SM_268: MDS

Question 1

Myelodysplastic syndrome is ___

Answer 1

Myelodysplastic syndrome is group of diseases caused by abnormal growth of abnormal-looking myeloid cells

• Myeloid neoplasm
• Myeloid cells: erythrocytes, granulocytes and monocytes, megakaryocytes

Question 2

Describe myeloid neoplasms

Answer 2

Myeloid neoplasms

• Chronic myeloid leukemia and myeloproliferative neoplasms
• Acute myeloid neoplasms
• Myelodysplastic syndrome

Question 3

Chronic myeloid leukemia and myeloproliferative neoplasms are ___

Answer 3

Chronic myeloid leukemia and myeloproliferative neoplasms are overgrowth of neoplastic myeloid cells in the bone marrow with full maturation and blood cytosis

Question 4

Acute myeloid leukemia is ___

Answer 4

Acute myeloid leukemia is overgrowth of neoplastic myeloid precursors (blast) in bone marrow without maturation and circulating blasts in blood

Question 5

Describe myelodysplastic syndrome

Answer 5

Myelodysplastic syndrome: group of clonal hematopoietic stem cell neoplasms characterized by

• Peripheral cytopenia: ineffective hematopoiesis in the bone marrow
• Morphologic dysplasia: abnormal looking cells in myeloid cell lines
• Risk of transformation to acute myeloid leukemia

Question 6

In normal hematopoiesis, a myeloid stem cell undergoes ___

Answer 6

In normal hematopoiesis, a myeloid stem cell undergoes a series of ordered and well-controlled differentiation and maturation steps to produce mature blood cells

(RBCs, neutrophils, and platelets)

Question 7

In myelodysplastic syndrome, ____ in a single stem cell ____ and confer a growth advantage

Answer 7

In myelodysplastic syndrome, genetic changes in a single stem cell disrupt normal maturation and confer a growth advantage

• Bone marrow is replaced by progenies of the abnormal stem cell
• Abnormal stem cells have deranged maturation and are not able to produce mature blood cells

Question 8

In myelodysplastic syndrome, there is an increased degree of ___ within bone marrow precursors

Answer 8

In myelodysplastic syndrome, there is an increased degree of apoptosis within bone marrow precursors

• Ineffective hematopoiesis
• Anemia, neutropenia, and thrombocytopenia
• Disease worsens over time
• MDS patients eventually succumb to complications of cytopenia

Question 9

Chronic myeloid leukemia and myeloproliferative neoplasm involves ____

Answer 9

Chronic myeloid leukemia and myeloproliferative neoplasm involves cytosis (< 20% blasts)

Question 10

Acute myeloid leukemia involve ___

Answer 10

Acute myeloid leukemia involve increased blasts (> 20% blasts)

Question 11

Myelodysplastic syndrome involves ___

Answer 11

Myelodysplastic syndrome involves cytopenia (< 20% blasts)

Question 12

Myelodysplastic syndromes typically occur at age ___

Answer 12

Myelodysplastic syndromes typically occur at age 70

Question 13

Describe risk factors for myelodysplastic syndrome

Answer 13

Myelodysplastic syndrome risk factors

• De novo (85%): etiology largely unknown, benzene and tobacco
• Therapy-related MDS (t-MDS): arises after treatment with chemo or radiation therapy
• Rare cases of familial MDS which are associated with germline mutations in RUNX1, CEBPA, GATA2, and other genes
• Some inherited disorders such as Fanconi anemia, dyskeratosis congenita have increased risk of MDS
• Acquired aplastic anemia is associated with increased risk of developing MDS

Question 14

Describe clinical features of MDS

Answer 14

MDS clinical features

• Anemia: fatigue, SOB, chest pain, palpitations, dizziness, and syncope
• Neutropenia: recurrent or severe infection
• Thrombocytopenia: petechiae, bruising, bleeding
• Organomegaly is infrequent
• Slow-onset and long-standing

Question 15

Describe diagnostic evaluation of MDS

Answer 15

Diagnostic evaluation of MDS

• Clinical history
• CBC and blood smear review: anemia, neutropenia, and thrombocytopenia
• Reticulocyte count: low
• Laboratory tests
  
  • Iron studies: no iron deficiency
  • B12, folate levels: normal
  • Copper level: normal
• Bone marrow aspirate and biopsy (morphologic evaluation): dysplasia, blast count
• Cytogenetics: chromosomal aberrations
• Molecular studies: gene mutations

Question 16

Describe MDS morphology

Answer 16

MDS morphology

• Hypercellular
• Erythroid hyperplasia (increased erythroid precursors)
• Dysplastic megakaryocyte

Question 17

Describe erythroid dysplasia in MDS

Answer 17

Erythroid dysplasia in MDS

• Nuclear budding
• Internuclear bridging
• Multinucleation
• Bizarre nuclei
• Ring sideroblasts (iron)

Question 18

Describe granulocytic dysplasia in MDS

Answer 18

Granulocytic dysplasia in MDS

• Hyposegmentation (pseudo Pelger-Huet)
• Hypogranularity

Question 19

Describe megakaryocytic dysplasia

Answer 19

Megakaryocytic dysplasia

• Small and hypolobulated nuclei
• Separate nuclear lobes

Question 20

Recurrent chromosomal abnormalities are more common in ____ than MDS

Answer 20

Recurrent chromosomal abnormalities are more common in treatment-related MDS than MDS

• -7 or del(71), del(5q),+8, i(17q) or t(17p), t(11q23;v)

Question 21

Genetic aberrations in MDS involve ___

Answer 21

Genetic aberrations in MDS involve gain or loss of a chromosome or part of a chromosome

• Copy number changes in key genes may contribute to MDS

Question 22

Describe del(5q) in MDS

Answer 22

Del(5q) in MDS

• Loss of long arm of chromosome 5 leads to haploinsufficiency in a number of genes including ribosomal protein RPS14: loss of one coppy of RPS14 causes ineffective erythropoiesis resulting in macrocytic anemia
• Haploinsufficiency of miR145 and miR146a in the 5q region may contribute to megakaryocytic abnormalities

Question 23

Describe recurrent gene mutations in MDS

Answer 23

Recurrent gene mutations in MDS

Question 24

Describe dyserythropoiesis in benign conditions

Answer 24

Dyserythropoiesis in benign conditions

• B12 / folate deficiency
• Exposure to heavy metals (arsenic)
• Copper deficiency
• Zinc deficiency
• Chemotheraoy
• Certain medications (isoniazid)
• Congenital dyserythropoietic anemia

Question 25

Describe dysplastic neutrophils in benign conditions

Answer 25

Dysplastic neutrophils in benign conditions * B12 / folate deficiency * G-CSF * Antibiotics: co-trimoxazone * Immunosuppressants * Chemo

Question 26

MDS diagnosis requires that \_\_\_\_

Answer 26

MDS diagnosis requires that non-neoplastic causes of cytopenia and dysplasia have been ruled out, particularly if no cytogenetic abnormalities are present

Question 27

Describe WHO classification of MDS

Answer 27

WHO classification of MDS * MDS with single lineage dysplasia: BM \< 5% blasts * MDS with multilineage dysplasia: BM \< 5% blasts * MDS with ring sideroblasts: BM \< 5% blasts * MDS with isolated del(5q): BM \< 5% blasts * MDS with excess blasts * MDS-EB-1: BM 5-9% or PB 2-4% * MDS-EB-2: blasts 10-19% or PB 5-19%

Question 28

Describe prognosis of MDS

Answer 28

MDS prognosis * Heterogeneous, highly variable natural history * Median survival of de novo: 9-29 months * Median survival of therapy-related: 4-8 months * Some have indolent course and live for more than 5 years

Question 29

Describe morphologic risk groups of MDS

Answer 29

Morphologic risk groups of MDS * Low risk: MDS with single lineage dysplasia, MDS with ring sideroblasts * Intermediate risk: MDS with multilineage dysplasia, MDS withe xcess blasts-1 (5-9%) * High risk: MDS with excess blasts-2 (10-19%)

Question 30

\_\_\_, \_\_\_, and ___ are most important prognostic factors for MDS

Answer 30

Blast count, cytogenetic abnormalities, and gene mutations are most important prognostic factors for MDS

Question 31

MDS treatment depends on \_\_\_

Answer 31

MDS treatment depends on symptoms, risk scores, performance status, and other facvtors * Asymptomatic low risk patients may be followed without treatment * Symptomatic patients: supportive care, low intensity therapy, or high intensity therapy

Question 32

Describe myelodysplastic syndrome with isolated del(5q)

Answer 32

Myelodysplastic syndrome with isolated del(5q) * Women more commen * Macrocytic anemia: normal or increased platelets * Increased megakaryocytes with hypo- or unilobulated nuclei * Median survival: 66-145 months * Lenalidomide is effective

Question 33

Describe MDS with excess blasts

Answer 33

MDS with excess blasts * 40% of all MDS * Cytogenetic abnormalities in 30-50% * Prognosis: progressive bone marrow failure, progression to AML common, and median survival is 9-16 months

Question 34

Summarize MDS

Answer 34

MDS * Clonal hematopoietic stem cell neoplasm * Affects older individuals * Always has cytopenia * Always has morphologic dysplasia * Most important prognostic factors: percentage of blasts, cytogenetic abnormalities * Likely due to acquired genetic aberrations that result in ineffective hematopoiesis