1. Myelodysplastic Syndromes
Nicole N. Balmer M.D.
June 3rd, 2005

2. History of MDS
First described in patients with refractory anemia were described; Subsequently, the terms "preleukemic anemia“ and “preleukemia” were used.
In 1963, a variant of acute leukemia was described, characterized by a prolonged and often benign clinical course, with a comparatively lower but variable percentage of bone marrow blasts; the authors termed this condition "smoldering acute leukemia"

3. History of MDS
In the 1970s, chronic myelomonocytic leukemia (CMML) was recognized as a unique preleukemic syndrome.
In 1976, the French-American-British (FAB) Cooperative Group initially defined refractory anemia with excess blasts (RAEB) and CMML as preleukemic states. Six years later, the FAB group added three more categories to this classification scheme and adopted the present term "myelodysplastic syndromes".
These disorders, and other members of the MDS "family“ were subsequently defined by the WHO.

5. The Myelodyplastic Syndromes
Six types of myelodysplastic syndromes according to WHO.
Refractory anemia
Refractory anemia with ringed sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory anemia with excess blasts
Myelodysplastic syndrome, unclassifiable
5q- syndrome (myelodysplastic syndrome associated with isolated del (5q) chromosome abnormality
Related syndromes:
Myelodysplastic/Myeloproliferative diseases

6. Myelodysplastic Syndromes
MDS Definition:
A group of disorders presenting with some evidence of bone marrow failure and dysplasia of one or more of the myeloid lineages, with <20% blasts in the blood or marrow.
Epidemiology:
Occur primarily in older patients (most common > 70 years).

7. MDS – Clinical Symptoms
Ecchymoses
Fatigue
Pallor
Ecchymoses/petechiae
Abnormal bleeding
Infection

8. MDS Etiology Two etiologic categories of MDS:
1.) De Novo:
Associated with:
-benzene exposure (gasoline)
-cigarettesmoking
-viruses Fanconi’s anemia
2.) Therapy related:
-alkylating agent chemotherapy
-radiation

9. Prognostic Groups
Two groups based on survival and evolution to acute leukemia
1.) “Good” group
Refractory anemia (RA)
Refractory anemia with ringed sideroblasts (RARS)
5q - syndrome
2.) “Bad” group
Refractory anemia with excess blasts (RAEB)
Refractory cytopenia with multilineage dysplasia (RCMD)
MDS unclassified can be either

10. Median Survival – Myelodysplastic Syndromes

11. Prognostic Scoring 0.5 1.0 1.5 2.0 <5 5-10 -- 11-20 20-30 0-1 2-3
The International Myelodysplastic Syndrome Working Group developed a scoring system based on 3 variables:
0.5
1.0
1.5
2.0
% Blasts
<5
5-10 --
11-20
20-30
Karyotype
Normal, -Y, del(5q), del(20q)
Abnormal-ities
NOS
≥ 3 abnormalities, chr 7 abnormalities
Cytopenia
0-1
2-3

12. International Prognostic Scoring System Data (IPSS)
Overall median survival was 5.7, 3.5, 1.2, and 0.4 years for patients with IPSS scores of zero (low risk), 0.5 to 1.0 (intermediate-1 risk), 1.5 to 2.0 (intermediate-2 risk), and 2.5 to 3.5 (high risk), respectively.     The time for 25 percent of the patients in each of the four risk groups to evolve into acute leukemia was 9.4, 3.3, 1.1, and 0.2 years, respectively.

13. IPSS
Other adverse prognostic factors which may improve the prognostic value of the IPSS include:
    -CD34 positivity of bone marrow nucleated cells    -Increased expression of the Wilms' tumor gene (WT1)  -Increased serum beta-2 microglobulin concentration   
 -Mutations of the FLT3 gene
 -Abnormal localization of immature precursors (ALIP).

14. Refractory Anemia RA Definition:
Dyplasia of the erythroid series only.
Clinically, anemia is refractory to hematinic therapy
Myeloblasts < 1% blood and < 5% marrow
<15% ringed sideroblasts in marrow
No Auer rods
Other etiologies of erythroid abnormalities must be excluded. These include:
drug/toxin exposure vitamin deficiency
viral infection congenital disease

15. Refractory Anemia Epidemiology: 5-10% of MDS cases. Older patients
Morphology:
Anisopoikilocytosis on peripheral smears
Dyserythropoiesis with nuclear abnormalities (megaloblastoid change)
< 15% ringed sideroblasts

16. Refractory Anemia Genetics: 25% may have genetic abnormalities
Prognosis:
Median survival is 66 months
6% rate of progression to acute leukemia

17. Peripheral Smear - Anisopoikilocytosis

18. Dyserythropoeisis on Bone Marrow Aspirate

19. Megaloblastoid Change on Bone Marrow Aspirate

20. Refractory Anemia with Ringed Sideroblasts
RARS definition:
Dyplasia of the erythroid series only.
Clinically, anemia is refractory to hematinic therapy
Myeloblasts < 5% in marrow, absent in blood
>15% ringed sideroblasts in marrow
No Auer rods
Other etiologies of ringed sideroblasts must be excluded. These include:
Anti- tuberculosis drugs
Alcoholism

21. Refractory Anemia with Ringed Sideroblasts
Epidemiology:
10-12% of MDS cases.
Older patients
Males > females
Morphology:
Dimorphic pattern on peripheral smears
Majority RBC’s normochromic, 2nd population hypochromic
Dyserythropoiesis with nuclear abnormalities (megaloblastoid change)

22. Refractory Anemia with Ringed Sideroblasts
Morphology (con’t.)
< 15% ringed sideroblasts (RS)
RS = Erythroid precursor with ≥ 10 siderotic granules encircling 1/3 or more of the nucleus.
If excess blasts present, this dictates diagnosis, despite percentage of RS’s.

23. Refractory Anemia with Ringed Sideroblasts
Genetics:
Clonal chromosomal abnormalities in
<10%; in fact, development of such an abnormality should prompt reassessment of diagnosis.
Prognosis:
Median survival 6 years (72 months)
1-2% rate of progression to acute leukemia

24. Dimorphic Red Cell Population

25. Ringed Sideroblasts

26. Ringed Sideroblasts

27. Megaloblastoid Change

28. Refractory Cytopenia with Multilineage Dysplasia
RCMD definition:
Dyplasia in 10% or more of cells in 2 or more myeloid lines.
Myeloblasts < 1% blasts in the blood and < 5% in marrow.
No Auer rods
< 1 x 109/L monocytes in blood

29. Refractory Cytopenia with Multilineage Dysplasia
Epidemiology:
24% of MDS cases.
Older patients
Morphology:
Neutrophil abnormalities may include:
Hypogranulation
Pseudo-Pelger-huet (hyposegmentation/barbells)
Megkaryocyte abnormalities may include
Hypolobation Micromegakaryocytes

30. Refractory Cytopenia with Multilineage Dysplasia
Morphology (con’t.)
Erythroid abnormalities may include nuclear abnormalities such as:
megaloblastoid change -multilobation
multinucleation
In addition:
Erythroid presursors may be PAS positive
If >15% of erythroid precursors are ringed sideroblasts, call = RCMD-RS

31. Refractory Cytopenia with Multilineage Dysplasia
Genetics:
Clonal chromosomal abnormalities found in up to 50% of RCMD and RCMD-RS cases. The abnormalities include:
Trisomy del(7q) del(5q)
Monosomy Monosomy del(20q)
Complex karyotypes
Prognosis:
Median survival 33 months
11% rate of progression to acute leukemia
RCMD and RCMD-RS = similar survival
Complex karyotypes = worse survival (10-18 months)

32. Pelgeroid (pseudo Pelger-Huet) Neutrophil

33. Pelgeroid (pseudo Pelger-Huet) Neutrophil

34. Dyserythropoiesis on Bone Marrow Aspirate

35. Hypersegmented Neutrophil

36. Micromegakaryocyte

37. Refractory Anemia with Excess Blasts
RAEB definition:
Refractory anemia with 5-19% myeloblasts in the bone marrow.
RAEB-1:
5-9% blasts in bone marrow and <5% blasts in blood.
RAEB-2:
10-19% blasts in the bone marrow
Auer rods present

38. Refractory Anemia with Excess Blasts
Epidemiology: 40% of MDS cases.
Older patients (over 50 years)
Morphology:
Dysplasia of all three cell lines often present
Neutrophil abnormalities may include:
Hypogranulation hypersegmentation
Pseudo-Pelger-huet (hyposegmentation/barbells)
Pseudo Chediak-Higashi granules
Megkaryocyte abnormalities may include
Hypolobation Micromegakaryocytes

39. Refractory Anemia with Excess Blasts
Morphology (con’t.)
Erythroid precursor abnormalities may include:
Abnormal lobulation -megaloblastoid change
Multinucleation
0-19% myeloblasts in the blood
5-19% in the marrow
Bone marrow:
Usually hypercellular (10-15% hypocellular)
Abnormal localization of immature precursors (ALIP) may be present
Immunophenotype:
Blasts express CD 13, CD33 or CD117
The only MDS with a relevant phenotype

40. Refractory Anemia with Excess Blasts
Genetics:
Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The abnormalities include:
– – del(5q)
– – del(7q) – Complex karyotypes
Prognosis:
Median survival, RAEB-1 = 18 months
Median survival, RAEB-2 = 10 months
RAEB-1 = 25% rate of progression to acute leukemia
RAEB-2 = 33% rate of progression to acute leukemia

41. Hypercellular Bone Marrow

42. Blasts and Hypogranulation

43. Myeloblast with Auer Rod

44. Chediak-Higashi-like Granules
Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology

45. Myelodysplastic Syndrome, Unclassifiable
MDS-U definition:
Dysplasia of the neutrophil and/or megkaryocytic lines and no increased blasts
Not otherwise classifiable as RA, RARS, RCMD and RAEB

46. Myelodysplastic Syndrome, Unclassifiable
Epidemiology:
Incidence unknown
Older or younger persons
Associated with a history of exposure to cytotoxic or radiation therapy
Morphology:
BmBx usually hypercellular
Dyplastic megakaryocytes may be prominent

47. Myelodysplastic Syndrome, Unclassifiable
Genetics:
May be normal, or clonal abnormalities the same as those found in other MDS syndromes.
Prognosis:
Unknown
Occasionally defining characteristics develop. Then case should be reclassified.

48. Myelodysplastic Syndrome Associated With Isolated del(5q) Chromosome Abnormality ( 5q- Syndrome)
5q- syndrome definition:
MDS with an isolated del(5q)
<5% blasts in blood and bone marrow
Epidemiology:
Middle age to older women
Clinical Presentation:
Refractory anemia, often severe
Thrombocytosis may be present.

49. Myelodysplastic Syndrome Associated with Isolated del(5q) Chromosome Abnormality ( 5q- Syndrome)
Morphology:
Peripheral Smear:
Marked macrocytic anemia.
Slight leukopenia
Normal to elevated platelets
BmBx:
Erythroid dysplasia, varying degrees
Small, hypolobated megakaryocytes
Scattered aggregates of small lymphocytes

50. Myelodysplastic Syndrome Associated with Isolated del(5q) Chromosome Abnormality ( 5q- Syndrome)
Genetics:
Deletion between bands q31 and q 33 on chromosome 5.
Size of deletion and breakpoints are variable.
Any additional cytogenetic abnormality excludes placement in this category.
Prognosis:
Good = long survival
Those who develop more than 5% blasts may have shorter survival

51. Hypolobated megakaryocytes

52. Myelodysplastic/myeloproliferative diseases
WHO category consists of 4 entities
Chronic myelomonocytic leukemia (CMML)
Formerly an MDS
Atypical chronic myeloid leukemia (aCML)
CML without BCR/ABL fusion gene
Juvenile myelomonocytic leukemia (JMML)
MDS/MPD-unclassified

53. CMML Diagnostic Criteria

54. MDS/MPD

55. High vs. low intensity treatment
 High intensity = treatment requiring hospitalization, and included intensive combination chemotherapy and hematopoietic cell transplantation.     Low intensity = outpatient-type treatments, such as use of hematopoietic growth factors, differentiation-inducing agents, biologic response modifiers, and low intensity chemotherapy.

56. MDS Treatment
    Patients < 60 years of age, who have good or excellent performance status and who are in the IPSS intermediate-2 or high risk categories (expected survival 0.3 to 1.8 years) = high intensity therapies.     Patients < 60 years of age, who have good or excellent performance status and who are in the low or intermediate-1 category (expected survival 5 to 12 years) = low intensity therapy or supportive care.     Patients >60 years of age with good performance status and who are in the IPSS intermediate-2 or high risk categories (expected survival 0.5 to 1.1 years) = low intensity therapy, although selected patients could be candidates for high intensity therapies.     Patients >60 years of age with good performance status and who are in the low or intermediate-1 category (expected survival 3 to 5 years) = supportive care or low intensity therapy     

57. Stem Cell Transplant
HEMATOPOIETIC CELL TRANSPLANTATION Allogeneic HCT should be considered for patients with MDS who are under the age of 60 and who have an HLA-matched sibling donor.
60 and 40% chance of cure after allo-HCT in low and intermediate risk patients respectively
Transplant-related mortality and the relapse rate at five years are as high as 40 percent.

58. Azacitidine Azacitadine (Vidaza) the first approved treatment of MDS
Azacitidine is a member of a class of drugs in development known as "hypomethylating" or "demethylating" agents..
About 15% of patients in the three trials had complete or partial responses to Vidaza. (complete or partial normalization of blood in the bone marrow and normal levels of blood cells and need for blood transfusions was eliminated)
Side effects = nausea, anemia, low platelets in blood, diarrhea, fatigue, irritation at the injection site, and constipation.

59. Revlimid
Thalidomide derivative (revlimid) — Revlimid is a thalidomide derivative without the neurologic toxicity of the parent compound. Used in MM and promising in MDS.
Restoration of a normal karyotype was noted in 11 of 17 informative patients.
Erythroid response was highest in patients with Low/Int-1 IPSS scores (71 percent) and in those with the 5q- syndrome (91 percent).
Dose-dependent myelosuppression was the most common adverse event.
The results of multicenter phase II trials of this agent are awaited.

60. Decitabine
Decitabine — Another pyrimidine nucleoside similar to 5-aza is 5-aza-2'-deoxycytidine (DAC, decitabine). Both agents strongly inhibit DNA methylation and are capable of inducing cell differentiation [86-88].
25-61% resopnse rate
Major cytogenetic responses were noted in 31 percent of those with abnormal pretreatment cytogenetics and were associated with a reduced risk of death
High toxicity = fever, infection, sepsis, neutropenia, anemia, and thrombocytopenia

61. Hypocellular MDS Treatment
Immunosuppressive drugs — Patients with hypocellular MDS are believed to have immune-mediated hematopoietic suppression, perhaps due to the presence of an abnormal T cell response
Some of these patients have responded to immunosuppressive therapies such as antithymocyte globulin (ATG)

62. Future Therapies
Valproic acid (VPA) has been shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro.
Recent studies have found that VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.

63. References
1.)Brunning, RD, Bennett, JM, Flandrin, G, et al. Myelodysplastic syndromes: Introduction. In Jaffe, ES, Harris, NL, Stein, H, Vardiman, JW, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2001.
2.)Wells, DA, Benesch, M, Loken, MR, et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood 2003; 102:394.

64. References
3.)Seo, IS, Li, CY, Yam, LT. Myelodysplastic syndrome: Diagnostic implications of cytochemical and immunocytochemical studies. Mayo Clin Proc 1993; 68:47.
4.)So, CC, Wong, KF. Valproate-associated dysmyelopoiesis in elderly patients. Am J Clin Pathol 2002; 118:225.
5.)Ooi, J, Iseki, T, Takahashi, S, et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 2003; 101:4711.
6.) Albitar, M, Manshouri, T, Shen, Y, et al. Myelodysplastic syndrome is not merely "preleukemia". Blood 2002; 100:791.

65. References
7.)Passmore, SJ, Chessells, JM, Kempski, H, et al. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 2003; 121:758
8.)Cheson, BD, Zwiebel, JA, Dancey, J, Murgo, A. Novel therapeutic agents for the treatment of myelodysplastic syndromes. Semin Oncol 2000; 27:560.
9.)Estey E, Schrier S. Treatment and prognosis of mds
10.)Coll DC, Landaw, SA Clnical manifestations and diagnosis of the myelodysplastic syndromes. Blood. 2004, 1;104(5):

66. Acknowledgments
Dr. John Ryder
Dr. Bryan Abbott