86 Myelodysplastic Syndromes Flashcards
Most common blood abnormality in MDS
Macrocytic anemia
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.
Dysplasia
TRUE OR FALSE
MDS can be diagnosed without dysplasia.
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.
TRUE OR FALSE
The majority of MDS cases are age-related without a clear precipitating factor or any family history.
TRUE
The majority of MDS cases are age-related without a clear precipitating factor or any family history.
WHO 2016 MDS subtypes
(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
Some patients diagnosed with MDS may have their diagnosis change to CMML once their monocyte count exceeds ________.
1 × 109/L
The median age at MDS diagnosis in the United States is
70 years
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
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
(Males/Females) are affected with MDS up to 1.5 times
Males
With the exception of MDS with isolated ____for which there is a female predominance
del(5q)
Risk factors for MDS
- 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
The mechanism of therapy-related MDS
Promotion of expansion of a preexisting small TP53 or PPM1D mutant hematopoietic clone during marrow stress
Mutation associated with a familial platelet disorder with predisposition to AML (FPDAML)
RUNX1
Syndrome comprising MDS, verrucae, and congenital lymphedema
Emberger syndrome
(GATA2)
Syndrome comprising monocytopenia and nontuberculous mycobacterial infections
MonoMAC syndrome
(GATA2)
The hallmark of clonal hematopoiesis in MDS is the
Presence of a somatic genetic abnormality
Percentage of patients with MDS will have a grossly abnormal karyotype
50%
Typically in the form of a partial or total chromosomal deletion
The most common somatic genetic lesions in MDS
Mutations of individual genes
Most common mutated gene in MDS
SF3B1
TET2
The only somatic mutations associated with a favorable prognosis.
Strongly associated with ring sideroblasts
SF3B1
Associated wit del(20q)
U2AF1
Mostly in men X-linked
ZRSR2
Associated with ATMDS (acquired thalassemia and myelodysplastic syndrome)
ATRX
Rarely translocated in MDS
ETV6
Associated with complex karyotypes
TP53
Enriched in MDS-RS-T/MDS with ring sideroblasts and thrombocytosis
JAK2
The most common karyotypic abnormality observed in MDS
Del(5q)
Occurring in approximately 15% of patients
Del(5q) has marked sensitivity to treatment with ______________.
Lenalidomide
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
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
Occur more frequently (~50%) in patients with prior exposure to alkylating agents
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))
This is the only large-scale amplification frequently encountered in MDS, present in approximately 5% of patients.
Trisomy 8
Intermediate prognosis
Nonspecific as it can occur in patients with MPN, AML, or aplastic anemia
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
Del(20q)
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
Same cytogenetic risk as patients with normal karyotypes
Genetic abnormalities identified in elderly patients without cytopenias and are considered pathogenic lesions in MDS
Teneleven translocation 2 (TET2) and DNMT3A
Patients with chromosome 17 abnormalities typically have a poor prognosis, particularly in the presence of a ______ mutation.
TP53
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
Complex karyotypes are defined as
Having three or more cytogenetic abnormalities of any sort and are strongly associated with an adverse prognosis
The most frequent abnormalities seen in both monosomal and complex karyotypes involve chromosomes ________
Chromosomes 5 and 7
The International Prognosis Scoring System–Revised (IPSS-R) considers complex, but not monosomal karyotype as an independent risk factor
Approximately 50% of patients with complex karyotypes have a concomitant ______mutation and account for the majority of patients with mutations of this gene.
TP53
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.
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
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
- SRSF2
- U2AF1
Other conditions associated with SF3B1 mutations
Chronic lymphocytic leukemia: 15% to 20%
Associated with treatment resistance and a poor prognosis
Uveal melanoma
The second most frequently mutated splicing factor, present in 10% to 15% of patients with MDS and 40% of those with CMML
SRSF2
The third most frequently mutated splicing factor in MDS, present in approximately 12% of patients
U2AF1
Associated with shorter overall survival and increased risk of transformation to AML.
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
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
mutated in approximately 15%
Poorer prognosis when SF3B1 is not co-mutated
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
TRUE OR FALSE
In MDS, IDH mutations appear to be poor prognostic markers.
TRUE
In MDS, IDH mutations appear to be poor prognostic markers.
The most frequently mutated transcription factor in patients with MDS
Mutated in 10% to 15% of patients with MDS
RUNX1
Associated with a poor prognosis, increased rates of leukemic progression, and thrombocytopenia
Most common Mutations of Growth Factor Signaling Pathway Genes
These lesions are associated with excess blasts and thrombocytopenia
NRAS mutations
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
More common in juvenile myelomonocytic leukemia where mutations are often germline lesions and part of a congenital syndrome
PTPN11
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.
A major complaint that is not necessarily related to degree of anemia
Fatigue
Hepatomegaly or splenomegaly occurs in approximately ___% or ___% of patients, respectively, primarily with MDS/MPN overlap syndromes
5% Hepatomegaly
10% splenomegaly
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
Acquired hemoglobin H disease in this setting has been dubbed the α-thalassemia– myelodysplastic syndrome and is the consequence of acquired mutations in ________________
ATRX
The gene associated with the X-linked α-thalassemia/mental retardation syndrome
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.
In this anomaly, neutrophils have very condensed chromatin and unilobed or bilobed nuclei that often have a pince-nez shape
Acquired Pelger-Huët anomaly
Mild thrombocytosis can occur in
5q-minus syndrome or
Abnormalities of chromosome 3q21q26
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
Cellularity is decreased in approximately _____of patients and may simulate aplastic anemia.
15%
Pathologic sideroblasts may be identified when the marrow is processed with the __________________
Prussian blue reaction (Perls stain)
Referred to as erythroblasts with an increased number and size of siderosomes (cytoplasmic ferritin-containing vacuoles)
Intermediate sideroblasts or type 2 sideroblasts
Referred to as erythroblasts with mitochondrial iron aggregates that take the form of a partial or complete circumnuclear ring of iron globules
Ring sideroblasts
Therapy-related MDS syndromes are common in abnormalities of chromosomes ________
Chromosomes 5, 7, and 8
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.
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
Present for 6 months or longer, if there is no typical cytogenetic abnormality identified.
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
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)
Loss of the Y chromosome, deletion of chromosome 20q, and trisomy 8 as sole abnormalities are not specific enough to be MDS-defining.
Most prevalent prognostic model in clinical use for MDS
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.
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
IPSSR Risk Categories
Low, 0
Intermediate-1, 0.5–1.0
Intermediate-2, 1.5–2.0
High, ≥2.5
IPSSR Cytogenetic Groups
Very good
del(11q)
−Y
IPSSR Cytogenetic Groups
Good
Normal
del(20q)
del(5q) alone or with 1 other anomaly
del(12p)
Normally get 20q, 5q and 12pesos mo
IPSSR Cytogenetic Groups
Intermediate
+8
del(7q)
i(17q)
+19
+21
any single or double abnormality not listed, or 2 or more independent clones
IPSSR Cytogenetic Groups
Poor
del(3q)
−7
double with del(7q)
complex with 3 abnormalities
33-777
IPSSR Cytogenetic Groups
Very poor
Complex with >3 abnormalities
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.
2 biomarkers that are strong enough predictors of treatment response as to permit selection or avoidance of individual drugs
del(5q)
Serum erythropoietin level
The second most common cause of death in patients with MDS
Hemorrhage
Epoetin alfa MDS dose
150–300 U/kg per day 3 times per week
Single weekly doses of 40,000–60,000 U
Darbepoetin alfa dose
500 mcg fixed dose once every 2–3 weeks
Combination of granulocyte-colony stimulating factor (G-CSF) with ESA is especially useful in patients with________
In patients with ring sideroblasts
Major cause of mortality in MDS
Infection
The most common adverse effects of G-CSF and GM-CSF
Bone pain, low-grade fevers, and soreness at the injection site
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
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)
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
Dose determined by early clinical studies, approximately 750 mcg SQ once weekly, is higher than that required for immune thrombocytopenia
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
Both eltrombopag and romiplostim improve platelet counts in some patient
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
Immunosuppressive Therapy is directed at
Autoreactive T-lymphocyte–mediated inhibition of hematopoiesis
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.
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)
Side effects of Thalidomide
Neuropathy, rashes, and constipation, risk of teratogenicity
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
Adverse effects of lenalidomide
Neutropenia and thrombocytopenia
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
A soluble TNF receptor fusion protein, FDA approved for rheumatoid arthritis, has produced mixed results in MDS.
Etanercept (p75 TNFR:Fc)
Azacitidine dose of MDS
75 mg/m2 once per day given SQ for 7 consecutive days each month
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)
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)
An oral formulation of decitabine combined with a cytidine deaminase inhibitor (E7727), showed comparable pharmacodynamics and clinical effectiveness to IV decitabine.
Cedazuridine (ASTX727)
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
Remains the only treatment that can cure patients with the disease.
AlloHCT
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
