presented at the arthritis advisory committee on july 15, 2003 by naomi winick, m.d
TRANSCRIPT
Years From Study Entry
Est
imat
ed S
urv
ival
Per
cen
tag
eImproved Survival in Childhood ALL
by Study Era
0
20
40
60
80
100
0 2 4 6 8 10 12
1996-2000(n=3421)
1989-1995(n=5121)
1983-1988(n=3711)
1978-1983(n=2984)
1975-1977(n=1313)
1972-1975(n=936)
1970-1972(n=499)
1968-1970(n=402)
6-Mercaptopurine
• Discovered 1951; introduced into clinical trials in 1952 and FDA approved 1953
• First clinically useful drug designed and synthesized specifically to act as an anti-purine
• Converted to thioguanine nucleotides which are incorporated into DNA
6-Mercaptopurine
• Component of virtually ALL regimens for more than 40 years
• Daily oral therapy x 2-3 yrs; limited toxicity
• Dose intensity of 6-MP correlates with EFS (Relling et al, 1999)
• Synergistic with Methotrexate
Thiopurine Methyltransferase
• Variability in TPMT activity (Weinshilboum & Sladek, 1980)
– 88.6% high enzyme activity; 11.1% intermediate; 0.3% undetectable activity
• Child with ALL (Evans et al, 1991) with severe myelosuppression; exorbitant RBC TGN and TPMT deficiency
TPMT Activity, 6MP, and Childhood ALL
• TPMT variation impacts clinical response
• Assessable by phenotype and genotype
• Can one titrate well without knowledge of pharmacogenetics?
• Should TPMT activity be determined prospectively in all children with ALL?
TPMT Activity Should Be Determined Prospectively
• 3-5 cc’s in a GTT
• Cost $100.00
• Avoid severe myelosuppression
• Prevent second malignancies
• Not likely to cause significant distress, regardless of genotype determination
Thiopurine Methyltransferase(TPMT) Polymorphism affects6MP Pharmacodynamics
10
8
6
4
2
00 5 10 15 20 25 30
TPMT Activity
2000
1000
0Mut/Mut Wt/Mut Wt/Wt
HPRT
TGNs DNAincorporation
MP MeMPTPMT
toxicityrisk of relapse
myelosuppressionrisk secondary cancer
wt/wt
wt/m
m/m
Leukemia 14:567-72, 2000Relling & Dervieux Nature Ca Rev 2001;1:99-108
Gene for TPMT hasA common variant thatCauses low activity, High levels of 6MP Metabolites
0
10
20
30
40
50
60
70
80
dose
(mg/d
ay)
mut/mut wt/mut wt/wt
Inherited differences in Metabolism
Inherited differencesIn drug levels
Optimal Dose for Each Child
TPMT Activity Should Not Be Mandated Prospectively
• 1/300 homozygous deficient; dose similar for heterozygotes
• COG std/low risk trial-projected enrollment- 1938 children/4 years– Seven children will be deficient,
nationwide over 4 years• Large institutions- 20-30 new pts/year;
one TPMT deficient patient per decade
SJCRH Total XII: Outcome not worse for pts with TPMT defect despite 6MP dose decreases
N=19
N=161
P = 0.096
Blood 93: 2817-2823, 1999
Complete Remission ExperienceAccording to TPMT Phenotype
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 1 2 3 4 5 6 7 8 9 10
Years
TPMT Wild Types
TPMT Defectives
ALLInduction Therapy
• A glucocorticoid (Dex vs Pred)
• Vincristine
• Asparaginase
• Intrathecal therapy
• An anthracycline for higher risk patients
ALL Therapy Consolidation/CNS Prophylaxis
• Standard Risk patients– Intrathecal therapy– Vincristine– MP and MTX– Glucocorticoid
• Higher risk patients– Add cyclophosphamide and cytarabine– Intermittent pulses VCR/asparaginase
ALL Therapy Delayed Intensification
-Vincristine
- Dexamethasone– Asparaginase– Doxorubicin– Cyclophosphamide– Cytarabine– 6-Thioguanine– Intrathecal Therapy
ALL Therapy Maintenance
• Two to Three years– Nightly oral 6-MP– Weekly oral MTX– Intrathecal MTX every 12 weeks– Vincristine/Dexamethasone pulses
• First introduction of 6-MP • Phase not significantly myelosuppressive;
protocols adjust to defined ANC
Low TPMT and Risk of 2nd Cancer Following Thiopurine Therapy
• Higher risk of radiation-induced brain tumors among children with high TGN or TPMT deficiency (Relling et al, 1999)
– Unique combination with delivery of oral 6-MP during the delivery of 18-24 Gy CRT
– 3/6 with brain tumors had TPMT deficiency
Low TPMT and Risk of sMDS/tAML Following Thiopurine Therapy
• Trend towards a higher incidence of Etoposide induced AML with lower TPMT activity (p = 0.16) (Relling et al 1998)
• Greater risk of sMDS/AML with TPMT activity < 14 U/ml RBC (p = 0.03) in NOPHO ALL-92 (Thomsen et al,1999)
• Therapy did not include Etoposide; total alkylating dose (cyclo)- 3 gm/m2
6-MP-Related Secondary AML
• 6-MP is ubiquitous among ALL therapies
• CCG review (Meadows et al, 1989): one t-AML among 9720 children with ALL treated without etoposide
• Dana Farber review (Kreissman et al, 1990): 2 of 752 t-AML with anthracycline intensive, CRT containing therapy
Dosing based on toxicity and thiopurine pcol results:
Pts with serious toxicity, or suspected noncompliance
Adjust doses based on thiopurine pcol results
Pts with TPMT defect
6MP dose decreased preferentially
Other drug doses not modified
Pts without TPMTDefect
All myelosuppressiveDrug doses adjusted
Demonstratednoncompliance
Pts confrontedWith results andRepeat testing
Pts with noToxicity and
WBC in target:NO CHANGE