What is MDS MDS comprises a heterogeneous group of clonal haematopoietic stem cell malignancies characterised by 1,2 –BM dysplasia hypercellular BM is.

What is MDS

• MDS comprises a heterogeneous group of clonal haematopoietic stem cell malignancies characterised by1,2 – BM dysplasia

• hypercellular BM is present in 90% of cases• hypocellular BM is present in ~10% of cases

– ineffective haematopoiesis

– peripheral cytopenias

– a risk of progression to AML and death

1. Kurzrock R. Semin Hematol 2002; 39:18–252. Leone G, et al. Haematologica 2002;87:1324–41

AML = acute myeloid leukaemiaBM = bone marrow

Incidence of MDS in Western Europe

• In 2008, the incidence of MDS was estimated to be 2.3–6.5 cases per 100,000 people per year in Western Europe1

• The reported incidence is higher in Germany and Spain compared with the rest of Western Europe– this may be due to

• differences in diagnostic methods2

• differences in age distribution in different countries3

• The increase in incidence of MDS over time observed in some studies may reflect improvements in geriatric medical care and diagnosis of haematological malignancies4

1. Data from The Mattson Jack Group Inc, A Kantar Health Company, 2008 2. Germing U, et al. Haematologica 2004;89:905–10

3. World Health Statistics, 2008. Available at www.who.int/whosis/whostat/EN_WHS08_Table6_Demography.pdf

Incidence of MDS in Western Europe in 20081

Inci

den

ce

per

100

,000

peo

ple

7

6

5

4

3

2

1

0France UK Germany Italy Spain

4. Aul C. Int J Hematol 2001;73:405–10

• Approximately 3.7–6.1 new diagnoses of MDS/year per 100,000 population (1991–2001)– median age at diagnosis: 72 years

– incidence (per 100,000)• all: 4.9• men: 5.5• women: 4.4

Germing U, et al. Haematologica 2004:89;905–10

Incidence of MDS in a reference population, Düsseldorf, Germany

Incidence of MDS increases with age

Williamson PJ, et al. Br J Haematol 1994;87:743–5

Age (years)

Age-specific incidence rates (per 100,000)

<50 years

0.5

50–59 years

5.3

60–69 years

15

70–79 years

49

≥80 years

89

2 1 2 2 49

16

26

52

59 61

0

10

20

30

40

50

60

70

30– 35– 40– 45– 50– 55– 60– 65– 70– 75– 80–

80

90

80+

89

Inci

den

ce o

f M

DS

p

er 1

00,0

00

Low 33%

Int-1 38%

Int-2 22%

High 7%

IPSS: distribution of risk groups in a retrospective study of 816 patients with MDS

Risk group Patients (n)

Total 816

Low 267

Int-1 314

Int-2 176

High 59

Greenberg P, et al. Blood 1997;89:2079–88

Pathogenesis of MDS

Primary and secondary MDS

• Primary (de novo) MDS– the most common form of MDS (approximately 80–90% of cases)1,2

– the majority of cases are idiopathic1

– occasionally cases can be familial/genetic1

– occasionally arises from previous haematological disease1

• Secondary MDS– approximately 10–20% of cases2

– the majority of patients have chromosomal abnormalities2

– occurs following exposure to chemotherapy or radiotherapy (especially alkylating agents, epipodophyllotoxins, anthracyclines)3

– has a rapid course and poor prognosis3

1. Understanding MDS – a primer for practicing clinicians, MDS Foundation Resource Center Available at: www.mdsresourcecenter.org. Accessed 11 Feb 2009

2. Pedersen-Bjergaard J, et al. Blood 1995;86:3542–52 3. Flandrin G. Classification of myelodysplastic syndromes

Available at: http://atlasgeneticsoncology.org/Anomalies/ClassifMDSID1239.html. Accessed 11 Feb 2009

Multistep pathogenesis of MDS1,2

Insult Alterations I Alterations II

Normal Clonal MDS early MDS late AMLstem cell haematopoiesis

ChemicalRadiationCytotoxicGenetic

Cell cycleIncreased apoptosisTranscriptioncheckpoints

DNA methylationTumour suppressorsDecreased apoptosisMutations

All DNMT isoforms may contribute to aberrant methylation in MDS3

1. Hofmann W-K. Cancer Treat Rev 2007;33(Suppl 1):S42–62. Grövdal M, et al. Clin Cancer Res 2007;13:7107–12

3. Hopfer O, et al. Leuk Res 2009;33:434–42DNMT = DNA methyltransferase

Aetiological factors for MDS can be heritable or acquired

Heritable

• Constitutional genetic disorder– trisomy of chromosome 8 due to

mosaicism– familial monosomy of

chromosome 7

• Neurofibromatosis type 1

• Embryonal dysgenesis

• Congenital neutropenia– Kostmann agranulocytosis,

Shwachman–Diamond syndrome

• DNA repair deficiency syndromes– Fanconi anaemia, ataxia

telangiectasia, Bloom syndrome

• Mutagen detoxification (GSTq1-null)

Acquired

• Senescence

• Mutagen/genotoxic stress– therapeutic use of alkylating agents

or topoisomerase-II-interactive agents

– radiotherapy (e.g. β-emitters [32P])– autologous BM transplantation– exposure to certain chemicals

(e.g. benzene)– tobacco

• Aplastic anaemia

• Paroxysmal nocturnal haemoglobinuria

List AF, Doll DC. In: Lee RG, et al. eds. Wintrobe’s Clinical Hematology. 10th ed. 1999:2320–41

Cytogenetic abnormalities and epigenetic changes are key drivers of MDS pathogenesis

Impairedapoptosis1

Epigenetic changes e.g. DNA

hypermethylation3

Stromal/angiogenic

factors2

Immune dysfunction1,2

Direct environmental

toxicity1

Cytogenetic abnormalities/DNA damage1

Stem cell dysfunction MDS

1. List AF, Doll DC. in: Lee RG, et al. eds. Wintrobe’s Clinical Hematology. 10th ed. 1999:2320–412. Greenberg PL, et al. Hematology Am Soc Educ Program 2002;136–61

3. Leone G, et al. Haematologica 2002;87:1324–41

DNA hypermethylation: a key driver in the pathogenesis and progression of MDS

• The extent of DNA hypermethylation in BM mononuclear cells is higher in patients with high risk vs low-risk MDS1

• DNA hypermethylation plays a key role in progression from MDS to AML2

– in particular, hypermethylation of p15INK4b has been shown to be strongly associated with progression to AML1,3

1. Tien HF, et al. Br J Hematol 2001;112:148–542. Jiang Y, et al. Blood 2009;113:1315–25

3. Aggerholm A, et al. Eur J Haematol 2006;76:23–32

In patients with MDS, median OS correlates with methylation status of p15INK4b

Quesnel B, et al. Blood 1998;91:2985–90

100

80

60

40

20

0

OS

(%

pat

ien

ts)

0 20 40 60 80 100 120 140

Time (months)

Methylated p15INK4b

Unmethylated p15INK4b

Median OS = 18 vs 48 months (p=0.049, log-rank test)

(n=33)

(n=20)

OS = overall survival

Aberrant DNA methylation is more frequent than chromosome aberrations in MDS

Jiang Y, et al. Blood 2009;113: 1315–25

Chromosome number

Aberrant methylation

Chromosome lesions

Signs and symptoms of MDS

Ineffective haematopoiesis causes peripheral cytopenias in patients with MDS

Anaemia

Thrombocytopenia Neutropenia

Cell lineage affected in

MDS

White blood cellsNon-granular leukocytesGranular leukocytes

Adapted from Bondurant MC, Koury MJ. Origin and development of blood cells.

In: Lee RG, et al. eds. Wintrobe’s Clinical Hematology. 10th ed. 1999:2320–41

Anaemia occurs in 60–80% of patients with MDS1

• MDS-associated anaemia (haemoglobin level <10g/dL)1 is– chronic2

– often macrocytic3

– associated with fatigue and exacerbation of heart failure2,3

• Patients with MDS-associated anaemia often become dependent on blood transfusions leading to iron overload2

• Transfusion dependence is associated with– organ damage4

– decreased OS compared with patients who do not require multiple transfusions (p<0.001)5

• The annual cost of treating anaemia is estimated to be approximately $41,000/year/patient (transfusions plus iron chelation therapy)6

1. Greenberg P, et al. Blood 1997;89:2079–882. Cazzola M, et al. Hematology Am Soc Hematol Educ Program 2008:166–75

3. Greenberg PL, et al. Hematology Am Soc Hematol Educ Program 2002:136–614. Cazzola M, et al. Blood 1988;71:305–12; 5. Malcovati L, et al. J Clin Oncol 2005;23:7594–603

6. Greenberg PL, et al. J Natl Compr Canc Netw 2008;6:942–53

Thrombocytopenia occurs in 40–65% of patients with MDS

• The prevalence of thrombocytopenia increases with IPSS risk classification– a retrospective review (all patients with MDS referred to

the University of Texas MDACC since 1980) reported the frequency of thrombocytopenia in each IPSS risk group:• low risk = 20%

• intermediate-1 risk = 64%

• intermediate-2 risk = 72%

• high risk = 82%

• Haemorrhagic complications of thrombocytopenia are one of the leading causes of death in patients with MDS

Kantarjian H, et al. Cancer 2007;109:1705–14MDACC = M.D. Anderson Cancer Center

Neutropenia occurs in 50–60% of patients with MDS1

• MDS-associated neutropenia leads to a high incidence of potentially life-threatening infection,2 including– bacterial infections2,3

– sepsis3

– invasive aspergillosis3

• Neutropenia-related infection is the principal cause of death in patients with MDS2

1. Greenberg PL, et al. Hematology Am Soc Hematol Educ Program 2002:136–61 2. List AF, Doll DC. in: Lee RG, et al. eds. Wintrobe’s Clinical Hematology. 10th ed. 1999:2320–41

3. Pomeroy C, et al. Am J Med 1991;90:338–44

Patients with MDS report their disease negatively impacts on their QoL

• Responses were assessed from 128 patients with MDS involved in 10 forums discussing QoL issues

• Patients reported that their disease negatively impacted on– daily functioning

– physical energy

– independence

– interpersonal relationships

– role within family

– emotional wellbeing

– personal time

– employment

Patients’ ability to perform daily activities (n=128)

Heptinstall K. Oncology (Williston Park) 2008;22:13–8QoL = quality of life

15%

35%

25%

16%

6% 3%

Normal

Carries on with normal life, with minor symptoms

Takes an effort to engage in normal activities

Cares for self but does no active work

Requires occasional assistance with personal needs

Requires considerable assistance

n=56

OS is inversely related to risk classification (IPSS)

n=314n=179

n=267

Risk group Median OS, years

Low 5.7

Int-1 3.5

Int-2 1.2

High 0.4

Su

rviv

al (

% p

atie

nts

)

Time (years)

Low Int-1 Int-2 High

Greenberg P, et al. Blood 1997;89:2079–88

Low Int-1 Int-2 High

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18

Time (years)

Approximately 30% of patients with MDS progress to AML1

• AML is characterised by uncontrolled proliferation of blasts and disrupted haematopoiesis, leading to bone marrow failure2

• Progression from MDS to AML is considered to have occurred when the proportion of BM blasts exceeds 20% (WHO classification system) or 30% (FAB classification system)1

• Risk factors for transformation to AML include:– >10% BM blasts3,4

– RAEB or RAEB-T, compared with RA or RARS (FAB classification)3,4

– complex karyotype (≥3 abnormalities) or chromosome 7 abnormalities3,4

– multiple cytopenias3,4

– transfusion dependence5

1. Mufti GJ, et al. Haematologica 2008;93:1712–72. Plass C, et al. Semin Oncol 2008;35:378–87

3. Greenberg PL, et al. Hematology Am Soc Educ Program 2002:136–614. Greenberg P, et al. Blood 1997;89:2079–88

5. Malcovati L. Leuk Res 2007;31 (Suppl. 3):S2–6

FAB = French–American–BritishRA = refractory anaemiaRARS = refractory anaemia with ringed sideroblastsRAEB = RA with excess of blastsRAEB-T = RAEB in transformation WHO = World Health Organization

Progression to AML is inversely related to risk classification (IPSS)

Risk group

Median time to progression to AML,*

years

Low 9.4

Int-1 3.3

Int-2 1.1

High 0.2

*measured as time for 25% of patients to progress to AML

Greenberg P, et al. Blood 1997;89:2079–88

n=295n=171

n=59

n=235

Low Int-1 Int-2 High

100

90

80

70

60

50

40

30

20

10

00 2 4 6 8 10 12 14 16 18

Pat

ien

ts n

ot

pro

gre

sse

d (

%)

Time (years)

Classification of MDS: FAB system

FAB system: introduction

• In 1980, pathologists from France, the USA and Britain met to derive the first classification of MDS

• The FAB system categorises MDS into one of five subtypes based on cytomorphological abnormalities, and BM and peripheral ‘blast counts’– refractory anaemia (RA)

– RA with ringed sideroblasts (RARS)

– RA with excess blasts (RAEB)

– RA with excess blasts in transformation (RAEB-t)

– chronic myelomonocytic leukaemia (CMML)

Bennett JM, et al. Br J Haematol 1982;51:189–99

FAB system: categories

Category BM blasts (%) PB blasts (%)Ringed

sideroblasts (%)

RA <5 <1 <15

RARS <5 <1 >15

RAEB 5–20 <5 N/A

RAEB-t 20–30 >5 N/A

CMML (>1x109 monocytes/L) <20 <5 N/A

PB = peripheral bloodN/A = not applicable Bennett JM, et al. Br J Haematol 1982;51:189–99

• With the FAB system patients with >30% BM blasts are diagnosed as having AML

FAB system: OS based on a retrospective analysis of 816 patients with MDS

Greenberg P, et al. Blood 1997;89:2079–88

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Su

rviv

al (

% p

atie

nts

)

RARS (n=125)

RA (n=294)

CMML (n=126)

RAEB (n=208)

RAEB-t (n=61)

Time (years)

100

90

80

70

60

50

40

30

20

10

0

OS = overall survival

WHO system: categories

Category Description BM blasts, %

RA RA with unilineage erythroid dysplasia <5

RARS RA with unilineage erythroid dysplasia and ringed sideroblasts (>15%)

<5

RCMD Refractory cytopenia with multilineage dysplasia <5

RCMD-RS RCMD and ringed sideroblasts (>15%) <5

RAEB-1 Subgroup of RAEB; <5% blasts in blood; no Auer rods 5–9

RAEB-2 Subgroup of RAEB; 5–19% blasts in blood; patients with Auer rods

10–19

MDS del(5q) MDS with isolated deletion of chromosome 5 <5

MDS unclassifiable

MDS-U; cannot be classified in above categories <5

.Vardiman JW, et al. Blood 2002;100:2292–302

• With the WHO system, patients with ≥20% BM blasts are diagnosed as having AML

WHO system: OS based on a retrospective analysis of 467 patients with MDS

Malcovati L, et al. J Clin Oncol 2005;23:7594–603

RA/RARS (n=110)RCMD/RCMD-RS (n=93)RAEB-1 (n=59)RAEB-2 (n=72)AML (n=47)

Time (months)

100

80

60

40

20

00 20 40 60 80 100 120 140

Su

rviv

al (

% p

atie

nts

)

From FAB (1982) to WHO (2001)

Therapy-related MDS Separate category, ≥10% of MDS

RA RA RCMDMDS del(5q)MDS-U

RARSRCMD-RS

RAEB-1RAEB-2

Mixed MPD/MDS disorders

AML

RA <5% blasts

RARS <5% blasts

RAEB 5–20% blasts

CMML 5–20% blasts

RAEB-t 21–30% blasts

FAB subgroup1 WHO subgroup2

1. Bennett JM, et al. Br J Haematol 1982;51:189–99; 2. Vardiman JW, et al. Blood 2002;100:2292–302

IPSS: introduction

• In 1997, an International MDS Risk Analysis Workshop was convened to improve pre-existing systems used for evaluating prognosis in MDS– particularly through refined BM cytogenetic classification

• Cytogenetic, morphological and clinical data were evaluated from seven studies that used previous independent risk-based systems to assess patients– critical prognostic variables were then re-evaluated to develop the

IPSS • The major variables predictive of survival and progression to

AML were– cytogenetic abnormalities– percentage of BM blasts– number of cytopenias

Greenberg P, et al. Blood 1997;89:2079–88

IPSS: risk classification

Risk group Score

Low 0

Int-1 0.5–1.0

Int-2 1.5–2.0

High ≥2.5

Score value BM blasts (%) Karyotype Cytopenias

0 <5 Good (normal, –Y, del[5q], 20q–)

0–1

0.5 5–10 Intermediate (other)

2–3

1.0 – Poor (complex or

chromosome 7)

1.5 11–20

2.0 21–30

Greenberg P, et al. Blood 1997;89:2079–88

Low 33%

Int-1 38%

Int-2 22%

High 7%

IPSS: distribution of risk groups in a retrospective study of 816 patients with MDS

Risk group Patients (n)

Total 816

Low 267

Int-1 314

Int-2 176

High 59

Greenberg P, et al. Blood 1997;89:2079–88

n=56

IPSS: OS based on a retrospective analysis of 816 patients with MDS

n=314n=179

n=267

Risk group Median OS, years

Low 5.7

Int-1 3.5

Int-2 1.2

High 0.4

Su

rviv

al (

% p

atie

nts

)

Time (years)

Low Int-1 Int-2 High

Greenberg P, et al. Blood 1997;89:2079–88

Low Int-1 Int-2 High

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18

Time (years)

Cytogenetic abnormalities: frequency in a dataset of 2,124 patients with MDS

350

300

250

200

150

100

50

0

Nu

mb

er o

f ca

ses

Cytogenetic abnormality

del(5

q)

–7/d

el(7

q)

triso

my(

8)

–18/

del(1

8q)

del(2

0q)

–5 –Y

–17/

del(1

7p)

triso

my(

21)

Inv/

t(3q)

–13/

del(1

3q)

–21

t(5q)

triso

my(

11)

triso

my(

1/1q

)

del(1

2p)

del(1

1q)

t(7q)

+Mar

Haase D, et al. Blood 2007;110:4385–95

Singular abnormality

Abnormality present + one additional aberration

Abnormality present within complex karyotype

• Of 2,072 patients successfully evaluated, 1,084 (52.3%) were found to have clonal abnormalities

Cytogenetic abnormalities: prognostic subgroups based on a dataset of 1,202 patients with MDS

Cytogenetic risk Cytogenetic abnormality

Good Normal karyotype

del(12p), del(9q), t(15q), del(15q), trisomy(21), del(5q), del(20q), –X, –Y, t(1q), t(7q), t(17q), –21

Intermediate-I Del(11q), trisomy(8)

Intermediate-2 t(11q23), any 3q abnormality, trisomy(19), –7, del(7q), complex (3 abnormalities)

Poor Complex (>3 abnormalities), t(5q)

Haase D. Ann Hematol 2008;87:515–26