Understanding Myelodysplastic Disorders - Symptoms, Diagnoses, and Treatments

1. Myelodysplastic disorders • Clonal disorder • Stable cytopenias for 2-6 weeks • Morphologic evidence of dysplastic changes in at least 2 hematopoietic cell lines • Hypercellular or normocellular bone marrow • Propensity to transform into AML in 20% of cases

2. Myelodysplastic disorders • Ineffective erythropoiesis due to increased apoptosis (programmed cell death) • Impaired cellular maturation due to intrinsic defects in cells of neoplastic clone • Altered responses to regulatory hormones

3. Myelodysplastic disorders • Most over age 60 • Slight male predominance • History of acquired or congenital risk factors • radiation, chemotherapy (alkylating agents, topoisomerase inhibitors) • Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma • ovarian CA, breast CA • NH3, diesel, benzene • aplastic anemia, paroxysmal nocturnal hemoglobinuria • Fanconi’s anemia, Down’s syndrome, Turner’s syndrome, Bloom’s syndrome

4. Myelodysplastic disorders Red Cells • Macrocytosis • Low reticulocyte count • Ringed sideroblasts • Nuclear-cytoplasmic asynchrony • Bizarre nuclear configurations • Abnormal Fe metabolism

5. Macrocytosis, biphenotypic population Ringed sideroblast Dysmorphic nucleated rbc’s Increased iron stores

6. Myelodysplastic disorders White Cells • Hypogranulation • Nuclear-cytoplasmic asynchrony • Pseudo-Pelger-Huet anomaly • Defective adhesion, phagocytosis, and bacterial killing

7. Hypogranulation, nuclear-cytoplasmic asynchrony Pseudo-Pelger-Huet anomaly Stodtmeister cell Aberrant granulation

8. Myelodysplastic disorders Platelets • Giant, agranular platelets • Micromegakaryocytes and mononuclear megakaryocytes • Abnormal platelet function

9. Hypogranular platelets Circulating micromegakaryocyte Abnormal megakaryocyte Mononuclear megakaryocyte

10. Myelodysplastic disorders Other manifestations: • Rheumatologic - vasculitis, arthritis, lupus-like syndromes • Neurologic - peripheral neuropathy • Metabolic - abnormal LFT’s • Dermatologic - urticaria pigmentosa, chloroma, Sweet’s syndrome

11. Chloroma Sweet’s Syndrome Granulocytic Sarcoma Extramedullary aggregates of blast cells Acute neutrophilic dermatosis Tender red plaques and nodules Benign infiltration of PMN’s in lower dermis

12. Myelodysplastic disorders • C.M.L. • M.D.S. - five types: • Refractory Anaemia • Refractory Anaemia with ring sideroblasts • Refractory Anaemia with excess blasts • Refractory Anaemia with excess blasts in transformation • Chronic myelomonocytic leukaemia

13. FAB Classification of MDS

14. Supportive care of MDS • Supportive care • Hormonal and immunosuppressive therapy • Hematopoietic growth factors • Differentiating agents • Chemotherapy • Bone marrow transplantation

15. Supportive care of MDS • RBC and platelet transfusions • Deferoxamine (Desferal) • Antibiotics • Avoidance of myelotoxic medications • Pyridoxine 200 mg QD

16. Immunotherapy in MDS • Antithymocyte globulin +/- cyclosporine • Complete remissions in hypoplastic MDS • Eliminated transfusion requirement in 44% with normocellular and hypercellular MDS • Monoclonal antibody against CD33 • Disproportionately expressed on blast cells • Effective in those with <10% blasts

17. Chemotherapy in MDS • Single agents • Low-dose cytarabine (LoDAC) • High-dose cytarabine (HiDAC) • Homoharringtonine • Topotecan • Combination therapy • Standard AML induction therapy • Fludarabine, cytarabine, idarubicin • Cyclophosphamide, cytarabine, topotecan

18. Bone Marrow Transplantation in Myelodysplastic Syndrome Allogeneic BMT • Best results with • young patients (DFS 75%) • marrow blasts counts < 5% • absence of marrow fibrosis • interval to BMT < 5 years • matched sibling donor Treatment-related mortality 34-55% Disease-free survival 26-45% Relapse 19-34%

19. Bone Marrow Transplantation in Myelodysplastic Syndrome Autologous BMT Higher relapse rate