Transcript Module 1: Introduction - TOP Recommended Websites

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
AML = acute myeloid leukaemia
BM = bone marrow
1. Kurzrock R. Semin Hematol 2002; 39:18–25
2. Leone G, et al. Haematologica 2002;87:1324–41
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
Incidence of MDS in Western Europe in 20081
Incidence per 100,000 people
•
7
6
5
4
3
2
1
0
France
UK Germany Italy
Spain
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
4. Aul C. Int J Hematol 2001;73:405–10
Incidence of MDS in a reference population,
Düsseldorf, Germany
• 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:
• men:
• women:
4.9
5.5
4.4
Germing U, et al. Haematologica 2004:89;905–10
Incidence of MDS increases with age
Age-specific incidence
rates (per 100,000)
Incidence of MDS per 100,000
90
<50 years
50–59 years
60–69 years
70–79 years
≥80 years
80
70
60
89
0.5
5.3
15
49
89
59
61
52
50
40
30
26
20
16
9
10
2
1
2
2
4
30–
35–
40–
45–
50–
0
55–
60– 65– 70–
75– 80–
80+
Age (years)
Williamson PJ, et al. Br J Haematol 1994;87:743–5
IPSS: distribution of risk groups in a
retrospective study of 816 patients with MDS
Risk group
Total
High
7%
Patients (n)
816
Low
267
Int-1
314
Int-2
176
High
59
Low
33%
Int-2
22%
Int-1
38%
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
Chemical
Radiation
Cytotoxic
Genetic
Normal
stem cell
Alterations II
Cell cycle
Increased apoptosis
Transcription
checkpoints
Clonal
haematopoiesis
MDS early
DNA methylation
Tumour suppressors
Decreased apoptosis
Mutations
MDS late
AML
All DNMT isoforms may contribute to aberrant methylation in MDS3
DNMT = DNA methyltransferase
1. Hofmann W-K. Cancer Treat Rev 2007;33(Suppl 1):S42–6
2. Grövdal M, et al. Clin Cancer Res 2007;13:7107–12
3. Hopfer O, et al. Leuk Res 2009;33:434–42
Aetiological factors for MDS can be heritable or
acquired
Heritable
Acquired
•
• Senescence
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)
• 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
Stromal/
angiogenic
factors2
Immune
dysfunction1,2
Cytogenetic
abnormalities/
DNA damage1
Direct
environmental
toxicity1
Epigenetic changes
e.g. DNA
hypermethylation3
Stem cell
dysfunction
MDS
Impaired
apoptosis1
1. List AF, Doll DC. in: Lee RG, et al. eds. Wintrobe’s Clinical Hematology. 10th ed. 1999:2320–41
2. 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 highrisk
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;112:148–54
2. 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
100
OS (% patients)
80
Median OS = 18 vs 48 months
(p=0.049, log-rank test)
60
Unmethylated p15INK4b
40
Methylated p15INK4b
(n=33)
20
(n=20)
0
0
OS = overall survival
20
40
60
80
Time (months)
100
120
140
Quesnel B, et al. Blood 1998;91:2985–90
Aberrant DNA methylation is more frequent than
chromosome aberrations in MDS
Aberrant methylation
Chromosome lesions
Chromosome number
Jiang Y, et al. Blood 2009;113: 1315–25
Signs and symptoms of MDS
Ineffective haematopoiesis causes peripheral
cytopenias in patients with MDS
Cell lineage
affected in
MDS
Granular leukocytes
Non-granular leukocytes
White blood cells
Anaemia
Thrombocytopenia
Neutropenia
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;89:2079–88
2. Cazzola M, et al. Hematology Am Soc Hematol Educ Program 2008:166–75
3. Greenberg PL, et al. Hematology Am Soc Hematol Educ Program 2002:136–61
4. 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
MDACC = M.D. Anderson Cancer Center
Kantarjian H, et al. Cancer 2007;109:1705–14
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
QoL = quality of life
Patients’ ability to perform
daily activities (n=128)
6%
3%
15%
16%
35%
25%
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
Heptinstall K. Oncology (Williston Park) 2008;22:13–8
OS is inversely related to risk classification (IPSS)
100
Survival (% patients)
Risk group
Median OS, years
80
Low
5.7
Int-1
3.5
Int-2
1.2
High
0.4
60
40
n=267
20
n=179
n=314
n=56
0
0
2
4
6
8
10 12 14 16 18
Time (years)
Low
Int-1
Int-2
High
Greenberg P, et al. Blood 1997;89:2079–88
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
FAB = French–American–British
RA = refractory anaemia
RARS = refractory anaemia
with ringed sideroblasts
RAEB = RA with excess of blasts
RAEB-T = RAEB in transformation
WHO = World Health Organization
1. Mufti GJ, et al. Haematologica 2008;93:1712–7
2. Plass C, et al. Semin Oncol 2008;35:378–87
3. Greenberg PL, et al. Hematology Am Soc Educ Program 2002:136–61
4. Greenberg P, et al. Blood 1997;89:2079–88
5. Malcovati L. Leuk Res 2007;31 (Suppl. 3):S2–6
Progression to AML is inversely related to risk
classification (IPSS)
Patients not progressed (%)
100
90
n=235
80
70
Risk group
Median time to
progression to AML,*
years
Low
9.4
Int-1
3.3
Int-2
1.1
High
0.2
60
50
40
n=171
n=295
30
20
10
n=59
0
0
2
4
6
8
10 12 14 16 18
Time (years)
Low
Int-1
Int-2
*measured as time for 25% of patients to
progress to AML
High
Greenberg P, et al. Blood 1997;89:2079–88
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
BM blasts (%)
PB blasts (%)
Ringed
sideroblasts (%)
RA
<5
<1
<15
RARS
<5
<1
>15
RAEB
5–20
<5
N/A
20–30
>5
N/A
<20
<5
N/A
Category
RAEB-t
CMML (>1x109 monocytes/L)
•
With the FAB system patients with >30% BM blasts are diagnosed as having AML
PB = peripheral blood
N/A = not applicable
Bennett JM, et al. Br J Haematol 1982;51:189–99
FAB system: OS based on a retrospective
analysis of 816 patients with MDS
100
Survival (% patients)
90
RARS
RA
CMML
RAEB
RAEB-t
80
70
60
50
(n=125)
(n=294)
(n=126)
(n=208)
(n=61)
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
Time (years)
OS = overall survival
Greenberg P, et al. Blood 1997;89:2079–88
WHO system: categories
Category
Description
RA
RA with unilineage erythroid dysplasia
<5
RARS
<5
RCMD
RA with unilineage erythroid dysplasia and ringed
sideroblasts (>15%)
Refractory cytopenia with multilineage dysplasia
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
MDS with isolated deletion of chromosome 5
MDS del(5q)
MDS
unclassifiable
•
BM blasts, %
MDS-U; cannot be classified in above categories
<5
10–19
<5
<5
With the WHO system, patients with ≥20% BM blasts are diagnosed as having AML
.
Vardiman JW, et al. Blood 2002;100:2292–302
WHO system: OS based on a retrospective
analysis of 467 patients with MDS
Survival (% patients)
100
RA/RARS (n=110)
RCMD/RCMD-RS (n=93)
RAEB-1 (n=59)
RAEB-2 (n=72)
AML (n=47)
80
60
40
20
0
0
20
40
60
80
100
120
140
Time (months)
Malcovati L, et al. J Clin Oncol 2005;23:7594–603
From FAB (1982) to WHO (2001)
FAB subgroup1
WHO subgroup2
RA <5% blasts
RA
RA RCMD
MDS del(5q)
MDS-U
RARS <5% blasts
RARS
RCMD-RS
RAEB 5–20% blasts
RAEB-1
RAEB-2
CMML 5–20% blasts
Mixed MPD/MDS disorders
RAEB-t 21–30% blasts
AML
Therapy-related MDS
Separate category, ≥10% of MDS
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
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
Risk group
Score
Low
0
Int-1
0.5–1.0
Int-2
1.5–2.0
High
≥2.5
Greenberg P, et al. Blood 1997;89:2079–88
IPSS: distribution of risk groups in a
retrospective study of 816 patients with MDS
Risk group
Total
High
7%
Patients (n)
816
Low
267
Int-1
314
Int-2
176
High
59
Low
33%
Int-2
22%
Int-1
38%
Greenberg P, et al. Blood 1997;89:2079–88
IPSS: OS based on a retrospective analysis of
816 patients with MDS
100
Survival (% patients)
Risk group
Median OS, years
80
Low
5.7
Int-1
3.5
Int-2
1.2
High
0.4
60
40
n=267
20
n=179
n=314
n=56
0
0
2
4
6
8
10 12 14 16 18
Time (years)
Low
Int-1
Int-2
High
Greenberg P, et al. Blood 1997;89:2079–88
Cytogenetic abnormalities: frequency in a
dataset of 2,124 patients with MDS
Of 2,072 patients successfully evaluated, 1,084 (52.3%) were found to
have clonal abnormalities
350
Singular abnormality
300
Abnormality present + one additional aberration
Number of cases
•
250
Abnormality present within complex karyotype
200
150
100
50
0
Cytogenetic abnormality
Haase D, et al. Blood 2007;110:4385–95
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