Unit 2: Introduction to Leukemias Flashcards by Sarah King

-progressive, malignant disease of hematopoietic system
-Characterized by unregulated proliferation of (usually) 1 cell
line

Leukemia

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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

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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

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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

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 Sudden onset
 Short, aggressive disease pattern
 Lots of infections & hemorrhaging

Acute Leukemia

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Acute leukemia:

 FAB defines by ____% blasts in bone marrow
 WHO defines by ___% blasts in bone marrow

> 30, >20

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 All stages of maturation seen, with predominantly mature cells.
 Insidious onset

Insidious= slow

Chronic Leukemia

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Lengthier, less aggressive disease pattern (lots of organ infiltration & massive leukocytosis).

Chronic Leukemia

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Chronic Leukemia:

FAB defines by ___% blasts in bone marrow
 WHO defines by ____% blasts in bone marrow

< 30, <20

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Chronic leukemia sometimes turns into acute! Called “__________”.

blast crisis

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Onset of acute and chronic leukemia?

acute- abrupt
chronic- insidious

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Death of acute and chronic leukemia?

acute- months
chronic- years

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Patient’s age of acute and chronic leukemia?

acute- all ages
chronic- adults

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WBC count with acute and chronic leukemia?

acute- variable (can be very low!)
chronic-high

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Cell maturity with acute and chronic leukemia?

acute- immature
chronic- mature

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Plt. count with acute and chronic leukemia?

acute- variable (can be very low!)
chronic- N. to increased

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Organomegaly with acute and chronic leukemia?

Organomegaly- abnormal enlargement of organs

acute- mild
chronic- severe

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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.

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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

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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

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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.

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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

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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

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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

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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?

1. ALL - Acute Lymphoblastic 2. CLL - Chronic Lymphocytic Leukemia 3. AML - Acute Myeloblastic 4. 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?

1. Eradicate leukemic cell mass. 2. 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?

1. chemotherapy 2. radiation therapy 3. supportive therapy 4. targeted therapy 5. 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),