Myelodysplastic Syndromes: An Update

1. Myelodysplastic Syndromes: An Update

2. 80 yo male: OSA, gout, CAD, and prostate cancer who was referred for progressive anemia. • Past few months: noticed his health started to decline. Localized prostate cancer: end of 2005, tx external beam radiation. • Prior to any radiation: wbc 4.1 Hg 9.5 Plt 193 and MCV of 102. • One month after radiation: Hg 8.6 and plt 138. Progressive weakness and DOE. No chest pain. No GIB. He received 2 units of prbcs while waiting for results of work-up.

3. A week later: shortness of breath, worsening DOE, and generalized weakness. • His hemoglobin dropped down to 8.2 from 10. • Admitted to the hospital: found to have a non-ST elevation myocardial infarction. • Underwent a cardiac catherization which showed a 3-vessel disease. • CABG was recommended. Path of the bone marrow biopsy showed MDS. • Question: Should this patient undergo a CABG?

4. PMH: OSA on CPAP; Gout • CAD: diagnosed 30 years ago; told to have blockage • Prostate cancer: diagnosed Dec 2005 undergoing radiation • Social: widow, 60 pack year, quit 30 years ago; occasional etoh; former lawyer • Meds: Lortab, Vytorin, Toprol XL, Digitek

5. Pex: appears tired, DOE from door to room • No LAD, no oral lesions • Chest: bilateral rales about ¼ up • CV: regular RR with 3/6 murmur • Abd: unremarkable • Ext: 1+ edema of LLE to knee • Neuro: non-focal, alert, oriented

6. Laboratory data: • Wbc 4.1 hg 8.9 hct 26.7 plt 158 mcv 103 ANC 3321 • Creatinine 1.2 Folate >24 Ferritin 222 B12 352 • Reticulocyte count 3.4 with an absolute of 84K • Serum erythropoeitin level 498

7. Bone marrow biopsy • Cellularity: 70-75%, increased for patient’s age • Myeloid: adequate, immature cells/blasts not increased • Megakaryocytes: many atypical megakaryocytes noted; mononuclear forms and micromegakaryocytes • Erythroid precursors: dyspoietic changes are present in up to 10% of erythroid series • Flow cytometry: normal, blasts not increased • Cytogenetics: normal

8. Hypercellular BM

9. Mononuclear megakaryocyte

10. Dyspoietic red cell precursors

11. Introduction • MDS: disorders of hematopoietic stem cells • Characterized by dysplastic and ineffective blood cell production • Peripheral blood cytopenias • Variable risk of transformation to acute leukemia • Arise de novo or years after exposure to mutagenic therapy (radiation or chemotherapy)

12. World Health Organization

16. Clinical Presentation • Signs and symptoms are non-specific • Many asymptomatic • Routine laboratory screening • Others present with sxs from anemia • Fatigue, weakness, angina, dizziness • Infection, easy bruising, bleeding: less common • Fever and wt loss: uncommon

17. Clinical presentation • Infection: while neutropenia is largely responsible for the high incidence of infection, granulocyte dysfunction may contribute • Bacterial infections predominate • Skin is most common • Infection: principal cause of death in pts with MDS • Fungal, viral, and mycobacterial infx can occur, rare without concurrent immunosuppressive agents

18. Physical Exam • Hepatomegaly, splenomegaly, LAD: uncommon • Except CMML • Cutaneous manifestations: uncommon • Sweet’s syndrome( neutrophilic dermatosis): transformation to acute leukemia ( IL-6) • Granulocytic sarcoma (chloroma): herald disease transformation into acute leukemia

19. Laboratory findings • Quantitative changes of one or more blood and bone marrow elements are the hallmark of the disease • Red cell series • Granulocytic series • Platelets • Bone marrow findings

21. Red cell series • Anemia is almost uniformly present • Inappropriately low reticulocyte response • Anemia may be the only cytopenia or be accompanied by thrombocytopenia or neutropenia • Less than 5% present with an isolated neutropenia or thrombocytopenia in the absence of anemia

22. Red cell series • Erythrocyte morphology: normocytic or macrocytic • Peripheral smear: basophilic stippling, Howell-Jolly bodies, and nucleated red cells • Ringed sideroblasts: iron granules occupy more than 1/3 of the nuclear rim

23. Ringed sideroblasts

30. Granulocytic series • Leukopenia: found in approximately 50% at time of diagnosis • Granulocytes: display reduced segmentation, aka pseudo-Pelger-Huet • Often with reduced or absent granulation

31. Pseudo-Pelger-Huet

32. Platelets • Thrombocytopenia: varying degrees are present in ~25% of pts with MDS • Rarely represent an isolated early manifestation of the disease • Giant plts or circulating megakaryocyte fragments may be present • May have increased bleeding tendency despite adequate plt number

33. Bone marrow alterations • BM: usually hypercellular • Accompanied by single or multilineage dysplasia • Hypercellular BM/pancytopenia: reflects premature cell loss via intramedullary cell death • Hypocellular: rare • See in therapy-related MDS • Megakaryocytes are normal or increased in number

34. Auer rods • Within leukemic blasts • FAB: belongs to category of RAEB-T • WHO: its presence should lead to the suspicion that patient has already transformed into AML

35. Auer Rods

37. Diagnosis • Considered in any patient with unexplained cytopenia(s) • Nuclear hyposegmentation of granulocytes (Huet anomaly) • Mononuclear megakaryocytes, micromegakaryocytes, or megakaryocytes with dysplastic nuclei • Hypogranular neutrophils • Macrocytic or acanthocytic red blood cells • Ring sideroblasts in developing red cell precursors

38. Differential diagnosis • Above findings not unique to MDS • Exclude other contributing conditions • Alcohol • Megaloblastic anemia • HIV • Medications • Heavy metals

39. Differential diagnosis • Other causes of macrocytic anemia • B12 and folate deficiency • Megaloblastic anemia have high MCV, reduced retic count, and pancytopenia • Reduced neutrophil lobulation is characteristic of MDS • Combination of increased neutrophil lobulation and macrocytosis is pathognomonic of megaloblastic anemia

40. Differential diagnosis • HIV: dysplastic hematopoiesis and variable degrees of cytopenia are common findings in HIV • Myelodysplasia was found up to 69% in BM of pts with HIV • Dysplasia can be reversible depending on the cause (meds vs infection) • Medications: associated with acquired dysplastic changes • Valproic acid, mycophenolate, gancyclovir, alemtuzumab • Reversible on reduction or discontinuation of medications

41. Diagnosis • Need bone marrow biopsy, flow cytometry, immunochemical studies, and cytogenetics • Clonal chromosomal abnormality of 5q- and monosomy 7 confirms the dx of MDS • Deletion 5q

42. IPSS

43. Median Survival in MDS

44. Treatment • Control of symptoms due to cytopenias • Improving quality of life, minimizing toxicity of therapy • Improving overall survival • Decreasing progression to AML

45. National Comprehensive Cancer Network • Age, performance status, IPSS-defined risk category • Low intensity • Outpatient tx, hematopoietic factors, differentiation-inducing agents, low intensity chemotherapy • High intensity • Intensive combination chemotherapy and hematopoietic cell transplantation • May reduce risk of death from disease

46. Hematopoietic cell transplantation • Very limited • donor availability, advanced age • Upper age limit for allogeneic HCT ~60 • 75% of pts with MDS >60 • Considered in pts <60, HLA-matched sibling donor, risk of disease progression, excellent PS • Transplant-related mortality and relapse rate at 5 years as high as 40% • Timing of transplantation: development of new cytogenetic abnormality, worsening cytopenia, progression to a higher IPSS group

47. Chemotherapy • High dose • young • MDS with >10% blasts in BM

48. Intermediate dose chemotherapy • Azacitidine: pyrimidine nucleoside analog of cytidine • Causes hypomethylation of DNA and direct cytotoxicity on abnormal BM hematopoietic cells • Median time to leukemia was 21 mos vs 13mos • Quality of life was significantly improved • No difference in overall survival • FDA: RA, RARS, RAEB and CMML

49. Low dose chemotherapy • Immunomodulatory agents • Thalidomide • Lenalidomide • Thalidomide • Low response rate • Adverse side effects: fatigue, constipation, peripheral neuropathy, and drowsiness • Lenalidomide (Revlimid) • Thalidomide derivative without the neurologic toxicity • FDA approved 12/27/05: transfusion-dependent anemia due to low or intermediate-1 risk MDS associated with deletion 5q.

50. 5q- syndrome • Karyotypic and clinical distinctiveness sets it apart from other subtypes • Female predominance (7:3) median age 68 at dx • Transfusion-dependent anemia 80% • Low incidence of neutropenia, thrombocytopenia, infection and bleeding • Low incidence of transformation into acute leukemia (16%) • May respond dramatically to lenalidomide