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37 Cards in this Set
- Front
- Back
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3 Cardinal features of Acute Leukemia
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Differentiation blockade -- cell stuck in immature state
Uncontrolled proliferation -- do NOT respond to regulatory signals REPLACEMENT of normal BM elements |
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Clinical defintion of Acute Leukemia
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Increase in blasts in BM and/or blood of > 20%
NOTE: normal marrow has < 5% blasts |
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Acute leukemia (comparative characteristics)
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Cells are IMMATURE
Rate of proliferation is HIGH Onset is RAPID Untreated course is FATAL in WEEKS-MONTHS Response to chemo is HIGH |
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Chronic leukemia (comparative characteristics)
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Cells are MATURE
Rate of proliferation is LOW Onset is GRADUAL Untreated, may SURVIVE FOR YEARS Response to chemo is RESISTANT (relatively) |
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% of all leukemias AML / ALL account for
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AML -- 70%
ALL -- 30% (BUT, 70% of all pediatric) |
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Predisposing factors for AML
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Age
Marrow disease DNA damaging agents Congenital -- DOWN's SYNDROME Hereditary -- FANCONI's; FAMILIAL PLATELET DISORDER |
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Hallmark findings in AML
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Auer Rods
Bone marrow REPLACEMENT |
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Cytogenetics of APL
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t(15;17)
Normal TF is Retinoic Receptor alpha Fusion represses neutrophil maturation Impacts prognosis FAVORABLY (~80% 5-yr) APL RESPONDS TO RETINOIC ACID THERAPY |
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Cytogenetics of AML w/ granulocytic differentiation
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t(8;21)
Fusion represses myeloid maturation (CBF complex) Impacts prognosis FAVORABLY (~60% 5-yr) |
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Cytogenetics of myelomonocytic AML w/ BM eosinophils
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Inv(16)
Fusion sequesters another TF Represses myeloid maturation (CBF complex) Impacts prognosis FAVORABLY (~60% 5-yr) |
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Cytogenetics of AML, Post-therapy
(Topo. II inhibitors) |
Translocations w/ 11q23
Impacts prognosis INTERMEDIATELY (~30-40% 5-yr) |
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Cytogenetics of AML, Post-therapy
(alkylating agents) |
-5/-5q or -7/-7q
Impacts prognosis POORLY (< 20% 5-yr) |
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Impact of NORMAL karyotype on AML prognosis
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INTERMEDIATE (~40% 5-yr)
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Two types of signaling mutations in AML
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Tandem duplication - Flt3(RTK) - Const. kinase activity
Single residue - Ras Family - Const. GTP signaling |
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Theorem of Gilliland
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BOTH defects (transcriptional and signaling) are required for AML
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Overall, long-term survival from AML
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~30 - 40%
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Prognostic factors for AML
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Age (> 55 y.o. is bad)
Cytogenetics (refer to other FCs) Pre-existing disorder [VERY chemoresistant] (< 20% 5-yr) Relapse of previously treated AML (Bad) |
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Treatment for AML
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Chemo (3 phases) -- Ara-C + Anthracycline + Others
Stem cell transplant for poor prognosis and < 55 y.o. |
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Treatment for APL
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Retinoic Acid
Chemo |
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Myelotarg
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New, anti-CD33 Ab conjugated with toxin
Therapy for poor prognoisis and > 55 y.o. |
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HDAC
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Enzymes used by abnormal (fusion) TFs
Inhibition of these can be used as AML treatment Therapy for poor prognoisis and > 55 y.o. |
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Tyrosine kinase inhibitors target this in AML
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Mutant Flt3
(Remember, this causes const. kinase activity) |
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Farnesyl transferase inhibitors
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Block Ras signaling
(Remember, mutant Ras causes const. signaling in AML) |
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Peak incidence age for ALL
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4-5 y.o.
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Cell type which majority of ALL cases involve
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B Cell precursor
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Predisposing factors for ALL
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Congenital -- DOWN's SYNDROME
Hereditary -- ATAXIA-TELANGIECTASIA Pre-exisiting Environment |
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Classic morphology of ALL
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L1 morphology: small blasts, virtually NO cytoplasm
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B-cell marker(s) in ALL
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CD19 & CD20
Increasing CD20 w/ maturity |
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T-cell marker(s) in ALL
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CD3, 2, 5, 7
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Lymphoid lineage marker(s) in ALL
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TdT
(DECREASES w/ maturity) Marker of an un-differentiated cell |
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Cytogenetic finding of Philadelphia chromosome
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t(9;22)
More frequent in adult (> 15 y.o.) cases Fusion (BCR-ABL) causes aberrant tyrosine kinase signaling Only in minority of cases (5% of kid; 25% of adult) POOR prognostic factor (< 20% 5-yr) |
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Cytogenetic finding of Infantile ALL
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t(4;11)
Most common in infant (< 1 y.o.) cases Results in UPregulation of HOX genes POOR prognostic factor (< 20% 5-yr) |
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Cytogenetic finding of Burkitt's lymphoma
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t(8;14)
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Cytogenetic finding in B cell precursor (BCP) ALL
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t(12;21), hyper diploidy
Assoc. w/ chilhood (1 - 15 y.o.) cases Fusion represses B + T cell maturation FAVORABLE prognosis (>80% 5-yr) |
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Cytogenetic finding in preB ALL
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t(1;19)
Fusion blocks B cell maturation |
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Treatment of ALL
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Chemo -- Vincristine, prednisone, asparaginase, anthracycline
For CNS disease -- intrathecal methotrexate Stem cell transplant for unfavorable cytogenetics, or adult pts. |
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Imatinib mesylate
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Inhibitor of bcr-abl kinase
Unfortunately, shows MINIMAL EFFICACY in t(9;22) |
