Myelodysplastic Syndromes Flashcards by LEDESMA, Anne Gelika

myelodysplastic comes from the words? (include their meanings)

“myelo” – myeloid cell lineage

“dysplasia” – abnormal cell development within tissues/organs

How well did you know this?

Not at all

Perfectly

MDS is formerly known as

refractory anemia
smoldering leukemia
oligoblastic leukemia
preleukemia

How well did you know this?

Not at all

Perfectly

progressive cytopenia in peripheral blood, reflecting defects in erythroid, myeloid, and/or megakaryocytic maturation

MYELODYSPLASTIC SYNDROMES (MDS)

How well did you know this?

Not at all

Perfectly

MDS has an increased risk to transform into

acute myeloid leukemia (AML)

How well did you know this?

Not at all

Perfectly

cell of origin for MDS

hematopoietic stem cells (HSCs) mutations

How well did you know this?

Not at all

Perfectly

have clonal hematopoiesis (mutation in HSC) but do not develop a hematologic disorder

Clonal Hematopoiesis of Indeterminate Potential (CHIP)

How well did you know this?

Not at all

Perfectly

T/F

Complex interactions among additional somatic mutations, epigenetic modifications, the BM microenvironment, and environmental stimuli determine whether CHIP develops into MDS

How well did you know this?

Not at all

Perfectly

Variations of MDS

de novo mutations (primary MDS)
result of therapy (therapy-related MDS)
secondary to exposure to chemicals/radiation
inherited

How well did you know this?

Not at all

Perfectly

Variation of MDS with changes in gene sequence; not inherited

de novo mutations (primary MDS)

How well did you know this?

Not at all

Perfectly

Variation of MDS due to chemotherapy, medications that causes mutation

result of therapy (therapy-related MDS)

How well did you know this?

Not at all

Perfectly

Variation of MDS not associated with prior disease treatment

secondary to exposure to chemicals or radiation

How well did you know this?

Not at all

Perfectly

2 morphologic findings common to all types of MDS

progressive cytopenias
dyspoiesis in 1 or more cell lines

How well did you know this?

Not at all

Perfectly

term for abnormal formation of blood cells

dyspoiesis

How well did you know this?

Not at all

Perfectly

may be responsible for the ineffective hematopoiesis in MDS

Disruption of apoptosis

How well did you know this?

Not at all

Perfectly

regulates cell population by decreasing cell survival in MDS

Apoptosis (programmed cell death)

How well did you know this?

Not at all

Perfectly

Apoptosis rate during early phase of MDS

INCREASED
when cytopenias are evident

How well did you know this?

Not at all

Perfectly

Apoptosis rate during late phase of MDS

DECREASED
when progression toward leukemia is apparent, which allows increased neoplastic cell survival and expansion of the abnormal clone

How well did you know this?

Not at all

Perfectly

3 morphologic abnormalities of MDS

Dyserythropoiesis
Dysmyelopoiesis
Dysmegakaryopoiesis

How well did you know this?

Not at all

Perfectly

Abnormal RBC formation

Dyserythropoiesis

How well did you know this?

Not at all

Perfectly

Immature RBCs, unusual shape, cannot develop into functional mature cells leading to healthy RBCs shortage

Dyserythropoiesis

How well did you know this?

Not at all

Perfectly

PB during Dyserythropoiesis

oval macrocytes (normal vit B12 and folate)
hypochromic microcytes (adeq. iron stores)
dimorphic RBC
poikilocytosis
basophilic stippling
Howell-Jolly bodies
siderocytes

How well did you know this?

Not at all

Perfectly

BM during Dyserythropoiesis

RBC precursors with >1 nucleus or abnormal nuclear shapes
nuclear fragments
abnormal cytoplasmic features
basophilic stippling, heterogenous staining, ring sideroblasts
megaloblastoid cellular development (normal Vit B12 & folate)

How well did you know this?

Not at all

Perfectly

Abnormal cell formation more on granulocytes and monocytes cell lines

Dysmyelopoiesis

How well did you know this?

Not at all

Perfectly

PB during Dysmyelopoiesis

persistent basophilia in cytoplasm of otherwise mature WBCs, indicating
nuclear-cytoplasmic asynchrony
abnormal granulation of neutrophils’ cytoplasm
abnormal nuclear features

How well did you know this?

Not at all

Perfectly

BM during Dysmyelopoiesis

* nuclear-cytoplasmic asynchrony * cytoplasmic changes - uneven staining * abnormal granulation of the cytoplasm * agranular promyelocytes (mistaken for blasts) * abnormal nuclear findings * granulocytic hypoplasia or hyperplasia * monocytic hyperplasia * abnormal localization of immature precursors

mistaken for blasts in Dysmyelopoiesis

agranular promyelocytes

term for abnormal NC ratio, appearance, and other components

nuclear-cytoplasmic asynchrony

abnormal granulation is either

hypogranulation hypergranulation agranulation

Abnormal formation of megakaryocytes

Dysmegakaryopoiesis

PB during Dysmegakaryopoiesis

* giant platelets, abnormal plt granulation * circulating micromegakaryocytes

BM during Dysmegakaryopoiesis

* large mononuclear megakaryocytes, micromegakaryocytes, or micromegakaryoblasts * nuclei may be bilobed or have multiple small, separated nuclei

T/F For Differential Diagnosis, a thorough history and physical examination, including questions about exposure to drugs and chemicals, are essential

granulocytes of MDS may have abnormal cellular functions such as

decreased adhesion deficient phagocytosis decreased chemotaxis impaired microbicidal capacity

cells when there is MDS have decreased levels of

myeloperoxidase alkaline phosphatase

plays a role in protein function, activity, and molecular interactions

alkaline phosphatase

T/F RBCs may exhibit shortened survival (apoptosis) in MDS

T/F Erythroid precursors may have a increased response to erythropoietin that may contribute to anemia

F DECREASED response to EPO --> anemia

T/F In MDS, patients may experience ↑ bleeding despite adequate plt. no.

FAB Classification of MDS

Refractory anemia Refractory anemia with ring sideroblasts (RARS) Refractory anemia with excess blasts (RAEB) Chronic myelomonocytic leukemia Refractory anemia with excess blasts in transformation (RAEB-t)

Classification that structures MDS by the amount of dysplasia and number of blasts in BM

FAB Classification

WHO Classification of MDS

MDS with single lineage dysplasia (MDS-SLD) MDS with ring sideroblasts (MDS-RS) MDS-RS and single lineage dysplasia MDS-RS and multilineage dysplasia MDS with multilineage dysplasia MDS with excess blasts (MDS-EB) Myelodysplastic syndrome with isolated del(5q) Myelodysplastic syndrome, unclassifiable Childhood myelodysplastic syndrome Refractory cytopenia of childhood (provisional)

dysplasia in at least 1 myeloid lineage

MDS With Single Lineage Dysplasia

cytogenetic abnormalities (abnormality in structure or no. of chromosomes) – seen in 50% of cases

MDS With Single Lineage Dysplasia

Symptoms of MDS With Single Lineage Dysplasia

fatigue/shortness of breath if anemia is present increased infections from neutropenia thrombocytopenia: petechiae, bruising, bleeding

has 1 or more cytopenias

MDS With Multilineage Dysplasia (MDS-MLD)

dysplasia in 2 or more myeloid cell lines

MDS With Multilineage Dysplasia (MDS-MLD)

myeloblasts in this classification do not contain Auer rods

MDS With Multilineage Dysplasia (MDS-MLD)

has gene SF3B1 mutation

MDS With Ring Sideroblasts (MDS-RS)

PB of MDS With Ring Sideroblasts (MDS-RS)

dimorphic mixed population of hypochromic cells and normochromic cells

erythroid precursor containing at least 5 iron granules/cell, and these iron-containing mitochondria must circle at least 1/3 of the nucleus

ring sideroblast

If a mutation in SF3B1 is identified, only ___ of nucleated erythroid cells must be ring sideroblasts.

If a mutation in SF3B1 is not detected, ___ of the bone marrow erythroid precursors must be ring sideroblasts to make this diagnosis.

15%

MDS classification with anemia and dyserythropoiesis

MDS With Ring Sideroblasts (MDS-RS)

2 subsets of MDS With Ring Sideroblasts (MDS-RS)

MDS-RS with single lineage dysplasia MDS-RS with multilineage dysplasia

accounts for 3-10% of all MDS cases and has a median age of presentation of 71

MDS-RS with single lineage dysplasia

1 or more cytopenias and dysplasia in 2 or more myeloid cell lines; has worse prognosis

MDS-RS with multilineage dysplasia

characterized by trilineage cytopenias; significant dysmyelopoiesis, dysmegakaryopoiesis, or both, with excess blasts

MDS With Excess Blasts (MDS-EB)

subsets of MDS With Excess Blasts (MDS-EB)

MDS-EB-1 MDS-EB-2

subset of MDS-EB with Auer rods, regardless of blast count and is more aggressive course, with a greater percentage of cases transforming to AML

MDS-EB-2

rare disorder caused by the loss of the part of the long arm (q arm) of chromosome 5; affects BM

MDS With Isolated del(5q) (5q- Syndrome)

only MDS with a defining cytogenetic abnormality

MDS With Isolated del(5q) (5q- Syndrome)

MDS affecting predominantly women and occurring at a median age of 70

MDS With Isolated del(5q) (5q- Syndrome)

anemia without other cytopenias or thrombocytosis, hypolobulated megakaryocytes, erythroid hypoplasia

MDS With Isolated del(5q) (5q- Syndrome)

proven to be effective in patients with isolated del(5q)

thalidomide analog lenalidomide (Revlimid)

initially lack specific changes necessary for classification into other MDS subtypes

MDS, Unclassifiable (MDS-U)

1% peripheral blood blasts, single linage dysplasia and pancytopenia, or an MDS-defining cytogenetic abnormality

MDS, Unclassifiable (MDS-U)

very rare; increased frequency of specific inherited gene mutations such as RUNX1, SOS1, GATA2, ANKRD26, and others

Childhood Myelodysplastic Syndromes

has cytopenia and dysplasia in at least 1 cell line

Childhood Myelodysplastic Syndromes

gene mutations in Childhood Myelodysplastic Syndromes

RUNX1 SOS1 GATA2 ANKRD26

% blasts in peripheral blood in MDS With Single Lineage Dysplasia

<1%

% blasts in BM in MDS With Single Lineage Dysplasia

<5%

Median Survival of MDS With Single Lineage Dysplasia

5 years

Risk of AML transformation in MDS With Single Lineage Dysplasia

2-12%

% blasts in peripheral blood in MDS With Multilineage Dysplasia

<1%

% blasts in BM in MDS With Multilineage Dysplasia

<5%

Median survival of MDS With Multilineage Dysplasia

31-38 months

Risk of AML transformation in MDS With Multilineage Dysplasia

10-12% (within 5 yrs)

% blasts in peripheral blood in MDS-EB-1

2-4%

% blasts in BM in MDS-EB-1

5-9%

% blasts in peripheral blood in MDS-EB-2

5-19%

% blasts in BM in MDS-EB-2

10-19%

MDS-EB subset with greater risk of AML transformation

MDS-EB-2

% blasts in peripheral blood of MDS With Isolated del(5q)

<1%

Median survival of MDS With Isolated del(5q)

54-146 months

% blasts in peripheral blood of MDS, unclassifiable

myeloid neoplasms with clinical, laboratory, and morphologic features that are characteristic of both MDS and MPN

MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS

Classifications of MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS

Chronic myelomonocytic leukemia (CMML) Atypical chronic myeloid leukemia (aCML), BCR/ABL1 negative Juvenile myelomonocytic leukemia (JMML) MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) Myelodysplastic/myeloproliferative neoplasm, unclassifiable

Chronic Myelomonocytic Leukemia (CMML) affects what cell

monocytes

value of persistent monocytosis of CMML

>1.0 monocyte x 10^9/L

myelodysplastic/myeloproliferative neoplasm with absence of the BCR/ABL1 fusion gene

Chronic Myelomonocytic Leukemia (CMML)

myelodysplastic/myeloproliferative neoplasm with absence of rearrangements involving PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2

Chronic Myelomonocytic Leukemia (CMML)

myelodysplastic/myeloproliferative neoplasm with <20% blasts and promonocytes in PB and BM

Chronic Myelomonocytic Leukemia (CMML)

myelodysplastic/myeloproliferative neoplasm with dysplasia in 1 or more myeloid cell line

Chronic Myelomonocytic Leukemia (CMML)

myelodysplastic/myeloproliferative neoplasm with mutations in > 90% of cases with TET2, SRSF2, ASXL1, and RUNX1 being the most common

Chronic Myelomonocytic Leukemia (CMML)

most common mutations found in > 90% of CMML cases

TET2 SRSF2 ASXL1 RUNX1

condition wherein Trisomy 8 and loss of all or portions of chromosome 7 is common

CMML

chromosome that controls cell growth and division

T/F The mutational landscape of CMML is complex with some patients having 8 to 14 distinct mutations in coding sequences.

myelodysplastic/myeloproliferative neoplasm with leukocytosis and dysgranulopoiesis

Chronic Myelomonocytic Leukemia (CMML)

myelodysplastic/myeloproliferative neoplasm wherein splenomegaly may be present as a result of infiltration of leukemic cells

Chronic Myelomonocytic Leukemia (CMML)

leukocytosis with morphologically dysplastic neutrophils and their precursors

Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative

myelodysplastic/myeloproliferative neoplasm with multilineage dysplasia

Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative

karyotype abnormalities are seen in a third of patients, with essentially all patients demonstrating at least 1 gene mutation

Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative

myelodysplastic/myeloproliferative neoplasm with dyspoiesis in all cell lines, but it is most remarkable in neutrophils, which may exhibit PelgerHuët-like cells, hypogranularity, bizarre segmentation

Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative

neutrophils in CMML may exhibit

PelgerHuët-like cells hypogranularity bizarre segmentation

myelodysplastic/myeloproliferative neoplasm with poor prognosis; commonly progress (2 yrs) to AML or succumb to BM failure

Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative

myelodysplastic/myeloproliferative neoplasm with proliferation of granulocytic and monocytic cell lines affecting children from 1 month to 14 y/o

Juvenile Myelomonocytic Leukemia

has somatic/germline mutations that activates RAS/MAPK pathway

Juvenile Myelomonocytic Leukemia

has strong association with congenital disorders such as Noonan syndrome and neurofibromatosis type 1

Juvenile Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia has strong association with these congenital disorders

Noonan syndrome Neurofibromatosis type 1

Tx for Juvenile Myelomonocytic Leukemia (effective in 50% of pt)

Allogeneic stem cell transplantation

Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis is formerly known as

MDS/MPN refractory anemia with ring sideroblasts and thrombocytosis

associated with mutations in SF3B1 and JAK2 V617F

Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis

Myelodysplastic/Myeloproliferative Neoplasm that presents with anemia, 15% or more ring sideroblasts, thrombocytosis, atypical megakaryocytes, and <1% blasts in peripheral blood and <5% blasts in BM

Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis

used for cases that meet the criteria for MDS/MPN but do not fit into one of aforementioned subcategories

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

time of diagnosis, clinical history, and the detection of molecular aberrations are important factors in properly diagnosing this condition

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

% of cases in de novo MDS where there is chromosome abnormalities

50%

% of cases in t-MDS where there is chromosome abnormalities

90% to 95%

most common abnormalities involve these chromosomes in MDS

chromosomes 5, 7, 8, 18, 20, and 13

most common single abnormalities besides del(5q)

trisomy 8 monosomy 7, 12p–, iso 17, –21, loss of the Y chromosome

MDS mutations affect 5 major groups of genes

RNA splicing DNA methylation activated cell signaling myeloid transcription factors chromatin modifiers

most common mutations of MDS

TET2 SF3B1 ASXL1 SRSF2 DNMT3A RUNX1

T/F MDS has changes in gene expression without altering DNA sequence

MDS epigenetic factors

diet drugs environmental pollutants (Cr, Cd, Hg, Ni, As)

3 different ways in which epigenetics of MDS may facilitate oncogenesis:

methylation of CpG islands histone modification alteration of microRNA expression

term for healthy cells transform to cancer cells

oncogenesis

Most widely used prognostic scoring models for MDS

International Prognostic Scoring System (IPSS) Revised International Prognostic Scoring System (IPSS-R)

3 “prognostic indicators” used by IPSS to predict the course of the patient’s disease

Percentage of leukemic blast cells in BM Type of chromosomal changes, if any, in the BM cells (cytogenetics) Presence of 1 or more low blood cell counts (cytopenias)

includes additional cytogenetic abnormalities and is more sensitive to the percentage of blasts and the degree of cytopenias. Other clinical features affecting survival but not transforming into AML include patient age, serum ferritin, patient performance status, and LDH levels

Revised International Prognostic Scoring System (IPSS-R)

factors noted in IPSS-R

Blasts Cytogenetics Hemoglobin Platelet count Absolute neutrophil count

T/F Prognostic systems and risk groups predict how MDS will respond to treatment

F Prognostic systems and risk groups do not predict how MDS will respond to treatment but instead how MDS is likely to behave over time without treatment.

treatment if there is favorable prognosis

supportive therapy: ✓ transfusions ✓ erythroid stimulating agents ✓ thrombopoietin ✓ granulocyte colony stimulating factor ✓ prophylactic antibiotics ✓ iron chelation

other treatments that have met with limited success for MDS

chemotherapeutic agents epigenetic modifiers

only cure for MDS

bone marrow or hematopoietic stem cell transplantation

future treatment possibilities for MDS

apoptosis-controlling drugs