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A. Overview navigator

  1. Clonal hematologic disorders with ineffective hematopoiesis
  2. Represents various stages of evolution to frank neoplastic hematopoiesis
  3. Refractory anemias with various degrees of bone marrow abnormalities
  4. Preleukemic disorders with established (neoplastic) clonal proliferation
  5. Detectable neoplastic event(s) occurs at the level of the committed myeloid precursor
  6. Most of these cases culminate in acute myelogenous leukemia (AML)
  7. Classified by the French-American-British (FAB) Scheme
  8. ~15,000 new cases per year in USA

B. Disease Entities [2] navigator

  1. WHO Classification [3]
    1. Refractory Anemia (RA)
    2. Refractory Anemia with Ring Sideroblasts (RARS)
    3. Refractory cytopenia with multilineage dysplasia
    4. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
    5. Refractory anemia with excess blasts (RAEB) Type 1
    6. RAEB Type 2
    7. MDS, unclassified
    8. MDS associated with isolated deletion of chromosome 5q, del(5q) or 5q-
    9. This classification is more complex than older, 5 subtype MDS schemes
  2. RA (17% of MDS)
    1. Decreased reticulocyte count
    2. Other lines not affected
    3. Blasts <5% of bone marrow (BM); Ringed sideroblasts <15% of BM
    4. Progression to AML is 10-20% per year
    5. Death from BM failure, but reasonably good prognosis
  3. Refractory Anemia with Ring Sideroblasts (RARS)
    1. Reasonably good prognosis
    2. Rings of iron deposited in BM cells (>1/3 of nuclear rim)
    3. Must have >4 ferritin granules per cell in >15% of cells
    4. Two Types of RARS:
    5. RARS confined to RBC (70% 5 year survival)
    6. RARS with Dysmorphic Granules and/or megaloblasts (20% 5 year survival)
    7. Overall progression to AML ~10-20% per year
  4. Refractory Anemia with Excess Blasts (RAEB)
    1. Accounts for ~5% of MDS
    2. Type 1: 5-9% blasts in BM, no Auer rods, uni- or multilineage dysplasia
    3. Type 2: 10-19% blasts in BM, occasional Auer rods, uni- or multilineage dysplasia
    4. Progression to AML (or ALL) is 40-50% per year (higher for Type 2 than Type 1)
  5. RAEB in Transformation (RAEBT)
    1. 70% likelihood of transformation to AML (or ALL) in one year
    2. Large number of chromosomal abnormalities
    3. Extremely poor response to therapy
    4. Median survival ~6 months from diagnosis
    5. >5% blasts in peripheral blood or 21-30% blasts in bone marrow
    6. Diagnosis of AML requires >30% blasts in bone marrow
  6. Chronic Myelomonocytic Leukemia (CMML) [7]
    1. AML development ~20-30% within one year
    2. Monocytic and granulocytic lineages involved, with >1000 monocytes / µL
    3. Diagnosis: unexplained monocytosis with Ph Chromosome Negative
    4. Cytogenic abnormalities commonly involve platelet derived growth factor receptor B (PDGFRB)
    5. PDGFRB on chr 5q33 fusions with TEL (chr 12p13), HIP1 (chr 7q11), RAB5 (17p13), or H4 (chr 10q21)
    6. Survival generally correlates with blast numbers in BM
    7. CMML is probably an entirely separate entity from other MDS

C. Pathophysiology [4]navigator

  1. Clonal stem cell disorder at level of myeloid precursor
    1. Clonality verified by X chromosome PG kinase
    2. Often transform into AML
    3. Very rare transformation to acute lymphocytic leukemia (ALL)
    4. Increased associated with autoimmune diseases, particularly Th1 type
  2. Abnormal Cell Development
    1. Impaired cell maturation originating in CD34+ precursor cell
    2. Abnormal RBC with ferritin granules
    3. Hypogranular and/or bilobed Pelger-Huet Neutrophils
    4. Immense neoangiogenesis
    5. Very high levels of inflammatory cytokines including TNFa and IL6
    6. May be due to chronic infection with bone marrow reaction
  3. Apoptosis (programmed cell death)
    1. Increased apoptosis is the cause of bone marrow failure in MDS
    2. Rate of cell division in MDS is significantly higher than normal
    3. In early phases of MDS, apoptosis is increased leading to failed marrow differentiation
    4. Therefore, increased production with destruction (futile cycle) is found in MDS
    5. As MDS progresses, pro-apoptotic proteins overwhelmed by antiapoptotic mechanisms
    6. Pelger-Huet bodies in neutrophils are apoptotic bodies in MDS
  4. Evolution to AML
    1. With increased severity of MDS, there is increased likelihood of progression to AML
    2. Antiapoptotic mechanisms lead to failure of normal apoptosis
    3. Most important factor is number of blasts in BM
    4. Rate of progression increases with increasing number of chromosomal anomalies
    5. Poor prognosis is seen with the chromosomal abnormalities: 5q- and deletion of 7
    6. Presence of multiple cytopenias is also a poor prognostic factor
  5. Chromosomal Abnormalities are Common in MDS [1]
    1. Loss of all or part of chromosome (chr) 5 (~13%)
    2. Loss of all or part of chromosome (chr) 7 (~5%)
    3. Trisomy 8 (~5%)
    4. Deletion 17p (<1%)
    5. Deletion 20q (2%)
    6. Loss of X or Y chromosome (2%)
  6. MDS and PNH [5]
    1. PNH is a syndrome of intermittent darkened urine due to hemolysis
    2. Erythrocytes are destroyed in the circulation
    3. PNH cells are deficient in glycosylphosphatidylinositol (GPI)-anchored proteins
    4. About 25% of patients with MDS have lost GPI-anchored proteins
    5. Patients with MDS and GPI-deficiency respond to anti-thymocyte globulin

D. Characteristics navigator

  1. Generally affects persons >65 years old
  2. Cytopenias in All Patients
    1. Refractory anemia and/or thrombocytopenia
    2. Neutropenia is less common initially
  3. Red Blood Cells
    1. Anisocytosis, Poikilocytosis
    2. Nucleated RBC
    3. Acanthocytes, Megaloblastic (macrocytic) Cells (MCV >100µm3)
    4. Howell-Jolly Bodies
  4. Diagnosis of MDS based on dyspoiesis of trilineage BM cells
  5. De novo AML should raise suspicion of previously existing MDS, particularly in elderly
  6. Chromosomal Abnormalities
    1. Very common in MDS
    2. Unlikely to be etiologic
    3. Deletion in chromosome 5q has a generally good prognosis
    4. Del 5q associated with ~25% progression to AML
  7. MDS associated AML has a much poorer prognosis than AML without MDS [4]
    1. High levels of antiapoptotic proteins
    2. High levels of expression of multidrug resistance pumps
  8. AML is never cured unless an allogeneic transplantation can be performed

E. Therapy navigator

  1. Overview
    1. Should be tailored to the patient and disease status
    2. International staging and prognostic system should be applied [4]
    3. Intermediate and high risk disease should be treated
    4. Supportive therapy is critical, including erythropoietin (EPO) for anemia
    5. Antimicrobial drugs for prophylaxis / treatment of opportunistic infections
    6. Lenalidomide, azacitidine, decitabine have been approved for MDS
  2. Azacitidine (Vidaza®) [11]
    1. Pyridimidine nucleoside analog of cytidine
    2. DNA demethylating agent which stimulates certain gene expression [14]
    3. Dose is 75mg/m2 sc once/d x 7 days, repeated every 4 weeks x 4 cycles
    4. Overall ~23% response rates, with 6 month increased median survival
    5. Unclear if superior to decitabine
  3. Decitabine (Dacogen®) [11]
    1. Pyridimidine nucleoside analog of cytidine, DNA demethylating agent [14]
    2. Standard dose is 50mg/m2 IV over 3 hours, q8 hours x 3 days
    3. Repeat dosing every 6 weeks, for minimum of 4 cycles
    4. Overall response rate 17% (9% complete response)
    5. Duration of response 10.3 months but no increase in overall survival
    6. Lower doses given for longer durations and shorter intervals had 34% response rate
  4. Lenalidomide (Revlimid®) [8,9,10]
    1. Thalidomide derivative approved for MDS with anemia (chr 5q- MDS)
    2. Dose is 10mg qd for 21 (or 28) days of 28 day cycle
    3. Clear benefit in ~55% of erythropoietin refractory anemias
    4. Cytogenic complete remissions in ~35% of patients with 5q- MDS [10]
    5. Reduces RBC transfusion dependence in >80% of patients with 5q- MDS
    6. Main side effects are neutropenia and thrombocytopenia
    7. Also approved for multiple myeloma
    8. Combination with chemotherapy in multiple myeloma associated with venous thromboemboli
  5. Myeloid Growth Factors (differentiation induction)
    1. G-CSF and GM-CSF can be used for neutropenia, although minimally effective
    2. Interleukin 3 has failed in early trials
    3. Other growth factors
  6. Anti-Thymocyte Globulin (ATG)
    1. May be useful in patients with GPI deficiency (MDS/PNH) [5]
    2. ATG 40mg/kg qd x 4 days in RA, RAEB, RARS led to 34% RBC transfusion independence [6]
    3. Response to ATG associated with survival prolonged versus historical controls [6]
  7. Treat as AML
    1. May need to induce rapid tumor lysis (such as Hydroxyurea)
    2. Therapy has <30% response rate initially
    3. Posaconazole is superior to fluconazole and itraconazole for prophylaxis of fungal infections and overall mortality in AML or MDS receiving chemotherapy [12,13]
  8. Stem Cell / Bone Marrow Transplantation
    1. Most effective modality to date
    2. Need for allogeneic donor limits availability of good matches
  9. Other Treatments
    1. Glucocorticoids
    2. Androgens (such as danazol)
  10. Supportive Care
    1. Chronic need for EPO ± packed RBC transfusions
    2. Iron chelation therapy is often required once toxic levels of iron are achieved
    3. Desferoxamine is generally used for iron chelation

E. Prognosis [1]navigator

  1. Scores based on sum of scores for bone marrow blast, karyotype, and cytopenias
  2. Overall Score and Median Survival
    1. Low (Zero, 0) Score: 5.7 years survival
    2. Intermediate Low (0.5-1.0): 3.5 years survival
    3. Intermediate High (1.5-2.0): 1.2 years survival
    4. High (2.5 or higher): ~5 months survival
  3. Blast Percentage and Score
    1. <5% blasts scores 0
    2. 5-10% blasts scores 0.5
    3. 11-20% blasts scores 1.5
    4. 21-30% blasts scores 2.0
  4. Cytogenic Features
    1. Normal karyotype, chr Y-, chr 5q-, or chr 20q- score 0
    2. Abnormal chr 7 or more than 2 chr abnormalities scores 1.0
    3. All other karyotypes score 0.5
  5. Cytopenia Scores
    1. None or one cytopenia: score 0
    2. Two ore three cytopenias: score 0.5
    3. Anemia defined as Hemoglobin (Hb) <10gm/dL
    4. Neutropenia as <1500 neutrophils/mL
    5. Thrombocytopenia as <100,000/mL

References navigator

  1. Heaney ML and Golde DW. 1999. NEJM. 340(21):1649 abstract
  2. Mintzer D and Bagg A. 2001. Am J Med. 2001. 111(6):480 abstract
  3. Cazzola M and Malcovati L. 2004. NEJM. 352(6):536
  4. Greenberg P. 2001. Lancet. 357(9262):1059 abstract
  5. Dunn DE, Tanawattanacharoen P, Boccuni P, et al. 1999. Ann Intern Med. 131(6):401 abstract
  6. Molldrem JJ, Leifer E, Bahceci E, et al. 2002. Ann Intern Med. 137(3):156 abstract
  7. Goldman JM and Melo JV. 2003. NEJM. 349(15):1451 abstract
  8. List A, Kurtin S, Roe DJ, et al. 2005. NEJM. 352(6):549 abstract
  9. Lenalidomide. 2006. Med Let. 48(1232):31 abstract
  10. List A, Dewald G, Bennett J, et al. 2006. NEJM. 355(14):1456 abstract
  11. Decitabine. 2006. Med Let. 48(1247):91 abstract
  12. Posaconazole. 2006. Med Let. 48(1248):93 abstract
  13. Cornely OA, Maertens J, Winston DJ, et al. 2007. NEJM. 356(4):348 abstract
  14. Esteller M. 2008. NEJM. 358(11):1148 abstract