pathobiology of acute leukemia

what is the definition of acute leukemia?
a block or arrest on maturation leading to accumuation of immature cells (myeloblasts/lymphoblasts) in the bone marrow/blood. these have a high N:C ratio, are larger and have nucleoli present
what are the histological differences between myeloblasts and lymphoblasts?
myeloblasts have flattened nuclei and are larger, both have visible nucleoli
what is a myeloblast with visible granules called?
what is AML characterized by?
massive accumulation of blast cells in marrow (>20%), which is fatal if untreated, incidence rises sharply with age and long-term survival rate is 20-40% for adult-onset leukemias
is AML seen in children?
this is exceedingly rare
what are risk factors for AML?
chemicals (benzene)/radiation, cytoxic drugs used in CA therapy, genetic factors (down’s syndrome pts @ increased risk), and infection with certain viruses (human T-cell lymphotropic virus type 1- HTLV-1 and EBV)
who gets AML slightly more?
what does the multistep process of AML pathobiology consist of?
genetic changes in hematopoietic precursor cells and uncoupling of normal hematopoietic growth and differentiation (tumor suppressor genes/oncogenes)
what are 2 common translocations that lead to AML?
t(15:17) M2, and t(8:21) M3
what is characteristic of chemo-induced AML?
accumulation of additional genetic lesions – classically after alkylating agents. the latency period varies (generally around 15 yrs)
what is significant about acute promyelocytic leukemia? what is the treatment specific for it?
it is caused by a unique translocation involving RAR alpha on chromosome 17, t(15:17), a chimeric fusion transcript. this causes RAR alpha to bind to the retinoid X receptor -> the resulting heterodimer then binds to retioic acid reponsive elements and regulate transcription. it is treated with high dose retionic acid, which can help unblock leukemias and progress forward
how does AML present clinically?
bruising, nonspecific fatigue, weakness, fever, weight loss, epistaxis
what are dx tests for AML?
*CBC, differential coagulation -including fibrinogen (tendency for DIC w/AML), blood electrolytes/chemistry (including creatinine, uric acid, calcium and phosphorus), examination of peripheral blood smear, examination of bone marrow aspirate smear/bx, leukemia blast cell surface phenotype (cytogenics and molecular genetics, and examination of CSF if indicated
what is the dx profile for AML?
anemia, thrombocytopenia (bone marrow being replaced w/leukemia cells), WBC count can be normal/reduced/elevated (b/c they may just stay in the marrow), peripheral smear should show blasts, blood chemistry should be normal (but there may be elevated creatinine – evidence of adavanced disease), and a **bone marrow bx is needed to make a final dx
what type of AML has the highest incidence?
M2 @ 25% (has myeloblasts with some maturation and t(8:21)), the next is M4 @ 20% (has no distinct genetic pattern)
what are prognostic factors for AML?
age (older: worse), antecedent hematological disorder/secondary AML (more complex cytogenetics), complex cytogenetics, poor performance status (high comorbidity), multidrug resistance (encodes p glycoprotein transmembranous protein “pumps out” chemotherapy ), high WBC at dx (extremely low is also bad)
what is the survival rate for pts with AML?
60% 5 yrs, 70-80% will have a complete response (leukemia is undetectable), 25-30% will be cured
what is the treatment goal for AML?
eradication of leukemic clone and re-establishment of normal hematopoiesis
what is the induction phase of chemo? consolidation phase?
induction: goal is to induce a CR (<5% blasts, may be mult rounds). consolidation: lengthen CR, eradicate residual leukemic cells
what is the chemotherapy used for AML?
anthracycline (tetracyline/topoisomerase II) and cytaramine (pyrimidine antimetabolite) and intensive postremission therapy is required for CR (no maintenance usually needed)
what is the specific treatment regimen for AML?
3+7 regimen, usually daunorubicin for 3 days, Ara-C for 7 (maybe have to be repeated to induce a full CR). (cardiotoxicity is dose dependent on anthracycline)
who does ALL generally occur in? what are clinical symptoms?
children under the age of 13. clinical symptoms of liver/spleen/node enlargement, cytopenias, and *bone pain
what are the FAB classifications of ALL?
L1 (small cells predominate), L2 (large cells predominate), L3 (large homogenous cells)
what is the more common leukemia?
what are some general characteristics of chronic leukemias?
no maturation arrest – *but not functional, predominance of mature (myeloid/lymphoid) cells (commonly named by by the predominant cell), and it occurs in older pts. they are much more common and manageable (all doctors except pediatricians will see it)
what is seen with CML?
clonal expansion of the myeloid lineage with *basophila (one of the few times you see this) and *splenomegaly. it is due to the philadelphia chromosome t(9:22) (bcr-abl rearrangement) and makes up 15-20% of all adult leukemias
what are the 3 phases of CML?
chronic phase (3-4 yrs, high WBC), accelerated phase (progressive maturation arrest, therapy resistance, more blasts in marrow, as the WBC count increases it will basically become acute leukemia), and blast crisis
what are clinical features of CML?
splenomegaly (generally asymptomatic, but early satiety can occur with impinging on stomach or upper L quadrant pain), anemia, hepatomegaly, purpura, fatigue, anorexia, weight loss, sweats, hyperleukocytosis (^WBC), and priapism
what laboratory tests are done for suspected CML pts?
LAP (leukocyte alkaline phosphatase which stains granulocytes for counting – high = reactive/low = CML), bcr:abl gene test (should be 0), and bone marrow bx (more important for lymphoma) and aspirate (more important for leukemia)
if a bone bx is really hard and white what is it likely?
a metastatic tumor
what is gleevec?
a drug which binds to the promoter region of the bcr:abl gene, preventing ATP from binding and cuasing the translocation -> is effective at all stages of CML. resistance can develop, but there are secondary drugs available
what is CLL?
a predominance of mature lymphocytes, which is exceedingly common in men >60. it has a low risk of thrombosis (high WBC counts are not as bad as with ALL/AML, these cells are small, relatively mature and non-sticky)
what is the clinical presentation for pts with CLL?
some are asymptomatic, lymphadenopathy, splenomegaly (very big), night sweats, fatigue, ealy satiety, bruising, and exaggerated response to insect bites
what is the RAI staging?
the classification of the 4 stages of CML with nodes/spleen/liver/anemia being stage 4 and lymphocytosis being stage 1
is CLL curable?
no, but pts generally do well for a good amount of time
what is the therapy for CLL?
none, fludarabine, alkylating agents, ritumimab, alemtuzumab and ofatumimab
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