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Myelodysplastic syndromes Achievements in understanding and treatment f. dr hab. med. Krzysztof Lewandowski
Myelodysplastic syndromes
Achievements in understanding and treatment
prof. dr hab. med. Krzysztof Lewandowski
Classification of Myeloid Neoplasms According tothe 2008 World Health Organization Classification Scheme
Myelodysplastic syndromes (MDS)
• The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML)
Some of the deregulated pathways for the upregulated and downregulated genes in
MDS CD34+ cells
Li J. Int. J. Cancer: 000, 000–000 (2012)
Deregulated pathways in CD34ţ cells from MDS subtypes RA and RAEB2 compared with in healthy controls
Li J. Int. J. Cancer: 000, 000–000 (2012)
Proposed mechanisms of miRNA in MDS pathogenesis
Genetic and epigenetic abnormalities may occur in bothosteoblasts and HSCs, which result in the deregulation of certainmiRNAs in those cells. MiRNA deregulation is followed by thesubsequent abnormal expression of HSC extrinsic regulators inosteoblasts or HSC intrinsic regulators in HSCs, both leading toHSC dysfunction and MDS development
Li J. Int. J. Cancer: 000, 000–000 (2012)
Frequency•
• In the US: The actual incidence is unknown. MDS was first considered a separate disease in 1976, and occurrence was estimated at 1500 new cases every year. At that time, only patients with less than 5% blasts were considered to have this disorder
• Statistics from 1999 show that 13,000 new cases occur per year (approximately 1000 cases each year in children)
• Internationally: The disease is found worldwide and is similar in characteristics throughout the world
Epidemiology• Sex: A slight male predominance is noted in all age
groups. • Age: MDS primarily affects elderly people, with the
median onset in the seventh decade of life. • The median age of these patients is 65 years, with ages
ranging from the early third decade of life to older than 80 years.
• The syndrome may occur in persons of any age group, including the pediatric population.
MDS diagnosis
• Is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy
• Information obtained from additional studies such as karyotype, flow cytometry, or molecular genetics is complementary but not diagnostic
MDS- diagnosis (2)
• Aplastic anaemia and some disease accompanied by marrow dysplasia, including wit. B12 and/or folate deficiency, exposure to heavy metals, recent cytotoxic therapy and ongoing inflammation (including HIV and chronic liver disease/alcohol use) should be ruled out
MDS – clinical findings
• These are non-specific, and are usually the consequences of cytopenias, including:
- symptoms of anaemia- infections due to neutropenia, but also to the frequently
associated defect in neutrophil function- bleeding due to thrombocytopenia (may also occur in
moderately thrombocytopenic patients or even in patients with normal platelets count, because of its abnormal function)
Myelodysplastic syndromes:• Refractory anemia (RA)With ringed sideroblasts (RARS)Without ringed sideroblasts• Refractory cytopenia (MDS) with multilineage dysplasia (RCMD)• Refractory anemia with excess blasts (RAEB)• 5q- syndrome Myelodysplastic syndrome, unclassifiable• Myelodysplastic/Myeloprolipherative diseases• Chronic myelomonocytic leukemia (CMML)• Atypic chronic myelogenous leukemia (aCML)
Myelodysplastic syndromesWHO classification system
WHO 2008 MDS classification
Garcia-Manero G. Am. J. Hematol. 2011;86:491–498
Marrow blast percentage:• < 5 0• 5-10 0.5• 11-20 1.5• 21-30 2.0
Cytogenetic features• Good prognosis 0(–Y, 5q- , 20q-)
• Intermediate prognosis 0.5 (+8, miscellaneous single abnormality, double abnormalities)• Poor prognosis 1.0(abnor. 7, complex- >3 abnor.)
Cytopenias
• None or one type 0• 2 or 3 type 0.5
Myelodysplastic syndromesIPSS risk-based classification system
Overall score: Median survival:low • 0 5.7 yearsIntermediate • 1 (0.5 or 1) 3.5 years• 2 (1.5 or 2) 1.2 yearsHigh • > 2.5 0.4 years
Myelodysplastic syndromesOverall IPSS score and survival
Refined WHO Classification–Based Prognostic Scoring System (WPSS) of Myelodysplastic Syndromes
Cazzola M et al. Semin Oncol 2011;38:627-634
Kaplan-Meier survival curves of 943 patientsdiagnosed with MDS according to the 2008 WHO criteria
Cazzola M et al. Semin Oncol 2011;38:627-634
Myelodysplastic syndromes: 2011 update on diagnosis, risk stratification, and management
American Journal of Hematology 2011; 86, 490-498, 18 MAY 2011 DOI: 10.1002/ajh.22047
Bone marrow biopsy
• Blood examination and bone marrow aspirate are sufficient for a diagnosis of MDS
- normal or increased cellularity is seen in 85-90% od cases
- abnormal localization of immature precursors (ALIP)- fibrosis (significant in 15-20% of cases)
Myelodysplastic features in MDS
MDS Bone marrow and/or peripheral blood findings
Dyserythropoiesis
Bone marrow: multinuclearity, nuclear fragments, megaloblastoid changes, cytoplasmic abnormalities, ringed sideroblasts
Peripheral blood:
poikilocytosis, anisocytosis, nucleated red blood cells
Myelodysplastic features in MDS
MDS Bone marrow and/or peripheral blood findings
Dysgranulopoiesis
Nuclear abnormalities including: hypolobulation, ring-shaped nuclei, hypogranulation
Dysmegakariopoiesis Micromegakariocytes
Large mononuclear forms
Multiple small nuclei
RAEB-2. Bone marrow, 100x
RAEB-2 . Bone marrow, 400x
RAEB-2. Bone marrow, 400x (2)
RAEB-2. Bone marrow 400x (2)
MDS with ring sideroblasts. Bone marrow 400x
Frequency of cytogenetic alternations in MDS
Garcia-Manero G. Am. J. Hematol. 2011;86:491–498
MDS therapyOptions for newly diagnosed patients with lower risk MDS
• Therapy in this subset of patients is based on the transfusion needs of the patients
• Patients that are transfusion independent are usually observed until they become transfusion dependent
• Erythroid growth factor and granulocyte growth factor support (ESA, G-CSF)
• Lenalidomide (is approved in the US for patients with lower risk MDS, anemia, and alteration of chromosome 5)
Management of progressive or refractory disease
• At the present time, there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include cytarabine-based therapy, transplantation, and participation on a clinical trial.
Myelodysplastic syndromes: 2011 update on diagnosis, risk stratification, and management
American Journal of HematologyVolume 86, Issue 6, pages 490-498, 18 MAY 2011 DOI: 10.1002/ajh.22047http://onlinelibrary.wiley.com/doi/10.1002/ajh.22047/full#fig2
Years
0 2 61 3 4 5
Probability of survival after allogeneic transplant for Probability of survival after allogeneic transplant for MDS, age MDS, age 20 years, by disease status and donor type, 20 years, by disease status and donor type,
1998-20081998-2008
Early, HLA-matched sibling (N=63)
SUM10_39.ppt
Early, unrelated (N=145)
Advanced, HLA-matched sibling (N=114)
Advanced, unrelated (N=190)
0
20
40
60
80
100
10
30
50
70
90
0
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Pro
babili
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ival, %
P = 0.002
Years
0 2 61 3 4 5
Probability of survival after allogeneic transplant for Probability of survival after allogeneic transplant for MDS, age MDS, age 20 years, by disease status and donor 20 years, by disease status and donor
type, 1998-2008type, 1998-2008
Early, HLA-matched sibling (N=599)
SUM10_40.ppt
Early, unrelated (N=509)
Advanced, HLA-matched sibling (N=1,237)
Advanced, unrelated (N=1,142)
0
20
40
60
80
100
10
30
50
70
90
0
20
40
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100
10
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Pro
babili
ty o
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ival, %
P < 0.0001
Years
0 2 61 3 4 5
Probability of survival after allogeneic transplant for Probability of survival after allogeneic transplant for MDS with reduced-intensity conditioning, by disease MDS with reduced-intensity conditioning, by disease
status and donor type, 1998-2008status and donor type, 1998-2008
SUM10_41.ppt
0
20
40
60
80
100
10
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0
20
40
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100
10
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Pro
babili
ty o
f Surv
ival, %
P < 0.0001
Early, unrelated (N=202)
Early, HLA-matched sibling (N=217)
Advanced, HLA-matched sibling (N=366)
Advanced, unrelated (N=383)
