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Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal stem cell disorders where the bone marrow cannot produce blood cells effectively. Patients present with varying degrees of cytopenias. MDS may progress to acute leukemia. The WHO classification system recognizes subtypes based on blast percentage and cytogenetics that provide prognostic information. MDS results from genetic mutations and epigenetic changes in hematopoietic stem cells. Presenting signs include anemia, infections, and bleeding due to cytopenias. Evaluation involves blood tests, bone marrow aspiration/biopsy, and cytogenetics. Refractory cytopenia with unilineage dysplasia is the most common subtype.

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Myelodysplastic Syndrome Dr. Mohammad Nurul Azam HMO, Department of Haematology CMCH
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.
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
Predisposing Factors
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
Morphological dysplasia in MDS Dyserythropoiesis Dysmyelopoiesis Dysmegakaryopoiesis Ring Sideroblast Type I, II & III blasts
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
 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
Hyposegmented/ hypogranular neutrophil Pelger-Huet hyposegmentation Dysgranulopoiesis ( contd…)
Blasts in MDS Dysgranulopoiesis ( contd…)
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
Abnormal platelets Micromegakaryocyte Dysmegakaryocytopoiesis
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)
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
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
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
WHO CLASSIFICATION OF MDS (2008)
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
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
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
PATHOGENESIS
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
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  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
MDS ENVIRONMENTAL EPIGENETIC APOPTOSIS STEM CELL DEFECT GENETIC LOSS OF SIGNAL ANGIOGENESI S IMMUNOLOGICAL MOLECULAR GAIN OF FUNCTION
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.
 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…)
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
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
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.
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
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
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
RCUD: Refractory Thrombocytopenia  Evaluate >30 mgk’cytes  D/D from chronic autoimmune thrombocytopenia is critical  Features: Micromegakaryocytes, hypolobation, multiple widely separated nuclei
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)
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
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
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
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
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
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
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
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
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
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
 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
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 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
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
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
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
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.
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
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 - - - - -
WHO Prognostic Scoring System *BM fibrosis grade 2-3 shifts risk group by one step
Advances in therapy of MDS
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
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
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%)
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%
Biological response modifiers ( Lenalidomide) del(5q) IPSS low or Int-1 platelets > 50K/mm3 neutrophils > 500/mm3 transfusion dependent
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
Results Frequency of Cytogenetic Response According to Karyotype Complexity
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
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
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
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
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
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
Myelodysplastic Syndrome

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Myelodysplastic Syndrome

  • 1.
    Myelodysplastic Syndrome Dr. MohammadNurul Azam HMO, Department of Haematology CMCH
  • 2.
    What Is MyelodysplasticSyndrome?  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 oftri-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.
  • 5.
    HEREDITARY ACQUIRED A) Constitutionalgenetic 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 inMDS 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.
  • 10.
  • 11.
    Dysmegakaryocytopoiesis  Peripheral Blood: Thrombocytopenia Largeplatelets 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.
  • 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 Classification1982 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 ofFAB 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.
  • 18.
    SUBTYPE BLOOD BONEMARROW 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 MDSClassifications 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 WHOAND 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.
  • 22.
    MDS : astem 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 inMDS  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 ofMDS  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  Refersto 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.
  • 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  Cutaneousmanifestations: 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 SUSPECTEDMDS  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 WITHUNILINEAGE 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 withRinged 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 withRinged 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 WITHMULTILINEAGE 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  Cytogeneticabnormalities 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 withExcess 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 withExcess 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 ISOLATEDdel 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  Subtypeof 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
  • 48.
     DIFFERENCE BETWEENADULT 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
  • 49.
    MINIMAL DIAGNOSTIC CRITERIAFOR 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%
  • 50.
    DIFFERENTIAL DIAGNOSIS 1. VitaminB 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
  • 51.
    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
  • 52.
    MDS-F (MDS withMyelofibrosis)  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
  • 53.
    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
  • 54.
    IPSS: Prognostic Variables 00.5 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.
  • 55.
    2012 Revised IPSS SchanzJ, 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
  • 56.
    IPSS-R Risk Category RiskScore 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 - - - - -
  • 57.
    WHO Prognostic ScoringSystem *BM fibrosis grade 2-3 shifts risk group by one step
  • 58.
  • 59.
    Treatment considerations  Treatmentconsiderations 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
  • 60.
    Tools to treatMDS  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
  • 61.
    Role of GrowthFactors 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%)
  • 63.
    Immunosuppressants  Immunologic suppressionof 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%
  • 64.
    Biological response modifiers (Lenalidomide) del(5q) IPSS low or Int-1 platelets > 50K/mm3 neutrophils > 500/mm3 transfusion dependent
  • 65.
    Study Design Dose Reduction 5mg 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
  • 66.
    Results Frequency of CytogeneticResponse According to Karyotype Complexity
  • 67.
    Lenalidomide in nondel(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
  • 68.
    Hypomethylating agents • Azacytidineand 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
  • 69.
    5 Azacytidine AZA Controls Mediansurvival 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
  • 70.
    Hypomethylating agents When tostart – 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
  • 71.
    MDS Low risk (low orInt 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
  • 72.
    Take Home Message Myelo-dysplasticsyndromes 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

Editor's Notes

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