1. Myelodysplastic Syndromes: An Update
Thuy Le, MD
Texas Cancer Associates
Internal Medicine Grand Round
April 19, 2006

2. HF
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 Plt 193 and MCV of 102.
One month after radiation: Hg 8.6 and plt Progressive weakness and DOE. No chest pain. No GIB. He received 2 units of prbcs while waiting for results of work-up.

3. HF
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. HF 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. HF 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. HF Laboratory data: Wbc 4.1 hg 8.9 hct 26.7 plt 158 mcv 103 ANC 3321
Creatinine 1.2 Folate >24 Ferritin B
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. Background MDS: first recognized in 1938
100 pts with refractory anemia without associated illness
1976 French-American-British (FAB): defined RA with excess blasts (RAEB) and CMML as preleukemic states
1982: added 3 more categories to this classification…adopted MDS
2001 WHO classification

13. French-American-British

14. World Health Organization

15. De novo MDS: incidence not known
Exceeds the incidence of AML in the elderly
10-15K cases per year in US
Risk increases with age
Per 100,000
0.5 for < age 50
5.3 for age 50-59
15 for age 60-69
49 for age 70-79
89 for age >80
Median age: 65

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. Sweet’s syndrome

20. 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

24. 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

25. Pseudo-Pelger-Huet
                                     

26. Pseudo-Pelger Huet

27. 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

28. 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

29. 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

30. Auer Rods

32. 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

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

34. 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

35. 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

36. 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

37. Prognosis FAB: less useful for determination of prognosis
International prognostic scoring system: 1997
Take into account age, sex, clinical data, cytopenias, and cytogenetics

38. IPSS

39. Median Survival in MDS

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

41. 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

42. Who to Treat Type of treatment Age PS IPSS survival High intensity
</= 60
good
Intermediate-2 or high
0.3 to 1.8 yrs
Low intensity or supportive care
Low or intermediate-1
5-12 years
Consider high intensity
>60
3-5 yrs
Supportive care
any
poor

43. 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

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

45. 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

46. Low dose chemotherapy Immunomodulatory agents Lenalidomide (Revlimid)
Thalidomide
Lenalidomide
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.

47. 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

48. Lenalidomide (Revlimid, CC-5013)
Efficacy of Lenalidomide in Myelodysplastic Syndromes. NEJ 352;6. Feb 2005
Dose: 25mg or 10mg per day; or 10mg per day for 21/28 days
All pts had no response to recombinant erythropoietin or high epo level so low chance of responding
Results
21/43 (49%) had either a >2g/dl increase in hg or became red cell transfusion independent
Restoration of normal karyocyte was noted in 10/20 pts
9/12 pts with 5q- had restoration of normal karyocyte
Neutropenia and thrombocytopenia most common adverse events

49. Hematopoietic growth factors
Recombinant human granulocyte colony-stimulating factor (GCSF) and recombinant human erythropoietin may be used
Decreased responsiveness commonly seen
Related to defective proliferation of hematopoietic precursors
Erythropoietin
Serum epo level: inversely related to the degree of anemia in pts with MDS
Level may be suboptimally elevated in MDS
Recombinant EPO : 20-40% with MDS respond
Responses more likely if serum EPO level <100mU/mL

50. Hematopoietic growth factors
Response to EPO
May be delayed
One study of 281 pts with MDS:
18% responded by 12 wks
45% responded by 26wks
Predictors of response: RA, good karyotype, EPO <150

51. Hematopoietic growth factors
Combination therapy (EPO+GCSF)
In pts with MDS, G-CSF are synergistic with EPO
Approximately 40-45% pts receiving combo have erythroid response
Nearly all had neutrophil responses
Responses more common in pts with Low or Intermediate-1 IPSS scores
Generally occur within 6-8 weeks

52. Newer Agents Tipifarnib ( Zarnestra R115777) Kurzrock et al Blood 2004
82 pts; median age 67
IPSS int-1 17%, int-2 39%, high 44%; prior tx 37%
Overall response 26/82 (32%)
Side effects: myelosuppression, fatigue, nausea, diarrhea, rashes
Lonafarnib (Sarasar SCH66336) Feldman et al ASH 2003
67 pts: RAEB-t 32; CMML 35
IPSS int int-2 high 25
Overall response 29%

53. TCA trial for MDS FGCL-SM2216-014
Objective: evaluate the efficacy of FG-2216 in lower-risk MDS
FG-2216: inhibitor of HIF-PH enzymes

54. Our patient WBC 4.1 ANC 3321 Hemoglobin 8.9 Platelets 158
Normal cytogenetics
Blasts in bone marrow <5%

55. Our patient

56. Our patient

57. Our patient
Low risk
Median survival of 4 years
CABG? Yes

58. After CABG

59. Before CABG