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

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Presentation on theme: "What is MDS MDS comprises a heterogeneous group of clonal haematopoietic stem cell malignancies characterised by 1,2 –BM dysplasia hypercellular BM is."— Presentation transcript:

1 What is MDS MDS comprises a heterogeneous group of clonal haematopoietic stem cell malignancies characterised by 1,2 –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; 39:18–25 2. Leone G, et al. Haematologica 2002;87:1324–41 AML = acute myeloid leukaemia BM = bone marrow

2 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 Europe 1 The reported incidence is higher in Germany and Spain compared with the rest of Western Europe –this may be due to differences in diagnostic methods 2 differences in age distribution in different countries 3 The increase in incidence of MDS over time observed in some studies may reflect improvements in geriatric medical care and diagnosis of haematological malignancies 4 1. Data from The Mattson Jack Group Inc, A Kantar Health Company, Germing U, et al. Haematologica 2004;89:905–10 3. World Health Statistics, Available at Incidence of MDS in Western Europe in Incidence per 100,000 people FranceUKGermanyItalySpain 4. Aul C. Int J Hematol 2001;73:405–10

3 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

4 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 years0.5 50–59 years5.3 60–69 years15 70–79 years49 80 years –35–40–45–50–55–60–65–70–75–80– Incidence of MDS per 100,000

5 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 Int High 59 Greenberg P, et al. Blood 1997;89:2079–88

6 Pathogenesis of MDS

7 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 idiopathic 1 –occasionally cases can be familial/genetic 1 –occasionally arises from previous haematological disease 1 Secondary MDS –approximately 10–20% of cases 2 –the majority of patients have chromosomal abnormalities 2 –occurs following exposure to chemotherapy or radiotherapy (especially alkylating agents, epipodophyllotoxins, anthracyclines) 3 –has a rapid course and poor prognosis 3 1. Understanding MDS – a primer for practicing clinicians, MDS Foundation Resource Center Available at: Accessed 11 Feb Pedersen-Bjergaard J, et al. Blood 1995;86:3542–52 3. Flandrin G. Classification of myelodysplastic syndromes Available at: Accessed 11 Feb 2009

8 Multistep pathogenesis of MDS 1,2 InsultAlterations IAlterations II Normal Clonal MDS early MDS late AML stem cellhaematopoiesis Chemical Radiation Cytotoxic Genetic Cell cycle Increased apoptosis Transcription checkpoints DNA methylation Tumour suppressors Decreased apoptosis Mutations All DNMT isoforms may contribute to aberrant methylation in MDS 3 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 DNMT = DNA methyltransferase

9 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 [ 32 P]) –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. Wintrobes Clinical Hematology. 10th ed. 1999:2320–41

10 Cytogenetic abnormalities and epigenetic changes are key drivers of MDS pathogenesis Impaired apoptosis 1 Impaired apoptosis 1 Epigenetic changes e.g. DNA hypermethylation 3 Stromal/ angiogenic factors 2 Immune dysfunction 1,2 Direct environmental toxicity 1 Cytogenetic abnormalities/ DNA damage 1 Stem cell dysfunction MDS 1. List AF, Doll DC. in: Lee RG, et al. eds. Wintrobes 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

11 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 MDS 1 DNA hypermethylation plays a key role in progression from MDS to AML 2 –in particular, hypermethylation of p15 INK4b has been shown to be strongly associated with progression to AML 1,3 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

12 In patients with MDS, median OS correlates with methylation status of p15 INK4b Quesnel B, et al. Blood 1998;91:2985– OS (% patients) Time (months) Methylated p15 INK4b Unmethylated p15 INK4b Median OS = 18 vs 48 months (p=0.049, log-rank test) (n=33) (n=20) OS = overall survival

13 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

14 Signs and symptoms of MDS

15 Ineffective haematopoiesis causes peripheral cytopenias in patients with MDS Anaemia ThrombocytopeniaNeutropenia Cell lineage affected in MDS White blood cells Non-granular leukocytes Granular leukocytes Adapted from Bondurant MC, Koury MJ. Origin and development of blood cells. In: Lee RG, et al. eds. Wintrobes Clinical Hematology. 10th ed. 1999:2320–41

16 Anaemia occurs in 60–80% of patients with MDS 1 MDS-associated anaemia (haemoglobin level <10g/dL) 1 is –chronic 2 –often macrocytic 3 –associated with fatigue and exacerbation of heart failure 2,3 Patients with MDS-associated anaemia often become dependent on blood transfusions leading to iron overload 2 Transfusion dependence is associated with –organ damage 4 –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– Greenberg PL, et al. J Natl Compr Canc Netw 2008;6:942–53

17 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;109:1705–14 MDACC = M.D. Anderson Cancer Center

18 Neutropenia occurs in 50–60% of patients with MDS 1 MDS-associated neutropenia leads to a high incidence of potentially life-threatening infection, 2 including –bacterial infections 2,3 –sepsis 3 –invasive aspergillosis 3 Neutropenia-related infection is the principal cause of death in patients with MDS 2 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. Wintrobes Clinical Hematology. 10th ed. 1999:2320–41 3. Pomeroy C, et al. Am J Med 1991;90:338–44

19 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;22:13–8 QoL = 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

20 n=56 OS is inversely related to risk classification (IPSS) n=314 n=179 n=267 Risk groupMedian OS, years Low5.7 Int-13.5 Int-21.2 High0.4 Survival (% patients) Time (years) LowInt-1Int-2High Greenberg P, et al. Blood 1997;89:2079–88 LowInt-1Int-2High Time (years)

21 Approximately 30% of patients with MDS progress to AML 1 AML is characterised by uncontrolled proliferation of blasts and disrupted haematopoiesis, leading to bone marrow failure 2 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 blasts 3,4 –RAEB or RAEB-T, compared with RA or RARS (FAB classification) 3,4 –complex karyotype (3 abnormalities) or chromosome 7 abnormalities 3,4 –multiple cytopenias 3,4 –transfusion dependence 5 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 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

22 Progression to AML is inversely related to risk classification (IPSS) Risk group Median time to progression to AML,* years Low9.4 Int-13.3 Int-21.1 High0.2 *measured as time for 25% of patients to progress to AML Greenberg P, et al. Blood 1997;89:2079–88 n=295 n=171 n=59 n=235 LowInt-1Int-2High Patients not progressed (%) Time (years)

23 Classification of MDS: FAB system

24 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

25 FAB system: categories CategoryBM blasts (%)PB blasts (%) Ringed sideroblasts (%) RA<5<1<15 RARS<5<1>15 RAEB5–20<5N/A RAEB-t20–30>5N/A CMML (>1x10 9 monocytes/L)<20<5N/A PB = peripheral blood N/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

26 FAB system: OS based on a retrospective analysis of 816 patients with MDS Greenberg P, et al. Blood 1997;89:2079– Survival (% patients) RARS (n=125) RA (n=294) CMML (n=126) RAEB (n=208) RAEB-t (n=61) Time (years) OS = overall survival

27 WHO system: categories CategoryDescriptionBM blasts, % RARA with unilineage erythroid dysplasia<5 RARSRA with unilineage erythroid dysplasia and ringed sideroblasts (>15%) <5 RCMDRefractory cytopenia with multilineage dysplasia<5 RCMD-RSRCMD and ringed sideroblasts (>15%)<5 RAEB-1Subgroup of RAEB; <5% blasts in blood; no Auer rods5–95–9 RAEB-2Subgroup 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

28 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) Survival (% patients)

29 From FAB (1982) to WHO (2001) Therapy-related MDS Separate category, 10% of MDS RA RA RCMD MDS del(5q) MDS-U RARS RCMD-RS RAEB-1 RAEB-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 subgroup 1 WHO subgroup 2 1. Bennett JM, et al. Br J Haematol 1982;51:189–99; 2. Vardiman JW, et al. Blood 2002;100:2292–302

30 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

31 IPSS: risk classification Risk group Score Low 0 Int-1 0.5–1.0 Int-2 1.5–2.0 High 2.5 Score valueBM blasts (%)KaryotypeCytopenias 0<5Good (normal, –Y, del[5q], 20q–) 0–1 0.55–10Intermediate (other) 2–3 1.0–Poor (complex or chromosome 7) 1.511– –30 Greenberg P, et al. Blood 1997;89:2079–88

32 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 Int High 59 Greenberg P, et al. Blood 1997;89:2079–88

33 n=56 IPSS: OS based on a retrospective analysis of 816 patients with MDS n=314 n=179 n=267 Risk groupMedian OS, years Low5.7 Int-13.5 Int-21.2 High0.4 Survival (% patients) Time (years) LowInt-1Int-2High Greenberg P, et al. Blood 1997;89:2079–88 LowInt-1Int-2High Time (years)

34 Cytogenetic abnormalities: frequency in a dataset of 2,124 patients with MDS Number of cases Cytogenetic abnormality del(5q) –7/del(7q) trisomy(8) –18/del(18q) del(20q) –5–5 –Y–Y –17/del(17p) trisomy(21) Inv/t(3q) –13/del(13q) –21 t(5q) trisomy(11) trisomy(1/1q) del(12p) del(11q) 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

35 Cytogenetic abnormalities: prognostic subgroups based on a dataset of 1,202 patients with MDS Cytogenetic riskCytogenetic abnormality GoodNormal 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-IDel(11q), trisomy(8) Intermediate-2t(11q23), any 3q abnormality, trisomy(19), –7, del(7q), complex (3 abnormalities) PoorComplex (>3 abnormalities), t(5q) Haase D. Ann Hematol 2008;87:515–26


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