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.