Intro to Leukemias Flashcards
Describe leukemia
Progressive, malignant disease of hematopoietic system
What characterizes leukemia?
Unregulated proliferation of typically 1 type of cell line in the bone marrow.
Where does leukemia start?
In the bone marrow and spread into peripheral blood.
How is leukemia grouped?
By cell lineage and by maturity of affected cells (acute or chronic)
Describe the approach of leukemia treatment.
Treat the whole patient not just one part because the disease is systemic in nature.
Acute leukemia is characterized by…?
The abnormally large number of immature cells.
Gap in normal maturation process in bone marrow
Sudden onset
Aggressive short disease pattern
Lots of infection and hemorrhaging
FAB defines acute leukemia by
Greater than 30% blasts in bone marrow
WHO defines acute leukemia by
Greater than 20% blasts in bone marrow
Chronic Leukemia is characterized by…
-All stages of maturation seen (mostly mature cells)
-Insidious onset
-Longer, less aggressive disease pattern that involves organ infiltration and massive leukocytosis
-Sometimes can turn into acute called blast crisis
FAB defines chronic leukemia as….
Less than 30% blasts in bone marrow
WHO defines chronic leukemia as…
Less than 20% blasts in bone marrow
Which age groups are vulnerable to acute leukemia?
All ages are vulnerable
Which age groups are vulnerable to acute leukemia?
All ages are. Adults have poor outcomes.
WBC count in acute leukemia is
variable, can be very low
WBC count in chronic leukemia can be…
High
Platelet counts in acute leukemia is
variable sometimes very low
Platelet counts in chronic leukemia can be
Normal to elevated
Between acute or chronic leukemia which is severe?
Chronic leukemia
What does FAB stand for and what does it do?
French-American-British system established to provide uniform criteria for classifying acute leukemias before treatment changed their cellular morphology.
Other goals
-Aid in correlating treatment response to outcome and prognosis
-Differentiating different leukemias
In the modified FAB system, what changed?
Emphasis on correlating cytogenetic and immunochemistry studies with specific leukemia subtypes and clinical outcomes. All this work is for fine tuning treatment modalities.
Note: FAB has difficulty classifying platelet disorders, lymphoproliferative disorders, and variant monoblastic presentations.
What are the four methodologies used for identifying and classifying leukemias?
- Morphologic review of bone marrow and peripheral blood smears
- Cytochemical stains such as NSE, LAP, etc.
- Immunophenotyping
- Cytogenetic & molecular analyses
What information does morphologic review of bone marrow and peripheral blood smear yield?
Bone marrow - useful for differentiating acute versus chronic.
Peripheral blood smear - Limited diagnostic utility and usually sent out for pathology review.
What information does cytochemical stains yield?
Identifies specific molecules in malignant cells ( e.g. lipids, enzymes) that are associated with specific cell lines.
Note: This lead to immunophenotyping and cytogenetic analysis.
What information does immunophenotyping yield?
Uses flow cytometry with fluorescent antibodies to get information about surface marker antigens/receptors, cytoplasmic proteins, and nuclear information.
What enzyme increase suggests all lymphoblastic leukemias
Terminal deoxynucleotidyl transferase (TdT)
Note: Not typically seen in AML (?) per slide 13
What does it mean if a tumor is aneuploid?
Increase risk of relapse
What techniques/methods are used in cytogenetic and molecular analyses of leukemias?
- Karyotyping
- FISH, Fluorescence in Situ Hybridization
- PCR
What is the purpose of using PCR in molecular analyses in leukemias?
Yields quantitative results. Normal gene rearrangement means no malignancy. Positive translocation means there is malignancy.
What is karyotyping?
Why is FISH used in cytogenetic and molecular analysis of leukemias?
Its an excellent tool to detect micro-deletion syndromes caused by mismatch during crossing over. Examples are alpha thalassemias or DiGeorge Syndrome.
What does ALL stand for?
Acute lymphoblastic. Less specifically, lymphocytic leukemia
What does CLL stand for?
Chronic lymphocytic leukemia
What does AML stand for?
Acute myeloblastic. Less specifcally, myelocytic or myeloid.
What does ANLL stand for?
Acute nonlymphocytic leukemia
What does CML stand for?
Chronic myelocytic / myelogenous / myeloid leukemia
What are the four known causes of malignancies?
- Genetics
- Leukemogens
- Viral infections
- Radiation
In the cases of malignancies caused by genetics they are usually…
Somatic translocation and aneuploidy
What is the etiology of leukemogens?
Chemicals causing bone marrow depression and aplasia predispose to leukemia later on in life.
What are some examples of leukemogens?
Benzene, chloramphenicol, sulfa drugs, insecticides, and antineoplastics
How does viruses cause malignancy?
Retroviruses transform normal cells by inserting their own oncogenes into host cell’s genome causing them to become malignant.
Whats a virus that can lead to a form of malignancy?
EBV; it is linked to Burkitt non-Hodgkin lymphoma
What are proto-oncogenes?
They are normal genes which become altered by mutation to become oncogenes. They lead to cancer mutations.
What is aneuploid?
A chromosome number that is abnormal
What do tumor supressor genes do?
Code for proteins which resist malignancy
What are two proto-oncogenes?
t(9;22) and t(8;14)
If t(9;22) mutates into a proto-oncogene what may develop in the patient?
CML
If t(8;14) mutates into a proto-oncogene what may develop in the patient?
Burkett Lymphoma
What would peripheral blood work look like for acute leukemia?
Normo-,normo anemia (myelophthisic anemia.
-Platelet markedly decrease in acute
-WBC elevated in acute
-Blasts & immature forms present. Chronic will have numerous mature forms.
What would peripheral blood work look like for chronic leukemia?
-Normo-,Normo anemia
-Platelet markedly decrease
-WBC count markedly elevated in chronic
- Numerous mature forms in chronic
Note: Acute form will have blasts and immature forms
In bone marrow aspirate and biopsy analysis, the minimum percentage blasts for acute diagnosis in FAB system is?
Minimum 30 % blasts
In bone marrow aspirate and biopsy analysis, the minimum percentage blasts for acute diagnosis in WHO system is?
Minimum 20 % blasts
Cytochemistry requires ______ for examining specimens
Special stains
Immunophenotyping requires _____ for examining specimens
Antibodies and fluorescent stains
What methods are used in the second stage workup?
Bone marrow aspirate and biopsy analysis
What methods are used in cytogenetic studies?
PCR and FISH
What is MRD?
Minimal residual disease. Its the lowest level of disease detectable in patients who are in continuous clinical remission.
What methodology has grossly visible sensitivity?
Clinical symptoms
What methodology is microscopically visible?
CBC
Cytogenetic assays has what sensitivity percentage?
95.00%
FISH assays have what sensitivity percentage?
99.50%
Flow cytometry have what sensitivity percentage?
99.9%
PCR assays have what sensitivity percentage?
99.99%
What is required for the best kind of therapy for a leukemia patient?
An accurate diagnosis
What are the two main goals of leukemia treatment?
- Eradicate leukemic cell mass
- Provide supportive care for symptoms
What factors play a role in prognosis and treatment?
- Pretreatment health status
- Age
- Concurrent infections
- Abnormal cytogenetics
What treatment is used for diffuse malignancies?
Chemotherapy in conjunctive antibiotics through IV
How are drugs classified in chemotherapy?
- Effect on cell cycle
- Biochemical mechanism of action
What are the three stages of therapeutic strategy?
- Induction - Complete remission
- Consolidation - low dose chem to prevent recurrence
- Maintenance of remission
What is considered complete remission in chemotherapy?
Normal bone marrow cellularity is 5% blasts or more.
What treatment is used for localized malignancies?
Radiotherapy
How does radiotherapy work in malignancy treatment?
Produces unstable ions that damage cancer cells’ DNA
What is the purpose of supportive therapy for malignancies?
Allows for more efficient and effective delivery of chemotherapy regimens by preventing delays or dose reductions due to low blood counts.
What is used in supportive therapy?
Colony stimulating factors and EPO
What is used in targeted therapy?
Monoclonal antibodies. They are used to bind directly to affected cells, activates compliment and cell lysis.
What is important in a patient for bone marrow or stem cell transplant?
-Patient should be in good clinical condition and in 1st clinical remission for best results
-Requires presence of normal stem cells and reduction of malignant cells (I think it belongs here slide 28)
Bone marrow or stem cell transplantation requires the patient to undergo ______ then ______.
Chemotherapy then total body irradiation
What kind of donors are involved in syngeneic?
Identical twin donor
What kind of donors are involved in allogeneic?
Donor genetically different from recipient
What kind of donors are involved in autologous donations?
Patient’s own bone marrow or peripheral blood stem cells.
What is involved an autologous bone marrow / stem cell transplantation?
Marrow is harvested, conditioned, and transplanted back in the patient.
What is a serious complication in bone marrow or stem cell transplantation?
Graft versus host disease (GVHD). Donor’s bone marrow T-cells destroy bone marrow and tissues of recipient.
What develops due to overcrowding in the bone marrow?
Myelophthisic anemia (normo-, normo- anemia)
What symptoms develop if a patient has anemia?
Malaise, fatigue, pallor and dyspnea if it is severe
A patient has petechiae and epistaxis is a sign of…?
Thrombocytopenia
What is the second main cause of death in leukemia patients?
Hemorrhage, it is also a sign of thrombocytopenia.
What can develop in a patient with extreme anemia?
Hepatosplenomegaly because of extramedullary hematopoiesis. Hepatosplenomegaly may exacerbate anemia by trapping RBCs
What is the primary cause of death in leukemia patients?
Overwhelming infections because of neutropenia
What is a leukemoid reaction?
A transient reactive leukocytosis due to infection or severe infection.
In the leukemoid reaction would there be a right or left shift?
Severe left shift and nRBCs (very rare). Total WBC would be over 50k / uL
What is the cause of leukoerythroblastic reaction?
Other names are leukoerythroblastic anemia or leukoerythroblastosis.
It is caused by bone marrow damage from a malignant, “space-occupying lesion”, with consequent extensive extramedullary hematopoiesis.
When does leukoerythroblastic reaction happen?
Occurs in CML and patients with lymphomas. It can be mild or severe.
What is the difference in blood between leukemoid rxn and leukemoid rxn?
In leukemoid rxn the peripheral blood smear will temporary look like a leukemic picture. It will also have a severe left shift and have very few nRBCs.
In leukoerythroblastic rxn will have presence of both nRBCs and left shift in peripheral blood.
How does the lab differentiate leukemoid rxn and leukoerythroblastic rxn using LAP?
They use leukocyte alkaline phosphatase (LAP) stain score. The normal LAP score range is 15 to 170.
The decrease in LAP in early leukemia (Ex. early CML).
The increase in LAP suggest leukemoid reaction due to the left shift.
Today, LAP score is no longer used. What is used instead?
Acceptance of WHO classification is used. PCR is used to find the presence of BCR/ABL1 gene or t(9;22) identifies CML
How does LAP stain work?
Substrate naphthol AS-B1 phosphate is hydrolyzed by the enzyme LAP at an alkaline pH, and dyed to produce a colored precipitate.
Why is there a decrease in LAP in early leukemia?
Leukemic neutrophils are too abnormal to express LAP. Normal mature bands and segs express LAP. Also a decrease in LAP would indicate a lot of nRBCs
Why is there an increase in LAP in leukemoid reaction?
It happens because of the left shift. There are tons of bands and segs full of secondary granules containing LAP for potential invaders. A high WBC count can indicate leukemia however there are very few nRBCs present.
