An interplay between the malignant clone and the bone marrow microenvironment Innate stem cell lesion Chromosomal rearrangements Gene silencing (hypermethylation) Gene mutations Cellular and cytokine mediated stromal defects Increased angiogenesis Immunologic derangements Silverman, LR. The Oncologist. 2001;6(suppl 5):8-14 .
Myelodysplastic syndrome by dr narmada
MODERATOR – Prof. DR. - ANIL KAPOOR
What Is Myelodysplastic Syndrome?The myelodysplastic syndromes are a group of disorders characterized by one or more peripheral blood cytopenias secondary to bone marrow dysfunction. In MDS the bone marrow cannot produce blood cells effectively, and many of the blood cells formed are defective.These abnormal blood cells are usually destroyed before they leave the bone marrow or shortly after entering the bloodstream.As a result, patients have shortages of blood cells, which are reflected in their low blood
CharacteristicsVarying degree of tri-lineage cytopenia ( red blood cells, white blood cells and platelets).DysplasiaNormocellular or hypercellular B.M.May progress to acute leukaemia
Incidence1- Disease of elderly.2- Median age is 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
Aetiological Agents Tobacco smoke. Ionizing radiation. Organic chemicals (such as benzene, toluene, xylene, and chloramphenicol). Heavy metals. Herbicides. Pesticides. Fertilizers. Stone and cereal dusts. Exhaust gases. Nitro-organic explosives. Petroleum and diesel derivatives. Alkylating agents. Marrow-damaging agents used in cancer chemotherapy.
Pathophysiology: Contributing Factors Immune Apoptosis dysfunction Stem cell Stem Cell dysfunction Epigenetic Dysfunction Environmental changes direct toxicity /Stromal /Mutations angiogenic factors MDS DNA damage. With Permission of J. Maciejewski, M.DTaussig Cancer Center/ Cleveland Clinic Foundation
Myelodysplastic SyndromeDyserythropoiesisDysmyelopoiesisDysmegakaryopoiesisRing SideroblastType I and II blasts
Chromosomal abnormalities and MDS Chromosomal abnormalities are present in up to 50%of de novo cases of MDS and in virtually all cases of secondary MDS. The most common are: Abnormality -7 +7 +8 5q- 7q- 11q- 12q- 13q- 20q- inv3 i(17q) t(1;3) t(1;7) t(3;3) Frequency(%) 15 5 19 27 4 7 5 2 5 1 5 1 2 1
Deletion of the long arm of chromosome 5 (5q- syndrome )Strongly associated with RA.5q- accounts for up to 70% of cytogenetic abnormalities in this subtype.The q arm of chromosome 5 is particularly rich in genes, which encoded haemopoietic growth factors and their receptors. For example , IL-3 , IL-4 , IL-5 , GM-CSF and the M-CSF receptor are located in this region.The potential for the loss of any or all of these genes contribute to the disruption of ordered haemopoiesis.
Monosmy 7 and 7q-Most strongly associated with secondary MDS.Associated with the loss of a major surface glycoprotein (gp 130) in neutrophile and susceptibility to bacterial infection secondary to impaired granulocyte monocyte chemotatic activity.
Deletion of the q arm of chromosome 11 (11q-)Account for 20% of the chromosomal abnormalities in RAS.This abnormality is associated with raised iron stores and high ring sidroblast counts. The presence of the gene , which encoded the H- subunit of ferritin at chromosome 11 , may explain this
Abnormalities of chromosome 17 (i17q)It involves the loss or disruption of the Р53 tumor suppressor gene are seen in CML in association with transformation to the blastic phase and in up to 5% of cases of primary MDS. This predisposes to certain dysplastic features and neutrophil vaculation.
Abnormalities of chromosome 3Dysmegakaryopiesis and thombocytosis appear to be associated with Abnormalities of chromosome 3
The importance of indication of chromosomalabnormalities To confirm diagnoses . To know the stage of disease. To know the direction of progression of disease. Multiple genetic abnormalities indicate late events in MDS.
Abnormal localization of immatureprecursors Presence of 3 or more small clusters of myeloblasts and promyelocytes (5 – 8 cells) in marrow trephine biopsy in the central portion of the marrow away from the vascular structure and the endosteal surface of the bone trabeculae
Signs and SymptomsExcessive tiredness, shortness of breath, and pale skin can be caused by anemia (shortage of red blood cells).Serious infections with high fevers can be caused by leukopenia (not having enough normal white blood cells) and, in particular, by having neutropenia or granulocytopenia (too few mature granulocytes).Excessive bruising and bleeding, for example, frequent or severe nosebleeds and/or bleeding from the gums, can be due to thrombocytopenia (not having enough of the blood platelets needed for plugging holes in damaged blood vessels).
Refractory AnemiaRA Definition:Dyplasia of the erythroid series only.Clinically, anemia is refractory to hematinic therapyMyeloblasts < 1% blood and < 5% marrow<15% ringed sideroblasts in marrowNo Auer rodsOther etiologies of erythroid abnormalities must be excluded. These include: drug/toxin exposure -vitamin deficiency viral infection -congenital disease
Refractory AnemiaEpidemiology:5-10% of MDS cases.Older patientsMorphology:Anisopoikilocytosis on peripheral smearsDyserythropoiesis with nuclear abnormalities (megaloblastoid change)< 15% ringed sideroblasts
Refractory AnemiaGenetics:25% may have genetic abnormalitiesPrognosis:Median survival is 66 months6% rate of progression to acute leukemia
Refractory Anemia with Ringed SideroblastsRARS definition:Dyplasia of the erythroid series only.Clinically, anemia is refractory to hematinic therapyMyeloblasts < 5% in marrow, absent in blood>15% ringed sideroblasts in marrowNo Auer rodsOther etiologies of ringed sideroblasts must be excluded. These include: Anti- tuberculosis drugs Alcoholism
Refractory Anemia with Ringed SideroblastsEpidemiology:10-12% of MDS cases.Older patientsMales > femalesMorphology:Dimorphic pattern on peripheral smears Majority RBC’s normochromic, 2nd population hypochromicDyserythropoiesis with nuclear abnormalities (megaloblastoid change)
Refractory Anemia with Ringed SideroblastsGenetics: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
Refractory Anemia with Excess BlastsRAEB definition: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
Refractory Anemia with Excess BlastsEpidemiology: 40% of MDS cases.Older patients (over 50 years) Morphology:Dysplasia of all three cell lines often presentNeutrophil abnormalities may include: Hypogranulation Pseudo-Pelger-huet (hyposegmentation/barbells)Megkaryocyte abnormalities may include Hypolobation -Micromegakaryocytes
Refractory Anemia with Excess BlastsMorphology (con’t.)Erythroid precursor abnormalities may include: Abnormal lobulation -megaloblastoid change Multinucleation0-19% myeloblasts in the blood5-19% in the marrowBone marrow: Usually hypercellular (10-15% hypocellular) Abnormal localization of immature precursors (ALIP) may be presentImmunophenotype: Blasts express CD 13, CD33 or CD117
Refractory Anemia with Excess BlastsGenetics:Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The abnormalities include: +8 – -5 – del(5q) – -7 – del(7q) – Complex karyotypesPrognosis:Median survival, RAEB-1 = 18 monthsMedian survival, RAEB-2 = 10 monthsRAEB-1 = 25% rate of progression to acute leukemiaRAEB-2 = 33% rate of progression to acute leukemia
Refractory Anemia with Excess Blasts in Transformation (RAEB-t) • 21-30 percent blasts in the marrow; more than 5 percent in the bloodstream • normal or hypercellular (filled with cells) marrow • accounts for about 25 percent of cases
Chronic Myelomonocytic Leukemia (CMML) • 5-20 percent blasts in the marrow; less than 5 percent in the bloodstream • cytopenia of at least two cell lines • normal or hypercellular (filled with cells) marrow • accounts for 15 to 20 percent of cases.
WHORefractory anemiaRefractory anemia e ringed siderblastRefractory cytopenia e multilineage dysplasiaRefractory cytopenia e multilineage dysplasia & ringed sideroblastsRefractory anemia e excess blast-1Refractory anemia e excess blast-2Myelodysplastic syndrome unclassifiedMDS associated e isolated del (5q)
WHOSubtype Blood Bone MarrowRA Anemia Erythroid dysplasia onlyRARS Anemia Erythroid dys >15% ringedRCMD Bi- pancytopenia >10%Dysp in 2 or more cell lineageRCMD-RS Bi-pancytopenia >10%Dys 2 or more cell lineage >15% ringed
WHOsubtype Blood Bone MarrowRAEB-1 Cytopenia Uni-multilineage <5% blast dys, 5-9%blastRAEB-2 Cytopenia, Uni-multi dys 5-19%blast or Auer 10-19%blast rods Or Auer rodsMDS-U cytopenia Myeloid or megakaryocte dysMDS with 5q Anemia,nor or Mega e hypolobated increased PLT nuclei, <5%blast
Prognostic GroupsTwo groups based on survival and evolution to acute leukemia1.) “Good” group Refractory anemia (RA) Refractory anemia with ringed sideroblasts (RARS) 5q - syndrome2.) “Bad” group Refractory anemia with excess blasts (RAEB) Refractory anemia with excess blasts in transformation (RAEB-t) CMMLMDS unclassified can be either
International Prognostic Scoring System (IPSS) Factors(1) the percentage of blasts in the bone marrow.(2)whether chromosome abnormalities are present and, if so, which ones.(3)how low the patients blood counts are. These are given a score; the lowest scores have the best outlook for survival.
Prognostic ScoringThe International Myelodysplastic Syndrome Working Group developed a scoring system based on 3 variables: 0 0.5 1.0 1.5 2.0% Blasts <5 5-10 -- 11-20 20-30Karyotyp Normal, -Y, Single ≥3 abnormalities,e del(5q), karyotypic chr 7 del(20q) anomaly, abnormalities Double Chr 3 abn. abnormaliyCytopenia 0-1 2-3
Prevention & Treatmentof InfectionsPrevention Prophylactic antibiotics no role Patient education know your nadir report a fever recognize signs of infection avoid illness, crowds update vaccinationsTreatment Febrile neutropenia guidelines www.nccn.org/MDS v1..2008
Iron Chelation OptionsDeferoxamine (Desferal®) Route: SQ t ½: 0.5 hours Dosing: Infused over 8-12 hrs 5-7 nights/weekDeferasirox (Exjade®) Route: PO t ½: 12-16 hours Dosing: Dissolved in solution, taken daily
Pharmacotherapy In MDSAzacitidineDecitabineLenalidomideAnti-thymocyte Globulin (ATG)
Differential Diagnosis Non-neoplastic simulators Other myelodysplastic disorderseoplastic disorders may simulate myelodysplasia Vitamin/micronutrient deficiencies B12/folate Copper Ring sideroblasts present Cytoplasmic vacuoles May be due to Zinc excess Gastrectomy Total parenteral nutrition Infections HIV Parvovirus HHV-6 in children Toxins Ethanol Heavy metals Growth factors -macrophage colony-stimulating factor (GMCSF Erythropoietin )Drugs (numerous