Myelodysplastic Syndromes: Clonal Myeloid Diseases

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 10-30 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 heterogeneousneoplastic 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