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84 Cards in this Set

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Malignant cancer of the WBCs involving bone marrow, circulating WBCs, spleen and lymph nodes
Leukemia
Rapid progression of accumulating IMMATURE poorly differentiated cells (usually blasts)
Acute Lymphocytic Leukemia (ALL)
Acute Myelogenous Leukemia (AML)
Acute Leukemia
Slower progression of more MATURE functional cells
Chronic Lymphocytic Leukemia (CLL)
Chronic Myelogenous Leukemia (CML)
Chronic Leukemia
Which is more common, acute or chronic leukemia?
Chronic leukemia is more common
is the most common type of leukemia in children
ALL
is the most common type of leukemia in adults followed by AML
CLL
What are the risk factors for Leukemia?
Exposure to ionizing radiation
Exposure to chemicals (Benzene)
Prior treatment with cancer drugs (Cyclophosphamide, Melphalen)
Exposure to herbicides (CLL), pesticides
Chromosomal Disorders
Down Syndrome, Fanconi’s Anemia (AML)
Myelodysplastic Syndrome
Progressive bone marrow failure, insufficient proportion of blasts (<30%) to diagnosis AML
Up to 60% evolve into AML
The biggest risk factor for leukemia is?
Exposure to ionizing radiation.
When is it most common to see leukemia in a patient after having had tx with cancer drugs?
4-6 years.
Which risk factor is attributed to a higher rate of leukemia?
Chormosomal disorders - Down Syndrome, Fanconi's Anemia (AML)
Normal cells in leukemia are replaced with malignant cells due to?
Abnormal proliferation, clonal expansion, and diminished apoptosis
What are the general manifestations of leukemia?
Due to suppression of normal functioning RBCs (anemia) , WBCs (infections & poor healing) & Platelets (bleeding or bruising)

Organ infiltration can lead to hepatomegaly, splenomegaly, lymphadenopathy

Meningeal infiltration can elevate intracranial pressure (headache, mental status changes)

A proportion of people with chronic leukemia are diagnosed during routine medical exam
Two-thirds of cases occur in children
Peak incidence in children between 2-7 years of age; second rise in incidence after age 45
Characterized by circulating blasts, replacement of normal bone marrow with malignant cells and potential for CNS and abdominal organ infiltration
Presence of Philadelphia (Ph) Chromosome associated with poorer prognosis
Classified by the French-American-British (FAB) System
ALL
The following are clinical manifestations of what?

Easy bruising
Prolonged bleeding from minor cuts
Lymphadenopathy
Fever of Unknown Origin
Frequent infections
Fatigue, Pallor
SOB on exertion
Splenomegaly
Vomiting
Headaches
Bone and joint pain
ALL
What is associated with poorer prognosis in ALL?
Presence of Philadelphia (Ph) Chromosome associated with poorer prognosis.
What is seen in the CBC with someone who has ALL?
WBC high in 50%; nml or low in remainder
WBC differential marked by Lymphoblasts
Anemia present in >90%, usually severe
Platelets low in >80%
What is seen in the peripheral smear with someone who has ALL?
Lymphoblasts
What is seen in the bone marrow aspirate and biopsy of someone with ALL?
Dominated by blast cells
Majority of ALL cells express what?
terminal deoxynucleotidyl transferase (TdT) - Protein marker, it is diagnostic for ALL if present.
What other studies, apart from CBC, Peripheral Smear and Bone Marrow Aspirate/Biopsy do you use to diagnose ALL?
Uric Acid Level, Liver Function, LDH, Kidney Function

CXR
Mediastinal mass may be present with ALL

Abdominal CT/MRI/US
Assess splenomegaly and abdominal organ involvement

Head CT
Rule out CNS involvement

Spinal Tap
Rule out CNS involvement
There are how many phases of chemotherapy for ALL?
4
ALL Treatment:
Remission Induction - Prednisone and chemo drugs:
Combination Chemotherapy to induce remission
Imatinib (Gleevac) added to Ph chromosome + cases
Phase 1 TX ALL
ALL TX:
CNS Prophylaxis: Methotrexate is used for Prophylaxis and treatment with intrathecal agents
Phase 2 TX ALL
ALL TX:
Post-Remission Consolidation
Combination chemotherapy to prevent regrowth
Stem cell transplant for Ph chromosome positive ALL or in 2nd or more relapses
Phase 3 TX ALL
ALL TX:
Therapy for approximately 2-3 years with either Methotrexate or Mercaptopurine
Phase 4 TX ALL - Maintenance
This is a maintenance drug used in phase four treatment of ALL that's long term use can cause cancer, but it is still the drug of choice.
Methotrexate
Relapse may appear in the bone marrow, the CNS or the testes
Bone marrow relapse is associated with a poorer long-term prognosis
May perform a new round of induction chemotherapy
Stem cell transplant may be appropriate not succesful in patients over 65.
ALL Relapse
Uncontrolled proliferation on an abnormally differentiated myeloid progenitor cell
Occurs in approximately 3.7 per 100,000 persons
Can occur in both children and adults but incidence increases with age
Median onset is 50 years of age
AML
How many subtypes of AML are there?
8, M0-M7, M3 Acute Promyelocytic Leukemia was highlighted.
What are the clinical manifestations of AML?
Fatigue, pallor
Easy bruising or bleeding, prolonged bleeding from minor cuts
Fever
Infection
SOB with exertion
Swollen gums
Bone and joint pain
½ have Splenomegaly
Rare Lymphadenopathy
Accounts for 10-15% of AML cases
Occurs at younger age (30s); more common in Hispanics
Characterized by the cytogenetic finding of t(15:17) and the fusion gene PML-RAR alpha
Treated with all-trans retinoic acid (ATRA) plus chemotherapy
90-95% of patients achieve remission; long-term survival in 65-70%
MOST CURABLE FORM OF AML
May also be treated with arsenic trioxide
Acute Promyelocytic Leukemia (APL)
What is seen in the CBC of a patient with AML?
WBC high in 60%; nml or low in remainder
WBC differential marked by Myeloblasts
Anemia present in >90%, usually severe
Platelets low in >90%
What is seen in the peripheral smear of a patient with AML?
Myeloblasts
What is seen in the bone marrow aspirate/biopsy of a patient with AML?
Dominated by Blast Cells
What is seen in diagnostics and is pathognomonic for AML?
Auer Rod
AML will usually express what?
Myeloid antigens CD13 or 33
How do you treat AML?
Induction Therapy
Combination Chemotherapy
Responds to fewer drugs than ALL
Consolidation
Combination Chemotherapy +/- Stem Cell Transplant
CNS prophylaxis usually not required
May be treated with high-doses chemotherapy and stem cell transplant
Most effective in younger patients whose remission lasted >1 year
AML Relapse
What is the most important prognostic factor in AML?
The Leukemic cell karyotype
In AML prognosis is better in what patients?
Younger patients.
Most common type of Leukemia

More common in persons over the age of 60

Twice as common in men than women

Involves mature appearing malignant lymphocytes with an abnormally long cell life - Apoptosis doesn't occur.

Onset often insidious and often discovered during routine blood tests
CLL
CLL are of what lineage
Almost always of B-Cell Lineage (95%)
Remainder are either of T Cell or NK Cell lineage.
Asymptomatic; identified during routine blood tests
Lymphadenopathy
Splenomegaly
Hepatomegaly
Infections
Fatigue
SOB on Exertion
Weight Loss
Herpes Zoster flair
CLL Clinical Manifestations
What is seen on the CBC with CLL?
WBC high in 98%; nml or low in remainder
WBC differential marked by lymphocytosis
Anemia present in 50%, usually mild
Platelets low in 20-30%
What is seen on the peripheral smear in CLL?
Small Mature Lymphocytes
What is seen in the bone marrow biopsy of CLL?
>30% Lymphocytes
What diagnostics are used in the diagnosis of CLL?
Immunophenotyping to determine B-Cell from T-Cell

CLL co-expresses CD 19 antigen with the T lymphocyte marker CD 5 (Mantle Cell Lymphoma)

CLL differentiated from Mantle Cell Lymphoma by expression of CD 23, low expression of surface immunoglobulin and the absence of overexpression of cyclin D1

Hypogammaglobulinemia present in ½ of patients
In CLL you will often see these three things happening as clinical manifestations?
Lymphadenopathy

Splenomegaly

Hepatomegaly
This is caused by a lack of lymphocyte function which leads to decreased immunoglobulins and decreased cells to fight infection. It is something that is seen in the diagnostics of CLL?
Hypogammaglobulinemia
Low Risk
Stage 0: Lymphocytosis Only
Stage I: Lymphocytosis + Lymphadenopathy
Intermediate Risk
Stage II: Organomegaly
High Risk
Stage III: Anemia
Stage IV: Thrombocytopenia
Rai Staging system from CLL
How is low risk CLL treated?
It is not initially treated.
What are two things that are monitored with CLL Treatment.
Blood lymphocyte is not initially treated - blood lymphocyte doubling time - lymphocyte number that doubles in one year.

Beta 2 Microglobulin - Higher levels of Beta 2 microglobulin associated with more CLL cells.
What is the basic parameter for treating a low risk case of CLL?
Treatment is reserved for symptomatic patients because it may take years to develop and don't' want to expose patients to chemo drugs that may need later.
How do you treat intermediate and high risk CLL?
Usually treated with combination chemotherapy
Fludarabine (Fludara), Cyclophosphamide (Cytoxan), Bendamustine (Treanda)
+/- Monoclonal antibody therapy
Monoclonal antibodies are immune proteins that aim for a specific target on CLL cell surfaces
Rituximab (Rituxan) & Alemtuzumab (Campath)

Hemolytic Anemia & Thrombocytopenia
Treated with Prednisone
Response may be brief

Radiation Therapy
Local radiation to areas of lymphadenopathy or enlarged liver or spleen
This is CLL that responded to therapy but then stopped responding six or more months after therapy.
Relapsing CLL
How do you TX relapsed CLL?
Treatment options are generally the same as initial treatment

Stem Cell transplant may also be attempted
Progression to this is associated with shorter survival in CLL?
Progression to bone marrow failure is associated with shorter survival
CLL patients are more likely to develop a secondary cancer later in life. Particularly this kind of cancer?
Skin Cancer
A myeloproliferative disorder characterized by overproduction of myeloid cells particularly granulocytes
Myeloid cells retain their capacity for differentiation
Bone marrow function remains normal in the early phases
Accounts for 15% of all adult leukemias
Both children and adults can get this; but most of the times it occurs in adults
Chronic Myelocytic Leukemia (CML)
Chronic myelocytic leukemia is uncommon in patients under what age?
10 years old.
Characterized by Philadelphia (Ph) Chromosome

Reciprocal translocation t(9;22)
A piece of chromosome 9 containing the oncogene ABL is translocated to chromosome 22 and fused to the BCR gene

The fusion gene BCR-ABL is the cancer causing gene initiating excessive production of granulocytes primarily in bone marrow but also extramedullary sites (spleen, liver)
Produces tyrosine kinase
CML pathophysiology
It is important to know the site of the cancer causing genes that are initiating excessive production of granulocytes because?
So that you can specifically target where the production is happening when picking a treatment
What phase of CML is symptomatic?
Chronic
What are the three phases of CML?
Chronic
Accelerated
Blast Crisis
Phase of CML:

Indolent Phase lasting from months to years Normal bone marrow function
White cells still able to fight infection
Chronic Phase of CML
Phase of CML:

Patients may develop anemia, thrombocytopenia
Spleen may enlarge
Rise in blast cells
Accelerated Phase of CML
Phase of CML:

Marked by blast cells in blood & marrow
Blast cell in extramedullary sites (bone, CNS, skin)
Resembles acute leukemia
Blast Crisis phase of CML
Patients may be asymptomatic and diagnosed from routine blood tests
Fatigue
Pallor
SOB on exertion
Splenomegaly: may be severe
Sternal Tenderness
Weight Loss
Night Sweats
Inability to tolerate warm temperatures
Clinical manifestations of CML
Why is sternal tenderness a clinical manifestation of CML?
Blast cell invasion into sternum.
What is seen in the CBC of a CML patient?
WBC high in 100%
Anemia present in 80%, usually mild
Platelets high in 60%
What is seen in the peripheral smear of a patient with CML?
Peripheral Smear
Immature Granulocytes and eosinophila and basophilia
Blast cells usually <5%
This is low in CML patients?
Leukocyte alkaline phosphatase
Leukocyte alkaline phosphatase measures alkaline phosphatase in WBCs it is used to?
Differentiate cause of neutrophilia. It is decreased in CML and increased in Polycythemia vera.
What is seen with the bone marrow biopsy of a patient with CML?
Hypercellular with left-shifted myelopoisis
Myeloblasts less than 5% of marrow cells
What test is done in CML on blood to detect BCR-ABL gene
Polymerase Chain Reaction (PCR)
This is done on bone marrow to detect the Philadelphia chromosome?
Cytogenetics
With progression to blast crisis in CML what occurs?
progressive anemia and thrombocytopenia occur, Leukocyte Alkaline Phosphatase may increase
Blast phase is diagnosed when blasts are ? of the bone marrow.
Blast phase is diagnosed when blasts are >20% of the bone marrow
How do you TX CML?
Tyrosine Kinase Inhibitors
Imatinib (Gleevac), Dasatinib (Sprycel) and Nilotinib (Tasigna)
Inhibit specific tyrosine kinase that results from the ABL-BCR gene product
Imatinib (Gleevac) is first line agent
Survival >90% at 5 years past diagnosis with Imatinib
In blast crisis, what is used to treat this stage of CML?
Combination chemotherapy and tyrosine kinase inhibitors.
This is the only curative TX for CML. It is most successful in younger patients (<40) and when performed within one year of diagnosis.
Stem cell transplant
This is a supplemental treatment of CML, tha tis only performed in rare cases of extereme hyperleukocytosis.
Emergent leukophoresis.
What are the symptoms of extreme hyperleukocytosis associated with CML?
Visual disturbances, respiratory distress, altered mental status and priapism.
Ph Chromosome negative has a ______ progonsis than a Ph chromosome positive CML.
Ph chromosome negative CML has a worse prognosis than Ph chromosome positive CML