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42 Cards in this Set
- Front
- Back
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What is ALL?
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ALL is a malignancy of a committed lymphoid progenitor cell.
The malignant cells lose the ability to differentiate. Homogeneous population of lymphoblasts. |
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What is CLL?
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CLL is a malignancy of mature B-cells.
Homogeneous population of mature lymphocytes. |
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What is AML?
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AML is a malignancy of a committed myeloid progenitor cell.
The malignant cells lose the ability to differentiate. Homogeneous population of myeloblasts. |
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What is CML?
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CML is a malignancy of a hematopoietic progenitor cell.
The malignant cells maintain the ability to differentiate (predilection for myeloid pathway.) Heterogeneous population of cells. |
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What is the clinical presentation of CML?
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Symptoms: fatigue/sweats/fever, weight loss, early satiety
PE: splenomegaly, hepatomegaly Lab: leukocytosis (neutrophilia, pasophilia, eosinophilia), anemia, thrombocytosis |
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What is the pathophysiology of CML?
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There is a a reciprocal translocation t(9;22) involving a hematopoietic stem cell (HSC) that gives rise to BCR-ABL. This is called the Philadelphia chromosome. Required for diagnosis of CML.
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What is BCR-ABL?
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BCR-ABL is a constitutively active intracellular tyrosine kinase that activates a number of downstream signaling events that lead to increased proliferation and decreased apoptosis.
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Why is BCR-ABL the exception to the multi-step model of cancer?
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BCR-ABL is necessary and sufficient to cause CML.
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How is CML diagnosed?
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Peripheral blood smear and bone marrow aspirate/biopsy to determine phase,
cytogenetic evaluation of blood/bone marrow to detect t(9;22), FISH (detects cryptic (9;22) translocations, PCR (most sensitive technique for detecting bcr-abl) |
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What is a pro of cytogenetic diagnostics that is not shared by FISH or PCR?
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It detects other cytogenetic abnormalities.
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What is the clinical course of CML?
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Chronic phase (3-5 years),
accelerated phase (6-9 months), blast crisis (3-6 months) and transformation to acute leukemia (66% AML, 33% ALL.) |
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How does Gleevec work?
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Imatinib mesylate (Gleevec) works by binding to the inactive conformation of BCR-ABL.
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What are the two types of imatinib resistance?
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Primary resistance: inadequate initial response (ex: low levels of imatinib through malabsorption or metabolism, reduced levels of the influx pump)
Secondary resistance: loss of previous reponse (ex: overexpression of bcr-abl, mutations in ABL kinase domain that block binding) |
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What is the only known curative option for CML?
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Allogenic stem cell transplantation (SCT.) Graft versus host disease associated with lower risk of relapse (graft vs. leukemia), but if the patient does relapse they can be treated with an infusion of donor-derived lymphocytes.
SCT associated with substantial morbidity and mortality. |
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What is the most common adult leukemia?
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CLL
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What are risk factors for developing CLL?
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Family member with CLL,
exposure to Agent Orange. |
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What is the clinical presentation of CLL?
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Symptoms: fatigue/sweats/fever, weight loss, early satiety, frequent infections
PE: Splenomegaly, lymphadenopathy, some hepatomegaly Labs: leukocytosis (lymphocytosis), anemia, thrombocytopenia, hypogammaglobulinemia. |
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What is the most common autoimmune phenomena to occur in CLL?
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Autoimmune hemolytic anemia. (AIHA)
AIHA + ITP = Evan's syndrome |
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What transformation events can occur with CLL?
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CLL can transform to
diffuse large B-cell non-Hodgkin's lymphoma (Richter's syndrome), or prolymphocytic leukemia. |
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What is the pathophysiology of CLL?
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Bcl-2, an anti-apoptotic factor, is overexpressed. Bcl-2 inhibits the release of cytochrome c from mitochondria, which triggers the activation of caspases.
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What are the stages of the Rai classification of CLL?
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Stage 0: lymphocytosis only
Stage 1: lymphocytosis and lymphadenopathy Stage 2: lymphocytosis and splenomegaly Stage 3: lymphocytosis and anemia Stage 4: lymphocytosis and thrombocytopenia |
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Is CLL a curable disease?
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No.
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What are the indications for chemotherapy in CLL?
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Progressive symptoms,
progressive adenopathy/organomegaly, autoimmune cytopenias, increased bacterial infections. |
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What categories of chemotherapeutic agents can be used for CLL?
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alkylating agents,
purine analogs, and monoclonal antibodies. |
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What are the risk factors for AML?
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Prior radiation/chemotherapy,
benzene exposure, history of a myeloproliferative disorder, or various familial syndromes. |
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What is the clinical presentation of AML?
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Symptoms: fatigue/sweats, weight loss, bleeding/brusing, changes in mental status, dyspnea.
PE: pallor, petechiae, eccymoses, hepatomegaly, splenomegaly. Lab: myeloblasts in peripheral blood, Auer rods, neutropenia, anemia, thrombocytopenia, DIC. |
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What are the two classes of acute leukemias?
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Class I mutations confer a survival and/or proliferative advantage.
Class II mutations lead to a block in hematopoietic cell differentiation. |
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What is an example of a type I mutation in AML?
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FLT-3 is a receptor tyrosine kinase. A point mutation activates FLT-3, leading to deregulated proliferation of AML cells.
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What is an example of a type II mutation in AML?
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RARalpha is a retinoic acid receptor that transcribes genes necessary for hematopoiesis/differentation. PML-RARalpha represses this transcription and leads to a block in differentiation. Pharmacologic doses of retinoids attempt to reverse this effect.
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What are some factors affecting prognosis?
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Good: certain cytogenetics t(15;17)
Bad: increased age, AML arising from MDS or MPD, and treatment-related AML |
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What are the steps for curing AML?
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7+3 chemotherapy (7 days of the pyrimidine analog cytarabine, 3 days of anthracycline), and
consolidation (high dose cytarabine for several cycles.) 30-40% cure rate in adults. |
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What is the treatment for APL?
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Induction chemotherapy + all-trans retinoic acid, consolidation chemotherapy.
80% cure rate. |
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How is the age distribution different in patients with ALL?
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Childhood disease, median age of 11.
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What are the risk factors for ALL?
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Radiation/chemotherapy,
various familial syndromes. |
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What is the clinical presentation of ALL?
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Symptoms: fatigue/fevers/sweats, weight loss, dyspnea, bleeding/bruising, opportunistic infection.
PE: Lymphadenopathy, hepatomegaly, splenomegaly. Lab: lymphoblasts in periperhal blood, neutropenia, anemia, thrombocytopenia. Other: tumor lysis syndrome, anterior mediastinal mass, CNS involvement, testicular involvement. |
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What is tumor lysis syndrome?
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Tumor lysis syndrome is a life-threatening manifestation of high cell turnover.
Characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and high LDH. Can cause acute renal failure due to uric acid deposition in the kidneys. |
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What are two cytogenetic abnormalities in ALL?
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t(9;22) is most common in adult ALL.
t(12;21) is most common in childhood ALL. |
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What is the pathophysiology of a t(9;22) abnormality?
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t(9;22) (Philadelphia chromosome) causes constitutive activation of BCR-ABL, causing increased proliferation.
Worse prognosis. |
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What is the pathophysiology of a t(12;21) abnormality?
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t(12;21) causes fusion of TEL to AML1, repression of AML1-mediated transcription.
Better prognosis. |
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What are the factors affecting ALL prognosis?
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Good: t(12;21), hyperdiploidy, between 1 and 10
Bad: t(9;22), hypodiploidy, younger than 1 or older than 10 |
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What is the backbone of induction therapy for ALL?
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Vincristine, L-asparaginase, daunorubicin.
AST reserved for high risk disease. |
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What are the cure rates for ALL?
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80% in children,
30-40% in adults. |
