myelodysplastic syndromes: clonal myeloid diseases haskell (gill) kirkpatrick m.d. 8/24/05
TRANSCRIPT
Myelodysplastic Syndromes: Clonal Myeloid Diseases
Haskell (Gill) Kirkpatrick M.D.8/24/05
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
CD34
CD117
MPO
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
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
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”
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
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
Clinical Features Asymptomatic Symptomatic anemia Recurrent infections due to
granulocytopenia 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,
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
Blood
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
Dysplastic RBCs - binucleation, multinucleation, nuclear budding, nuclear bridging, karryorhexis, vacuoles, PAS+
Aspirate
Megaloblastoid changes
Ringed sideroblasts
Macrophage storage
Megakaryocytes:
Small, hypolobulated nuclei
Larger with widely spaced nuclei
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
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
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
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
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)
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
Supportive Care
Transfusions Erythropoietin G-CSF
If no blasts
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)
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)
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
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
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
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
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
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
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