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