MIDTERM LECTURE L1: ACUTE LYMPHOBLASTIC LEUKEMIA Flashcards
The broad term “leukemia” is derived from what ancient Greek words?
leukos (white) and haima (blood)
Refers to the rapid clonal proliferation in the bone marrow of lymphoid or myeloid progenitor cells
acute leukemia
Acute leukemia is the rapid clonal proliferation in the bone marrow of progenitor cells known as?
lymphoblasts (lymphocytes) and myeloblasts (neutrophil)
When proliferation of blasts overwhelms the bone marrow, the blasts are seen in the?
peripheral blood
Most causes of the development of malignancy are
unknown
Some of the known causes of leukemia include
- exposure to organic solvent (e.g. benzene)
- familial cancer predisposition syndromes
- alkylating agents and other forms of chemotherapy
- radiation
Alkylating agents and other forms of chemotherapy could result to what type of leukemia?
therapy-related leukemia
Development of leukemia is best believed due to progression of mutations or “___________” that hinders proliferation
multiple hits
In leukemia, hematopoietic stem cells become what kind of cells?
Leukemic stem cells
(LSCs)
Leukemic stem cell continuous to proliferate, but forgets how to mature and differentiate due to what 2 reasons?
- genetic deletion
- genetic inhibition
Initiate, proliferate, and sustain the leukemia (full of blasts)
Leukemic stem cells (LSCs)
2 types of classification schemes for acute leukemia
- French-American-British (FAB) classification
- WHO classification
In FAB classification, lymphoblasts and myeloblasts are distinguished based on
morphological examination along with cytochemical stains
FAB classification was devised in what year?
1970s
Techniques commonly used to diagnose hematopoietic malignancies
flow cytometry and genetic/molecular studies
According to WHO classification, to diagnose the majority of acute leukemias, there must be at least how many percent of blasts in the bone marrow?
20%
Leukemia that is primarily a disease of childhood and adolescence
Acute Lymphoblastic Leukemia (ALL)
Acute lymphoma can either be?
T cell ALL or B cell ALL
The peak incidence of ALL in children is between what ages?
2-5 years
Most adult patients of ALL are older than what age
older than 50 years of age
How many percent of adults with ALL experience complete remission?
80-90%
Cure rate of adults with ALL is less than how many percent?
<40%
An important prognostic indicator for survival
subtype of ALL
Patients with B cell ALL typically present with what symptoms? (enumerate)
● Fatigue (anemia)
● Fever (neutropenia & infection)
● Mucocutaneous bleeding
(thrombocytopenia)
● Lymphadenopathy
● Splenomegaly & Hepatomegaly
(infiltration of malignant
cells and extramedullary
hematopoiesis-present to
compensate the inability of BM to produce other cell)
● Bone Pain
(intramedullary growth of leukemic cells)
T cell ALL presents with the same symptoms, although the degree of leukopenia is often (less/more?) severe
LESS
2 morphologic types of lymphoblast
small lymphoblast and large lymphoblast
The most common morphologic type of lymphoblast
small lymphoblast
With prominent nucleoli and nuclear membrane irregularities
large lymphoblast
With scant blue cytoplasm and indistinct nucleoli
small lymphoblast
The small lymphoblast is how many times larger than the normal lymphocyte
1.0-2.5x than normal lymphocyte
The large lymphoblast is how many times larger than the normal lymphocyte?
2-3x than normal lymphocyte
The prognosis of ALL depends on
- age at the time of diagnosis
- lymphoblastic load (tumor burden)
- immunophenotype
- genetic abnormalities
T/F: ALL is common in adults
F (it is rare)
T/F: ALL is rare in adults, but risk increases with age
T
Who has a poorer outlook of ALL, the children or adults?
adults
This mutation is the strongest prediction of adverse treatment outcomes
chromosomal translocation
Peripheral blood lymphoblast count that is associated with worse outcomes
> 20-30x10^9/L
Other symptoms associated with worse outcomes (aside from >20-30x10^9/L lymphoblast count)
- hepatosplenomegaly
- lymphadenopathy
The most reliable indicators of a cell’s origin
immunophenotyping and genetic analysis
The first tool used to distinguish ALL from AML
immunophenotyping
4 types of ALL
● Early (pro/pre-pre) B-ALL
● Intermediate (common) B-ALL
● Pre-B-ALL
● T-ALL
Both B and T cell are derived from lymphoid progenitors, and both usually express?
- CD34
- Terminal deoxynucleotidyl transferase (TdT)
- Human leukocyte antigen, DR subregion (HLA-DR)
Characterized by specific B cell antigens that are expressed at different stages of B cell development
B-ALL
In general B cells expresses
- CD10
- CD19
- CD20
- CD22
- CD24
- CD79a
- cytoplasmic μ
- PAX-5
Other name for CD10
common acute lymphoblastic leukemia antigen
or
common acute leukemic leukemia antigen
B cell specific activator protein
PAX-5
Early (pre-pre-/pro) B-ALL expresses?
- CD34
- CD19
- cytoplasmic CD22
- terminal deoxynucleotidyl transferase (TdT)
Intermediate (common) B-ALL expresses?
- CD34
- CD19
- cytoplasmic CD22
- terminal deoxynucleotidyl transferase (TdT)
- CD10
Pre-B-ALL expresses?
- CD34
- CD19
- cytoplasmic CD22
- TdT (variable)
- Cytoplasmic μ
T-ALL expresses most of the common T cell markers which are
- CD2
- CD3
- CD4
- CD5
- CD7
- CD8
- TdT (most cases express this)
The most mature B-ALL is called
pre-B-ALL
In pre-B-ALL, CD34 is typically
negative
Incidence of pro-B-ALL is about how many percent in children?
5% in children
Incidence of pro-B-ALL is about how many percent in adults?
11% in adults
Pre-B-ALL accounts for how many percent of childhood cases?
15%
Pre-B-ALL accounts for how many percent of adult B-ALL?
10%
T/F: T-ALL is most often teenage females
F (teenage males)
T cell ALL is seen most often in teenage males with
- mediastinal mass
- elevated peripheral blast count
- meningeal involvement
- infiltration of extra marrow sites
A distinct subtype of T-ALL that often shows expression of myeloid markers and was thought to have the capacity for myeloid differentiation
Early T cell precursor ALL (ETP-ALL)
What year did WHO classification subcategorizes T-ALL into ETP-ALL?
2017
T/F: ETP-ALL has poor prognosis to therapy
T
Majority of T-ALL have been shown to have gain-of-function mutations involving what gene?
NOTCH1 gene
Mutations in NOTCH1 gene alters Notch receptor signaling pathway which is responsible for
normal T cell development
In T-ALL, the cytogenetic alterations show (less/more?) specificity and (less/more?) correlation with the prognosis and treatment outcome than in B-ALL
less
less
according to WHO classification, B-lymphoblastic leukemia (B-ALL) is subdivided into how many subtypes?
9
9 subtypes of B-ALL
● B-ALL with t(9;22)(q34.1;q11.2);BCR-ABL1
● B-ALL with t(v;11q23.3);KMT2A (MLL) rearranged
● B-ALL with t(12;21)(p13.2;q22.1);TEL-AML1 (ETV6-RUNX1)
● B-ALL with hyperdiploidy
● B-ALL with hypodiploidy
● B-ALL with t(5;14)(q31.1;q32.1);IGH/IL3
● B-ALL with t(1;19)(q23;p13.3);TCF3-PBX1 (E2A-PBX1)
● B-ALL, BCR-ABL1-like
● B-ALL with iAMP21
The 9 subtypes of B-ALL are linked with
- unique clinical, phenotypic, or prognostic features
B-ALL that do not exhibit specific genetic abnormalities
B-lymphoblastic leukemia/lymphoma, not otherwise
specified
The mutation in B-ALL with the t(9;22)(q34.1;q11.2)
BCR-ABL1 mutation
Chromosome that has the worst prognosis among ALLs
Philadelphia chromosome–positive ALL
T/F: BCR-ABL1 mutation (Philadelphia chromosome–positive ALL) is more common in children
F (more common in adults)
Mutation in B-ALL with t(v;11q23)
KMT2A(MLL)-rearranged
Mutation in t(12;21)(p13.2;q22.1)
ETV6-RUNX1 translocation (childhood ALL)
Common in very young infants and has a very poor prognosis
B-ALL with t(v;11q23); KMT2A(MLL)-rearranged
t(12;21)(p13.2;q22.1);ETV6-RUNX1
translocation, accounts for how many percent of childhood ALL cases?
25%
Cure rate of t(12;21)(p13.2;q22.1);ETV6-RUNX1
translocation
90%
T/F: t(12;21)(p13.2;q22.1);ETV6-RUNX1
translocation is rare in adults
T
In B-ALL with t(v;11q23); KMT2A(MLL)- rearranged, the translocation may occur in
utero
T/F: Cytogenetic abnormalities are seen in the majority of B cell ALL only
F
(seen in the majority of B and T cell ALL)
Greater than 46 chromosomes and has a very favorable prognosis in children
hyperdiploidy
Less that 46 chromosomes and has poor prognosis in both children and adults
hypodiploidy
B-ALL with hyperdiploidy is common in childhood B-ALL, accounting to how many percent of cases?
25%
T/F: 50-70% of patients with T-lymphoblastic leukemia have abnormal gene rearrangement, but none of the abnormalities are associated with specific biologic features
T
Has limited early T cell differentiation
early T-cell precursor ALL (ETP-ALL)
Medicine that has shown success in treating chronic myeloid leukemia and has improved survival
imatinib
