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MYELODYSPLASTIC SYNDROMES 2009. Marion Sternbach, MD, FRCP(C) FACP. Myelodysplastic Syndromes ( MDS ). Definition: Myelo = marrow in Greek Dys = irregular in Greek Plasia = proliferation in Greek

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myelodysplastic syndromes 2009

MYELODYSPLASTIC SYNDROMES2009

Marion Sternbach, MD, FRCP(C)FACP

myelodysplastic syndromes mds
Myelodysplastic Syndromes ( MDS )
  • Definition: Myelo = marrow in Greek

Dys = irregular in Greek

Plasia = proliferation in Greek

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

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

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

myelodysplasia mds nucleo cytoplasmic asynchrony
Myelodysplasia (MDS)Nucleo – Cytoplasmic asynchrony

Giant metamyelocyte

Immature nucleus,loose

Chromatin.

Hemoglobinized orthochromic

erythroblast with still immature

Alk. PO4-ase granules

Peroxidase granules

Nucleus with visible

Chromosomes ready to

Divide.

myelodysplasia mds history and nomenclature
Myelodysplasia (MDS)History and nomenclature
  • As early as 1938 “ refractory anemias “ were worrying hematologists, since they saw that they were “ preleukemic states “.
  • In the 1950-ies Dameshek described and classified “ Myeloproliferative Disorders “ the way we still do now.
  • Somewhat related but with Pancytopenia and rarely huge splenomegaly myelodysplasias were recognized and classified in the 1970 –ies .
fab classification of mds and myeloproliferative mpd disorders
FAB classification of MDS and Myeloproliferative ( MPD ) disorders.
  • MDS MPD
  • Refractory Anemia ( RA ) Polycythemia Vera ( PV )
  • Refractory Anemia with Essential Thrombocthemia (E T )

Sideroblasts ( RAS ) Idiopathic Myelofibrosis with

  • Refractory 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 patient presentations
Myelodysplasia Patient 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 patient presentations 2 cont
Myelodysplasias (MDS)Patient presentations 2 (cont.)
  • Pt. No.1: Investigations:
  • Leucocytes : 2.8; N – 1.3, Ly – 1.2, Mono – 0.3
  • Hb. -120 g/l; MCV -102, ; Platelets – 92 X 10^9 / l
  • B12 – 604, , Folate – 1,200,
  • Creatinine -95, Uric Acid – 380, Ferritin – 420, ; LFT – N.
  • Prot. Eph.- N. ; Quantit. Immunoglob. – N, ANA – Neg.
  • Urine – N, Direct and Indirect Coombs’ – Neg.
  • Bone Marrow –Myeloid hyperplasia, Nucleo-cytoplasmic asynchrony. Hemosiderin – 3+/6.
  • Cytog. –del. 5q ( 5q - ). Pt counselled. Ref. to MUMC for Lenalidomide ( Revlimid ) therapy. 4 yrs later in CR
myelodysplasia mds patient no 2
Myelodysplasia (MDS) : Patient No. 2
  • 1993 – 58 year old female, mother of 3.
  • Ref. for: fatigue, recurrent sore throats, colds, UTI-s , Pancytopenia.
  • Past Hx : Heavy smoker, developed bladder Ca. Treated with intravesical chemotherapy for several months and BCG.
  • Exam: pallor, few submandibular and cervical nodes, firm, mobile, non tender, tip of spleen.

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

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

myelodysplasia mds pt no 2 cont
Myelodysplasia (MDS): Pt. No 2 ( cont. )
  • Pertinent Labs:

Hb.-108, MCV- 92 Lc -3.2, N- 0.6, Ly – 1.2, Mono – 1.2, Blasts – 0.4, Plat. -76 X 10^9 / l .

B12 , folate – N., Creatinine – 75, Ferritin – 700,

Urine – RBC-s in sediment. LFT- N., ANA – Neg.,

Coombs’ – Neg.

B.M – Myeloid hyperplasia, blasts – 12%, Hemosiderin – ring sideroblasts.

Cytogenetics – multiple nonspecific anomalies.

Diagnosis – RAEB –T

Therapy: Allopurinol, Cytosar subcut., + 6TG.

Went in less than 3 mos. Into AMML , refractory, died.

myelodysplasia mds patient no 3
Myelodysplasia (MDS): Patient No.3
  • 2004 – 91 year old Italian Canadian male.
  • Ref. for anemia and severe fatigue and dyspnea.
  • Past Hx: worked in steel plant for 30 years with little or no protective clothing. Smoked and drank wine all his life.
  • Exam: PALLOR, no nodes, large spleen- visible and palpable 9.0 cm BCM. Liver edge also palp.

Crrackles at both lung bases.

myelodysplasia mds patient no 3 cont
Myelodysplasia (MDS): Patient No. 3 (cont.)
  • Pertinent Labs: Hb. 78 g/l, MCV -103, Leucoc. -17,600, N- 8,000, Mono – 7,600, Ly- 1,800, Eos – 200. Plat. 112,000. Leuco-Erythroblastic PB blood picture.

Uric Acid – 550 .

  • Bone Marrow: Heavy myelo-Monocytic infiltration. Cytogenetics – Deletion of Y chromosome. (-Y)
  • Therapy: Refused chemotherapy.
  • Rx : Allopurinol.
  • Regular blood transfusions 1 X /month X 5 years.
how frequent is mds
How frequent is MDS ?
  • Prevalence:
  • 10,000 new cases /year in USA, compared to:
  • 2.1 / 100,000 AML
  • 4.1 / 100,000 MDS
  • Incidence increases with age:
  • 0.5/100,000 in individuals < 50 years,
  • 5.3/100,000 “ “ 50 - 59 years
  • 15.0/100,000 “ “ 60 - 69 “
  • 49.0/100,000 “ “ 70 -79 “
  • 89.0/100,000 “ “ > 89 “
mds in children and youth
MDS in children and youth
  • Rare in kids, median age 6 years.
  • Juvenile CMML: splenomeg., leucocytosis, monocytosis, polyclonal gammopathy. Thrombocytopenia, skin involvement.
  • Monosomy 7 (-7 ) syndrome: susceptibility to AML, frequent infections, familial tendency.
  • Congenital Fanconi’s Pancytopenia: megaloblastoid BM, skeletal and renal anomalies.
  • Aplastic or hypoplastic MDS +/- PNH
mds clinical and lab characteristics
MDS : Clinical and lab. characteristics
  • Early on asymptomatic and incidentally discovered as anemia or multilineage cytopenia.
  • Anemia symptoms: fatigue, dyspnea, palpitations, dizziness, angina, CHF, slowing of mental processes.
  • Leuco-Neutropenia: also impaired chemotaxis, phagocytosis, bactericidal activity, often skin inf.
  • Thrombocytopenias and impaired hemostasis.
  • Paraneoplastic autoimmune manifestations: vasculitis, arthritis, edema, pulm. Infiltrates, pleural and peric. Effusions, iritis, myositis, skin ulcers , chloromas, neuropathies,
  • Acquired Pure Red Cell Aplasia
mds laboratory characteristics
MDS – Laboratory characteristics
  • Normo – or – macrocytic anemia, aniso-poikilocytosis.
  • Normal B12, folate.
  • Leuco-erythroblastosis may be present, when MDS advanced.
  • Basophilic stippling, Howell-Jolly bodies, giant bands and hypogranular granuloc., Pelger-Huett anomaly, hypersegmentation.
  • BM – hypercell., megaloblastoid = nucleo-cytoplasmic asynchrony, micro- and- very polyploid megakaryocytes.
  • PNH – like defects in RBC-s ( CD55 and CD59 )-high complement sensitivity.
mds lab characteristics continued
MDS – Lab. Characteristics continued
  • Lymphopenia, esp. CD 4 after many transf., elev. CD 8
  • Hypo-or – hypergammaglob.
  • MGUS – especially with CMML
  • Lympho-plasmacytic neoplasms may coexist or follow.
  • Occas. Myelofibrosis – on BM biopsy due to PDGF- alpha with pos. JAK 2 617F (MPD cytog. Feature)
  • Immuno-cytochemistry: Myeloperoxidase in myeloid cells.
  • Alpha Naphtyl Esterase in Monocytes,
  • CD 13, CD 14, CD33 - in myeloid precursors
  • Antibodies to F.VIII & v.W.F in Megakaryocytes.
mds necessary diagnostic criteria
MDS – Necessary diagnostic criteria
  • 1. Persistent, unexplained cytopenia with the known morphologic anomalies.
  • 2. Older adults with normo- or – macrocytic anemia without B12, folate deficiency.
  • 3. Hyper ( rarely hypo ) cellular BM with megaloblastoid and asynchronous maturation features. Ineffective hematopoiesis.
  • 4. Cytogenetic anomalies in 40-60% of pts.: 5q -; 7 – etc.
  • 5. Blast count: Myeloblasts or monocytes over 1,000 / ul., CD34 is proof of blast, but not all blasts are CD 34 +.
mds differential diagnosis
MDS – Differential diagnosis
  • 1. Anemia of the “ Elderly “ – probably no such entity, since even at a cellularity of 30 % with adequate substrates of : Albumin, Fe++, B12, Folate, BM is capable of increasing its production up to 6 X basal, in the absence of
  • 2. Chronic Inflammatory, neoplastic, renal hepatic orthyroid and other endocrine disease.
  • 3. MDS often accompanies in elderly other comorbidities, which render diagnosis and therapy quite difficult.
mds differential diagnosis continued
MDS – Differential diagnosis continued
  • 4. PNH clones may be found in both MDS and Aplastic Anemia (AA)

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

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

  • 5. MDS with Myelofibrosis (MDS-F )
  • 6. Acute Megakaryocytic Leukemia (M7 by FAB) accomp. By fibrosis and branching reticulin.
  • 7. Acute Panmyelosis with Fibrosis (APMF) – up to 20-25 % blasts in BM, dysplasia and pancytopenia.
mds international prognostic scoring system ipss
MDS – International Prognostic Scoring System ( IPSS)

SCORE

  • 1. Blasts
  • 5% or less 0.0.
  • 5-10% 0.5
  • 11 – 20 % 1.5
  • 21 – 30 % 2.0
  • 2. Cytogenetics
  • A. Good : 5q -; 20 q - ; Y – 0.0
  • B. Intermediate : Any other anomaly 0.5
  • C. Poor : > 3 anomalies ; Monosomy 7 ;
  • Trisomy 8 ( 8 + ) 1.0
mds international prognostic scoring system ipss continued
MDS – International Prognostic Scoring System ( IPSS ) continued

Score

  • 3. Cytopenias
  • Leucoc. < 1,800/ul 0.0
  • Hemoblobin < 100 g/l 0.5
  • Platelets < 100.000/ul 2/3
  • A. Low Risk Group 0.0
  • 50% survival 5.7 yrs
  • 25% develop AML in 9.4 yrs.
  • B. Intermed. Risk I - 0.5
  • 50% survival 3.5 yrs.
  • 25% develop AML in 3.3 yrs
mds ipss continued
MDS – IPSS continued

Score

  • C.Intermed. Risk II 1.5 – 2.0
  • 50% survival one year
  • 25% develop AML within one year
  • D. High Risk Group > 2.0
  • 50% survival 4.5 months
  • 75% develop AML during that time
myelodysplasia mds clinical issues
Myelodysplasia (MDS) Clinical Issues
  • MDS present with significant clinical and biological heterogeneity.
  • Considerable variability among pts. Of the same subtype.
  • There are very different outcomes in pts. Assigned to the same IPSS.
  • MDS is not static and changes occur over months and years in the same pt.
  • Comorbid medical problems in elderly complicate MDS and aggravate prognosis.
  • MDS is often underdiagnosed: anemia attributed to chr. Inflamm., renal , other neoplastic disease or advancing age.
myelodysplasia mds etiopathogenesis
Myelodysplasia (MDS)Etiopathogenesis.
  • 1. Genetic somatic mutations and abnormal DNA repair, more frequent as age advances,
  • 2. Heritable predisposition:
  • Fanconi’s Pancytopenia,
  • Congenital Neutropenia ( Schwachman-Diamond )
  • Down Syndrome ( trisomy 21 )
  • Familial Monosomy 7 (7 - )
  • Trisomy 8 Mosaicism ( 8 + )
  • Neurofibromatosis. etc
myelodysplasia mds etiopathogenesis cont
Myelodysplasia (MDS)Etiopathogenesis (cont.)
  • 3. Acquired:
  • Vit. B12 and /or folate deficiency, +/- chr. Liver dis.
  • Chemotherapy : Alkylators – mutagenic, antimetabolites e.g. – Methotrexate, Purine – 6MP or Pyrimidine DNA intercalators
  • Radiation – therapeutic or nuclear ( Chernobyl 1986 )
  • Benzene and its derivatives,
  • Bone Marrow conditioning and transplantation,
  • Paroxysmal Nocturnal Hemoglobinuria (PNH) with clonal expansion of cells hypersensitive to Complement.
mds mechanisms of ineffective hematopoiesis early apoptosis in b m
MDS – Mechanisms of ineffective Hematopoiesis : early apoptosis in B.M.
  • “Intrinsic mechanism” “Extrinsic Mech.”

Mitochondria

Cytochrome C

Caspases

Cytotoxic T - cell

Death ligands

Death receptors : Fas, TNF-R

Trail

Oncoprotein ratios

BM Microenvironment

MDS Clone

myelodysplasia therapy
Myelodysplasia - Therapy
  • A. Supportive
  • Early stage and low IPSS do not require treatment for some time if slowly evolving.
  • RBC Transfusions according to symptoms:
  • Hb.< 90 g/l in elderly will cause dyspnea, angina, CHF.
  • EPO and G-CSF have been used succesfully in a series of pts., but on occasion have accelerated leukemic transformation.
myelodysplasia therapy cont
Myelodysplasia – Therapy ( cont. )
  • Complications of transfusions:
  • 1. Iron overload : each Unit of PRBC-s of ~ 250 ml contains 250 mg of Fe++.
  • In addition – ineffective erythropoiesis with ring sideroblasts in the mitochondria, causes also unutilized Fe++ in the RES. – liver, spleen, BM, heart and pancreas – hemosiderosis .
  • Canadian guide lines recommend Iron chelation therapy when Ferritin reaches 1,000.
  • 2. Alloimmunization due to repeat transfusions is bound to occur.
  • T 4 lymphopenia occurs after repeat transfusions.
myelodysplasia chemotherapy
Myelodysplasia - chemotherapy
  • Hypomethylating agents – DNA binding / competing: 5 Azacytidine and recently – Decytabine ( Dacogen )
  • Anti-angiogenic – related to Thalidomide –

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

  • Allogeneic stem cell transplant with moderate conditioning regimen has been successful in 5q - , as well as in overlap MDS-MPD even in elderly vigorous septagenerians.
  • Immune suppression in Hypoplastic MDS with ATG has been also succesful.
mds st joe s retrospective review of 60 charts 2004 2008
MDS – St.Joe’s Retrospective review of 60 charts2004 - 2008
  • 1. AGES : 39 - 94 years.
  • Average : 74.2
  • Median : 78.7
  • Young : between 39 and 68 years – 9 pts .
  • 2. GENDER : 29 - Males; 31 - Females.
mds st joe s retrospective review 2004 2008 60 charts
MDS – St. Joe’s :Retrospective review 2004 – 2008 60 charts.
  • DIAGNOSES:
  • 1. Refractory Anemia (RA) – 5 ; one – 5q –
  • 2. Refractory Anemia with Ring Sideroblasts (RAS) – 2
  • 3. Refractory Anemia with Excess of Blasts

(RAEB) – 3 ; one 5q –

  • 4. Refractory Anemia with Excess of Blasts in Transformation (RAEB – T) – 5
  • 5. RA with Multilineage Dysplasia - 16
mds st joe s retrospective review 2004 2008 60 charts1
MDS – St. Joe’s : Retrospective Review 2004 – 2008 60 charts
  • 6. MDS – Undefined – 10 ; One - Trisomy 15, Y- ; One – Loss of X chromosome.
  • 7. MDS – MPD overlap syndrome – 3. These were JAC 2 – Neg., BCR-ABL – Neg., one had a picture of Polycythemia Vera and

LAP = 183 ( Normal up to 130 )

  • 8. Chronic Myelo-Monocytic Leukemia (CMML) – 14 patients
  • 9. Acute Myelog. Leukemia (AML) from MDS – one patient .
mds at st joe s retrospective review 2004 2008 comorbidities for admission
MDS – at St. Joe’sRetrospective Review 2004 – 2008Comorbidities for admission
  • G – I bleeds due to thrombocytopenia +/- anticoagulants for atrial fibrillation,
  • CHF – due to anemia; Ac. Coronary syndr.
  • Preceding or concomitant neoplasias : breast, esophagus, colon etc.
  • MGUS; previously treated Myeloma.
  • Severe infections and often septicemia.
  • Autoimmune diseases: vasculitis, Rheum. Arthritis, Chr. Renal disease and failure.
  • Ferritin in two patients: 2,000 and 3,500
myelodysplasia summary and conclusions
Myelodysplasia – Summary and Conclusions
  • 1. MDS are quite frequent in aging populations, but are occas. present in young persons and children.
  • 2. Since MDS involves the pluripotential stem cell, any or all hematopoietic progenitors may be affected.
  • 3. MDS in elderly is often accompanied by comorbidities, thus detracting our attention from symptoms and signs of MDS – cause of anemia, bleeding tendency, recurrent infections.
myelodysplasia summary and conclusions cont
Myelodysplasia – Summary and Conclusions ( cont. )
  • 4. The biology and evolution of MDS depends on a variety of factors:
  • Subtype of MDS,
  • IPSS
  • Patient’s age and physical condition but mainly
  • Comorbidities.
  • 5. In patients with severe and irreversible comorbidities supportive therapy is compelling.
  • In healthier constitutions, chemotherapy should be considered and even stem cell transplant with curative intent.
slide48

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