Accepted Definitions of FailureResistance ELN Criteria

1
Accepted Definitions of Failure/ResistanceELN
Criteria
CCyR complete cytogenetic response CHR
complete hematologic response PCyR partial
cytogenetic response. Baccarani M et al. Blood.
20061081809-1820.
2
Accepted Definitions of Suboptimal ResponseELN
Criteria
CCyR complete cytogenetic response PCyR
partial cytogenetic response MMR major
molecular response. Baccarani M et al. Blood.
20061081809-1820.
3
Should I check an imatinib trough level?IRIS
Estimated Cumulative CCyR and MMR Rates by PK
Category of Steady-State Imatinib Trough Levels
gt1170 ng/mL
6471170 ng/mL
lt647 ng/mL

(n 86)
(n 178)
(n 87)

• Overall Cmin significantly higher in patients
  with CCyR vs no CCyR (1009 ng/mL vs 812 ng/mL, P
  0.004)
• Patients with CCyR (Q2-Q4) have a significantly
  greater probability of achieving MMR (P 0.008)

351 (of 553) patients on initial imatinib (400
mg/d), with imatinib plasma levels available on
treatment day 29. Larson et al. Blood.
20081114022-4028.
4
Mutations Rarely Account for Primary Resistance
to Imatinib
Primary Imatinib Resistance
30
Imatinib-resistant patients with BCR-ABL point
mutations
Failure to achieve a HR by 3 months, failure to
achieve a CCyR by 12 months. Soverini S, et al.
Clin Cancer Res. 2006127374-7379.
5
Mutations Occur in the Majority of Secondary
Resistance to Imatinib
60
Secondary Imatinib Resistance
Imatinib-resistant patients with BCR-ABL point
mutations
Loss of CCyR, loss of HR or progression.
Soverini S, et al. Clin Cancer Res.
2006127374-7379.
6
Major Predictors of Poor Adherence to Medication
Presence of psychological problems (eg,
depression) Presence of cognitive impairment
Treatment of asymptomatic disease Inadequate
follow-up or discharge planning Side effects of
medication Patients lack of belief in benefit
of treatment Patients lack of insight into the
illness Poor provider-patient relationship
Presence of barriers to care or medications
Missed appointments Complexity of treatment
Cost of medication, copayment, or both
Data adapted from Osterberg L, et al. N Engl J
Med. 2005 353487-497.
7
Barriers to Adherence
Poor provider-patient communication Patient has
a poor understanding of the disease Patient has
a poor understanding of the benefits and risks of
treatment Patient has a poor understanding of
the proper use of medication Physician
prescribes overly complex regimen
Provider
Patient
Patients interactionwith the health care
system Poor knowledge of drug costs Poor
knowledge of insurance coverage of different
formularies Low level of job satisfaction
Patients interactionwith the health care
system Poor access or missed clinic
appointments Poor treatment by clinic staff
Poor access to medications Switching to a
different formulary Inability of patient to
access pharmacy High medication costs
HealthCareSystem
Data adapted from Osterberg L, et al. N Engl J
Med. 2005 353487-497.
8
Concomitant Medications
Cyp3A4 inhibitors may increase TKIs
Ketoconazole, itraconazole, erythromycin, and
clarithromycin, grapefruit, star fruit
CYP3A4 inducer may decrease TKIs
Dexamethasone, phenytoin, carbamazepine,
rifampin (80), phenobarbital or St. John's
Wort CYP3A4, CYP2C8, CYP2C9, CYP2D6 are
competitively inhibited by TKIs Warfarin,
midazolam, macrolides, caffeine
9
Randomized Study of Imatinib Plasma Testing
SARC-019
Advanced GIST on Imatinib 400 mg/day (N400)
Measure Imatinib Plasma Level
lt1,100 ng/mL (N100)
gt1,100 ng/mL (N300)
Randomize
Control Cohort (N50)
Arm C Imatinib 400mg/d No Dose Adjustment
Arm D (Exon 9) Imatinib 800mg/day No Dose
Adjustment
Arm B Imatinib 600mg/d Adjust Dose
Arm A Imatinib 400mg/d No Dose Adjustment
10
KIT Mutations Predict Overall Survival(on
imatinib independent of dose)
100
90 80 70 60 50 40 30 20 10 0
KIT exon 11 (n85)
KIT exon 9 (n22)
Overall Survival ()
No kinase mutation (n9)
P-value0.0004
0 250 500 750 1000 1250
1500
Days
Heinrich et al, J Clin Oncol 2007
11
Kit Mutation in GISTResponse to Imatinib (n332)
Therapeutic dosing
Sub-therapeutic dosing
Heinrich MC et al ASCO 2006
12
Kit Exon 11 vs. Exon 9
Kit Exon 11 mutation
Best response to imatinib Minimal benefit
in starting patients on high doses of
imatinib (PFS 24 vs 25 months) High rate of
secondary mutations upon resistance (62)
Mutations and deletions occur widely across this
exon
Kit Exon 9 mutation
Also respond to imatinib Significant
benefit in starting patients on high dose
imatinib (PFS 4 vs 20 months) Mutations are
almost always A502-Y503 duplication
PFSprogression-free survival.