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Myelodysplastic Syndrome

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  • AML, acute myeloid leukemia; IPSS, International Prognostic Scoring System; IPSS-R, revised IPSS; MDS, myelodysplastic syndromes; NR, not reached; OS, overall survival.
  • Transcript

    • 1. Myelodysplastic Syndrome Dr. Mohammad Nurul Azam HMO, Department of Haematology CMCH
    • 2. What Is Myelodysplastic Syndrome?  Heterogeneous group of clonal hematopoietic stem cell disorders.  In MDS the bone marrow cannot produce blood cells effectively, and many of the blood cells formed are defective.  MDS is best considered a preleukemic disorder in which the neoplastic clone that has been established may or may not fully progress to acute leukemia.
    • 3. Characteristics Varying degree of tri-lineage cytopenia ( red blood cells, white blood cells and platelets). Dysplasia Normocellular or hypercellular B.M May progress to acute leukaemia Incidence 1- Disease of elderly. 2- Median age 65 years. 3- <10% are younger than 50 years. 4- Incidence rates 1/100,000 pop./ years. 5- Incidence rise to 1/1000 / years in > 60 years old. 6- Male slightly higher than female
    • 4. Predisposing Factors
    • 5. HEREDITARY ACQUIRED A) Constitutional genetic disorders Downs Syndrome Trisomy 8 Monosomy 7 B) Neurofibromatosis C) Congenital neutropenia syndrome Kostmann Agranulocytosis Shwachman Diamond syndrome D) DNA repair defects Fanconi anemia, Ataxia telangiectasia Bloom syndrome E) Mutagen detoxification a)Mutagen exposure Genotoxic therapy- alkylating agents Beta-emitter phosphorus; Used in the treatment of Polycythemia Vera- 10-15% increased risk. Topoisomerase(Topo-II) interactive agents like anthracycline, etoposide. 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, Insectide. c) Tobacco Tobacco smoke contains a number of leukemogens like nitrosamines, benzene and polonium-210
    • 6. Morphological dysplasia in MDS Dyserythropoiesis Dysmyelopoiesis Dysmegakaryopoiesis Ring Sideroblast Type I, II & III blasts
    • 7. Dyserythropoiesis  Peripheral blood:  Anemia  Reticulocytopenia  Anisocytosis  Poikilocytosis  Basophilic stippling  Macrocytosis  Bone Marrow:  Ineffective erythropoiesis  Erythroid hyperplasia  Ringed sideroblasts  Megaloblastoid maturation:  Multinuclearity  Nuclear fragments  Cytoplasmic abnormalities Bizarre erythroid precursors Ring sideroblast
    • 8.  Peripheral blood:  Neutropenia  Decreased or abnormal neutrophil granules  Neutrophil nuclear changes with:  Hyposegmentation (pseudo-Pelger-Huet anomaly)  Hypersegmentation  Bizarre shapes  Bone Marrow:  Granulocytic hyperplasia  Abnormal or decreased granules in neutrophil precursors  Increased numbers of blast cells <20%  Type I and type II blasts Dysgranulopoiesis
    • 9. Hyposegmented/ hypogranular neutrophil Pelger-Huet hyposegmentation Dysgranulopoiesis ( contd…)
    • 10. Blasts in MDS Dysgranulopoiesis ( contd…)
    • 11. Dysmegakaryocytopoiesis  Peripheral Blood: Thrombocytopenia Large platelets with abnormal or decreased granularity Abnormal platelet function  Bone Marrow:  Reduced numbers of megakaryocytes  Micromegakaryocytes  Megakaryocytes with large, single nuclei or multiple small nuclei
    • 12. Abnormal platelets Micromegakaryocyte Dysmegakaryocytopoiesis
    • 13. FAB Classification Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts (RARS) Refractory Anemia with Excess Blasts (RAEB) Refractory Anemia with Excess Blasts in Transformation (RAEB-T) Chronic Myelomonocytic Leukemia (CMML)
    • 14. MDS: FAB Classification 1982 FAB subtype Blast % RS% Monocyte s >1x109/l Survival (months) PB BM RA <1 <5 <15 - 50 RARS <1 <5 >15 - 75 RAEB <5 5-20 variable - 11 CMML <5 <20 variable + 11 RAEB-T >5; Auer rods 20-30; Auer rods variable +/- 5
    • 15. MDS: Limitations of FAB Classification  Multilineage cytopenia with <5% BM blasts  Rough prediction of prognosis  Cytogenetics not given importance  Ill defined entities: childhood MDS, T-MDS & other secondary MDS  Immunophenotyping and genetic techniques not included
    • 16. WHO Classification System( 2001)  Refractory Anemia (RA)  Refractory Anemia with ringed sideroblasts  Refractory Cytopenia (MDS) with Multilineage Dysplasia (RCMD) – with & without sideroblasts  Refractory Anemia with Excess Blasts (RAEB)  5q- syndrome  Myelodysplastic syndrome, unclassifiable
    • 17. WHO CLASSIFICATION OF MDS (2008)
    • 18. SUBTYPE BLOOD BONE MARROW RCUD: 1.RA 2.RN 3.RT ANEMIA; NO OR RARE BLASTS UNICYTOPENIA BICYTOPENIA UNILINEAGE DYSPLASIA > 10% CELLS IN ONE MYELOID LINE WITH < 5% BLASTS <15%RINGED SIDEROBLASTS REFRACTORY ANEMIA WITH RINGED SIDEROBLASTS ANEMIA; NO OR RARE BLASTS >15%RINGED SIDEROBLASTS; ERYTHROID DYSPLASIA; <5%BLASTS; REFRACTORY CYTOPENIA WITH MULTILINEAGE DYSPLASIA (RCMD) BI / PAN CYTOPENIAS; NO OR RARE BLASTS; NO AUER RODS; <1X109/L MONOCYTES DYSPLASIA IN >10% OF THE CELLS >2 MYELOID LINES <5%BLASTS IN BM >15%RINGED SIDEROBLAST NO AUER RODS RAEB - 1 BI / PAN CYTOPENIAS; < 5%BLASTS; NO AUER RODS; <1X109/L MONOCYTES UNI OR MULTILINEAGE DYSPLASIA; 5-9%BLASTS; NO AUER RODS RAEB – 2 CYTOPENIAS; 5-19%BLASTS; AUER RODS PRESENT; <1X109/L MONOCYTES UNI OR MULTILINEAGE DYSPLASIA; 10-19%BLASTS; AUER RODS PRESENT MYELODYSPLASTIC SYNDROME, UNCLASSIFIED(MDS-u CYTOPENIAS; NO OR RARE BLASTS; NO AUER RODS; UNILINEAGE DYSPLASIA; <5% BLASTS; NO AUER RODS 5q-SYNDROME ANEMIA; NORMAL/INCREASED PLATELET COUNT; <5%BLASTS NORMAL/INCREASED MEGAKARYOCYTES; <5%BLASTS; NO AUER RODS CHILDHOOD MDS < 2 % BLASTS DYSPLASTIC CHANGES IN >10 % NEUTROPHILS DYSPLASTIC CHANGES IN > 10 % ERYTHROID PRECURSORS DYSPLASTIC CHANGES IN > 10 % GRANULOCYTE PRECURSORS MICROMEGAKARYOCYTES,DYSPLASTIC CHANGES IN MGKS
    • 19. Comparison of MDS Classifications FAB classification WHO Classsification 2001 WHO Classification 2008 RA RA Refractory cytopenia with unilineage dyplasia • Refractory anemia • Refractory neutropenia • Refractory thrombocytopenia RARS RARS Refractory anemia with ring sideroblasts (RARS) RCMD RCMD RCMD-RS RCMD-RS RAEB RAEB I and 2 RAEB I and 2 RAEB-T RAEB II/ AML RAEB II/ AML CMML MDS-UC MDS-UC MDS associated with isolated del(5q) MDS associated with isolated del(5q) Childhood myelodysplastic syndrome • Refractory cytopenia of childhood
    • 20. 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
    • 21. PATHOGENESIS
    • 22. MDS : a stem cell disorder  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,  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
    • 23. 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
    • 24. Molecular basis of MDS  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
    • 25. 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
    • 26. MDS ENVIRONMENTAL EPIGENETIC APOPTOSIS STEM CELL DEFECT GENETIC LOSS OF SIGNAL ANGIOGENESI S IMMUNOLOGICAL MOLECULAR GAIN OF FUNCTION
    • 27. Signs and Symptoms  Excessive tiredness, shortness of breath, and pale skin can be caused by anemia.  Serious infections with high fevers can be caused by leukopenia and, in particular, by having neutropenia or granulocytopenia.  Excessive bruising and bleeding, for example, frequent or severe nosebleeds and/or bleeding from the gums, can be due to thrombocytopenia.
    • 28.  splenomegaly,hepatomegaly  Cutaneous manifestations: Uncommon  Sweet’s syndrome( neutrophilic dermatosis)  Granulocytic sarcoma (chloroma): herald disease transformation into acute leukemia Sweet’s syndrome Signs and Symptoms (contd…)
    • 29. EVALUATION OF SUSPECTED MDS  HISTORY Prior exposure to CT/RT Recurrent infections, bleeding gums  EXAMINATION Pallor/ bruising Splenomegaly  INVESTIGATION CBC PBF: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
    • 30. 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 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
    • 31. OTHER INVESTIGATIONS  A) Immunophenotyping- do not play a major role in the diagnosis of MDS and need not be routinely performed  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.
    • 32. 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
    • 33. RCUD: Refractory Anaemia  Dyplasia of the erythroid series only.  Clinically, anaemia is refractory to hematinic therapy  Myeloblasts < 1% blood and < 5% marrow  No Auer rods  Other etiologies of erythroid abnormalities must be excluded. These include:  drug/toxin exposure -vitamin deficiency  viral infection -congenital disease  Epidemiology:  5-10% of MDS cases.  Older patients  Morphology:  Anisopoikilocytosis on peripheral smears  Dyserythropoiesis with nuclear abnormalities (megaloblastoid change)  < 15% ringed sideroblasts  Genetics:  25% may have genetic abnormalities  Prognosis:  Median survival is 66 months  6% rate of progression to acute leukemia
    • 34. RCUD: Refractory Neutropenia  Most important to exclude secondary causes eg. drugs ,toxins  Characteristics of Dysgranulopoiesis  Nuclear: hypolobation (pseudo-Pelger Huet), irregular hypersegmentation  Cytoplasmic: hypogranularity, Auer rods, small or abnormally large size
    • 35. RCUD: Refractory Thrombocytopenia  Evaluate >30 mgk’cytes  D/D from chronic autoimmune thrombocytopenia is critical  Features: Micromegakaryocytes, hypolobation, multiple widely separated nuclei
    • 36. Refractory Anemia with Ringed Sideroblasts  Dyplasia of the erythroid series only.  Clinically, anemia is refractory to hematinic therapy  Myeloblasts < 5% in marrow, absent in blood  >15% ringed sideroblasts in marrow  No Auer rods  Other etiologies of ringed sideroblasts must be excluded. These include:  Anti- tuberculosis drugs  Alcoholism  Epidemiology:  10-12% of MDS cases.  Older patients  Males > females  Morphology:  Dimorphic pattern on peripheral smears  Majority RBC’s normochromic, 2nd population hypochromic  Dyserythropoiesis with nuclear abnormalities (megaloblastoid change)
    • 37. Refractory Anemia with Ringed Sideroblasts  Genetics:  Clonal chromosomal abnormalities in <10%; in fact, development of such an abnormality should prompt reassessment of diagnosis.  Prognosis:  Median survival 6 years (72 months)  1-2% rate of progression to acute leukemia Contd… Ring sideroblast Megaloblastoid Change
    • 38. 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  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 Epidemiology  30 % of cases of MDS  Slight predominance in males  Age 70- 79
    • 39. RCMD: contd... Genetics  Cytogenetic abnormalities include Trisomy 8,Monosomy 7,del 7q , del 20q as well as complex karyotype Prognosis  Frequency of AML development at 2 yrs – 10 %  Overall survival – 30 months  Pts with complex karyotype have survival rate similar to RAEB
    • 40. Refractory Anemia with Excess Blasts  Refractory anemia with 5-19% myeloblasts in the bone marrow.  RAEB-1:  5-9% blasts in bone marrow and <5% blasts in blood.  RAEB-2:  10-19% blasts in the bone marrow  Auer rods present  Epidemiology: 40% of MDS cases.  Older patients (over 50 years) Morphology:  Dysplasia of all three cell lines often present  Neutrophil abnormalities may include:  Hypogranulation  Pseudo-Pelger-huet (hyposegmentation/barbells)  Megkaryocyte abnormalities may include  Hypolobation -Micromegakaryocytes
    • 41. Refractory Anemia with Excess Blasts: Contd…  Morphology (con’t.)  Erythroid precursor abnormalities may include:  Abnormal lobulation -megaloblastoid change  Multinucleation  0-19% myeloblasts in the blood  5-19% in the marrow  Bone marrow:  Usually hypercellular (10-15% hypocellular)  Abnormal localization of immature precursors (ALIP) may be present  Immunophenotype:  Blasts express CD 13, CD33 or CD117  Genetics:  Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The abnormalities include:  +8 – -5 – del(5q) – -7 – del(7q) – Complex karyotypes  Prognosis:  Median survival, RAEB-1 = 18 months  Median survival, RAEB-2 = 10 months  RAEB-1 = 25% rate of progression to acute leukemia  RAEB-2 = 33% rate of progression to acute leukemia
    • 42. MDS 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  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
    • 43. Contd…  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.  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
    • 44. MDS UNCLASSIFIABLE  Subtype of MDS which lacks findings appropriate for classification into any other MDS category  3 possible instances for MDS-U 1. Patients with findings of refractory cytopenia with unilineage dysplasia (RCUD) or refractory cytopenia with multilineage dysplasia (RCMD) but with 1% blasts in PB 2. Cases of MDS with unilineage dysplasia which are associated with pancytopenia 3. Patients with persistent cytopenia with 1 % or fewer blasts in the blood and fewer than 5% in BM , unequivocal dysplasia in less than 10% of cells in one or more of the myeloid lineage and who have cytogenetic abnormalities considered as presumptive evidence of MDS  Some cases associated with prior aplastic anemia and monosomy 7
    • 45. 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
    • 46. Childhood MDS: Contd...  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
    • 47.  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
    • 48. 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%
    • 49. DIFFERENTIAL DIAGNOSIS 1. Vitamin B 12 and folic acid deficiency 2. AML M6 3. HIV infection 4. Parvo virus B 19 infection 5. Exposure to arsenic and other heavy metals 6. Congenital Dyserythropoietic anemia 7. G- CSF Therapy
    • 50. 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  D/D- Aplastic anaemia and hypocellular AML
    • 51. 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 +ve  JAK2 - negative
    • 52. SECONDARY/THERAPY RELATED MDS  Occur post-chemotherapy or post-radiation therapy, benzene toxins  Mean age of presentation is 10 yrs earlier than primary  Most cases are or RAEB type  t- MDS are of 2 types a) MDS occuring many years after alkylating drugs use. b) MDS occuring 2 yrs after Topoisomerase II inhibitors  Both subtypes frequently evolve into AML
    • 53. IPSS: Prognostic Variables 0 0.5 1.0 1.5 2.0 Marrow blasts % <5 5-10 — 11-20 21-30 Karyotype Good Intermediate Poor Cytopenias 0/1 2/3 - - - Overall score is the sum of the scores for following parameters: BM blasts %: score 0 =< 5%; 0.5=5-10%; 1.5=11-19%; 2.0=20-30%. Cytopenias: score 0 = no/ one cytopenia; 0.5 = 2 or 3 cytopenias. Cytogenetics: score 0 (good)= Normal karyotype, -Y, 5q- or 20q-; score 1.0 (poor)= 7q- or -7, complex translocations; score 0.5 (intermediate)= all others. Risk group Overall score Median survival (years) Low 0 5.7 Intermediate 1 0.5 or 1.0 3.5 Intermediate 2 1.5 or 2.0 1.2 Poor >/= 2.5 0.4 Greenberg P et al. Blood 1997;89:2079-2088.
    • 54. 2012 Revised IPSS Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465. Prognostic Subgroup Cytogenetic Abnormality Median OS, Mos Median Time to AML, Mos Very good del(11q), -Y 60.8 NR Good Normal, del(20q), del(5q) alone or double, del(12p) 48.6 NR Intermediate +8, del(7q), i(17q), +19, any other single or double, independent clones 26.0 78.0 Poor inv(3)/t(3q)/del(eq), -7, double including del(7q), complex (3) 15.8 21.0 Very poor complex (≥ 3) 5.9 8.2 Fine tune the prognostic impact of •Cytogenetic abnormalities •Depth of cytopenia
    • 55. IPSS-R Risk Category Risk Score Very low ≤ 1.5 Low >1.5 - 3 Intermediate >3 – 4.5 High >4.5 - 6 Very High >6 Variable 0 0.5 1 1.5 2 3 4 Cytogenetics V. good - Good - Int Poor V. poor BM blast% ≤2 - >2 - <5 - 5-10 >10 - Hb ≥10 - 8-<10 <8 - - - Platelets ≥100 50-100 <50 - - - - ANC ≥0.8 <0.8 - - - - -
    • 56. WHO Prognostic Scoring System *BM fibrosis grade 2-3 shifts risk group by one step
    • 57. Advances in therapy of MDS
    • 58. Treatment considerations  Treatment considerations must take into account many factors, including the  Pathologic diagnosis  The prognosis based on the IPSS-R or WPSS  Cell line /s affected  Feasibility of performing a clinical trial
    • 59. Tools to treat MDS  Supportive therapy (Transfusions)  Hematopoietic growth factors ( Epo, G-CSF )  Iron chelation  Lenalidomide (Revlimid, Lenalid)  Hypomethylating agents  Azacitidine  Decitabine • Immunosuppression (Antithymocyte globulin (ATG), Cyclosporin, Thalidomide ) • Chemotherapy (High/low Dose AraC, Topotecan + AraC)  Allogeneic stem cell transplantation ( only curative Rx )  Newer agents
    • 60. Role of Growth Factors GCSF Support improves ANC (75% patients) Has no impact on overall survival. Not recommended for routine infection prophylaxis Thrombopoietic agents Most have no significant impact on transfusion needs: Main utility –Fewer dose modifications of disease modifying agents –Romiplostim: 500/750mcg weekly –Eltrombopag: under study Erythropoiesis stimulating agents (ESA) –First line therapy for IPSS low or Int-1 risk MDS with EPO <500U/L (NCCN guidelines) –Response rates; 20-30%, durability:2 years –Epoeitin alpha: 60,000-80,000 U once per week –Darbopoietin alpha: 500mcg once 3 weekly Most widely prescribed class of medications for MDS (55%)
    • 61. Immunosuppressants  Immunologic suppression of normal BM function, similar to the situation in aplastic anemia, has been postulated to account for cytopenias in some MDS patients  Specific candidates- Refractory anemia with relatively hypoplastic marrow  Predictor of Response to Immunosuppressant  HLA-DR-15-positivity  RA (<5% blasts)  IPSS Low/Int-1  Age <60 years  Brief transfusion history  Trisomy 8 abnormality  Normal cytogenetics  Marrow cellularity <30%
    • 62. Biological response modifiers ( Lenalidomide) del(5q) IPSS low or Int-1 platelets > 50K/mm3 neutrophils > 500/mm3 transfusion dependent
    • 63. Study Design Dose Reduction 5 mg qd 5 mg qod Week: 0 4 8 12 16 20 24 Eligible Patients R e g i s t e r R e s p o n s e 10 mg po x 21 NO Off study YES Continue
    • 64. Results Frequency of Cytogenetic Response According to Karyotype Complexity
    • 65. Lenalidomide in non del(5q) MDS  Can be considered for low risk, adequate ANC and platelet counts  Expected response rates are similar to other treatment alternatives  Use in high risk MDS remains investigational Raza et al. Blood 2008
    • 66. Hypomethylating agents • Azacytidine and decitabine are potent DNMT inhibitors • This leads to hypomethylation of CpG dinucleotides in gene promoters and reactivation of previously silent genes • Cytotoxic activity similar to cytarabine
    • 67. 5 Azacytidine AZA Controls Median survival 24.5 months 15 months Progression to AML 27 months 13 months Transfusion independence 45% 11% Fennaux et al. Lancet Oncol 2009 Decitabine DAC Controls Overall survival 10 months 8.5 months Progression to AML at 1 yr 22% 33% CR/ PR/ HI 13/6/5% 0/0/2% Lubbert et al . JCO 2011
    • 68. Hypomethylating agents When to start – Int/ high risk MDS (IPSS) – Transfusion dependent/ EPO failure – Not yet known if early treatment is better than late treatment in MDS Which drug – NCCN recommends Azacitidine preference over Decitabine – MDACC regimen (5 day 20mg/m2/d) highest CR – Aza vs Decitabine head to head trial results awaited Optimal dose, schedule, route – Azacitidine: – 7 day 75mg/m2/d sc 28 days (5-2-2 or 50mg/m2 5-2-5 schedule) – Decitabine: – 3 day 15mg/m2/dose IV 8 hrly (total dose 135mg/m2) inpatient – 5 day 20mg/m2 /d over 1 hr (total dose 100mg/m2) outpatient Duration – Optimal duration- not known – To treat responding pts till disease progression, as long as tolerated – At least 4 cycles recommended for adequate response
    • 69. MDS Low risk (low or Int 1, BM blasts <10%) Any age Iron Chelation Growth factors DMT Inhibitors Lenolidomide Immunomodulation Clinical trial Progression/ failure HSCT High Risk (Int 2, High risk, blasts>10%) Age <60 Age≥60 Intensive chemo DMTI Clinical trial DMTI Clinical trial Intensive Chemo Failure Attallah: Cancer Therap 2008;26:208-16 Failure
    • 70. Take Home Message Myelo-dysplastic syndromes are heterogeneous disorders Prognostic scores are evolving with use of cyto-genetics and molecular markers Treatment depends upon the prognostic and host factors HSCT is the only curative treatment Treatment paradigms are evolving