MYELODYSPLASTIC SYNDROMESMYELODYSPLASTIC SYNDROMES20092009

Marion Sternbach, MD, FRCP(C)Marion Sternbach, MD, FRCP(C)FACPFACP

Myelodysplastic Syndromes ( MDS )Myelodysplastic Syndromes ( MDS )

Definition: Myelo = marrow in GreekDefinition: Myelo = marrow in Greek Dys = irregular in GreekDys = irregular in Greek Plasia = proliferation Plasia = proliferation in in

GreekGreekMDS is a heterogenous stem cell disease with a MDS is a heterogenous stem cell disease with a

very active and abnormal proliferation of very active and abnormal proliferation of hematopoiesis in the bone marrow with hematopoiesis in the bone marrow with asynchronous and delayed maturation of the asynchronous and delayed maturation of the different cell lines and early apoptosis ( cell different cell lines and early apoptosis ( cell death ) leading to ineffective hematopoiesis death ) leading to ineffective hematopoiesis and peripheral blood (PB) cytopenia.and peripheral blood (PB) cytopenia.

Myelodysplasia (MDS)Myelodysplasia (MDS)Patho-physiologyPatho-physiology

1. Since the stem cell is diseased any or all of 1. Since the stem cell is diseased any or all of the erythroid, myeloid or megakaryocytic cell the erythroid, myeloid or megakaryocytic cell lines may be affected.lines may be affected.2. An acquired somatic mutation of the stem cell 2. An acquired somatic mutation of the stem cell CD 34 may cause one or several cytogenetic CD 34 may cause one or several cytogenetic anomalies, influencing to a great extent the anomalies, influencing to a great extent the clinical evolution of the disease.clinical evolution of the disease.3. In addition to peripheral cytopenia, there is 3. In addition to peripheral cytopenia, there is also shortened survival of the affected cells as also shortened survival of the affected cells as well as qualitative deficiencies of these cells:well as qualitative deficiencies of these cells:

e.g. defic. Chemotaxis of granuloc., bleeding, etc.e.g. defic. Chemotaxis of granuloc., bleeding, etc.

Myelodysplasia (MDS)Myelodysplasia (MDS)Nucleo – Cytoplasmic asynchrony Nucleo – Cytoplasmic asynchrony

Hemoglobinized orthochromicHemoglobinized orthochromic

erythroblast with still immature erythroblast with still immature

Nucleus with visible Chromosomes ready toDivide.

Giant metamyelocyte Immature nucleus,loose Chromatin.

Peroxidase granules

Alk. PO4-ase granules

Myelodysplasia (MDS)Myelodysplasia (MDS)History and nomenclatureHistory and nomenclature

As early as 1938 “ refractory anemias “ were As early as 1938 “ refractory anemias “ were worrying hematologists, since they saw that they worrying hematologists, since they saw that they were “ preleukemic states “.were “ preleukemic states “.In the 1950-ies Dameshek described and In the 1950-ies Dameshek described and classified “ Myeloproliferative Disorders “ the classified “ Myeloproliferative Disorders “ the way we still do now.way we still do now.Somewhat related but with Pancytopenia and Somewhat related but with Pancytopenia and rarelyrarely huge splenomegaly myelodysplasias huge splenomegaly myelodysplasias were recognized and classified in the 1970 –ies .were recognized and classified in the 1970 –ies .

FAB classification of MDS and Myeloproliferative ( MPD ) disorders.

MDS MPDRefractory Anemia ( RA ) Polycythemia Vera ( PV )Refractory Anemia with Essential Thrombocthemia (E T )

Sideroblasts ( RAS ) Idiopathic Myelofibrosis withRefractory Anemia with Myeloid Metaplasia (MF)

Excess of Blasts ( RAEB )Refractory Anemia with Chronic Myelogenous Leukemia

Excess of Blasts in transformation (CML)( RAEB – T )

Chronic Myelo-Monocytic Chronic Myelo-Monocytic Leuk Leukemia ( CMML ) ( CMML )

Acute Myeloid or Monocytic leuk.

Myelodysplasia Myelodysplasia Patient presentationsPatient presentations

Patient No.1 :2005 – 51 year old fire fighter previously healthy,Exposed to the large tire fire in Hagersville in late

90 – ies.Ref. for fatigue and Pancytopenia.Past Hx. Not contributory. Family Hx : no

neoplasias.Funct. Enq. : fatigue and easy bruising.Phys. Exam: tall, fit, slim. No nodes, no hep-

spl.megaly. Lung, CVS, abdomen, CNS – intact.

Myelodysplasias (MDS)Myelodysplasias (MDS)Patient presentations 2 (cont.)Patient presentations 2 (cont.)

Pt. No.1: InvestigationsPt. No.1: Investigations::Leucocytes : 2.8; N – 1.3, Ly – 1.2, Mono – 0.3Leucocytes : 2.8; N – 1.3, Ly – 1.2, Mono – 0.3Hb. -120 g/l; MCV -102, ; Platelets – 92 X 10^9 / lHb. -120 g/l; MCV -102, ; Platelets – 92 X 10^9 / lB12 – 604, , Folate – 1,200, B12 – 604, , Folate – 1,200, Creatinine -95, Uric Acid – 380, Ferritin – 420, ; LFT – N.Creatinine -95, Uric Acid – 380, Ferritin – 420, ; LFT – N.Prot. Eph.- N. ; Quantit. Immunoglob. – N, ANA – Neg.Prot. Eph.- N. ; Quantit. Immunoglob. – N, ANA – Neg.Urine – N, Direct and Indirect Coombs’ – Neg. Urine – N, Direct and Indirect Coombs’ – Neg. Bone Marrow –Myeloid hyperplasia, Nucleo-cytoplasmic Bone Marrow –Myeloid hyperplasia, Nucleo-cytoplasmic asynchrony. Hemosiderin – 3+/6. asynchrony. Hemosiderin – 3+/6. Cytog. –del. 5q ( 5q - ). Pt counselled. Ref. to MUMC for Cytog. –del. 5q ( 5q - ). Pt counselled. Ref. to MUMC for Lenalidomide ( Revlimid ) therapy. 4 yrs later in CRLenalidomide ( Revlimid ) therapy. 4 yrs later in CR

Myelodysplastic bone marrow – Patient Myelodysplastic bone marrow – Patient No.1No.1

Myelodysplasia : Bone marrow Myelodysplasia : Bone marrow hemosiderin with ringed sideroblastshemosiderin with ringed sideroblasts

Myelodysplasia (MDS) : Patient No. 2 Myelodysplasia (MDS) : Patient No. 2

1993 – 58 year old female, mother of 3.1993 – 58 year old female, mother of 3.

Ref. for: fatigue, recurrent sore throats, colds, UTI-s , Ref. for: fatigue, recurrent sore throats, colds, UTI-s , Pancytopenia.Pancytopenia.

Past Hx : Heavy smoker, developed bladder Ca. Treated Past Hx : Heavy smoker, developed bladder Ca. Treated with intravesical chemotherapy for several months and with intravesical chemotherapy for several months and BCG.BCG.

Exam: pallor, few submandibular and cervical nodes, Exam: pallor, few submandibular and cervical nodes, firm, mobile, non tender, tip of spleen. firm, mobile, non tender, tip of spleen.

Lungs clear, CVS – Reg.S1-S2, systolic ejection M.2/6 over Lungs clear, CVS – Reg.S1-S2, systolic ejection M.2/6 over entire precordium.entire precordium.

MSK, CNS – intact. Integument – ecchymoses on shins.MSK, CNS – intact. Integument – ecchymoses on shins.

Myelodysplasia (MDS): Pt. No 2 ( cont. )Myelodysplasia (MDS): Pt. No 2 ( cont. )

Pertinent Labs:Pertinent Labs:Hb.-108, MCV- 92 Lc -3.2, N- 0.6, Ly – 1.2,Hb.-108, MCV- 92 Lc -3.2, N- 0.6, Ly – 1.2, Mono – 1.2, Mono – 1.2,

Blasts – 0.4, Plat. -76 X 10^9 / l .Blasts – 0.4, Plat. -76 X 10^9 / l .B12 , folate – N., Creatinine – 75, B12 , folate – N., Creatinine – 75, Ferritin – 700Ferritin – 700, , Urine – RBC-s in sediment. LFT- N., ANA – Neg.,Urine – RBC-s in sediment. LFT- N., ANA – Neg.,Coombs’ – Neg.Coombs’ – Neg.B.M – Myeloid hyperplasia, blasts – 12%, Hemosiderin – B.M – Myeloid hyperplasia, blasts – 12%, Hemosiderin –

ring sideroblasts. ring sideroblasts. Cytogenetics – multiple nonspecific anomalies.Cytogenetics – multiple nonspecific anomalies.Diagnosis – RAEB –TDiagnosis – RAEB –TTherapy: Allopurinol, Cytosar subcut., + 6TG.Therapy: Allopurinol, Cytosar subcut., + 6TG.Went in less than 3 mos. Into AMML , refractory, died.Went in less than 3 mos. Into AMML , refractory, died.

Myelodysplasia : Bone Marrow with Myelodysplasia : Bone Marrow with ringed sideroblasts Pt. No.2ringed sideroblasts Pt. No.2

Acute Myelo-Monocytic LeukemiaAcute Myelo-Monocytic Leukemia

Myelodysplasia (MDS): Patient No.3Myelodysplasia (MDS): Patient No.3

2004 – 91 year old Italian Canadian male.2004 – 91 year old Italian Canadian male.

Ref. for anemia and severe fatigue and Ref. for anemia and severe fatigue and dyspnea.dyspnea.

Past Hx: worked in steel plant for 30 years with Past Hx: worked in steel plant for 30 years with little or no protective clothing. Smoked and little or no protective clothing. Smoked and drank wine all his life.drank wine all his life.

Exam: PALLOR, no nodes, large spleen- visible Exam: PALLOR, no nodes, large spleen- visible and palpable 9.0 cm BCM. Liver edge also palp. and palpable 9.0 cm BCM. Liver edge also palp.

Crrackles at both lung bases.Crrackles at both lung bases.

Myelodysplasia (MDS): Patient No. 3 Myelodysplasia (MDS): Patient No. 3 (cont.) (cont.)

Pertinent Labs: Hb. 78 g/l, MCV -103, Leucoc. -Pertinent Labs: Hb. 78 g/l, MCV -103, Leucoc. -17,600, 17,600, N- 8,000, Mono – 7,600, N- 8,000, Mono – 7,600, Ly- 1,800, Eos – 200. Plat. Ly- 1,800, Eos – 200. Plat. 112,000. Leuco-Erythroblastic PB blood picture. 112,000. Leuco-Erythroblastic PB blood picture.

Uric Acid – 550 .Uric Acid – 550 .

Bone Marrow: Heavy myelo-Monocytic infiltration. Bone Marrow: Heavy myelo-Monocytic infiltration. Cytogenetics – Deletion of Y chromosome. (-Y)Cytogenetics – Deletion of Y chromosome. (-Y)

Therapy: Refused chemotherapy. Therapy: Refused chemotherapy.

Rx : Allopurinol.Rx : Allopurinol.

Regular blood transfusions 1 X /month X 5 years.Regular blood transfusions 1 X /month X 5 years.

MDS/ MPD – Chronic Myelo-Monocytic MDS/ MPD – Chronic Myelo-Monocytic Leukemia Leukemia

How frequent is MDS ?How frequent is MDS ?

Prevalence:Prevalence:10,000 new cases /year in USA, compared to:10,000 new cases /year in USA, compared to:2.1 / 100,000 AML2.1 / 100,000 AML4.1 / 100,000 MDS4.1 / 100,000 MDSIncidence Incidence increases with age:increases with age:0.5/100,000 in individuals < 50 years,0.5/100,000 in individuals < 50 years,5.3/100,0005.3/100,000 ““ “ 50 - 59 years“ 50 - 59 years15.0/100,00015.0/100,000 ““ “ 60 - 69 “ 60 - 69 ““49.0/100,00049.0/100,000 ““ “ 70 -79“ 70 -79 ““89.0/100,00089.0/100,000 ““ “ > 89 ““ > 89 “

MDS in children and youthMDS in children and youth

Rare in kids, median age 6 years.Rare in kids, median age 6 years.

Juvenile CMML: splenomeg., leucocytosis, Juvenile CMML: splenomeg., leucocytosis, monocytosis, polyclonal gammopathy. monocytosis, polyclonal gammopathy. Thrombocytopenia, skin involvement.Thrombocytopenia, skin involvement.

Monosomy 7 (-7 ) syndrome: Monosomy 7 (-7 ) syndrome: susceptibility to AML, susceptibility to AML, frequent infections, familial tendency.frequent infections, familial tendency.

Congenital Fanconi’s Pancytopenia: Congenital Fanconi’s Pancytopenia: megaloblastoid BM, skeletal and renal anomalies.megaloblastoid BM, skeletal and renal anomalies.

Aplastic or hypoplastic MDS +/- PNHAplastic or hypoplastic MDS +/- PNH

Fanconi’s congenital and familial Fanconi’s congenital and familial PancytopeniaPancytopenia

Hypoplastic MDS in Fanconi’sHypoplastic MDS in Fanconi’sPancytopeniaPancytopenia

MDS : Clinical and lab. characteristicsMDS : Clinical and lab. characteristics

Early on asymptomatic and incidentally discovered as Early on asymptomatic and incidentally discovered as anemia or multilineage cytopenia.anemia or multilineage cytopenia.Anemia symptoms:Anemia symptoms: fatigue, dyspnea, palpitations, fatigue, dyspnea, palpitations, dizziness, angina, CHF, slowing of mental processes.dizziness, angina, CHF, slowing of mental processes.Leuco-Neutropenia: Leuco-Neutropenia: also impaired chemotaxis, also impaired chemotaxis, phagocytosis, bactericidal activity, often skin inf.phagocytosis, bactericidal activity, often skin inf.Thrombocytopenias and impaired hemostasis.Thrombocytopenias and impaired hemostasis.Paraneoplastic autoimmune manifestations:Paraneoplastic autoimmune manifestations: vasculitis, arthritis, edema, pulm. Infiltrates, pleural and vasculitis, arthritis, edema, pulm. Infiltrates, pleural and peric. Effusions, iritis, myositis, skin ulcers , chloromas, peric. Effusions, iritis, myositis, skin ulcers , chloromas, neuropathies,neuropathies,Acquired Pure Red Cell AplasiaAcquired Pure Red Cell Aplasia

MDS – Laboratory characteristicsMDS – Laboratory characteristics

Normo – or –Normo – or – macrocytic anemia, aniso- macrocytic anemia, aniso-poikilocytosis.poikilocytosis.Normal B12, folate.Normal B12, folate.Leuco-erythroblastosis Leuco-erythroblastosis may be present, when MDS may be present, when MDS advanced.advanced.Basophilic stippling, Howell-Jolly bodies, giant bands and Basophilic stippling, Howell-Jolly bodies, giant bands and hypogranular granuloc., Pelger-Huett anomaly, hypogranular granuloc., Pelger-Huett anomaly, hypersegmentation.hypersegmentation. BM – hypercell., megaloblastoid = nucleo-cytoplasmic BM – hypercell., megaloblastoid = nucleo-cytoplasmic asynchrony, micro- and- very polyploid megakaryocytes.asynchrony, micro- and- very polyploid megakaryocytes.PNH – like defects in RBC-s ( CD55 and CD59 )-high PNH – like defects in RBC-s ( CD55 and CD59 )-high complement sensitivity.complement sensitivity.

MDS – Lab. Characteristics MDS – Lab. Characteristics continued continued

Lymphopenia, esp. CD 4 after many transf., elev. CD 8Lymphopenia, esp. CD 4 after many transf., elev. CD 8Hypo-or – hypergammaglob.Hypo-or – hypergammaglob.MGUS – especially with CMMLMGUS – especially with CMMLLympho-plasmacytic neoplasms may coexist or follow.Lympho-plasmacytic neoplasms may coexist or follow.Occas. Myelofibrosis – on BM biopsy due to PDGF- Occas. Myelofibrosis – on BM biopsy due to PDGF- alpha with pos. JAK 2 617F (MPD cytog. Feature)alpha with pos. JAK 2 617F (MPD cytog. Feature)Immuno-cytochemistry: Immuno-cytochemistry: Myeloperoxidase in myeloid Myeloperoxidase in myeloid cells.cells.Alpha Naphtyl Esterase in Monocytes,Alpha Naphtyl Esterase in Monocytes,CD 13, CD 14, CD33 - in myeloid precursorsCD 13, CD 14, CD33 - in myeloid precursorsAntibodies to F.VIII & v.W.F in Megakaryocytes.Antibodies to F.VIII & v.W.F in Megakaryocytes.

MDS – Necessary diagnostic criteriaMDS – Necessary diagnostic criteria

1. Persistent, unexplained cytopenia with the known 1. Persistent, unexplained cytopenia with the known morphologic anomalies.morphologic anomalies.

2. Older adults with normo- or – macrocytic anemia 2. Older adults with normo- or – macrocytic anemia without B12, folate deficiencywithout B12, folate deficiency..

3. Hyper ( rarely hypo ) cellular BM with megaloblastoid 3. Hyper ( rarely hypo ) cellular BM with megaloblastoid and asynchronous maturation features. Ineffective and asynchronous maturation features. Ineffective hematopoiesis.hematopoiesis.

4. Cytogenetic anomalies in 40-60% of pts.: 5q -; 7 – etc.4. Cytogenetic anomalies in 40-60% of pts.: 5q -; 7 – etc.

5. Blast count: Myeloblasts or monocytes over 1,000 / 5. Blast count: Myeloblasts or monocytes over 1,000 / ul., CD34 is proof of blast, but not all blasts are CD 34 ul., CD34 is proof of blast, but not all blasts are CD 34 +.+.

MDS – Differential diagnosisMDS – Differential diagnosis

1. Anemia of the “ Elderly “ – probably no such 1. Anemia of the “ Elderly “ – probably no such entity, since even at a cellularity of 30 % with entity, since even at a cellularity of 30 % with adequate substrates of : Albumin, Fe++, B12, adequate substrates of : Albumin, Fe++, B12, Folate, BM is capable of increasing its Folate, BM is capable of increasing its production up to 6 X basal, in the production up to 6 X basal, in the absence ofabsence of 2. Chronic Inflammatory, neoplastic, renal 2. Chronic Inflammatory, neoplastic, renal hepatic orhepatic or thyroid and other endocrine thyroid and other endocrine disease.disease. 3. MDS often accompanies in elderly other 3. MDS often accompanies in elderly other comorbidities, which render diagnosis and comorbidities, which render diagnosis and therapy quite difficult.therapy quite difficult.

MDS – Differential diagnosis MDS – Differential diagnosis continuedcontinued

4. PNH clones may be found in both MDS and Aplastic 4. PNH clones may be found in both MDS and Aplastic Anemia (AA)Anemia (AA)

These type of MDS may respond to immunosuppression These type of MDS may respond to immunosuppression ( steroids and ATG )( steroids and ATG )

AA treated may recover with clonal hematopoiesis, develop AA treated may recover with clonal hematopoiesis, develop PNH, MDS and finally AMLPNH, MDS and finally AML

5. MDS with Myelofibrosis (MDS-F )5. MDS with Myelofibrosis (MDS-F )

6. Acute Megakaryocytic Leukemia (M7 by FAB) 6. Acute Megakaryocytic Leukemia (M7 by FAB) accomp. By fibrosis and branching reticulin.accomp. By fibrosis and branching reticulin.

7. Acute Panmyelosis with Fibrosis (APMF) – up to 20-7. Acute Panmyelosis with Fibrosis (APMF) – up to 20-25 % blasts in BM, dysplasia and pancytopenia.25 % blasts in BM, dysplasia and pancytopenia.

MDS – WHO classificationMDS – WHO classification

Subtype of MDSSubtype of MDS % % Blasts BMBlasts BM % Blasts % Blasts PBPB

Refractory Anemia (RA)Refractory Anemia (RA) < 5< 5 None/rareNone/rare

Refr.Anemia w. R. S. Refr.Anemia w. R. S. < 5 < 5 None/rareNone/rare

Refr. Cytop. Multil. DysplasiaRefr. Cytop. Multil. Dysplasia

(RCMD)(RCMD)

< 5< 5 None /rareNone /rare

Refr. Cytop MD-RSRefr. Cytop MD-RS < 5< 5 None /rareNone /rareRefr.Anemia w. Excess BlastsRefr.Anemia w. Excess Blasts

(RAEB – 1 )(RAEB – 1 ) 5 – 95 – 9 < 5< 5

RAEB - 2RAEB - 2 10 -1910 -19 5 -195 -19

MDS – unclassified MDS-UMDS – unclassified MDS-U < 5< 5 None /rareNone /rare

MDS – Del 5 q (5 q - )MDS – Del 5 q (5 q - ) < 5< 5 < 5< 5

MDS – International Prognostic Scoring MDS – International Prognostic Scoring System ( IPSS)System ( IPSS)

SCORESCORE

1. Blasts1. Blasts 5% or less5% or less 0.0. 0.0. 5-10%5-10% 0.5 0.5 11 – 20 %11 – 20 % 1.5 1.5 21 – 30 % 21 – 30 % 2.0 2.0

2. Cytogenetics2. Cytogenetics A. Good : 5q -; 20 q - ; Y – A. Good : 5q -; 20 q - ; Y – 0.0 0.0 B. Intermediate : B. Intermediate : Any other anomalyAny other anomaly 0.5 0.5 C. Poor : > 3 anomalies ; Monosomy 7 ;C. Poor : > 3 anomalies ; Monosomy 7 ; Trisomy 8 ( 8 + )Trisomy 8 ( 8 + ) 1.0 1.0

MDS – International Prognostic Scoring MDS – International Prognostic Scoring System ( IPSS ) continuedSystem ( IPSS ) continued

ScoreScore

3. Cytopenias3. CytopeniasLeucoc. < 1,800/ulLeucoc. < 1,800/ul 0.0 0.0

Hemoblobin < 100 g/lHemoblobin < 100 g/l 0.5 0.5

Platelets < 100.000/ul 2/3 Platelets < 100.000/ul 2/3

A. Low Risk GroupA. Low Risk Group 0.0 0.0

50% survival 5.7 yrs50% survival 5.7 yrs

25% develop AML in 9.4 yrs. 25% develop AML in 9.4 yrs.

B. Intermed. Risk I - B. Intermed. Risk I - 0.5 0.5

50% survival 3.5 yrs.50% survival 3.5 yrs.

25% develop AML in 3.3 yrs25% develop AML in 3.3 yrs

MDS – IPSS continuedMDS – IPSS continued

ScoreScore

C.Intermed. Risk IIC.Intermed. Risk II 1.5 – 2.01.5 – 2.0

50% survival one year50% survival one year

25% develop AML within one year25% develop AML within one year

D. High Risk Group D. High Risk Group > 2.0> 2.0

50% survival 4.5 months50% survival 4.5 months

75% develop AML during that time75% develop AML during that time

Myelodysplasia (MDS) Myelodysplasia (MDS) Clinical IssuesClinical Issues

MDS present with significant clinical and biological MDS present with significant clinical and biological heterogeneity.heterogeneity.Considerable variability among pts. Of the same Considerable variability among pts. Of the same subtype.subtype.There are very different outcomes in pts. Assigned to the There are very different outcomes in pts. Assigned to the same IPSS.same IPSS.MDS is not static and changes occur over months and MDS is not static and changes occur over months and years in the same pt.years in the same pt.Comorbid medical problems in elderly complicate MDS Comorbid medical problems in elderly complicate MDS and aggravate prognosis.and aggravate prognosis.MDS is often underdiagnosed: anemia attributed to chr. MDS is often underdiagnosed: anemia attributed to chr. Inflamm., renal , other neoplastic disease or advancing Inflamm., renal , other neoplastic disease or advancing age.age.

Myelodysplasia (MDS)Myelodysplasia (MDS)Etiopathogenesis.Etiopathogenesis.

1. Genetic somatic mutations and abnormal 1. Genetic somatic mutations and abnormal DNA repair, more frequent as age advances,DNA repair, more frequent as age advances,

2. Heritable predisposition:2. Heritable predisposition:Fanconi’s Pancytopenia,Fanconi’s Pancytopenia,

Congenital Neutropenia ( Schwachman-Diamond )Congenital Neutropenia ( Schwachman-Diamond )

Down Syndrome ( trisomy 21 )Down Syndrome ( trisomy 21 )

Familial Monosomy 7 (7 - )Familial Monosomy 7 (7 - )

Trisomy 8 Mosaicism ( 8 + )Trisomy 8 Mosaicism ( 8 + )

Neurofibromatosis.Neurofibromatosis. etc etc

Myelodysplasia (MDS)Myelodysplasia (MDS)Etiopathogenesis (cont.)Etiopathogenesis (cont.)

3. Acquired:3. Acquired:Vit. B12 and /or folate deficiency, +/- chr. Liver dis.Vit. B12 and /or folate deficiency, +/- chr. Liver dis.Chemotherapy : Alkylators – mutagenic, Chemotherapy : Alkylators – mutagenic, antimetabolites e.g. – Methotrexate, Purine – 6MP or antimetabolites e.g. – Methotrexate, Purine – 6MP or Pyrimidine DNA intercalators Pyrimidine DNA intercalators Radiation – therapeutic or nuclear ( Chernobyl 1986 )Radiation – therapeutic or nuclear ( Chernobyl 1986 )Benzene and its derivatives,Benzene and its derivatives,Bone Marrow conditioning and transplantation,Bone Marrow conditioning and transplantation,Paroxysmal Nocturnal Hemoglobinuria (PNH) with Paroxysmal Nocturnal Hemoglobinuria (PNH) with clonal expansion of cells hypersensitive to clonal expansion of cells hypersensitive to Complement.Complement.

MDS – Mechanisms of ineffective MDS – Mechanisms of ineffective Hematopoiesis : early apoptosis in B.M.Hematopoiesis : early apoptosis in B.M.

““Intrinsic mechanism”Intrinsic mechanism” “Extrinsic “Extrinsic Mech.”Mech.”

Cytotoxic T - cell

MDS Clone BM Microenvironment

Oncoprotein ratios

Caspases

MitochondriaCytochrome C

Death ligandsDeath receptors : Fas, TNF-RTrail

Myelodysplasia - TherapyMyelodysplasia - Therapy

A. Supportive A. Supportive Early stage and low IPSS do not require Early stage and low IPSS do not require treatment for some time if slowly evolving.treatment for some time if slowly evolving.

RBC Transfusions according to symptoms: RBC Transfusions according to symptoms:

Hb.< 90 g/l in elderly will cause dyspnea, Hb.< 90 g/l in elderly will cause dyspnea, angina, CHF.angina, CHF.

EPO and G-CSF have been used succesfully in EPO and G-CSF have been used succesfully in a series of pts., but on occasion have a series of pts., but on occasion have accelerated leukemic transformation.accelerated leukemic transformation.

Myelodysplasia – Therapy ( cont. )Myelodysplasia – Therapy ( cont. )

Complications of transfusions:Complications of transfusions: 1. Iron overload1. Iron overload : each Unit of PRBC-s of ~ 250 ml : each Unit of PRBC-s of ~ 250 ml contains 250 mg of Fe++. contains 250 mg of Fe++. In addition – ineffective erythropoiesis with ring In addition – ineffective erythropoiesis with ring sideroblasts in the mitochondria, causes also sideroblasts in the mitochondria, causes also unutilized unutilized Fe++ in the RES. – liver, spleen, BM, heart and Fe++ in the RES. – liver, spleen, BM, heart and pancreas – hemosiderosis .pancreas – hemosiderosis .Canadian guide lines recommend Iron chelation Canadian guide lines recommend Iron chelation therapy when Ferritin reaches 1,000.therapy when Ferritin reaches 1,000.2. Alloimmunization due to repeat transfusions is 2. Alloimmunization due to repeat transfusions is bound to occur.bound to occur.T 4 lymphopenia occurs after repeat transfusions.T 4 lymphopenia occurs after repeat transfusions.

Myelodysplasia - chemotherapyMyelodysplasia - chemotherapy

Hypomethylating agents – DNA binding / competing: Hypomethylating agents – DNA binding / competing: 5 Azacytidine and recently – Decytabine ( Dacogen ) 5 Azacytidine and recently – Decytabine ( Dacogen )

Anti-angiogenic –Anti-angiogenic – related to Thalidomide – related to Thalidomide –

Lenalidomide ( Revlimid ) – very effective in 5q- Lenalidomide ( Revlimid ) – very effective in 5q- syndrome.syndrome.

Allogeneic stem cell transplant with moderate Allogeneic stem cell transplant with moderate conditioning regimen has been successful in 5q - , conditioning regimen has been successful in 5q - , as well as in overlap MDS-MPD even in elderly as well as in overlap MDS-MPD even in elderly vigorous septagenerians.vigorous septagenerians.

Immune suppression in Hypoplastic MDS with ATG Immune suppression in Hypoplastic MDS with ATG has been also succesful.has been also succesful.

MDS – St.Joe’s MDS – St.Joe’s Retrospective review of 60 chartsRetrospective review of 60 charts

2004 - 20082004 - 20081. AGES : 39 - 94 years.1. AGES : 39 - 94 years.

Average : 74.2Average : 74.2

Median : 78.7Median : 78.7

Young : between 39 and 68 years – 9 pts .Young : between 39 and 68 years – 9 pts .

2. GENDER : 29 - Males; 31 - Females.2. GENDER : 29 - Males; 31 - Females.

MDS – St. Joe’s :MDS – St. Joe’s :Retrospective review 2004 – 2008 Retrospective review 2004 – 2008

60 charts.60 charts.DIAGNOSES:DIAGNOSES:

1. Refractory Anemia (RA) – 5 ; one – 5q – 1. Refractory Anemia (RA) – 5 ; one – 5q –

2. Refractory Anemia with Ring Sideroblasts 2. Refractory Anemia with Ring Sideroblasts (RAS) – 2 (RAS) – 2

3. Refractory Anemia with Excess of Blasts3. Refractory Anemia with Excess of Blasts

(RAEB) – 3 ; one 5q –(RAEB) – 3 ; one 5q –

4. Refractory Anemia with Excess of Blasts 4. Refractory Anemia with Excess of Blasts in Transformation (RAEB – T) – 5in Transformation (RAEB – T) – 5

5. RA with Multilineage Dysplasia - 165. RA with Multilineage Dysplasia - 16

MDS – St. Joe’s : Retrospective Review MDS – St. Joe’s : Retrospective Review 2004 – 2008 2004 – 2008

60 charts60 charts 6. MDS – Undefined – 10 ; One - Trisomy 15, 6. MDS – Undefined – 10 ; One - Trisomy 15, Y- ; One – Loss of X chromosome.Y- ; One – Loss of X chromosome.7. MDS – MPD overlap syndrome – 3. These 7. MDS – MPD overlap syndrome – 3. These were JAC 2 – Neg., BCR-ABL – Neg., one had were JAC 2 – Neg., BCR-ABL – Neg., one had a picture of Polycythemia Vera and a picture of Polycythemia Vera and

LAP = 183 ( Normal up to 130 )LAP = 183 ( Normal up to 130 ) 8. Chronic Myelo-Monocytic Leukemia 8. Chronic Myelo-Monocytic Leukemia (CMML) – 14 patients (CMML) – 14 patients 9. Acute Myelog. Leukemia (AML) from MDS 9. Acute Myelog. Leukemia (AML) from MDS – one patient .– one patient .

MDS – St.Joe’sMDS – St.Joe’sRetrospective Review 2004 -2008Retrospective Review 2004 -2008

60 charts60 charts

RA

RAS

RAEB

RAEB-T

MDS-U

MDS.MP

MULT.dys

CMML

AML

MDS – at St. Joe’sMDS – at St. Joe’sRetrospective Review 2004 – 2008Retrospective Review 2004 – 2008

Comorbidities for admissionComorbidities for admissionG – I bleeds due to thrombocytopenia +/- G – I bleeds due to thrombocytopenia +/- anticoagulants for atrial fibrillation,anticoagulants for atrial fibrillation,CHF – due to anemia; Ac. Coronary syndr.CHF – due to anemia; Ac. Coronary syndr. Preceding or concomitant neoplasias : Preceding or concomitant neoplasias : breast, esophagus, colon etc.breast, esophagus, colon etc.MGUS; previously treated Myeloma.MGUS; previously treated Myeloma.Severe infections and often septicemia.Severe infections and often septicemia.Autoimmune diseases: vasculitis, Rheum. Autoimmune diseases: vasculitis, Rheum. Arthritis, Chr. Renal disease and failure.Arthritis, Chr. Renal disease and failure.Ferritin in two patients: 2,000 and 3,500Ferritin in two patients: 2,000 and 3,500

Myelodysplasia – Summary and Myelodysplasia – Summary and ConclusionsConclusions

1. MDS are quite frequent in aging populations, 1. MDS are quite frequent in aging populations, but are occas. present in young persons and but are occas. present in young persons and children.children.2. Since MDS involves the 2. Since MDS involves the pluripotential stem pluripotential stem cell, any or all hematopoietic progenitors cell, any or all hematopoietic progenitors may be affected.may be affected.3. MDS in elderly is often accompanied by 3. MDS in elderly is often accompanied by comorbidities, thus detracting our attention from comorbidities, thus detracting our attention from symptoms and signs of MDS – cause of anemia, symptoms and signs of MDS – cause of anemia, bleeding tendency, recurrent infections.bleeding tendency, recurrent infections.

Myelodysplasia – Summary and Myelodysplasia – Summary and Conclusions ( cont. )Conclusions ( cont. )

4. The biology and evolution of MDS depends on a 4. The biology and evolution of MDS depends on a variety of factors:variety of factors:Subtype of MDS,Subtype of MDS,IPSS IPSS Patient’s age and physical condition but mainlyPatient’s age and physical condition but mainlyComorbidities.Comorbidities.5. In patients with severe and irreversible comorbidities 5. In patients with severe and irreversible comorbidities supportive therapy is compelling.supportive therapy is compelling.In healthier constitutions, chemotherapy should be In healthier constitutions, chemotherapy should be considered and even stem cell transplant with curative considered and even stem cell transplant with curative intent.intent.

Thank You

MDS – St.Joe’s:MDS – St.Joe’s:Retrospective Review : 2004 -2008Retrospective Review : 2004 -2008

60 charts.60 charts.

0

2

4

6

8

10

12

14

16

RA

RAS

RAEB

RAEB-T

CMML

MDS-und.

MDS-MPD

Mult.Dysp

AML