1. Myelodysplastic Syndromes: Clonal Myeloid Diseases
Haskell (Gill) Kirkpatrick M.D.
8/24/05

2. Case Report
74 y/o man with hx prostate cancer (XRT 2004) and ETOH intake presented with dyspnea
Exam pertinent for decreased pallor. No lymphadenopathy or organomegaly.
Labs: WBC 1.5, Hct 15, reticulocyte count 1%, platelets 44,000

6. CD34

7. CD117

8. MPO

10. MDS
Arise from somatic mutations in hematopoietic (myeloid) stem cell causing:
Ineffective hematopoiesis
Cytopenia(s)
Qualitative disorders of blood cells and their precursors
Variable predilection to undergo evolution to florid AML
Stem cells have a defective capacity for self-renewal and differentiation

11. History of Terminology
“Odo-leukemia” coined in 1942
Disorders on the threshold of leukemia
“Pre-leukemic anemia” soon replaced
Described cases of cytopenias that preceded the onset of AML
“Hemopoietic dysplasia” later shortened to “Myelodysplasia”
1975 conference on unclassifiable leukemias

12. Myelodysplasia: Misnomer
Nomenclature coined at a time when Dysmorphogenesis thought to be single abnormality
Dysplasia is a pathologic term that implies a non-clonal, non-neoplastic process
Encompasses heterogeneous spectrum:
From acquired indolent idiopathic anemia…
No discernable leukemic blasts
To oligoblastic myelogenous leukemia
Increased leukemic blast cells (>2%)
“refractory anemia with excess blasts”

13. World Health Organization (WHO) Classification
FAB criteria introduced in 1982
2001 WHO published new classification scheme
Modifications made to improve prognostic value
Major changes:
Lower threshold for defining AML (Blasts count)
Eliminated RA with excess blasts in transformation (RAEBT)
Divided categories into single or multi-lineage dysplasia
Divided RAEB into 2 categories
Eliminated CMML from MDS category
Categories not addressed: hypocellular MDS & MDS with fibrosis

15. Incidence and Etiology
15,000 new cases in U.S. annually
5 per 100,000 persons per year
Increases to 20 to 50 per 100,000 after the age of 60
As common as CLL (most common form leukemia)
Idiopathic
Secondary (treatment related)
Chemotherapy (particularly alkylating agents)
Radiation

16. Clinical Features Asymptomatic Symptomatic anemia
Recurrent infections due to granulocytopenia
Bleeding due to thrombocytopenia and/or qualitative platelet defect

17. Laboratory features Blood Red cells: Anemia 85% patients at diagnosis
MCV often increased
Anisocytosis
Poikilocytosis: oval, elliptical, teardrop, spherical, fragmented
Usually low reticulocyte count
Granulocytes and Monocytes
Monocytosis and neutropenia not uncommon
Pseudo-Pelger-Hüet cells
Hypogranular neutrophils
Platelets
Mild to moderate thrombocytopenia 25% cases
Abnormal function assays can reflect qualitative defects

18. Blood

19. Laboratory features Marrow Normal or increased cellularity
20% are hypoplastic
Dysplasia in one or more cell line
Erythroid hyperplasia and variation in erythroblasts
Ringed Sideroblasts: erythroblasts with mitochondrial iron aggregates
Hypogranulated neutrophils
Unilobed/bilobed megakaryocytes
Fibrosis
Increase in reticulin and collagen fibers can be seen in oligoblastic leukemia

20. Aspirate
Dysplastic RBCs - binucleation, multinucleation, nuclear budding, nuclear bridging, karryorhexis, vacuoles, PAS+

21. Megaloblastoid changes

22. Ringed sideroblasts
Macrophage storage

23. Megakaryocytes:
Small, hypolobulated nuclei
Larger with widely spaced nuclei

24. Morphology: Pitfalls and Problems
Morphologic dysplasia not specific for MDS
Other conditions: megaloblastic anemia, exposure to toxins (i.e. arsenic), congenital dyserythropoietic anemia, growth factors, HIV etc..
Small number of dysplastic cells can be seen in normal individuals
Guidelines (WHO): 10% of cells must be dysplastic in a single lineage
Quality of specimen can be an obstacle
Make sure adequate staining to call hypogranularity (neutrophils)
Biopsies should be at least 1-2 cm extending into marrow
Inter-observer reproducibility of dysplasia is poor
Especially with low-grade MDS
Studies have shown this especially with dyserythropoiesis

25. Cytogenetic Characterization of MDS
Role: confirmation of diagnosis & predicting outcome
Contributed to understanding of pathogenesis
Suspected multi-step process of insults to stem cell genome
Routine karyotyping
De Novo MDS: Abnormal 40-70% cases
Therapy-related (t-MDS): Abnormal 95% cases
Predict survival and assess risk of transformation to acute leukemia
Often same abnormal chromosomes seen in AML
No cytogenetic abnormality specific for MDS
One unique case: 5q- syndrome

26. 5Q- Syndrome
Deletion of chromosome 5q is one of most common abnormalities in MDS
Common deleted region mapped to 5q31-q32 (1.5 Mb)
“5q- syndrome”
Isolated 5q deletion
Severe anemia, normal or elevated platelets
Atypical megakaryocytes
No blasts
Typically indolent coarse

27. International Prognostic Scoring System (IPSS)
Derived from data from over 800 patients managed with supportive care
(Greenberg et al, Blood 1997)
Compliments both classification schemes
WHO and FAB
Morphologic classification alone insufficient

29. Bone Marrow Transplant
Allogeneic hematopoetic stem-cell transplant
Currently only treatment that can significantly prolong survival
Approximately 1/3 of transplanted patients cured
Significant morbidity and treatment related mortality
Only 8-10% of all MDS patients eligible and have a donor (HLA-matched sibling)
Young patients (45 or younger)

30. Therapeutic Goals When Transplant Not an Option
Consider natural history of the disease & patient preference
Low or Intermediate-1 patients (IPSS): longer survival
Principle goal: amelioration of hematologic deficits
Need to be durable improvements
Int-2/high risk patients:
Extending survival becomes more “immediate priority”
Prolonging time to development of AML

31. Supportive Care
Transfusions
Erythropoietin
G-CSF
If no blasts

32. Targeting Angiogenesis in MDS
Angiogenic molecules generated by the neoplastic clone
Vascular endothelial growth factor-A (VEGF-A)
medullary neovascularity
clonal expansion of receptor-competent myeloblasts
Ineffective hematopoiesis in receptor naïve progenitors
Inflammatory cytokines potentiate ineffective hematopoiesis
Small molecule inhibitors of angiogenesis are a potential class of therapeutics
Thalidomide
Lenalidomide (Revlamid)

33. Thalidomide and MDS Anti-angiogenic and TNFα inhibitory properties
Phase II trials done
Around 18% response rate (red cell transfusion independence or >50% decrease in transfusion requirement)
Non-erythroid lineage improvement uncommon
Prolonged treatment necessary for maximal benefit
Median interval to response: 16 weeks
Side effect profile becomes problematic (i.e. neuropathy)

34. Lenalidomide (Revlimid)
Derivative of thalidomide
More potent and lacks neurologic toxicities
Safety and efficacy trial (List et al NEJM 2/05)
RBC transfusion independence with cytogenetic response in 10/12 (83%) patients with del 5q31
Transfusion independence in non-5q patients 39%
Sustained > 2years

35. Lenalidomide (Revlimid)
Phase II trial (List et al ASCO 5/05)
148 patients
Low or intermediate-1 risk (IPSS score)
Del 5q isolated (as well as other abnormalities)
66% transfusion independence (median duration > 47 weeks)
Cytogenetic response 70% (complete reponse 44%)
Myelosuppression common

36. Other Novel Therapeutic Targets: DNA methylation and Epigenetics
Addition of a CH3 (methyl) group to a molecule (cytosine base)
DNA methyltransferase
Epigenetics: Regulation of gene expression without altering DNA sequence
Epigenetic silencing
Gene promoter regions get methylated
Leads to histone modifications
Chromatin is remodeled and becomes “invisible” to transcription factors
Gene is “silenced”
Important role in embryogenesis
Thought to be exploited by cancers to help express their malignant phenotype
silence tumor-suppressor genes

39. DNA Methylation in MDS
Multiple genes known to be hyper-methylated/silenced
P15 (cyclin dependent kinase inhibitor): frequent target
Inactivation associated with risk of progression to AML
Associated with disease progression

40. DNA Methylation Inhibitors
5-Azacytidine (AZA) and 5-aza-2’-deoxycytidine (DAC)
Cytosine analogs: inhibit DNA methylation by trapping DNA methyltransferases
Irreversible bond, degredaded
Cells then divide in absence of DNA methyltransferases
Dosage key
Hypomethylating at low doses, cytotoxic at high doses
Maximally tolerated dose (MTD) determined in 70’s
Recent low-dose studies show response (and hypomethylation) at times lower than MTD
Current studies exploring optimal dosing schedules ongoing

41. 5-Azacytidine (Vidaza)
Phase III randomized trial (Silverman et al JCO 2002)
compared AZA to supportive care
Treatment-naïve patients (various stages)
60% response rate (hematologic) that was durable
Improved quality of life
Prolongation of median time to leukemic transformation or death
21 months vs. 13 months (statistically significant)
Not powered for OS and cross-over permitted
Sub-cutaneous injection daily X 7 days every 28 days
FDA approval 2004 for treatment of MDS

43. Summary MDS represents a group of heterogeneous neoplastic disorders
Cytogenetics compliment morphology and help determine prognosis and treatment goals
New novel therapies such as 5-Azacytidine (Vidaza) and soon to be approved Lenalidomide (Revlimid) have added options for non-transplant candidates