Transcript ppt

Myelodysplastic Syndromes:
Clonal Myeloid Diseases
Haskell (Gill) Kirkpatrick M.D.
Case Report
 74 y/o man with hx prostate cancer (XRT
2004) and ETOH intake presented with
 Exam pertinent for decreased pallor. No
lymphadenopathy or organomegaly.
 Labs: WBC 1.5, Hct 15, reticulocyte count
1%, platelets 44,000
 Arise from somatic mutations in
hematopoietic (myeloid) stem cell causing:
 Ineffective hematopoiesis
 Cytopenia(s)
 Qualitative disorders of blood cells and their
 Variable predilection to undergo evolution to
florid AML
 Stem cells have a defective capacity for
self-renewal and differentiation
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
 1975 conference on unclassifiable leukemias
Myelodysplasia: Misnomer
 Nomenclature coined at a time when
Dysmorphogenesis thought to be single
 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”
World Health Organization (WHO)
 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
 Divided categories into single or multi-lineage
 Divided RAEB into 2 categories
 Eliminated CMML from MDS category
 Categories not addressed: hypocellular MDS & MDS
with fibrosis
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
 Idiopathic
 Secondary (treatment related)
 Chemotherapy (particularly alkylating agents)
 Radiation
Clinical Features
 Asymptomatic
 Symptomatic anemia
 Recurrent infections due to
 Bleeding due to thrombocytopenia and/or
qualitative platelet defect
Laboratory features
 Blood
 Red cells: Anemia 85% patients at diagnosis
 MCV often increased
 Anisocytosis
 Poikilocytosis: oval, elliptical, teardrop, spherical,
 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
Laboratory features
 Marrow
 Normal or increased cellularity
 20% are hypoplastic
 Dysplasia in one or more cell line
 Erythroid hyperplasia and variation in
 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
Dysplastic RBCs binucleation, multinucleation,
nuclear budding, nuclear
bridging, karryorhexis,
vacuoles, PAS+
Megaloblastoid changes
Ringed sideroblasts
Macrophage storage
Small, hypolobulated
Larger with widely
spaced nuclei
Morphology: Pitfalls and
Morphologic dysplasia not specific for MDS
Small number of dysplastic cells can be seen in normal
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
Biopsies should be at least 1-2 cm extending into marrow
Especially with low-grade MDS
Studies have shown this especially with dyserythropoiesis
Other conditions: megaloblastic anemia, exposure to toxins
(i.e. arsenic), congenital dyserythropoietic anemia, growth
factors, HIV etc..
Inter-observer reproducibility of dysplasia is poor
Cytogenetic Characterization of
 Role: confirmation of diagnosis & predicting outcome
 Contributed to understanding of pathogenesis
 Suspected multi-step process of insults to stem cell
 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
5Q- Syndrome
 Deletion of chromosome 5q is one of most
common abnormalities in MDS
 Common deleted region mapped to 5q31q32 (1.5 Mb)
 “5q- syndrome”
Isolated 5q deletion
Severe anemia, normal or elevated platelets
Atypical megakaryocytes
No blasts
Typically indolent coarse
International Prognostic Scoring System
 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
Bone Marrow Transplant
 Allogeneic hematopoetic stem-cell
 Currently only treatment that can
significantly prolong survival
 Approximately 1/3 of transplanted patients
 Significant morbidity and treatment related
 Only 8-10% of all MDS patients eligible and
have a donor (HLA-matched sibling)
 Young patients (45 or younger)
Therapeutic Goals When Transplant
Not an Option
 Consider natural history of the disease & patient
 Low or Intermediate-1 patients (IPSS): longer
 Principle goal: amelioration of hematologic deficits
 Need to be durable improvements
 Int-2/high risk patients:
 Extending survival becomes more “immediate
 Prolonging time to development of AML
Supportive Care
 Transfusions
 Erythropoietin
 If no blasts
Targeting Angiogenesis in MDS
 Angiogenic molecules generated by the neoplastic
 Vascular endothelial growth factor-A (VEGF-A)
 medullary neovascularity
 clonal expansion of receptor-competent myeloblasts
 Ineffective hematopoiesis in receptor naïve
 Inflammatory cytokines potentiate ineffective
 Small molecule inhibitors of angiogenesis are a
potential class of therapeutics
 Thalidomide
 Lenalidomide (Revlamid)
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
 Non-erythroid lineage improvement uncommon
 Prolonged treatment necessary for maximal benefit
 Median interval to response: 16 weeks
 Side effect profile becomes problematic (i.e.
Lenalidomide (Revlimid)
 Derivative of thalidomide
 More potent and lacks neurologic toxicities
 Safety and efficacy trial (List et al NEJM
 RBC transfusion independence with cytogenetic
response in 10/12 (83%) patients with del 5q31
 Transfusion independence in non-5q patients
 Sustained > 2years
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
 66% transfusion independence (median
duration > 47 weeks)
 Cytogenetic response 70% (complete
reponse 44%)
 Myelosuppression common
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
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
silence tumor-suppressor genes
DNA Methylation in MDS
 Multiple genes known to be hypermethylated/silenced
 P15 (cyclin dependent kinase inhibitor): frequent
 Inactivation associated with risk of progression to
 Associated with disease progression
DNA Methylation Inhibitors
 5-Azacytidine (AZA) and 5-aza-2’-deoxycytidine
 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
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
 MDS represents a group of heterogeneous
neoplastic disorders
 Cytogenetics compliment morphology and
help determine prognosis and treatment
 New novel therapies such as 5-Azacytidine
(Vidaza) and soon to be approved
Lenalidomide (Revlimid) have added
options for non-transplant candidates