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Myelodysplastic syndrome

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quite updated according to recent guidelines..covers all aspects to it...recent advances, classification and management.

Publicada em: Saúde e medicina
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Myelodysplastic syndrome

  1. 1. MYELODYSPLASTIC SYNDROME Ajay Kumar Yadav PGY3,Medicine IOM-TUTH, Kathmandu 2075/05/16
  2. 2. LAYOUT • Introduction • Classification and risk stratification • Diagnosis • Treatment • Summary
  3. 3. INTRODUCTION • MDS is defined by • Ineffective hematopoiesis resulting in blood cytopenia, and • Clonal instability with a risk of clonal evolution to AML. • Anemia, often with thrombocytopenia and neutropenia, occurs with dysmorphic (abnormal appearing) and usually cellular bone marrow. • Thrombocytosis may be a/w 5q-syndrome, RARS-T
  4. 4. • MDS may be fatal due to the complications of pancytopenia or the incurability of leukemia. • Atypical MDS • Combination of cellular dysplasia and marrow fibrosis • Hypoplastic marrow (overlap
  5. 5. HISTORY • FAB classification in 1983  Five entities were defined: • Refractory anemia (RA), • Refractory anemia with ringed sideroblasts (RARS), • Refractory anemia with excess blasts (RAEB), • Refractory anemia with excess blasts in transformation (RAEB-t), and • Chronic myelomonocytic leukemia (CMML).
  6. 6. • LIMITATIONS OF FAB STUDY  WHO classification (2002) recognized that the distinction between RAEB-t and AML is arbitrary  group them together as acute leukemia.  CMML behaves as a myeloproliferative disease.
  9. 9. • Limitations of the dataset on which the IPSS was based include (1) Lack of inclusion of secondary (after prior cytotoxic therapy) MDS (2) Inclusion of many patients now considered to have AML, (3) Lack of “treated” cases, and (4) Unknown impact of currently available therapies.
  11. 11. EPIDEMIOLOGY • Age : • Idiopathic MDS is a disease of the elderly; the mean age at onset is ≥70 years. • MDS is rare in children, but monocytic leukemia can be seen. • Secondary or therapy-related MDS is not age related. • Sex : slight male preponderance. • Incidence : 35 to >100 per million persons in the general population andn120 to >500 per million in the older adult.
  12. 12. ETIOLOGY AND PATHOPHYSIOLOGY • Environmental exposures : radiation and benzene. • Secondary MDS  Late toxicity of cancer t/t, usually a combination of radiation and  Radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5–7 years) or  DNA topoisomerase inhibitors (2-year latency). • Acquired AA, Fanconi anemia, and other constitutional marrow failure syndromes. • MDS is a disease of aging, suggesting random cumulative intrinsic and environmental damage to marrow cells.
  13. 13. • CYTOGENETIC ABNORMALITIES • Found in approximately one half of pts. • Aneuploidy (chromosome loss or gain) is more frequent than translocations. • Karyotypic analysis of marrow cells often reveals loss of the long arm or all of chromosome 5, loss of the long arm or all of chromosome 7, an extra chromosome 8, or complex abnormalities. • Karyotype grading : strongly correlate with the probability of leukemic transformation and survival. • Good : -Y, -5q ,NL • Poor : -7, complex(≥ abnorm alities ) • Intermediate : all others.
  14. 14. CLINICAL FEATURES • Anemia dominates the early course. • At least one-half of the pts are asymptomatic, and is discovered only incidentally on routine blood counts • Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. • MDS in childhood is rare and, when diagnosed, increases the likelihood of an underlying genetic disease. • Children with Down syndrome are susceptible to MDS. • Family history may indicate a hereditary form of sideroblastic anemia, Fanconi anemia, or a telomeropathy.
  15. 15. PHYSICAL EXAMINATION • Anemia • Approx. 20% of pts have splenomegaly. • Unusual skin lesions, including Sweet syndrome. • Stereotypical anomalies point to a constitutional syndrome • Short stature, abnormal thumbs : Fanconi anemia • Early graying : Telomeropathies • Cutaneous warts : GATA2 deficiency.
  16. 16. LABORATORY STUDY • PBS • Anemia is present in most cases, either alone or as part of bi or pancytopenia • Isolated neutropenia or thrombocytopenia is more unusual. • RBCs : large. • Platelets : large and lack granules. • Neutrophils : hypo granulated; hypo segmented, ringed, or abnormally segmented nuclei; contain Döhle bodies; and may be functionally deficient. • Circulating myeloblasts usually correlate with marrow blast numbers.
  17. 17. • BONE MARROW • Usually normal or hypercellular • 20% of cases : hypocellular to be confused with AA. • No single characteristic feature of marrow morphology distinguishes MDS, but the following are commonly observed: • Dyserythropoietic changes (especially nuclear abnormalities) and ringed sideroblasts in the erythroid lineage; • Hypogranulation and hyposegmentation in granulocytic precursors, with an increase in myeloblasts; • Megakaryocytes showing reduced numbers of or disorganized nuclei.
  18. 18. DIFFERENTIAL DIAGNOSIS • Vitamin B12 or folate deficiency • Vitamin B6 deficiency : • Can be assessed by a therapeutic trial of pyridoxine if the bone marrow shows ringed sideroblast. • AML : • WHO considers the presence of 20% blasts in the marrow as the criterion that separates AML from MDS.
  19. 19. PROGNOSIS • The median survival varies greatly from years for pts with 5q– or sideroblastic anemia to a few months in refractory anemia with excess blasts or severe pancytopenia associated with monosomy 7. • The outcome in therapy-related MDS, regardless of type, is extremely poor, and most pts will progress within a few months to refractory AML.
  20. 20. TREATMENT
  21. 21. TO TREAT OR NOT? • Only if there are symptoms resulting from anemia or other cytopenia or perhaps pre-symptomatic anemia or severe thrombocytopenia.
  22. 22. TO TRANSPLANT OR NOT? • The only curative modality in the t/t of pts with MDS is allogeneic HSCT. • Patients can reasonably safely be transplanted in the standard (myeloablative) fashion up to age 55 to 60 years. • Recent data suggest that lower risk patients (according to the WHO or WPSS) do very well with allogeneic transplantation, whereas those with 5% to 20% marrow blasts have only a 25% to 28% 5-year overall survival. • It is appropriate to refer young patients with MDS with a relatively poor prognosis for an allogeneic transplantation.
  23. 23. HEMATOPOIETIC GROWTH FACTORS? • A several-month trial of erythropoietin is a reasonable option in anemic pts, mainly in those with low-risk disease and baseline serum erythropoietin levels less than 500 IU/ml. • If no benefit is seen or if a response has waned, the drug s/b stopped. • 25% of patients will respond (reduce their transfusion requirement by at least 50% or increase hemoglobin by 1 g/dL). • Response can take 8 weeks or more.
  24. 24. • The optimal dose of erythropoietin in MDS is unclear, but recent studies have called for at least 40,000 to 60,000 units weekly. • Long acting recombinant erythropoietin, darbopoietin : 200 to 300 mcg every week or every other week • The effect of erythropoietin may be enhanced by the addition of low-dose G-CSF. • The hemoglobin response to erythropoietin may be improved from 25% to 40% with this combined approach. • A recent report of a phase 1 trial demonstrated that the thrombopoietin agonist AMG531 (romiplostim) improved platelet counts in MDS patients, both as a single agent and in support of 5-azacitidine-treated patients.
  25. 25. TO CHELATE OR NOT? • It is reasonable to use deferasirox at a starting dose of 20 mg/kg per day in chronically transfused patients who, by virtue of low IPSS scores, are expected to live for many years.
  26. 26. Is 5q- present? • Approx. 5% of pts : “5q- syndrome”  middle-aged to older females with profound anemia, well-preserved platelet counts, and 5q- as a sole karyotypic abnormality in a diagnostic bone marrow specimen. • DOC : Lenalidomide • Immunomodulatory thalidomide congener • 67% rate of transfusion independence and major increase in hemoglobin. • S/E : Myelosuppression , DVT/PE
  27. 27. IMMUNOSUPPRESIVE THERAPY (IST ) • Indications of IST  HLAD15 positive,  Younger,  Lower platelet count irrespective of marrow cellularity  Hypocellularity and  Low IPSS score
  28. 28. • IST options  ATG  Cyclosporine  Anti-CD52 monoclonal antibody : alemtuzumab
  29. 29. ROLE OF HYPO-METHYLATING AGENTS • Indication : High-risk patient who is not a candidate for HSCT. • Epigenetic modulators : believed to act through demethylating mechanism  alter gene regulation  allow differentiation to mature blood cells from the abnormal MDS stem cell. • Azacitidine and decitabine are two epigenetic modifiers.
  30. 30. • Azacitidine is usually administered S/C 75 mg/m2 daily for 7 days, at 4-week intervals, for at least four cycles before assessing for response. • Decitabine is usually administered by continuous IV infusion in regimens of varying doses and durations of 3 to 10 days in repeating cycles. • The major toxicity of azacitidine and decitabine is myelosuppression, leading to worsened blood counts.
  31. 31. NEW KIDS IN TOWN ??? • Histone deacetylase inhibitors • Epigenetic approach : US intergroup trial involving a combination of 5- azacitidine plus MS275,one such drug in development. • Farnesyl transferase inhibitors • C-Jun modification • MAP kinase inhibition.
  34. 34. REFERENCE • Harrison 19th edition • UpToDate 2018 • Wintrobe’s clinical hematology 13th Edition • How I treat patients with MDS : Blood journal 2017 • Myelodysplastic syndromes current treatment algorithm 2018 Blood Cancer Journal
  35. 35. THANK YOU