86 Myelodysplastic Syndromes Flashcards
(107 cards)
1
Q
Most common blood abnormality in MDS
A
Macrocytic anemia
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
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.
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.
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
6
Q
Some patients diagnosed with MDS may have their diagnosis change to CMML once their monocyte count exceeds ________.
A
1 × 109/L
7
Q
The median age at MDS diagnosis in the United States is
A
70 years
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
9
Q
(Males/Females) are affected with MDS up to 1.5 times
A
Males
10
Q
With the exception of MDS with isolated ____for which there is a female predominance
A
del(5q)
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
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
13
Q
Mutation associated with a familial platelet disorder with predisposition to AML (FPDAML)
A
RUNX1
14
Q
Syndrome comprising MDS, verrucae, and congenital lymphedema
A
Emberger syndrome
(GATA2)
15
Q
Syndrome comprising monocytopenia and nontuberculous mycobacterial infections
A
MonoMAC syndrome
(GATA2)
16
Q
The hallmark of clonal hematopoiesis in MDS is the
A
Presence of a somatic genetic abnormality
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
18
Q
The most common somatic genetic lesions in MDS
A
Mutations of individual genes
19
Q
Most common mutated gene in MDS
A
SF3B1
TET2
20
Q
The only somatic mutations associated with a favorable prognosis.
Strongly associated with ring sideroblasts
A
SF3B1
21
Q
Associated wit del(20q)
A
U2AF1
22
Q
Mostly in men X-linked
A
ZRSR2
23
Q
Associated with ATMDS (acquired thalassemia and myelodysplastic syndrome)
A
ATRX
24
Q
Rarely translocated in MDS
A
ETV6
25
Associated with complex karyotypes
TP53
26
Enriched in MDS-RS-T/MDS with ring sideroblasts and thrombocytosis
JAK2
27
The most common karyotypic abnormality observed in MDS
Del(5q)
## Footnote
Occurring in approximately **15%** of patients
28
Del(5q) has marked sensitivity to treatment with ______________.
Lenalidomide
29
Syndrome characterized by **dyserythropoietic anemia, micromegakaryocytes with a normal or elevated platelet count, female predominance, and lower risk of transformation to AML**
5q-minus syndrome
## Footnote
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**
30
Occur more frequently (~50%) in patients with prior **exposure to alkylating agents**
Monosomy 7 and Del(7q)
## Footnote
Studies indicate that **isolated monosomy 7 is a more adverse abnormality** than a deletion of the long arm (del(7q))
31
This is **the only large-scale amplification** frequently encountered in MDS, present in approximately 5% of patients.
Trisomy 8
## Footnote
*Intermediate prognosis*
*Nonspecific as it can occur in patients with MPN, AML, or aplastic anemia*
32
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.
## Footnote
Not considered specific enough to define MDS by itself
Sometimes observed in individuals with **immune thrombocytopenia or without any hematologic disorder**
Del(20q)
33
Not a pathogenic lesion in MDS, but instead an **age-related event** that can occur in men without cytopenias, akin to CHIP
Loss of Y
## Footnote
Same cytogenetic risk as patients with normal karyotypes
34
Genetic abnormalities identified in elderly patients without cytopenias and are considered **pathogenic lesions in MDS**
Teneleven translocation 2 (TET2) and DNMT3A
35
Patients with **chromosome 17** abnormalities typically have a **poor prognosis**, particularly in the presence of a ______ mutation.
TP53
36
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**
SETBP1
37
Complex karyotypes are defined as
Having **three or more** cytogenetic abnormalities of any sort and are strongly associated with an adverse prognosis
38
The most frequent abnormalities seen in both **monosomal and complex karyotypes** involve chromosomes ________
Chromosomes 5 and 7
## Footnote
The International Prognosis Scoring System–Revised (IPSS-R) considers complex, but not monosomal karyotype as an independent risk factor
39
Approximately **50% of patients with complex karyotypes** have a concomitant ______mutation and account for the majority of patients with mutations of this gene.
TP53
40
# TRUE OR FALSE
Acquired mutations of individual genes are significantly more common than karyotypic abnormalities in patients with MDS.
TRUE
**Acquired mutations of individual genes are significantly more common** than karyotypic abnormalities in patients with MDS.
41
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.
Splicing factor proteins
42
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**
SF3B1
## Footnote
2. SRSF2
3. U2AF1
43
Other conditions associated with SF3B1 mutations
**Chronic lymphocytic leukemia:** 15% to 20%
*Associated with treatment resistance and a poor prognosis*
**Uveal melanoma**
44
The second most frequently mutated splicing factor, present in **10% to 15% of patients with MDS** and **40% of those with CMML**
SRSF2
45
The third most frequently mutated splicing factor in MDS, present in approximately **12%** of patients
U2AF1
## Footnote
*Associated with shorter overall survival and increased risk of transformation to AML.*
46
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
Epigenetic changes
47
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.
DNMT3A
## Footnote
*mutated in approximately 15%*
Poorer prognosis when SF3B1 is not co-mutated
48
**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**
TET2
49
# TRUE OR FALSE
In MDS, IDH mutations appear to be poor prognostic markers.
TRUE
In MDS, **IDH** mutations appear to be **poor** prognostic markers.
50
The most frequently mutated **transcription factor** in patients with MDS
Mutated in 10% to 15% of patients with MDS
RUNX1
## Footnote
Associated with a poor prognosis, increased rates of leukemic progression, and **thrombocytopenia**
51
Most common Mutations of **Growth Factor Signaling Pathway Genes**
These lesions are associated with **excess blasts and thrombocytopenia**
NRAS mutations
52
Found in 3% to 5% of patients with MDS, are associated with **monocytosis**, and consequently, are more common in **MDS/MPN overlap syndromes**
CBL mutations
53
More common in **juvenile myelomonocytic leukemia** where mutations are often germline lesions and part of a congenital syndrome
PTPN11
54
Features of V617F mutation in Janus kinase 2 (JAK2) mutation in MDS
* 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
A major complaint that is not necessarily related to degree of anemia
Fatigue
56
Hepatomegaly or splenomegaly occurs in approximately ___% or ___% of patients, respectively, primarily with **MDS/MPN overlap syndromes**
5% Hepatomegaly
10% splenomegaly
57
# TRUE OR FALSE
Massive organomegaly should prompt a search for another non-MDS cause
TRUE
Massive organomegaly should prompt a search for another non-MDS cause
58
**Acquired hemoglobin H disease** in this setting has been dubbed the **α-thalassemia– myelodysplastic syndrome** and is the consequence of acquired mutations in ________________
**ATRX**
## Footnote
The gene associated with the **X-linked α-thalassemia/mental retardation syndrome**
59
# TRUE OR FALSE
A white cell count greater than 13 × 109/L may be commonly seen in typical MDS.
FALSE
A white cell count **greater than 13 × 109/L may be seen in MDS/MPN overlap** and is rare in typical MDS.
60
In this anomaly, neutrophils have **very condensed chromatin and unilobed or bilobed nuclei** that often have a **pince-nez shape**
Acquired Pelger-Huët anomaly
61
Mild thrombocytosis can occur in
5q-minus syndrome or
Abnormalities of chromosome 3q21q26
62
# INCREASE OR DECREASE
Serum iron, transferrin, and ferritin:
Erythroferrone:
Hepcidin:
Lactic dehydrogenase and uric acid:
Microglobulin:
Serum iron, transferrin, and ferritin: increase
Erythroferrone: increase
Hepcidin:decrease
Lactic dehydrogenase and uric acid:increase
Microglobulin:increase
63
**Cellularity is decreased** in approximately _____of patients and may simulate aplastic anemia.
15%
64
Pathologic sideroblasts may be identified when the marrow is processed with the __________________
Prussian blue reaction (Perls stain)
65
Referred to as erythroblasts with an increased number and size of siderosomes (cytoplasmic ferritin-containing vacuoles)
Intermediate sideroblasts or type 2 sideroblasts
66
Referred to as erythroblasts with mitochondrial iron aggregates that take the form of a partial or complete circumnuclear ring of iron globules
Ring sideroblasts
67
Therapy-related MDS syndromes are common in abnormalities of chromosomes ________
Chromosomes 5, 7, and 8
68
# TRUE OR FALSE
The presence of acquired chromosomal abnormalities is indicative of clonal hematopoiesis and can aid in the diagnostic evaluation.
TRUE
The presence of acquired chromosomal abnormalities is indicative of clonal hematopoiesis and can aid in the diagnostic evaluation.
69
# Diagnostic Criteria for Myelodysplastic Syndromes
Presence of 1 or more otherwise unexplained cytopenias
Hemoglobin :
Absolute neutrophil count :
Platelet count :
Hemoglobin : <110 g/L
Absolute neutrophil count : <1.5 × 109/L
Platelet count : <100 × 109/L
## Footnote
*Present for **6 months or longer**, if there is no typical cytogenetic abnormality identified.*
70
# Diagnostic Criteria for Myelodysplastic Syndromes
______ dysplastic cells in erythroid, myeloid, and/or megakaryocyte lineages
______ marrow blasts
>10% dysplastic cells in erythroid, myeloid, and/or megakaryocyte lineages
5–19% marrow blasts
71
Cytogenetic abnormality typical for MDS
* −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)
## Footnote
*Loss of the Y chromosome, deletion of chromosome 20q, and trisomy 8 as sole abnormalities are not specific enough to be MDS-defining.*
72
Most prevalent prognostic model in clinical use for MDS
IPSS-R
## Footnote
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
The IPSS considers 3 risk factors:
The percentage of blasts in the marrow,
The presence of specific cytogenetic abnormalities
The number of cytopenias present in the blood
74
IPSSR Risk Categories
Low, 0
Intermediate-1, 0.5–1.0
Intermediate-2, 1.5–2.0
High, ≥2.5
75
# IPSSR Cytogenetic Groups
Very good
del(11q)
−Y
76
# IPSSR Cytogenetic Groups
Good
Normal
del(20q)
del(5q) alone or with 1 other anomaly
del(12p)
| Normally get 20q, 5q and 12pesos mo
77
# IPSSR Cytogenetic Groups
Intermediate
+8
del(7q)
i(17q)
+19
+21
any single or double abnormality not listed, or 2 or more independent clones
78
# IPSSR Cytogenetic Groups
Poor
del(3q)
−7
double with del(7q)
complex with 3 abnormalities
| 33-777
79
# IPSSR Cytogenetic Groups
Very poor
Complex with >3 abnormalities
80
# 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.
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
2 biomarkers that are strong enough predictors of treatment response as to permit selection or avoidance of individual drugs
del(5q)
Serum erythropoietin level
82
The second most common cause of death in patients with MDS
Hemorrhage
83
Epoetin alfa MDS dose
150–300 U/kg per day 3 times per week
Single weekly doses of 40,000–60,000 U
84
Darbepoetin alfa dose
500 mcg fixed dose once every 2–3 weeks
85
Combination of granulocyte-colony stimulating factor (G-CSF) with ESA is especially useful in patients with________
In patients with ring sideroblasts
86
Major cause of mortality in MDS
Infection
87
The most common adverse effects of G-CSF and GM-CSF
Bone pain, low-grade fevers, and soreness at the injection site
88
# 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.
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
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.
IL-11 (oprelvekin)
90
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
Romiplostim
## Footnote
*Dose determined by early clinical studies, approximately **750 mcg SQ once weekly**, is higher than that required for immune thrombocytopenia*
91
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
Eltrombopag
## Footnote
Both eltrombopag and romiplostim improve platelet counts in some patient
92
Dose of low-dose Cytrabine
5–20 mg/m2 per day by SQ injection every 12 hours for 8–16 weeks or by continuous IV infusion
93
Immunosuppressive Therapy is directed at
Autoreactive T-lymphocyte–mediated inhibition of hematopoiesis
94
# TRUE OR FALSE
The mortality with ATG-based therapy is higher in MDS patients than in aplastic anemia.
TRUE
The mortality with ATG-based therapy is higher in MDS patients than in aplastic anemia.
95
Predicted response to immunosuppressive therapy
* Hypocellular marrow
* Younger age
* Normal karyotype or trisomy 8
* Lack of transfusion dependence
* Presence of a PNH clone
* HLA-DR15 (DR2)
96
Side effects of Thalidomide
Neuropathy, rashes, and constipation, risk of teratogenicity
97
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**
Lenalidomide
98
Adverse effects of lenalidomide
Neutropenia and thrombocytopenia
99
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
Luspatercept
100
A soluble TNF receptor fusion protein, FDA approved for rheumatoid arthritis, has produced mixed results in MDS.
Etanercept (p75 TNFR:Fc)
101
Azacitidine dose of MDS
75 mg/m2 once per day given SQ for 7 consecutive days each month
102
Adverse events associated with azacitidine
Cytopenias, rash
Injection-site soreness (which may respond to evening primrose oil)
Mucositis
Renal insufficiency
Pulmonary infiltrates (uncommon)
Constipation (common)
103
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
5-Aza-2′-deoxycytidine (decitabine)
104
An oral formulation of **decitabine combined with a cytidine deaminase inhibitor (E7727),** showed comparable pharmacodynamics and clinical effectiveness to IV decitabine.
Cedazuridine (ASTX727)
105
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.
6 months
106
Remains the only treatment that can cure patients with the disease.
AlloHCT
107
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**
CPX-351
