Leukemias Flashcards
CML rseults from
acquired mutations + proliferation of myeloblasts
what is characterized by the philadelphia chromosome
CML
what is the philadelphia chromosome
Translocation between long arms of chromosomes 9 and 22 = joining of ABL gene of chromosome 9 and BCR gene of chromosome 22 = formation of BCR-ABL fusion oncogene
Results in super long chromosome 9 and shorter chromosome 22 (philadelphia chromosome, Ph+)
joining of ABL gene of chromosome ___ and BCR gene of chromosome ___= formation of BCR-ABL fusion oncogene
9, 22
what does the BCR-ABL gen cause
production of BCR-ABL protein = abnormal TK that has an ATP bindng site that can transfer phosphate groups to protein substrate, causing CML cells proliferate and avoid apoptosis
CML S/S
splenomegaly
suppression of hematopoiesis
leukocytosis or leukostasis
up to 50% asumptomatic due to initial indolent phase of disease
what is leukocytosis
WBC >25
what is leukostasis
WBC >100
dx of CML requires
cytogenetics for philadephia chromosome
molecular testing of QPCR
staging
describe the 3 stages of CML and the amount of myeloblasts
chronic phase <10%
accelerated phase 10-20% or persistent leukocytosis, thrombocytosis, thrombocytopenia, splenomegaly unresponsive to tx
blast crisis >20%
leukostasis in CML requires
asap hydroxyurea to rapidly lower WBCs + allopurinol to prevent tumor lysis syndrome
MOA of BCR-ABL TKis
competitively binds to ATP binding site on BCR-ABL kinase = inhibits phosphorylation of proteins involved with signal transduction for CMl clone proliferation
name the 3 TKis for CML
imatinib, dasatinib, nilotinib
which TKis should be taken with food
imatinib, dasatinib
which TKis should be taken without food? why
nilotinib - increases bioavailability
which TKi is acid dependent absorption
dasatinib
AEs of BCR-ABL TKis
myelosuppression
fluid retention
N/V
QT interval prolongation
hepatotoxicity
drug rash
diarrhea
which TKis has a black box warning for QT prolongation
nilotinib and dasatinib- baseline ECG rec
which TKi is most associated with fluid retention
dasatinib
reasons for Tki failure
compliance
drug interactions
resistance- point mutation in ABL kinase domain that activates it
what is the only cure for CML
allogenic stem cell transplant
can CML pts ever d/c TKis
yes if they’ve been on BCR-ABL TKi for at least 5yrs + undetectable disease for 2yrs consecutively (monitor QPCR q1mth)
- may result in 50% relapse rate