Unit 2: Introduction to Leukemias Flashcards
-progressive, malignant disease of hematopoietic system
-Characterized by unregulated proliferation of (usually) 1 cell
line
Leukemia
Abnormal cells originate in bone marrow & then spread into peripheral blood
Leukemias are grouped by ___________ and by the maturity of affected cells (acute or chronic)
cell lineage
What is usually the cause of leukemias?
type of treatment?
-Cause of malignancy is usually unknown (a few exceptions)
-Not localized, but are systemic in nature. Most treatment options are systemic
Acute leukemia is characterized by preponderance of _____________ cells.
immature
-You see a gap in N.
maturation process in bone marrow The N. “pyramid” of
cell development instead has many blasts, some mature
forms, & a few intermediate stages = leukemic hiatus
Sudden onset
Short, aggressive disease pattern
Lots of infections & hemorrhaging
Acute Leukemia
Acute leukemia:
FAB defines by ____% blasts in bone marrow
WHO defines by ___% blasts in bone marrow
> 30, >20
All stages of maturation seen, with predominantly mature cells.
Insidious onset
Insidious= slow
Chronic Leukemia
Lengthier, less aggressive disease pattern (lots of organ infiltration & massive leukocytosis).
Chronic Leukemia
Chronic Leukemia:
FAB defines by ___% blasts in bone marrow
WHO defines by ____% blasts in bone marrow
< 30, <20
Chronic leukemia sometimes turns into acute! Called “__________”.
blast crisis
Onset of acute and chronic leukemia?
acute- abrupt
chronic- insidious
Death of acute and chronic leukemia?
acute- months
chronic- years
Patient’s age of acute and chronic leukemia?
acute- all ages
chronic- adults
WBC count with acute and chronic leukemia?
acute- variable (can be very low!)
chronic-high
Cell maturity with acute and chronic leukemia?
acute- immature
chronic- mature
Plt. count with acute and chronic leukemia?
acute- variable (can be very low!)
chronic- N. to increased
Organomegaly with acute and chronic leukemia?
Organomegaly- abnormal enlargement of organs
acute- mild
chronic- severe
system established in 1976 to provide uniform criteria for classifying acute leukemias before treatment changed their cellular morphology.
FAB (French-American-British) system
-FAB also wanted to aid in correlating treatment response to outcome, & to eventual prognosis.
FAB system is based on…
cell lineage and cytochemical response
Goal was to distinguish lymphoid from myeloid leukemias.
-Worked ok for differentiating the basic acute vs. chronic and lymphocytic vs. myeloid
Massive information explosion, along with advent of advanced techniques, caused World Health Organization (WHO) to develop_________
system in 2001 – updated in 2008 and 2016.
modified FAB
Modified FAB system:
WHO emphasized correlation of cytogenetic & immunochemistry studies with specific leukemia
subtypes AND with _______________, in order to fine-tune treatment modalities.
FAB had difficulty with
clinical outcomes
FYI: FAB has difficulty classifying plt. disorders, lympho-proliferative disorders, & variant monoblastic presentations.
What are the four methodologies used for identifying and classifying leukemias?
-Morphologic review of bone marrow and Morphologic review of peripheral blood smears
-Cytochemical stains (Ex., NSE, LAP, etc.)
-Immunophenotyping
-Cytogenetic & molecular analyses
Methodology for identifying leukemias:
Historically most used, but really inadequate except
for differentiating acute vs. chronic! Cannot really be used by itself!
Morphologic review of bone marrow
Methodology for identifying leukemias:
What we use in lab, but of limited diagnostic utility.
Cannot ever be used by itself – send out for path review.
Morphologic review of peripheral blood smears
Methodology for identifying leukemias:
Historically very useful.
Identifies specific molecules in malignant cells (Ex., lipids, enzymes) that are associated with specific cell
lines.
Cytochemical stains (Ex., NSE, LAP, etc.)
-giving way to immunophenotyping & cytogenetic analyses . .
Methodology for identifying leukemias:
- Via fluorescent Abs
- Used for specific cell lineage &/or specific maturation stage markers.
-Done by flow cytometry (very good for acute leukemias) using 5-color immunofluorescence.
(Markers may be surface, cytoplasmic, or nuclear.)
Immunophenotyping
Methodology for identifying leukemias:
Immunophenotyping example:
_________ expression of ABO antigens is common in leukemias.
decreased
Immunophenotyping:
What are some flow cytometry marker examples?
Tdt
Surface marker Ags/receptors – CD, HLA, etc. Certain cell
surface Ags associated with specific tumor phenotypes.
Cytoplasmic
Nuclear
a. Enzymes - Terminal deoxynucleotidyl Transferase (TdT) =
unique enzyme present only in early lymphoid cells. Thus ↑ levels seen in lymphoblastic leukemias (ALL), but not
typically seen in AMLs (?)
b. Aneuploidy – if tumor is aneuploid, ↑ aneuploidy = ↑risk of relapse
Acute myelocytic / myelogenous / myeloid /
myeloblastic / nonlymphocytic????
AML
Methodology for identifying leukemias:
the “Supreme Court of
Diagnosis”, using…
-karyotyping
-FISH
-PCR
Cytogenetic & molecular analyses
“Molecular remission” =
PCR negative
Cytogenetic & molecular analyses:
microscopic whole chromosome analysis.
Karyotyping
Cytogenetic & molecular analyses:
can use any sample type. FYI: Excellent for micro-deletion syndromes (caused by mismatch during crossing over.) (Ex., some ą-thalassemias, DiGeorge Syndrome)
FISH (Fluorescence In Situ Hybridization)
Cytogenetic & molecular analyses:
yields quantitative results; old favorite technique.
Normal gene rearrangement = NO (malignancy);
Positive translocation = YES (malignancy)
PCR
What are the 4 major types of leukemia?
- ALL - Acute Lymphoblastic
- CLL - Chronic Lymphocytic Leukemia
- AML - Acute Myeloblastic
- CML - Chronic Myelocytic / Myelogenous / Myeloid
Leukemia
Myeloid (AML) and Lymphoid (ALL) acute or chronic?
acute
What are the subtypes that fall under acute Lymphoid (ALL)?
-T lymphocytic
-B lymphocytic
-Null cell (?)
What are the subtypes that fall under acute Myeloid (AML)?
-Myelocytic/ Myelogenous
-Promyelocytic
-Monocytic
-Myelomonocytic
(AMML)
What are the subtypes that fall under chronic myeloid?
-Myelocytic/Myelogenous (CML)
-Myelomonocytic (CMML)
What are the subtypes that fall under chronic lymphoid?
-Lymphocytic (CLL)
-Plasmocytic
-Hairy Cell (HCL)
-Prolymphocytic (PLL)
For most leukemias the cause of malignancy is unknown, but with what exceptions?
-genetics
-Leukemogens
-Viral infections
-Radiation
chemicals causing bone marrow depression &
aplasia predispose to leukemia later on (Ex., benzene, chloramphenicol, sulfa drugs, insecticides, antineoplastics)
Leukemogens
How can viruses cause cancers?
EBV linked to
some retroviruses transform N. cells by
inserting their own oncogenes into host cell’s genome, causing
them to become malignant.
[EBV linked to Burkitt non-Hodgkin
lymphoma]
Proto-oncogenes are normal genes which become altered by mutation to become ___________
oncogenes
genes that cause cancer mutations.
Oncogenes
-Mutated version of a proto-oncogene
Example of oncogene?
CML t(9;22) and Burkitt Lymphoma t(8;14)
-CML: ABL proto-oncogene on chromosome 9 is activated when fused with the BCR component of chromosome 22
-Burkitt Lymphoma:
MYC proto-oncogene on chromosome 8 is activated when fused with Ig on chromosome 14
a chromosome number that is abnormal.
Aneuploid
code for proteins which resist malignancy.
tumor suppressor genes
What does laboratory evaluation include?
-Preliminary Workup of peripheral blood: CBC with plts. and diff.
-Second Stage Workup: bone marrow aspirate & biopsy analysis
Laboratory evaluation:
RBCs…
CBC with plts. and diff.
RBCs – have normo-, normo- anemia (usually).
Typically this is myelophthisic anemia (?)
Laboratory evaluation:
Plt. & WBC counts…
variable: mkd. ↓ in acute,
↑ in acute or chronic, to mkd. ↑ in chronic.
Laboratory evaluation:
On differential?
usually see blasts & immature forms… if acute, numerous mature forms if chronic.
Laboratory evaluation, Second Stage Workup: bone marrow aspirate & biopsy analysis:
- Minimum ___ % blasts in bone marrow required
for acute diagnosis in FAB system - Minimum ___ % blasts in bone marrow required
for acute diagnosis in WHO system
30
20
Second Stage Workup: bone marrow aspirate &
biopsy analysis:
Cytochemistry – using _____________
special stains
Why do leukemia patients have hyperproliferative bone marrow?
due to replacement of hematopoietic tissue by
leukemic cells
Second Stage Workup: bone marrow aspirate &
biopsy analysis:
Immunophenotyping – using ______________
Abs & fluorescent stains
Second Stage Workup: bone marrow aspirate & biopsy analysis:
Cytogenetic studies – using what techniques?
PCR & FISH
cytogenetic studies are also used to detect…
Minimal Residual Disease (MRD) – the lowest level of disease detectable in pts. who are in continuous clinical remission
Treatment:
the best therapy must start with…
an accurate diagnosis
What are the two main goals of leukemia treatment?
- Eradicate leukemic cell mass.
- Provide supportive care for symptoms.
What are factors playing roles in prognosis and treatment modalities are the pt.’s…
Pretreatment health status
Age
Concurrent infection(s)
Abnormal cytogenetics
Treatment:
categories of therapy?
- chemotherapy
- radiation therapy
- supportive therapy
- targeted therapy
- stem cell transplantation
Chemotherapy
Typically given IV in conjunction with antibiotics;
for diffuse __________.
malignancies
How are chemotherapy drugs classified?
by their effects on the cell
cycle and by their biochemical mechanism of
action.
Some affect specific phases of the cell cycle
Some affect any phase of the cell cycle
FYI: Three stages of therapeutic strategy?
Induction – of complete remission (N. bone
marrow cellularity = < 5% blasts!)
Consolidation - low dose chemo. to prevent recurrence.
Maintenance - of remission.
- Produces unstable ions that damage cancer cells’ DNA.
- Used for localized malignancies.
Radiotherapy (“radiation”)
Supportive Therapy:
Used to support cancer patients
Allow for more efficient and effective delivery of
chemotherapy regimens by preventing delays or dose
reductions due to low blood counts.
Examples?
colony stimulating factors & EPO
Monoclonal antibodies which bind directly to affected cell, activates compliment, and cell lysis.
This is an example of what kind of treatment?
Targeted Therapy
What will give best results for Bone marrow or Stem Cell Transplantation
(BMT, SCT)?
There’s been great strands in isolating
Pt. should be in good clinical condition & in 1st clinical
remission for best results.
(note: The effort to isolate stem cells from non-embryonic sources is making tremendous strides)
Bone marrow or Stem Cell Transplantation (BMT, SCT):
classic approach typically requires…
intensive chemotherapy, then total body irradiation.
What are the 3 types of bone marrow donors?
Syngeneic
Allogeneic
Autologous
Bone marrow/stem cell donor type:
identical twin donor
Most rare and the most desired
Syngeneic
Bone marrow/stem cell donor type:
donor genetically different from recipient
Most serious transplant complication is GVHD (?
____________________), in which donor’s bone marrow T-cells destroy bone marrow & tissues of recipient.
Allogeneic
Bone marrow/stem cell donor type:
patient’s own marrow or peripheral blood stem cells
Autologous
Marrow is harvested, conditioned, and transplanted back in the
patient
Requires the presence of normal stem cells and reduction of malignant cells
Common Clinical Symptoms of All Leukemias?
-Myelophthisic anemia (due to bone marrow overcrowding)
-anemia: malaise, fatigue, pallor (dyspnea if severe)
-thrombocytopenia: Petechiae (pinpoint bruising),
Epistaxis (nosebleed),
Hemorrhage
What is the 2nd main cause of death in leukemias?
Hemorrhage
Common Clinical Symptoms of All Leukemias:
Due to extreme anemia:
____________________________, causing hepatosplenomegaly.
extramedullary hematopoiesis
NOTE: Hepatosplenomegaly may actually exacerbate anemia by inadvertently trapping RBCs (sequestration.)
Common Clinical Symptoms of All Leukemias:
Due to neutropenia, increased incidence overwhelming
____________; this is primary cause of death in leukemia!
infections
Transient, reactive leukocytosis due to infection
Temporary resemblance of peripheral blood
picture to “leukemic picture”
Severe left shift & very rare nRBCs. (WBCT > 50,000/uL!)
Leukemoid reaction
Leukoerythroblastic reaction aka…
Leukoerythroblastic anemia, or Leukoerythroblastosis)
Leukoerythroblastic reaction:
Presence of both ________ & _____ shift in peripheral blood.
nRBCs, left
Leukoerythroblastic reaction may be mild or severe, and occurs in _____ and in _________.
CML, lymphomas
Caused by bone marrow damage from a malignant, “space-occupying
lesion”, with consequent extensive extramedullary hematopoiesis.
Leukoerythroblastic reaction
Historically, how can you tell Leukemoid rxn. vs.
Leukoerythroblastic rxn?
a Leukocyte Alkaline Phosphatase (LAP) stain score
What is Leukocyte Alkaline Phosphatase (LAP)?
An enzyme found in the secondary granules of neutrophils
LAP stain score principle?
The substrate naphthol AS-B1 phosphate is hydrolyzed
by the enzyme at an alkaline pH, and dyed to produce a
colored precipitate
LAP stain score:
TWO slides are obtained per patient, and activity is
graded from 0 to 4+ (performed by ____ techs, and must agree within __%)
2, 10
Early leukemia:
Is LAP increased or decreased? Why?
-decreased
-(Ex., early CML) because leukemic neutrophils are too abnormal to express the LAP that N., mature bands & segs would. Also, you see real
leukoerythroblastosis
(Lots of nRBCs!!)
Leukemoid reaction:
Is LAP increased or decreased? Why?
-increased
-due to left shift, because there are tons of bands & segs full of secondary granules containing LAP, just waiting to attack the infectious invaders – it only looks like a leukemia because of the high WBC count. Also, you see only very rare nRBCs!!
Normal LAP score range?
15-170
With the acceptance of the WHO classification, LAP score is no longer used. Instead, the presence of the
_________ gene, or _______ identifies CML.
BCR/ABL1, t(9;22),
