Transcript 1 Day - National CML Society

The National CML Society
2012 CML UPDATE
“What’s New?
What’s Coming?”
Luke Akard MD
Co-Director Indiana Blood and
Marrow Transplantation Program
Ph + CML Clinical Issues
• About 5000 cases per year in the US
• Incidence increases with age
– About half of patients are over age 65
– More frequent in men: 1.9:1 ration
– Incidence 1.5 per 100,000 per year
• Survival has improved over the past decade
• Most are asymptomatic, 85% chronic phase at
diagnosis
CML Overview
• Malignant bone marrow disease
– Increased numbers of bone marrow cells
– Increased numbers of mature white blood cells in the
blood stream,
– Often with an increase in the red cells and platelets
as well
• In 1961 the Philadelphia Chromosome was
found to be associated with CML
Chromosome analysis—requires cultured cells analyzed in metaphase
DNA
RNA
Protein
CML Overview
• Three phases of disease
– Chronic Phase 3-5 years
– Accelerated Phase 3-18 months
– Blast Phase 3-6 months
• Treatment overview (non-HSCT)
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–
–
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1970s chemotherapy busulfan, hydroxyurea
1980’s-1990’s interferon +/- Ara-C
2000 imatinib
2006, 2007 dasatinib, nilotinib
IRIS Trial: 5 Year Response to Gleevec
Druker B et al. N Engl J Med 2006;355:2408-2417
IRIS trial data from the first 6 years of
Imatinib as initial therapy of CML
• At 6 years, 98% of patients will have had a
complete hematologic response, 88% OS
• 83% will have had a complete cytogenetic response
• What about loss of response or failures?
Year
1
2
3
4
5
6
Events
3.3%
7.5
4.8
1.5
0.9
0.4
AP/BC
1.5%
2.8
1.6
0.9
0.6
0.0
Hochhaus et al Blood 110:15a, 2007
Imatinib Has Changed
CML Monitoring
Complete hematologic response
Complete cytogenetic response
Major molecular response
Hematologic Response
• Complete CHR
Platelets < 450,000, WBC < 10,000, no immature
granulocytes or basophils, no spleen
• Anything less is not complete
• LeukemiaNet guidelines for CBC
– Every 2 weeks until CHR confirmed
– Every 3 months thereafter
• If not in CHR at 3 months on Gleevec,
virtually no chance of responding to it.
Baccarani et al Blood 108:1809, 2006
Cytogenetic Response
•
•
•
•
•
•
•
•
Bone Marrow Exam (vs. blood FISH)
Complete: Ph+ 0%
CCyR
Partial: Ph+ 1%-35%
Minor: 36%-65%
Minimal: 66%-95%
None: Ph+ >95%
Major: Complete + partial MajCyR
LeukemiaNet guidelines for monitoring
– Baseline then every 6 months until CCyR then every
12 months
IRIS trial data:
Cytogenetic Response
• Impact of failure to respond to imatinib
Survival:
– No MCyR @ 12 months: 81% vs 97% 5y OS
– No CyCR @ 18 months: 90% vs 99% 5y OS
– No MCyR @ 18 months: 80% vs. 95% 5y OS
• Future response if stay on imatinib:
– No CyR at 6 months, <20% chance CCyR
– If PCyR @ 12 months, 64% likely to obtain CCyR
– If no MCyR @ 12 months, still 36% obtain CCyr
Fluorescent in situ
hybridization (FISH)
does not require cultured
Cells in metaphase
Molecular Response
• Complete: no transcript detectable
• Major: <=0.10 (3 log or 1000 fold decrease)
– Requires quantitative pcr for bcr-abl to assess falling
level
– Can not assess response, other than complete, from
qualitative pcr bcr-abl.
• LeukemiaNet guidelines
– Check every 3 months
– Perform mutational analysis in case of failure or suboptimal
response
Baccarani et al Blood 108:1809, 2006
• Mutation analysis available using
– Molecular MD, 2611 SW 3rd Ave. Portland OR 97201 tel 503-459-4975.
Molecular Testing in CML
PCR products
LEVELS
QRT-PCR
Tube
RNA
cDNA
QRT- PCR
WT T315I
MUTATION
T315I FRET
5%
0.5 Day
MUTATION
SEQ
Extraction
1 Day
RT
Long range PCR
Sequencing
Report
0.5 Day
1 Day
1.0 Day
0.5 Day
BCR-ABL/control gene (%)
IRIS study MMR definition*
MEDIAN STANDARDIZED BASELINE
VALUE ON 30 UNTREATED PATIENTS
100
10
3 log reduction from standard baseline
1
MMR = 0.1% International Scale
0.1
0.01
•Internation
al Scale
0.001
Date
* Hughes et al. NEJM 349; October 9 2003
•Log reduction
from standardized
baseline
•0.10%
•3 log
•0.01%
•4 log
•0.0032%
•4.5 log
Molecular Response to
Imatinib
• IRIS trial 4 year follow-up data
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–
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MMoR 53% @ 1 year
CMoR 7% @ 1 year
MMoR 80% @ 4 years
4 log reduction
• 22% 1 year
• 44% 4 years
– If CCyR at 1 year, impact of MMoR
• MMoR @ 12 months 100% 5 yr RFS
• Less than MMoR @ 12 months 97% 5 yr RFS
Druker et al NEJM 355:2408-17, 2006
Side Effects of Imatinib
Decrease Over Time
Adverse Event, All Grades
2yr
4yr
Superficial edema
Nausea
Muscle cramps
Musculoskeletal pain
Diarrhea
Rash
Fatigue
Headache
Abdominal pain
18%
15%
23%
21%
23%
14%
11%
12%
15%
5%
3%
7%
6%
5%
2%
3%
3%
3%
Kantarjian et al Blood 108:605a, 2006
Pregnancy and Imatinib
• 180 mothers 71% exposed in 1st trimester, 26% in all
trimesters
• Outcome known in 125 pregnancies
• 63 (50%) normal live infants
• 35 elective abortions (3 after fetal defects)
• 18 (14%) spontaneous abortions
• 12 fetal abnormalities, including 4 cases with bony
defects
Pye et al Blood 108:132a, 2006
• Half of pregnancies have progressive disease
following interruption of imatinib Ault et al JCO 24:1204, 2006
Failure to respond to Imatinib
3 months
6 months
12 months
18 months
Anytime
No HR stable/prog dis
Less than CHR, no CgR
Ph+ > 95%
Less than PCgR Ph+>35%
Less than CCgR
Loss of CHR, loss of CCgR
Suboptimal Response to Gleevec
3 months
6 months
12 months
18 months
Anytime
Less than CHR
Less than PCgR Ph+>35%
Less than CCgR
Less than MMolR 3 logs or
more
Additional chromosome abn
in Ph+ cells, loss of MMolR
Why Do Some Patients Fail
To Respond To Imatinib?
Multiple Causes For Drug Resistance
1.
Mutations in the tyrosine kinase (50-75+%)
•
2.
3.
4.
5.
Multiple sites of mutation have been found, with T315I being the
most unresponsive to imatinib, dasatinib, and nilotinib
Increased transcription of bcr-abl or increased
tyrosine kinase activity (10%)
Diminished cellular uptake of drug, drug pumps
(5%)
Bcr-abl independent pathways
Patients do not take their medication.
Mutant Kinase Domains in bcr-abl
• Over 50 mutations have been identified to date
• Some mutations confer only moderate resistance, so
dose escalation can be successful
• Evaluating for mutations in imatinib resistance may have
clinical usefulness in the future.
Treatment Options If Imatinib Fails
• Young patients with
appropriate bone
marrow donors—
consider allogeneic
transplant
• Four other tyrosine
kinase inhibitors with
demonstrated benefit for
Gleevec failures
Second line TKI Therapy
• Dasatinib
Haematologica
95:232, 2010
– 85 patients treated with 70 mg bid or 100 qd
– 75% MCyR, 68% CCyR
– 90% OS at 2 years
• Nilotinib
Blood 117:1141,
2011
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321 patients failed 600 mg + imatinib
59% MCyR, 44% CCyR
If CCyR 56% MMR
CCyR durable 84% CCyR at 2 years, OS 87%
Second Line TKI Therapy
• Bosutinib
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–
–
Blood 118:4567, 2011
200 patients imatinib resistant
53% MCyR, 41% CCyR
If CCyR 64% MMR
OS 2 years 92%
• Ponatinib early results PACE trial ASH 118:abs 109, 2011
– 3-6 month follow-up, 94% failed > 2 TKI’s
– 188 CP patients (48 with T315I mutation)
– 46% MCyR, 32% CCyR (51% MCyR, 48% CCyR
with T315I mutation)
Selected Comparisons
Feature
Imatinib
Dasatinib
Nilotinib
T315I responses
Peripheral edema
Pleural effusions
Grade 3-4 heme
Median dose
admininstered
0
20%
0
18%
0
<1%
<10%
20%
400 qd
10-35%
49%
101 mg qd
140 mg planed
1%
29%
799 mg qd
800 mg planned
TKI’s:
Drug-Drug Interactions
– Inhibitors = Drugs that may
↑ plasma levels of imatinib
or nilotinib
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•
•
•
Clarithromycin
Erythromycin
Itraconazole
Ketoconazole
•Inducers = Drugs that may
↓ plasma levels of imatinib
or nilotinib
• Carbamazepine
• Dexamethasone
• Phenobarbital
• Phenytoin
• Rifampin
• St. John’s wort
•Substrates = Drugs whose
plasma levels may be increased
by imatinib & nilotinib
– Acetaminophen
– Cyclosporine
– Dihydropyridine Ca++ channel
blockers
– HMG-CoA reductase inhibitors
(eg, simvastatin)
– Pimozide
– Triazolobenzodiazepines
– Warfarin
Grapefruit juice is also an inhibitor of
Cytochrome P450- would increase levels
of imatinib and nilotinib
Second generation TKI vs.
imatinib as initial therapy
Drug
CCyR %
MMR %
Imatinib/dru Imatinib/dru
g
g
Nilotinib
Progression
OS %
to AP/BP %
Imatinib/dru Imatinb/drug
g
77 / 87
44 / 71
7/1
96 / 97
82 / 86
46 / 64
5/ 2.3
95.2 / 95.3
68 / 70
27 / 41
5/2
95 / 99
2 yr data
Lancet Oncol
2011
Dasatinib
2 yr data
Blood 2012
Bosutinib
18 month data
ASH 2011 abs
455
Can You Stop Treatment?
• Mechanism of action TKI vs. interferon
• Stop during pregnancy
– Initial year of treatment vs. planned pregnancy
• Clinical trial Stop Imatinib STIM trial
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–
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100 patients in CMR for at least 2 years
Molecular monitoring monthly X 1 yr, then q 2 mo
61 relapses (all molecular), 3 after 7 months
5 did not return to CMR with retreatment
ASH 2011 abs 603
The Future in CML
• Can we identify patients who can receive imatinib
without risk as initial therapy
– Molecular response at 1, 3, or 6 months
• Can the addition of interferon improve long term
outcome?
• European trial suggests may be able to stop
treatment after interferon maintenance.
• Will new combinations of treatments work better
than tyrosine kinase inhibitors alone?
Serial vs. sequential
• T315I mutation trials: HHT, Aurora kinase inhibition
MK-0457, new TKI inhibitors KW-2449, XL-228
CML Treatments In Development
• Tyrosine kinase inhibitors
– Ponatinib AP24534 multi kinase inhibitor trial (Ariad) T315I plus
– DCC-2036 binds to different domain on bcr-abl, active in T315I
– Non-ATP binding site inhibitors: AG957, ON 012380, ON01910
• Aurora kinase inhibitors:
• Histone deacetylase inhibitors
– SAHA (vorinostat), LAQ 824, LBH 589
• Hedgehog pathway inhibitors
– PF-04449913
– BMS833923
• Homoharringtonine Omapro—plant alkaloid (Ceflatonin)
• CML vaccines: short bcr-abl peptides, PR1 (proteinase 3 a
neutrophilic protease), HSP chaperone proteins
CML Treatment 2012
• Newly diagnosed
– 400 mg/d imatinib or nilotinib 400 mg 2x/d or dasatinib 100 mg/d
– Clinical trials: duration of therapy, second agents, target response
• Failure to achieve response or progressive disease
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–
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Switch to alternative TKI
Omapro if fail more than 2 TKI’s
Allogeneic marrow transplant for appropriate patients
Ponatinib clinical trials
Other clincal trials
• If present with accelerated or blast phase, use higher doses of
imatinib or dasatinb and consider early allogeneic marrow
transplant
Contact
Luke Akard MD
1500 Albany Street
Suite 911
Beech Grove IN 56107
317-528-5500
Fax 317-782-6316
E-mail [email protected]
National CML Society
Indianapolis
CML Connection Group
http://www.nationalcmlsociety.org/cml-connection-indianapolis