Chronic Leukemia Flashcards
philadelphia chromosome
excession mature neutrophil production
t(9;22) promotes fusion of 2 genes, BCR-ABL. protein p210 ->upregulated TK activity->promotes continuous cell cycling, inh apoptosis, inc mature neutrophil proliferation
CML - hematologic response
nml peripheral, WBC <450k, no immature cells
CML - cytogenetic response
complete: BMBx 0% Ph+ cells
partial: BMBx 1-34% Ph+ cells
Major = CR +PR
Minor = 35-95% Ph+ cells
CML - molecular response
complete: negative BCR-ABL by RT-PCR
major: cytogenetic remission with 3 log or greater reduction in BCR-ABL by RT-PCR
CML - tx goals
#1 maintain chronic phase - sustained cytogentic / molecular remission #2 prevent progression to accelerate/ blast #3 minimize toxicity of chronic tx #4 cure (only proven alloHSCT) #4 if accelerated/blast - induce 2nd chronic phase
CML - imatinib - phase III iris trial
1st trial - 100% hematologic response
yr 4,5,6,7,8 tox is less than tx during yr 1,2,3 (paradigm shift)
8yr OS: 85% (if CML related OS: 93%)
imatanib AE’s
hematologic (neutropenia, anemia, thrombocytopenia), LFTs
CML - nilotinib vs imatinib
24 mo MMR (primary): 71% N 300bid, 66% N 400bid, 44% I 400qd
12 mo CCyR: 87%, 85%, 77%
Progression to AP/BC: <1%, 1.8%, 4.6%
nilotinib 300mg bid AE’s
neutropenia (12%), thrombocytopenia (10%), anemia (3%), Rash (1%), t bili (4%), ALT (4%), AST (1%), lipase (6%), dec phos (5%)
CML - dasatinib vs imatinib
24 mo CCyR: 86% d 100qd vs 82% i 400qd
24 mo MMR: 64 vs 46%
CML - bosutinib vs imatinib
12 mo CCyR: 70 b vs 68 i%
12 mo MMR: 41 vs 27%
dz progression: 3 vs 10%
imatinib ADME keys
400mg qd
take with food
inhibits 3A4 / 2D6
metabolism: 3A4
dasatinib ADME keys
100mg qd
with or without food (avoid acid reducers)
metabolism: maybe 3A4
nilotinib ADME keys
300mg bid empty stomach metabolism 3A4 inhibits 3A4, 2C8, 2C9, 2D6 induces 2B6, 2C8, 2C9
bosutinib ADME keys
500mg daily
take with food
metabolism: 3A, P-gp
ponatinib ADME keys
45md daily
with or without food
metabolism: 3A, P-gp
mechanisms of resistance to TKI’s
#1 bcr-abl gene amplification / overexpression #2 mutation in the kinase domain (cell growth dependent of bcr-abl for 1 and 2) #3 secondary genetic alterations (cell growth independent of bcr-abl activity, clonal evolution)
TKI point mutations
T315I R to imatinib, dasatinib, nilotinib
CML - 2nd line tx
#1 dose escalation of i #2 2nd gen TKI (d, n, b) #3 3rd gen TKI (p) #4 omacetaxine #5 alloHSCT #6 clinical trial
CML - 2nd line dasatinib (data very similar for nilotinib)
chronic phase: 91% CHemR, 49% CCyR, 59% major CyR
accelerated phase: 63, 24, 34
blast crisis: 35, 32, 39
CML - salvage - 2 prior TKI’s - bosutinib
28.5mo median f/u: CHemR 73%, CCyR 24%, MMR 15%
CML - ponatinib - phase I - T315I mutation (made NEJM)
CHemR 100%, MCyR 92%, CCyR 75%, MMR 67%
CML - ponatinib - phase II
majorCyR 70%
CML - salvage - omacetaxine - T315I mutation
1.25 mg/m2 subQ bid x14day each 28day cycle (maintenace 7 day q28d)
CHR 77%, MajCyR 23%, CCyR 16%
median PFS 7.7 mo