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WILLIAM'S HEMATOLOGY > 86 Myelodysplastic Syndromes > Flashcards

86 Myelodysplastic Syndromes Flashcards

1
Q

Most common blood abnormality in MDS

A

Macrocytic anemia

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2
Q

Refers to the abnormal morphology that can be observed in neoplastic mature blood cells and maturing marrow erythroid, granulocytic, and megakaryocytic precursor cells, and is one of the distinguishing characteristics of MDS.

A

Dysplasia

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3
Q

TRUE OR FALSE

MDS can be diagnosed without dysplasia.

A

TRUE

MDS can be diagnosed without dysplasia.

Dysplasia is helpful for diagnosis, but is an epiphenomenon of driver mutations causing clonal expansion and cytopenias, and in the presence of excess blasts or certain chromosomal abnormalities, MDS can be diagnosed without dysplasia.

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4
Q

TRUE OR FALSE

The majority of MDS cases are age-related without a clear precipitating factor or any family history.

A

TRUE

The majority of MDS cases are age-related without a clear precipitating factor or any family history.

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5
Q

WHO 2016 MDS subtypes

A

(a) MDS with unilineage dysplasia (MDS-ULD) alone, or with ring sideroblasts (MDS-ULD-RS);
(b) MDS with multilineage dysplasia, again with or without ring sideroblasts (MDS-MLD-RS);
(c) MDS with isolated del(5q);
(d) MDS with excess blasts, type 1 or type 2 depending in the proportion of marrow or blood blasts (MDS-EB1 and MDS-EB2); and
(e) unclassifiable MDS

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6
Q

Some patients diagnosed with MDS may have their diagnosis change to CMML once their monocyte count exceeds ________.

A

1 × 109/L

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7
Q

The median age at MDS diagnosis in the United States is

A

70 years

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8
Q

TRUE OR FALSE

Onset of MDS before the age of 50 years is uncommon, except in patients with a germline predisposition or those patients who have received irradiation or cytotoxic chemotherapy for another malignancy

A

TRUE

Onset of MDS before the age of 50 years is uncommon, except in patients with a germline predisposition or those patients who have received irradiation or cytotoxic chemotherapy for another malignancy

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9
Q

(Males/Females) are affected with MDS up to 1.5 times

A

Males

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10
Q

With the exception of MDS with isolated ____for which there is a female predominance

A

del(5q)

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11
Q

Risk factors for MDS

A
  • Benzene (exposure of ≥40 parts per million [ppm]-years)
  • Cigarette smoking
  • Family history of myeloid malignancy
  • Chemotherapeutic agents, particularly alkylating agents and topoisomerase inhibitors
  • Radiation
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12
Q

The mechanism of therapy-related MDS

A

Promotion of expansion of a preexisting small TP53 or PPM1D mutant hematopoietic clone during marrow stress

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13
Q

Mutation associated with a familial platelet disorder with predisposition to AML (FPDAML)

A

RUNX1

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14
Q

Syndrome comprising MDS, verrucae, and congenital lymphedema

A

Emberger syndrome

(GATA2)

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15
Q

Syndrome comprising monocytopenia and nontuberculous mycobacterial infections

A

MonoMAC syndrome

(GATA2)

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16
Q

The hallmark of clonal hematopoiesis in MDS is the

A

Presence of a somatic genetic abnormality

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17
Q

Percentage of patients with MDS will have a grossly abnormal karyotype

A

50%

Typically in the form of a partial or total chromosomal deletion

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18
Q

The most common somatic genetic lesions in MDS

A

Mutations of individual genes

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19
Q

Most common mutated gene in MDS

A

SF3B1
TET2

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20
Q

The only somatic mutations associated with a favorable prognosis.
Strongly associated with ring sideroblasts

A

SF3B1

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21
Q

Associated wit del(20q)

A

U2AF1

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22
Q

Mostly in men X-linked

A

ZRSR2

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23
Q

Associated with ATMDS (acquired thalassemia and myelodysplastic syndrome)

A

ATRX

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24
Q

Rarely translocated in MDS

A

ETV6

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25
Q

Associated with complex karyotypes

A

TP53

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26
Q

Enriched in MDS-RS-T/MDS with ring sideroblasts and thrombocytosis

A

JAK2

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27
Q

The most common karyotypic abnormality observed in MDS

A

Del(5q)

Occurring in approximately 15% of patients

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28
Q

Del(5q) has marked sensitivity to treatment with ______________.

A

Lenalidomide

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29
Q

Syndrome characterized by dyserythropoietic anemia, micromegakaryocytes with a normal or elevated platelet count, female predominance, and lower risk of transformation to AML

A

5q-minus syndrome

Del(5q) is frequently found as one of several chromosomal abnormalities in patients with complex disease karyotypes (defined in MDS as 3 or more chromosomal abnormalities)–> adverse prognosis, a poor response to lenalidomide, and frequently co-occurs with mutations of TP53 or abnormalities of 17p

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30
Q

Occur more frequently (~50%) in patients with prior exposure to alkylating agents

A

Monosomy 7 and Del(7q)

Studies indicate that isolated monosomy 7 is a more adverse abnormality than a deletion of the long arm (del(7q))

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31
Q

This is the only large-scale amplification frequently encountered in MDS, present in approximately 5% of patients.

A

Trisomy 8

Intermediate prognosis
Nonspecific as it can occur in patients with MPN, AML, or aplastic anemia

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32
Q

More likely to have thrombocytopenia and are enriched in mutations of the splicing factor gene U2AF1

An isolated lesion it is associated with disease risk comparable to that of MDS patients with normal karyotypes.

Not considered specific enough to define MDS by itself

Sometimes observed in individuals with immune thrombocytopenia or without any hematologic disorder

A

Del(20q)

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33
Q

Not a pathogenic lesion in MDS, but instead an age-related event that can occur in men without cytopenias, akin to CHIP

A

Loss of Y

Same cytogenetic risk as patients with normal karyotypes

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34
Q

Genetic abnormalities identified in elderly patients without cytopenias and are considered pathogenic lesions in MDS

A

Teneleven translocation 2 (TET2) and DNMT3A

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35
Q

Patients with chromosome 17 abnormalities typically have a poor prognosis, particularly in the presence of a ______ mutation.

A

TP53

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36
Q

Chromosome 17 Abnormalities Including del(17p) can co-occur with mutations of _______, abnormalities that are found more often in patients with both dysplastic and proliferative disease features

A

SETBP1

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37
Q

Complex karyotypes are defined as

A

Having three or more cytogenetic abnormalities of any sort and are strongly associated with an adverse prognosis

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38
Q

The most frequent abnormalities seen in both monosomal and complex karyotypes involve chromosomes ________

A

Chromosomes 5 and 7

The International Prognosis Scoring System–Revised (IPSS-R) considers complex, but not monosomal karyotype as an independent risk factor

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39
Q

Approximately 50% of patients with complex karyotypes have a concomitant ______mutation and account for the majority of patients with mutations of this gene.

A

TP53

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40
Q

TRUE OR FALSE

Acquired mutations of individual genes are significantly more common than karyotypic abnormalities in patients with MDS.

A

TRUE

Acquired mutations of individual genes are significantly more common than karyotypic abnormalities in patients with MDS.

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41
Q

The most frequently mutated class of genes in patients with MDS encode _________ proteins involved in the excision of introns and the ligation of exons from maturing pre-mRNA strands.

A

Splicing factor proteins

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42
Q

The most frequently mutated splicing factor gene and encodes the U2 small nuclear riboprotein complex subunit responsible for branch site recognition

Very tightly associated with the presence of ring sideroblasts

A

SF3B1

  1. SRSF2
  2. U2AF1
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43
Q

Other conditions associated with SF3B1 mutations

A

Chronic lymphocytic leukemia: 15% to 20%
Associated with treatment resistance and a poor prognosis

Uveal melanoma

44
Q

The second most frequently mutated splicing factor, present in 10% to 15% of patients with MDS and 40% of those with CMML

A

SRSF2

45
Q

The third most frequently mutated splicing factor in MDS, present in approximately 12% of patients

A

U2AF1

Associated with shorter overall survival and increased risk of transformation to AML.

46
Q

Defined as heritable covalent modifications of chromatin that do not alter the DNA base sequence, play a role in the development of MDS and other malignancies

A

Epigenetic changes

47
Q

The only DNA methyltransferase gene frequently mutated in MDS

Also the most commonly mutated gene in individuals with CHIP

Found in older persons without cytopenias or other elements of disease.

A

DNMT3A

mutated in approximately 15%

Poorer prognosis when SF3B1 is not co-mutated

48
Q

Most frequently mutated MDS genes present in 25% to 30% of patients, and in more than 40% of patients with CMML

Demonstrate increased global DNA methylation, lower levels of 5-hydroxymethylcytosine and are more likely to have an elevated monocyte count

A

TET2

49
Q

TRUE OR FALSE

In MDS, IDH mutations appear to be poor prognostic markers.

A

TRUE

In MDS, IDH mutations appear to be poor prognostic markers.

50
Q

The most frequently mutated transcription factor in patients with MDS

Mutated in 10% to 15% of patients with MDS

A

RUNX1

Associated with a poor prognosis, increased rates of leukemic progression, and thrombocytopenia

51
Q

Most common Mutations of Growth Factor Signaling Pathway Genes

These lesions are associated with excess blasts and thrombocytopenia

A

NRAS mutations

52
Q

Found in 3% to 5% of patients with MDS, are associated with monocytosis, and consequently, are more common in MDS/MPN overlap syndromes

A

CBL mutations

53
Q

More common in juvenile myelomonocytic leukemia where mutations are often germline lesions and part of a congenital syndrome

A

PTPN11

54
Q

Features of V617F mutation in Janus kinase 2 (JAK2) mutation in MDS

A
  • It does not appear to have prognostic significance
  • It is not associated with an increased red cell mass as it is in polycythemia vera.
  • Enriched in patients with MDS/MPN-RS-T, and other MDS/MPN overlap diseases.
55
Q

A major complaint that is not necessarily related to degree of anemia

A

Fatigue

56
Q

Hepatomegaly or splenomegaly occurs in approximately ___% or ___% of patients, respectively, primarily with MDS/MPN overlap syndromes

A

5% Hepatomegaly

10% splenomegaly

57
Q

TRUE OR FALSE

Massive organomegaly should prompt a search for another non-MDS cause

A

TRUE

Massive organomegaly should prompt a search for another non-MDS cause

58
Q

Acquired hemoglobin H disease in this setting has been dubbed the α-thalassemia– myelodysplastic syndrome and is the consequence of acquired mutations in ________________

A

ATRX

The gene associated with the X-linked α-thalassemia/mental retardation syndrome

59
Q

TRUE OR FALSE

A white cell count greater than 13 × 109/L may be commonly seen in typical MDS.

A

FALSE

A white cell count greater than 13 × 109/L may be seen in MDS/MPN overlap and is rare in typical MDS.

60
Q

In this anomaly, neutrophils have very condensed chromatin and unilobed or bilobed nuclei that often have a pince-nez shape

A

Acquired Pelger-Huët anomaly

61
Q

Mild thrombocytosis can occur in

A

5q-minus syndrome or
Abnormalities of chromosome 3q21q26

62
Q

INCREASE OR DECREASE

Serum iron, transferrin, and ferritin:
Erythroferrone:
Hepcidin:
Lactic dehydrogenase and uric acid:
Microglobulin:

A

Serum iron, transferrin, and ferritin: increase
Erythroferrone: increase
Hepcidin:decrease
Lactic dehydrogenase and uric acid:increase
Microglobulin:increase

63
Q

Cellularity is decreased in approximately _____of patients and may simulate aplastic anemia.

A

15%

64
Q

Pathologic sideroblasts may be identified when the marrow is processed with the __________________

A

Prussian blue reaction (Perls stain)

65
Q

Referred to as erythroblasts with an increased number and size of siderosomes (cytoplasmic ferritin-containing vacuoles)

A

Intermediate sideroblasts or type 2 sideroblasts

66
Q

Referred to as erythroblasts with mitochondrial iron aggregates that take the form of a partial or complete circumnuclear ring of iron globules

A

Ring sideroblasts

67
Q

Therapy-related MDS syndromes are common in abnormalities of chromosomes ________

A

Chromosomes 5, 7, and 8

68
Q

TRUE OR FALSE

The presence of acquired chromosomal abnormalities is indicative of clonal hematopoiesis and can aid in the diagnostic evaluation.

A

TRUE

The presence of acquired chromosomal abnormalities is indicative of clonal hematopoiesis and can aid in the diagnostic evaluation.

69
Q

Diagnostic Criteria for Myelodysplastic Syndromes

Presence of 1 or more otherwise unexplained cytopenias
Hemoglobin :
Absolute neutrophil count :
Platelet count :

A

Hemoglobin : <110 g/L
Absolute neutrophil count : <1.5 × 109/L
Platelet count : <100 × 109/L

Present for 6 months or longer, if there is no typical cytogenetic abnormality identified.

70
Q

Diagnostic Criteria for Myelodysplastic Syndromes

______ dysplastic cells in erythroid, myeloid, and/or megakaryocyte lineages

______ marrow blasts

A

> 10% dysplastic cells in erythroid, myeloid, and/or megakaryocyte lineages

5–19% marrow blasts

71
Q

Cytogenetic abnormality typical for MDS

A
  • −7 or del(7q)
  • del(12p) or t(12p)
  • t(1;3)(p36.3;q21.1)
  • −5 or del(5q)
  • del(9q)
  • t(2;11)(p21;q23)
  • i(17q) or t(17p)
  • idic(X)(q13)
  • inv(3)(q21q26.2)
  • −13 or del(13q)
  • t(11;16)(q23;p13.3)
  • t(6;9)(p23;q34)
  • del(11q)
  • t(3;21)(q26.2;q22.1)

Loss of the Y chromosome, deletion of chromosome 20q, and trisomy 8 as sole abnormalities are not specific enough to be MDS-defining.

72
Q

Most prevalent prognostic model in clinical use for MDS

A

IPSS-R

Much broader range of cytogenetic abnormalities which are given greater weight in the overall risk calculation

Currently, somatic mutations are not considered by any prognostic scoring system in widespread clinical use, even though these lesions have been shown to have independent prognostic significance.

73
Q

The IPSS considers 3 risk factors:

A

The percentage of blasts in the marrow,
The presence of specific cytogenetic abnormalities
The number of cytopenias present in the blood

74
Q

IPSSR Risk Categories

A

Low, 0
Intermediate-1, 0.5–1.0
Intermediate-2, 1.5–2.0
High, ≥2.5

75
Q

IPSSR Cytogenetic Groups

Very good

A

del(11q)
−Y

76
Q

IPSSR Cytogenetic Groups

Good

A

Normal
del(20q)
del(5q) alone or with 1 other anomaly
del(12p)

Normally get 20q, 5q and 12pesos mo

77
Q

IPSSR Cytogenetic Groups

Intermediate

A

+8
del(7q)
i(17q)
+19
+21
any single or double abnormality not listed, or 2 or more independent clones

78
Q

IPSSR Cytogenetic Groups

Poor

A

del(3q)
−7
double with del(7q)
complex with 3 abnormalities

33-777

79
Q

IPSSR Cytogenetic Groups

Very poor

A

Complex with >3 abnormalities

80
Q

TRUE OR FALSE

Currently, somatic mutations are not considered by any prognostic scoring system in widespread clinical use, even though these lesions have been shown to have independent prognostic significance.

A

TRUE

Currently, somatic mutations are not considered by any prognostic scoring system in widespread clinical use, even though these lesions have been shown to have independent prognostic significance.

81
Q

2 biomarkers that are strong enough predictors of treatment response as to permit selection or avoidance of individual drugs

A

del(5q)

Serum erythropoietin level

82
Q

The second most common cause of death in patients with MDS

A

Hemorrhage

83
Q

Epoetin alfa MDS dose

A

150–300 U/kg per day 3 times per week
Single weekly doses of 40,000–60,000 U

84
Q

Darbepoetin alfa dose

A

500 mcg fixed dose once every 2–3 weeks

85
Q

Combination of granulocyte-colony stimulating factor (G-CSF) with ESA is especially useful in patients with________

A

In patients with ring sideroblasts

86
Q

Major cause of mortality in MDS

A

Infection

87
Q

The most common adverse effects of G-CSF and GM-CSF

A

Bone pain, low-grade fevers, and soreness at the injection site

88
Q

TRUE OR FALSE

G-CSF is not generally recommended for those with intermediate-2 risk or high-risk IPSS scores or comparable IPSS-R scores because of the risk of leukemoid reactions.

A

TRUE

G-CSF is not generally recommended for those with intermediate-2 risk or high-risk IPSS scores or comparable IPSS-R scores because of the risk of leukemoid reactions

89
Q

A megakaryocyte growth factor, was studied in patients with symptomatic thrombocytopenia associated with marrow failure syndromes including MDS, but efficacy was low and adverse effects, such as fluid retention and atrial dysrhythmias, were common.

A

IL-11 (oprelvekin)

90
Q

A peptibody that stimulates the thrombopoietin receptor (c-Mpl), can decrease thrombocytopenia and reduce platelet transfusion needs and clinically significant bleeding events in patients with MDS and severe thrombocytopenia

A

Romiplostim

Dose determined by early clinical studies, approximately 750 mcg SQ once weekly, is higher than that required for immune thrombocytopenia

91
Q

An orally administered small molecule c-Mpl agonist approved for the treatment of immune thrombocytopenia (ITP) and aplastic anemia, has also shown efficacy in MDS studies with respect to reducing platelet transfusion needs and clinically significant bleeding events

A

Eltrombopag

Both eltrombopag and romiplostim improve platelet counts in some patient

92
Q

Dose of low-dose Cytrabine

A

5–20 mg/m2 per day by SQ injection every 12 hours for 8–16 weeks or by continuous IV infusion

93
Q

Immunosuppressive Therapy is directed at

A

Autoreactive T-lymphocyte–mediated inhibition of hematopoiesis

94
Q

TRUE OR FALSE

The mortality with ATG-based therapy is higher in MDS patients than in aplastic anemia.

A

TRUE

The mortality with ATG-based therapy is higher in MDS patients than in aplastic anemia.

95
Q

Predicted response to immunosuppressive therapy

A
  • Hypocellular marrow
  • Younger age
  • Normal karyotype or trisomy 8
  • Lack of transfusion dependence
  • Presence of a PNH clone
  • HLA-DR15 (DR2)
96
Q

Side effects of Thalidomide

A

Neuropathy, rashes, and constipation, risk of teratogenicity

97
Q

A thalidomide analogue with a more favorable risk-to-benefit ratio than the parent compound, promotes the degradation of CSNK1A1, which is encoded on chromosome 5q

A

Lenalidomide

98
Q

Adverse effects of lenalidomide

A

Neutropenia and thrombocytopenia

99
Q

A fusion antibody that acts as a ligand trap for activin receptor ligands, including growth and differentiation factor 11 and other members of the transforming growth factor-β superfamily that inhibit erythropoiesis

Alter intracellular SMAD2/3 signaling and augment erythroid differentiation and ameliorate anemia

A

Luspatercept

100
Q

A soluble TNF receptor fusion protein, FDA approved for rheumatoid arthritis, has produced mixed results in MDS.

A

Etanercept (p75 TNFR:Fc)

101
Q

Azacitidine dose of MDS

A

75 mg/m2 once per day given SQ for 7 consecutive days each month

102
Q

Adverse events associated with azacitidine

A

Cytopenias, rash
Injection-site soreness (which may respond to evening primrose oil)
Mucositis
Renal insufficiency
Pulmonary infiltrates (uncommon)
Constipation (common)

103
Q

Differs from azacitidine in that it is primarily incorporated into DNA, has a distinct profile of sensitive cell lines among the NCI-60 panel

May work faster

A

5-Aza-2′-deoxycytidine (decitabine)

104
Q

An oral formulation of decitabine combined with a cytidine deaminase inhibitor (E7727), showed comparable pharmacodynamics and clinical effectiveness to IV decitabine.

A

Cedazuridine (ASTX727)

105
Q

In patients with higher-risk disease in whom azacitidine or decitabine has failed, overall life expectancy is less than __________ and patients who receive only supportive/palliative care have a life expectancy of only 3–4 months.

A

6 months

106
Q

Remains the only treatment that can cure patients with the disease.

A

AlloHCT

107
Q

A liposomal nanoparticle with cytarabine and daunorubicin in a fixed 5:1 ratio, is FDA approved for patients with AML arising from MDS or AML with MDS-related changes

A

CPX-351

WILLIAM'S HEMATOLOGY (109 decks)

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