the Myelodysplastic Syndromes:

what they are, what they mean and what are we doing about it

Anthony Woods, MDSeptember 30, 2006

outline

• what is myelodysplasia?• diagnosis & classification• treatment strategies• specialty clinics

What is…?

“clonal disorder affecting hematopoietic maturation, characterized by ineffective hematopoiesis and bone marrow failure

with resultant cytopenias, often culminating in florid acute leukemia”

huh?

historically

• reports of cytopenic disorders began appearing in the early 20th century

1942: “odo-leukemia” • odo = threshold (Chevalier et al)

1949: “preleukemic anemia” (Hamilton-Paterson)

1953: expanded definition to include all blood lines “clonal myeloid hemopathy”

(Block et al)

historically

• other terms used over the last 50 years:– herald state of leukemia– refractory anemia– sideroachrestic anemia– idiopathic refractory sideroblastic anemia– pancytopenia with hyperplastic marrow– oligoblastic leukemia

soapbox

no surprise that there is confusion and ignorance about this disorder:

historical coupling of MDS to acute myeloid leukemia

• there is a relationship• has hindered consideration of MDS as

a distinct entity– biased investigational and therapeutic

efforts towards the leukemia

historically

• Paris, 1975: hemopoietic dysplasia– subsequently shortened to

myelodysplasia

• 1982: French-American-British classification scheme (FAB)

• 1999-2002: World Health Organization classification scheme

What is myelodysplasia?

• disordered production of one or more cell lines

“dysplasia”

abnormal growth and differentiation of hematopoietic precursors

• abnormal appearance under the microscope

normal blood

dysplastic features - blood

dysplastic features - blood

normal

dysplastic features - blood

normal bone marrow

normal bone marrow

dysplasia – bone marrow

dysplasia – bone marrow

dysplasia – bone marrow

dysplasia – bone marrow

what goes wrong with marrow cells?

• multistep process• sequence of successive DNA

mutations in an early blood cell precursor cell

• evolution of this cell into a “clone”– self-reproducing abnormal cell– growth advantage over normal marrow

cells

what goes wrong with marrow cells?

complex multistep process:• DNA mutations in an early blood cell

precursor cell• emergence as an abnormal clone

– self-reproducing, abnormal cell– growth advantage over normal marrow

cells BUT at the same time incapable of producing normal blood cells

what goes wrong with marrow cells?

expansion of the abnormal clone results in ineffective hematopoiesis– marrow looks full– no useful blood cell production actually

occurring– suppression and inhibition of normal

marrow growth

“weeds growing in the garden”Dr. R. Wells

what goes wrong with marrow cells?

• worse, over time the clone becomes more and more unstable

• ~ 25% of persons with MDS develop acute myeloid leukemia

what goes wrong with marrow cells?

C. Willman, ASH Education Program, 2000

MDS AML

causes

• may follow exposures to bone marrow toxins– chemotherapy– radiation– organic compounds

• some follow inherited tendencies• Fanconi anemia, disorders of DNA repair

• > 80% have no identifiable exposure or cause

in whom and how often

• can affect people of any age– including children

• more common in advancing age– North America: mid-late 60’s– China: 50

• 10000-15000 new diagnoses per year in USA– Canada 10% ?

in whom and how often

MDS Foundation estimates that in people older than 70 there are

15 - 50 new diagnoses / 100,000 persons per year

extrapolating USA estimates, perhaps 3000 - 6000 Canadians have an MDS

diagnosis at any given time

diagnosis

• requires suspicion• typically 2 settings where MDS

should be suspected:

1. signs or symptoms of a blood disorder

– fatigue, exercise intolerance, pale– serious or recurrent infections– inappropriate bleeding and bruising

diagnosis

2. unexpected finding in blood suggesting MDS:

– low blood count of any kind• > 80% have anemia ± others• 30 – 45% have low platelets

– macrocytosis (large red cells)– high monocyte count– abnormal appearing blood cells

diagnosis

required evaluation:• complete history and examination• complete blood counts and diff• iron, B12 and folate levels• bone marrow aspirate & biopsy

– chromosome analysis: “cytogenetics”

• serum erythropoietin levels– prior to transfusions

diagnosis

• tests that are useful in some clinical circumstances

– HLA tissue typing (if BMT a consideration)

– HIV testing– other specific tests

• PNH• other HLA determinations

diagnosis

• no perfect diagnostic test• no absolute diagnostic criteria

• combination of findings:– appearance of dysplasia in blood and

marrow– abnormal cytogenetic testing

complications

related to low blood counts• fatigue, decreased exercise tolerance• serious, recurrent infection• bleeding

• the latter two are responsible for the majority of severe and life-threatening complications of MDS

complications

• approximately 25% of patients undergo a transformation to acute myeloid leukemia

• arbitrary distinction of having 20% blast cells in bone marrow

• represents an increase in the aggressiveness of their MDS

• associated with a worse prognosis

complications

suspected if:

• drop in baseline blood counts• higher blast cell numbers showing up

in blood• higher transfusion requirements• non-specific symptoms

– weight loss

classification

2 classification systems still in use

• FAB System

• newer WHO classification

FAB classification

• many clinicians still primarily use this system

• framework upon which newer classifications are built

• FAB grouping gives prognostic information: all tables from Steensma et al, May Clin Proc, 2006

FAB classification

FAB median survival % progressing to class (months) acute leukemia

RA 37 11RARS 49 5RAEB 9 23

RAEB-t 6 48CMML 22 20

WHO Classification

meant to refine the FAB system:• incorporated new information

– cytogenetics

• added subcategories for recognized specific sub-entities– 5q- syndrome

• also takes into account changes in AML diagnostic criteria– 20% vs 30%

WHO Classification

International Prognostic Scoring System

• need for a better system to predict prognosis in certain patient groups

• IPSS: a tool specifically designed for prognostic purposes

• arose out of a 1997 international workshop on MDS Risk Analysis

• analyzed factors in 816 patients

IPSS calculation

therapy

• many potential therapies available to & tried in MDS patients

• most show some benefit

• most benefits are– small– only in a minority subset of patients

• hard to know who should receive them and what to expect

transfusion and general supportive measures

• most persons with MDS require transfusion support at some time during their course

• most people do not tolerate hemoglobin < 80 g/L– at least 80 or for comfort/symptoms– CMV negative products in potential BMT

recipients

therapy

• platelet transfusion is individualized based on baseline counts and bleeding symptoms– alloimmunization to platelets– local blood bank guidelines

• adjunctive agents can be used– tranexamic acid

therapy

• management of iron overload– Dr. Wells

therapy

• prompt attention given to infectious symptoms

• primary care physicians should be aware of increased importance of infections in persons with MDS

• trials of growth factors with infections– inpatient setting– selected outpatients

therapy

growth factors: erythropoietin and G-CSF

• rationale is to encourage hematopoiesis

• responses are variable

• expensive, not readily obtainable to everyone– 3rd party insurance– “sneak” past renal guidelines

therapy• EPO compounds (Eprex) have

generally shown response rates of 15-20%

• better responses seen in:– RCMD-RS– low EPO levels– lighter transfusion needs

• responses generally last 1-2 years• doses: 40-60,000 units SC weekly• newer compounds appear equally

effective– darbepoietin (Aranesp)

therapy

• response rates may increase up to twofold if recombinant granulocyte colony stimulating factor (G-CSF) is added

• generally done in a stepwise fashion• doses of 1 µcg/kg day typical starting

point

• similar difficulties in obtaining drug

therapy

chemotherapy

• high-risk MDS patients with high blast counts or those who have transformed are candidates for treatment with traditional chemotherapy regimens

• similar to AML therapy

therapy

epigenetic therapy

• DNA transcription (and normal cell growth and development) in MDS can be altered by factors not directly related to DNA sequences– chemical alterations of DNA itself– chemical changes in support proteins

• histones

therapy

• demethylation agents: allow transcription of key tumor suppressor genes

• histone deacetylation agents: alter binding of DNA to histones and increase “accessibility” of DNA to transcription factors

therapy

5-azacytidine• methyltransferase inhibitor

• delays progression of MDS• improvements in blood counts in ~

20% patients• improvements in quality of life• neutropenia observed as side effect

(!)

therapy

5-aza-2’-deoxycytabine (decitabine)• similar mechanism• less neutropenia & similar response

rates– perhaps substantially better in some

European studies

• availability and difficulties with awkward approved dosing schedules have been obstacles

therapy

immune suppression• antithymocyte globulin, cyclosporine

– responses of 20-30% in trials– pts with relatively hypoplastic marrows

appear to be better candidates

immunomodulatory therapy• thalidomide and lenalidomide

therapy

thalidomide has shown promise, but has an unfavorable toxicity profile in MDS

• have had > 33% drop-out rates in studies

therapy

lenalidomide (Revlimid): exciting!• large improvements seen in

transfusion requirements– best in 5q- patients, but also in other

karyotypes– normalization of cytogenetics

• appears much less toxic– reversible neutropenia and

thrombocytopenia

• availability!

therapy

• vitamins: high-dose B complex• danazol: thrombocytopenia• monoclonal antibodies• splenectomy

all may have roles in individual patients

therapy

• stem cell transplantation– Dr. L. Savoie

• definite role in select patients– higher-risk disease– younger patients

therapy: general algorithm

BMT transplant candidate:

•young

•good performance status

•high risk MDS

•suitable donor

YES consider BMT

NO

Low risk MDS:•clinical trials•growth factors•biological agents•immune therapy

High risk MDS:•clinical trials•leukemia-styletherapy•biological agents

The Role of the Specialty Clinic:

1. provide guidance for primary caregivers

2. maximize supportive care3. optimize individualized

management5. dissemination of current state of

knowledge

4. clinical trials &5. data collection: