Presentation on theme: "MYELODYSPLASTIC SYNDROMES 2009 Marion Sternbach, MD, FRCP(C) FACP."— Presentation transcript:
MYELODYSPLASTIC SYNDROMES 2009 Marion Sternbach, MD, FRCP(C) FACP
Myelodysplastic Syndromes ( MDS ) Definition: Myelo = marrow in Greek Dys = irregular in Greek Dys = irregular in Greek Plasia = proliferation 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 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. e.g. defic. Chemotaxis of granuloc., bleeding, etc.
Myelodysplasia (MDS) Nucleo – Cytoplasmic asynchrony Hemoglobinized orthochromic erythroblast with still immature Nucleus with visible Chromosomes ready to Divide. Giant metamyelocyte Immature nucleus,loose Chromatin. Peroxidase granules Alk. PO4-ase granules
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. MDSMPD 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 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.) 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 : Bone marrow hemosiderin with ringed sideroblasts
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. ) 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 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.) 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 ? 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 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 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 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. 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 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 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 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 or thyroid and other endocrine disease. 2. Chronic Inflammatory, neoplastic, renal hepatic or thyroid and other endocrine disease. 3. MDS often accompanies in elderly other comorbidities, which render diagnosis and therapy quite difficult. 3. MDS often accompanies in elderly other comorbidities, which render diagnosis and therapy quite difficult.
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) SCORE SCORE 1. Blasts 5% or less 0.0. 5% or less 0.0. 5-10% 0.5 5-10% 0.5 11 – 20 % 1.5 11 – 20 % 1.5 21 – 30 % 2.0 21 – 30 % 2.0 2. Cytogenetics 2. Cytogenetics A. Good : 5q -; 20 q - ; Y – 0.0 A. Good : 5q -; 20 q - ; Y – 0.0 B. Intermediate : Any other anomaly 0.5 B. Intermediate : Any other anomaly 0.5 C. Poor : > 3 anomalies ; Monosomy 7 ; C. Poor : > 3 anomalies ; Monosomy 7 ; Trisomy 8 ( 8 + ) 1.0 Trisomy 8 ( 8 + ) 1.0
MDS – International Prognostic Scoring System ( IPSS ) continued Score 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 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 Score 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 50% survival 4.5 months 75% develop AML during that time 75% develop AML during that time
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. 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.) 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. “Intrinsic mechanism” “Extrinsic Mech.” Cytotoxic T - cell MDS Clone BM Microenvironment Oncoprotein ratios Caspases Mitochondria Cytochrome C Death ligands Death receptors : Fas, TNF-R Trail
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. ) Complications of transfusions: 1. Iron overload : each Unit of PRBC-s of ~ 250 ml contains 250 mg of Fe++. 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 Hypomethylating agents – DNA binding / competing: 5 Azacytidine and recently – Decytabine ( Dacogen ) Anti-angiogenic – related to Thalidomide – Lenalidomide ( Revlimid ) – very effective in 5q- syndrome. 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 1. AGES : 39 - 94 years. Average : 74.2 Average : 74.2 Median : 78.7 Median : 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 : Retrospective review 2004 – 2008 60 charts. DIAGNOSES: 1. Refractory Anemia (RA) – 5 ; one – 5q – 2. Refractory Anemia with Ring Sideroblasts (RAS) – 2 2. Refractory Anemia with Ring Sideroblasts (RAS) – 2 3. Refractory Anemia with Excess of Blasts 3. Refractory Anemia with Excess of Blasts (RAEB) – 3 ; one 5q – (RAEB) – 3 ; one 5q – 4. Refractory Anemia with Excess of Blasts in Transformation (RAEB – T) – 5 4. Refractory Anemia with Excess of Blasts in Transformation (RAEB – T) – 5 5. RA with Multilineage Dysplasia - 16 5. RA with Multilineage Dysplasia - 16
MDS – St. Joe’s : Retrospective Review 2004 – 2008 60 charts 6. MDS – Undefined – 10 ; One - Trisomy 15, Y- ; One – Loss of X chromosome. 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 ) LAP = 183 ( Normal up to 130 ) 8. Chronic Myelo-Monocytic Leukemia (CMML) – 14 patients 8. Chronic Myelo-Monocytic Leukemia (CMML) – 14 patients 9. Acute Myelog. Leukemia (AML) from MDS – one patient. 9. Acute Myelog. Leukemia (AML) from MDS – one patient.
MDS – at St. Joe’s Retrospective Review 2004 – 2008 Comorbidities 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. 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 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. ) 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.