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Myelodysplastic syndromes (MDS)biology, clinical aspects and prognosis
Dr. Dimitri Breems, MD, PhD
Department of Hematology
Ziekenhuis Netwerk Antwerpen
MDS: First publication
Rhoads and Barker, Refractory anemia: An analysis of onehunderd cases, JAMA, March 12, 1938
Myelodysplastic syndromes (MDS)
Heterogeneous group of malignant hematopoietic stem cell disorders
Dysplastic and ineffective blood cell production
Peripheral cytopenias
Abnormal clonally expanded diseased cells
Increased risk of transformation to acute leukemia
De novo or after exposure to mutagenic therapy
MDS: Evolution 1
Walter MJ et al. N Engl J Med 2012;366:1090-1098
MDS: Evolution 2
MDS: Gene mutations
Somatic point mutations are common in MDS
Identification of recurrent mutations provides insights in
pathophysiology of MDS
Mutations of TP53, EZH2, ETV6, RUNX1 and ASXL1
are predictors of poor survival
Mutations affecting histone function
Histone proteins regulate gene expression by dynamically organizing DNA in zones of active (“open”) and inactive (“closed”) chromatin
Mutations in histone regulators decrease gene expression and transcription in MDS
MDS: Gene mutations
Mutations in regulators of DNA methylation
Alterations in DNA methylation in MDS
Clinical benefit to MDS patients treated with hypomethylating agents
MDS genomes contain somatic mutations in genes regulating cytosine methylation
DNMT3A, TET2, IDH1/IDH2
MDS: Gene mutations
MDS: Gene mutations
Median age >65 years
Male predominance
Annual incidence per 100.000:
<50 year 0,5
50-59 year 5,3
60-69 year 15
70-79 year 49
≥80 year 89
Williamson et al, Br J Haematol 1994
MDS: Prevalence
MDS:Risk factors
MDS: Clinical presentation
Majority asymptomatic
Symptoms of cytopenia
Anemia (85%)
Neutropenia (50%)
Trombocytopenia (25%)
Systemic symptoms
Fever, weight loss
Autoimmune manifestations
Vasculitis, arthritis, pericarditis, …
Infection is principal cause of death
MDS: Physical findings
Pale (60%, anemia)
Bleeding symptomes (trombocytopenia)
Splenomegaly
Hepatomegaly, lymphadenopathy (uncommon)
Cutaneous leukemic infiltrates
Pleural and pericardial effusions
Myeloid sarcoma (granulocytic sarcoma, chloroma)
MDS: Laboratory findings
Peripheral blood
Anemia with low reticulocytes
Trombocytopenia
Trombocytosis
5q-, 3q21q26, RARS
Neutropenia
Monocytosis
MDS: Morphology
MDS:Morphology
MDS: Peripheral blood
MDS:Morphology
Auer rods within blast
Bone marrow
MDS: Bone marrow
MDS: Bone marrow
MDS: Bone marrow withringed sideroblasts
MDS: Karyotype
MDS:Karyotype
MDS: Making the diagnosis
Unexplained cytopenia
Dysplastic cytologic features in peripheral blood
Exclude other causes
Nutritional, vitamin deficiencies, alcohol, drugs, medications, toxic chemicals, chemotherapy, radiotherapy, viral infections
Bone marrow (aspirate and biopsy)
Morphology/immunohistochemical studies
Cytogenetic analysis
Molecular genetics
Immunoflowcytometry
MDS: Differential diagnosis
MPD
MDS: Survival and WHO classification
Greenberg et al, Blood 1997
MDS: Median survival (years) using IPSS risk group and age
Score 0 0.5-1.0 1.5-2.0 ≥2.5
Risk group LowIntermediate
-1Intermediate
-2High
< 50 years >30.0 14.7 0.7 0.6
< 60 years 11.8 5.7 1.8 0.3
>60 years 4.8 2.7 1.1 0.5
Greenberg et al, Blood 2012
MDS 5q-
MDS 5q-: Karyotype
MDS 5q- syndrome
MDS 5q-: Peripheral blood
Hypolobulated micromegakaryocytes
42
43
Hypolobulated micromegakaryocytes
44
Hypolobulated micromegakaryocytes
45
Hypolobulated micromegakaryocytes
MDS: Literature
Rhoades and Barker, Refractory anemia: An analysis of onehunderd cases, JAMA 1938, 794-795.
Foran and Shammo, Clinical presentation, diagnosis, and prognosis of myelodysplastic syndromes, Am J Med 2012, S6-13
Graubert and Walter, Genetics of myelodysplastic syndromes: New insights, Hematology 2011, 543-548.
Meers, Breems, Bries, et al, Management of myelodysplasticsyndromes in adults: guidelines from the Belgian HaematologicalSociety, Acta Clin Belg 2013, 68:253-262.
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