIA WITH RING SIDEROBLASTS• RARS is the MDS chacterized by anemia, morphological dysplasia in erythroid lineage and ring sideroblast ≥ 15 % of BM with no significant dysplasia in non erythrod lineage• 3-11 % of MDS cases• Median age 60-73 yrs• Male : female - equal
• Ring sideroblasts – erythroid precursor with abnormal accumulation of iron within mitochondria• RARS represents a clonal stem cell defects that manifests as abnormal iron metabolism in the erythroid lineage and results in ineffective erythropoiesis• C/F anaemia – usually moderate degree thrombocytopenia or neutropenia
• Symptoms due to iron overload MORPHOLOGY PBS- Normochromic macrocytic/ Normochromic normocytic anaemia Dimorphic pattern with majority normochromic rbc’s and minor population of hypochromic cells BM BM normocellular to markedly hypercellular
increase in erythroid precursors with lineage dysplasia eg nuclear lobation & megaloblastoid features Hemosiderin laden macrophages - often abundant Myeloblasts ≤ 10% On iron stain ≥ 15 % of rbc precursors are ring sideroblasts• Prognosis 1-2% cases of RARS evolve to AML Median survival 69-108 months
REFRACTORY CYTOPENIA WITH MULTILINEAGE DYSPLASIA• MDS with one or more cytopenias and dysplastic changes in two or more of the myeloid lineage• ≤ 1% blasts in PBS and ≤ 5% in the BM• 30 % of cases of MDS• Slight predominance in males• Age 70- 79
• More aggressive than refractory anemia, more likely to progress to AML• Some consider it an intermediate disorder between refractory anemia and refractory anemia with excess blasts• Poor prognosis if even 1% blasts in peripheral blood• Proposed modified criteria are refractory anemia, >10% pseudo-Pelger-Huet anomalies, dysmegakaryopoiesis in ≥40% or micromegakaryocytes in ≥10%, and no 5q- syndrome• Termed RCMD with ringed sideroblasts if ≥15% ringed sideroblasts
• Cytogenetic abnormalities include Trisomy 8,Monosomy 7 del 7q , del 20q as well as complex karyotype• Frequency of AML development at 2 yrs – 10 %• Overall survival – 30 months• Pts with complex karyotype have survival rate similar to RAEB
• C/F – due to BM failure with cytopenia• Morphology BM is hypercellular Neutrophil dysplasia characterised by Hypogranulation nuclear hyposegmentation Pseudo pelger huet nuclei
Bone marrow aspirate showing erythroid population with marked megaloblasticchange and dyserythropoiesis. Blast cells with round and opened up chromatinand scant to moderate amount of pale blue cytoplasm. Most of these cellsshowed cytoplasmic vacuolation and had fine granules. (Inset) PAS staining onperipheral blood showing globular as well as diffuse PAS positivity in blasts aswell as the nucleated RBCs
REFRACTORY ANAEMIA WITH EXCESS BLASTS• MDS with 5-19 % myeloblasts in the BM or 2-19 % blasts in PB• Because of difference in survival and evolution to AML,2 categories of RAEB are recognized RAEB 1 – 5-9 % blasts in BM or 2-4 % in PB RAEB 2 - 10-19% blasts in BM or 5-19 % in PB Presence of Auer rods in blasts qualifies as RAEB 2irrespective of blast % .
• Approx 40 % of all MDS• Affects individuals over 50 yrs of age• Risk factors Environmental toxins eg pesticides Petroleum products Cigarette smoking Heavy metals
• PB smear shows abnormality in all three lines• Red cell anisopoikilocytosis• Large , giant or hypogranular platelets• Abnormal cytoplasmic granularity & nuclear segmentation of neutrophils . Blasts are commonly present• BM is hypercellular• Degree of dysplasia varies• Erythropoiesis may be increased with macrocytic/ megaloblastoid changes
• Dyserythropoiesis includes internuclear bridging and lobulated nuclei• Granulopoiesis characterized by small size with nuclei hypolobation (Pseudo pelger huet nuclei)/ nuclear hypersegmentation, cytoplasmic hypogranularity and /or pseudo Chediak- Higashi granules• Megakaryopoiesis is normal to increased, shows tendency of cluster formation• Dysmegakaryopoietic features include micromegakaryocytes but all forms and sizes can be seen
• Both erythropoiesis and megakaryopoiesis appears frequently towards the paratrabecular areas that are normally occupied by granulopoietic cells• In minority of cases BM is hypocellular or normocellular. RAEB with hypocellular BM represents only a small proportion of hypoplastic MDS• Blasts in RAEB form clusters and are located away from bony trabeculae and vascular structures – ALIP• ALIP – CD 34 +
• Flow cytometry in RAEB – Precursor antigens like CD 34 and /or CD 117 .These cells are also positive for CD 38, HLA – DR and myeloid associated antigens CD13 and /or CD 33• Asynchronous expression of Granulocytic maturation antigens CD15 ,CD 11b, and /or CD 65 in blast cells• Antibody to CD 61 or CD 42b – idenification of micromegakaryocyte and other dysplastic forms
• Cytogenetic abnormalities – in 30-50 % of RAEB +8, del 5q , ,del 7q , del 20 q• RAEB is characterized by progressive BM failure and increasing cytopenia• RAEB 1 – 25 %• RAEB 2- 33 %• Median survival of 16 months for RAEB-1 and 9 months for RAEB-2• CD7 expression associated with poor prognosis
MYELODYSPLASTIC SYNDROME WITH ISOLATED del 5q• Anaemia with or without other cytopenia and/or thrombocytosis in which the sole genetic abnormality is del 5q• Myeloblasts ≤ 5% of nucleated BM cells and ≤ 1% of PB leucocytes• Auer rods are absent• More in women• Median age 67 yrs
• Etiology Presumes loss of a tumour suppressor gene in deleted region Early growth phase response (EGR 1) and α – catenin (CTNNA1), and as yet unidentified gene in 5q32 The RPS 14 gene that encodes a ribosomal protein has been proposed as a candidate in the 5q syndrome
• Anaemia is often severe and usually macrocytic• Thrombocytosis is seen in majority of cases while thrombocytopenia is uncommon• BM is usually hypercellular or normocellular and frequently exhibits erythroid hyperplasia• Megakaryocytes are increased in no and are normal to slightly decreased in size with conspicuously hypolobated and nonlobated nuclei
• Genetic abnormality Sole cytogenetic abnormality interstitial deletion of Chr 5 Recent report a small subset of patients with isolated del 5q may show a concomitant JAK2 V617F mutation but it is prudent to report them as del 5q and to note the presence of JAK2 V617F• Subtype of refractory anemia with good prognosis• Stable clinical course but often transfusion dependent causing frequent hemochromatosis
• 10% progress to AML• lenalidomide, a thalidomide analogue and immunomodulating drug, has high response rate
Increased megakaryocytes withoverall PAS +vecytoplasm,nuclear hypolobulation
MDS UNCLASSIFIABLE• Subtype of MDS which lacks findings appropiate for classification into any other MDS category• 3 possible instances for MDS-U1. Patients with findings of refractory cytopenia with unilineage dysplasia (RCUD) or refractory cytopenia with multilineage dysplasia (RCMD) but with 1% blasts in PB2. Cases of MDS with unilineage dysplasia which are associated with pancytopenia
3. Patients with persistent cytopenia with 1 % or fewer blasts inthe blood and fewer than 5% in BM , unequivocal dysplasia inless than 10% of cells in one or more of the myeloid lineage andwho have cytogenetic abnormalities considered as presumptiveevidence of MDS
Findings• Often Auer rods but less than 5% blasts,• isolated neutropenia without anemia, isolated thrombocytopenia without anemia,• significant thrombocytosis, significant leukocytosis, hypocellular bone marrow (<30% in younger individuals, <20% if age 60 or more) or myelofibrosis• Some cases associated with prior aplastic anemia and monosomy 7• Myelofibrosis: when present, often is difficult to obtain bone marrow aspirate; patients often have pancytopenia with dysplasia in 3 lineages
CHILDHOOD MYELODYSPLASTIC SYNDROME• MDS in children is very uncommon ,accounting less than 5% of all hematopoietic neoplasms in patients less than 14 yrs• This entity should be distinguished from ― secondary MDS” that follow congenital or acquired BM failure syndromes and from MDS that follows cytotoxic therapy for a previous neoplastic or non neoplastic condition• This entity should be distinguished from MDS with Down Syndrome
• Most of childhood MDS become symptomatic rather early and transform to AML in a very short span• Has an aggressive clinical couse irrespective of WHO subtype• Often associated with preexisting BM failure syndromes or congenital abnormalities like Kostmann Syndrome Schwachmann Diamond syndrome, Fanconi anaemia NF 1 down syndrome, juvenile xanthogranuloma• JMML is the commonest• Cytogenetic abnormalities- occurs in 60-70% of primary MDS in children. Monosomy 7 is the most common
• DIFFERENCE BETWEEN ADULT AND CHILDHOOD MDS Pts may not have increased blasts in their PB or BM RARS and MDS with del 5q are exceedingly rare in children Neutropenia or Thrombocytopenia is more likely seen Hypocellular bone marrow is more commonly observed in childhood MDS
REFRACTORY CYTOPENIA OF CHILDHOOD (RCC)• It’s a type of MDS characterized by persistent cytopenia with <5% blasts in BM and < 2% blasts in PB• BM trephine biopsy specimen is indispensable• 75% of children with RCC shows BM hypocellularity• Down syndrome related myeloid neoplasms are excluded• RCC is the most common MDS in childhood accounting for 50% of the cases• Equal incidence in both sexes
• Clinical features Malaise, bleeding , fever, infection Lymphadenopathy – secondary to local infection Hepatosplenomegaly is absent Platelet count < 150 x 10 9/L seen in 75% cases Hb <10g/dL seen in 50% cases WBC decreased with severe neutropenia seen in 25%
• PB Anisopoikilocytosis with macrocytosis, anisochromasia Platelets show anisocytosis and occasionally giant platelets Neutropenia with pseudo-Pelger Huet nuclei/ hypogranular cytoplasm• BM Dysplastic changes in two different myeloid cell lineages or exceed 10% in one single cell line
• Cytoplasm- nucleus maturation asynchrony Megakaryocytic changes• Detection of micromegakaryocytes is a strong indicator of RCC
MINIMAL DIAGNOSTIC CRITERIA FOR MDS IN CHILDREN• At least two of the following Sustained unexplained cytopenia( neutropenia, thrombocytopenia , anemia) At least bilineage morphological myelodysplasia Acquired clonal cytogenetic abmormality in hematopoietic cells Increased blasts > 5%
DIFFERENTIAL DIAGNOSIS1. Vitamin B 12 and folic acid deficiency2. AML M63. HIV infection4. Parvo virus B 19 infection5. Exposure to arsenic and other heavy metals6. Congenital Dyserythropoietic anemia7. Paroxysmal nocturnal hemoglobinemia8. G- CSF Therapy
DIFFERENCE BETWEEN AML M6 AND MDS COUNT 500 BM CELLS All nucleated cells counted Erythroblast > 50% Erythroblast <50% < 20% total blasts and AML M0-M5 EP >50 % of all cells Count non erythroid cells>20 % <20 %NEC NECAML MDSM6
HYPOPLASTIC MDS• 10-15% of MDS are of hypocellular type• Higher prevalence in women• Severe cytopenia and cellularity of the marrow <30% in those who are <60 yrs of age OR < 20% in those > 60 yrs age• Majoriy of pt present with refractory anaemia• BM is hypocellular• No independent prognostic significance per se• D/D- Aplastic anaemia and hypocellular AML
MDS-F (MDS with Myelofibrosis)• Significant marrow fibrosis in 10-15% MDS• Most cases: excess blasts, aggressive course• Unclear whether fibrosis has independent prognostic value• Blast % from aspirate smears alone may understage the disease• CD34 on BMB may help• Cytogenetic abnormalities+• JAK2 - negative
SECONDARY/THERAPY RELATED MDS• Occur post-chemotherapy or post-radiation therapy, benzene toxins• Mean age of presentation is 10 yrs earlier than primary• PS – Anisopoikilocytosis & nucleated rbc• BM – normal or increased cellularity,trilineage dysplasia• Most cases are or RAEB type• t- MDS are of 2 types a) MDS occuring many years after alkylating drugs use andassociated with
• t- MDS are of 2 types a) MDS occuring many years after alkylating drugs use & associated with del 7q and del 5q b) MDS occuring 2 yrs after Topoisomerase II inhibitors• Both subtypes frequently evolve into AML
IPSS risk-based classification systemMarrow blast percentage:<5 05-10 0.511-20 1.521-30 2.0Cytogentic featuresGood prognosis 0(–Y, 5q- , 20q-)Intermediate prognosis 0.5(+8, miscellaneous single abnormality,double abnormalities)Poor prognosis 1.0(abnor. 7, complex- >3 abnor.)CytopeniasNone or one type 02 or 3 type 0.5
INTERNATIONAL PROGNOSTIC SCORING SYSTEM(IPSS) RISK SCORE AML MEDIAN TRANSFOR SURVIVAL MATION % (YEARS)LOW 0 19 5.7INTERMEDIATE -1 0.5- 1.0 30 3.5INTERMEDIATE -2 1.5 -2.0 33 1.2HIGH 2.5 45 0.4
Applying WHO to Indian settings• Indian MDS differs from MDS of West Younger age at presentation Cytopenias more severe at presentation Patients opted for less aggressive treatment Poorer treatment outcomes Infections, nutritional disorders: commoner Follow-up: Not always available Majority of pts had MDS-RA, MDS RAEB 1 & 2
PRINCIPLE OF MANAGEMENT OF MDS• Management is individualized and guided by pt age, prognosis and toxicity of treatment Low risk MDS (low and intermediate 1 risk grp of IPSS) is associated with longer survival High risk MDS (high and intermediate 2 risk grp of IPSS) have high risk of transformation and shorter survival• Low risk MDS – Erythropoietin , G-CSF, GM-CSF Immunosupressive therapy – ATG/ALG Antiangiogenic agents – Thalidomide For treatment of neutropenia – G- CSF, GM CSF
• HIGH RISK MDS Allogenic stem cell transplantation (SCT) Chemotherapy Newer therapy including 5-Azacytidine- methyl tranferase inhibitor is the most promising therapy for improving the quality of life in MDS
CONCLUSION• MDS can be effectively diagnosed and classified as per WHO 2008 classification• MDS diagnosis and classification is currently in a transitional phase from reliance almost entirely on cell morphology supplemented by cytochemistry and G-banded karyotyping, towards a new era in which molecular and perhaps immunophenotypic findings will be fully incorporated• But in developing countries it is essential to rule out infections/ nutritional deficiencies especially among the elderly before considering MDS
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