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37 Cards in this Set

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3 Cardinal features of Acute Leukemia
Differentiation blockade -- cell stuck in immature state
Uncontrolled proliferation -- do NOT respond to regulatory signals
REPLACEMENT of normal BM elements
Clinical defintion of Acute Leukemia
Increase in blasts in BM and/or blood of > 20%

NOTE: normal marrow has < 5% blasts
Acute leukemia (comparative characteristics)
Cells are IMMATURE
Rate of proliferation is HIGH
Onset is RAPID
Untreated course is FATAL in WEEKS-MONTHS
Response to chemo is HIGH
Chronic leukemia (comparative characteristics)
Cells are MATURE
Rate of proliferation is LOW
Onset is GRADUAL
Untreated, may SURVIVE FOR YEARS
Response to chemo is RESISTANT (relatively)
% of all leukemias AML / ALL account for
AML -- 70%
ALL -- 30% (BUT, 70% of all pediatric)
Predisposing factors for AML
Age
Marrow disease
DNA damaging agents
Congenital -- DOWN's SYNDROME
Hereditary -- FANCONI's; FAMILIAL PLATELET DISORDER
Hallmark findings in AML
Auer Rods
Bone marrow REPLACEMENT
Cytogenetics of APL
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
Cytogenetics of AML w/ granulocytic differentiation
t(8;21)

Fusion represses myeloid maturation (CBF complex)
Impacts prognosis FAVORABLY (~60% 5-yr)
Cytogenetics of myelomonocytic AML w/ BM eosinophils
Inv(16)

Fusion sequesters another TF
Represses myeloid maturation (CBF complex)
Impacts prognosis FAVORABLY (~60% 5-yr)
Cytogenetics of AML, Post-therapy
(Topo. II inhibitors)
Translocations w/ 11q23

Impacts prognosis INTERMEDIATELY (~30-40% 5-yr)
Cytogenetics of AML, Post-therapy
(alkylating agents)
-5/-5q or -7/-7q

Impacts prognosis POORLY (< 20% 5-yr)
Impact of NORMAL karyotype on AML prognosis
INTERMEDIATE (~40% 5-yr)
Two types of signaling mutations in AML
Tandem duplication - Flt3(RTK) - Const. kinase activity

Single residue - Ras Family - Const. GTP signaling
Theorem of Gilliland
BOTH defects (transcriptional and signaling) are required for AML
Overall, long-term survival from AML
~30 - 40%
Prognostic factors for AML
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)
Treatment for AML
Chemo (3 phases) -- Ara-C + Anthracycline + Others

Stem cell transplant for poor prognosis and < 55 y.o.
Treatment for APL
Retinoic Acid
Chemo
Myelotarg
New, anti-CD33 Ab conjugated with toxin

Therapy for poor prognoisis and > 55 y.o.
HDAC
Enzymes used by abnormal (fusion) TFs
Inhibition of these can be used as AML treatment

Therapy for poor prognoisis and > 55 y.o.
Tyrosine kinase inhibitors target this in AML
Mutant Flt3
(Remember, this causes const. kinase activity)
Farnesyl transferase inhibitors
Block Ras signaling
(Remember, mutant Ras causes const. signaling in AML)
Peak incidence age for ALL
4-5 y.o.
Cell type which majority of ALL cases involve
B Cell precursor
Predisposing factors for ALL
Congenital -- DOWN's SYNDROME
Hereditary -- ATAXIA-TELANGIECTASIA
Pre-exisiting
Environment
Classic morphology of ALL
L1 morphology: small blasts, virtually NO cytoplasm
B-cell marker(s) in ALL
CD19 & CD20
Increasing CD20 w/ maturity
T-cell marker(s) in ALL
CD3, 2, 5, 7
Lymphoid lineage marker(s) in ALL
TdT
(DECREASES w/ maturity)
Marker of an un-differentiated cell
Cytogenetic finding of Philadelphia chromosome
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)
Cytogenetic finding of Infantile ALL
t(4;11)

Most common in infant (< 1 y.o.) cases

Results in UPregulation of HOX genes

POOR prognostic factor (< 20% 5-yr)
Cytogenetic finding of Burkitt's lymphoma
t(8;14)
Cytogenetic finding in B cell precursor (BCP) ALL
t(12;21), hyper diploidy

Assoc. w/ chilhood (1 - 15 y.o.) cases

Fusion represses B + T cell maturation

FAVORABLE prognosis (>80% 5-yr)
Cytogenetic finding in preB ALL
t(1;19)

Fusion blocks B cell maturation
Treatment of ALL
Chemo -- Vincristine, prednisone, asparaginase, anthracycline

For CNS disease -- intrathecal methotrexate

Stem cell transplant for unfavorable cytogenetics, or adult pts.
Imatinib mesylate
Inhibitor of bcr-abl kinase
Unfortunately, shows MINIMAL EFFICACY in t(9;22)