Dr Howard L McLeod

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TPMT clinical utility in Childhood ALL

• Dr Howard L McLeod
• Associate Professor of Medicine,
• Genetics, and PharmacologyWashington University,
  St Louis, USA

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A surgeon who uses the wrong side of the scalpel
cuts his own fingers and not the patient if the
same applied to drugs they would have been
investigated very carefully a long time
ago Rudolph Bucheim Beitrage zur
Arzneimittellehre, 1849
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Thiopurine Pharmacologic Measures

• RBC TPMT activity (phenotype)
• RBC TGN/MeTIMP concentrations (phenotype)
• TPMT genotype

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What is the relationship between TPMT genotype
and clinical phenotype?
6-Mercaptopurine
TPMT
6-MeMP
6-TU
Thioguanine nucleotides
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TPMT genotype and weeks with no therapy data
from less intensive protocols (MRC UKALL X, XI,
ALL97)
neutropenia
red cell aplasia
50
neutropenia
40
Percent of weeks with no therapy
30
20
10
0
wild type
heterozygous
homozygous mutant
TPMT genotype
McLeod et al, Br J Haem 1999
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Can one wait to observe degree of
myelosuppression prior to modifying 6MP?

• Or should one determine TPMT status
  prospectively, prior to the 6MP dosing?

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Disadvantage of adjusting 6MP doses based only on
toxicity

• Some regimens have so many myelosuppressive
  agents early in therapy, that profound
  myelosuppression early may delay subsequent
  therapy---so 6MP dose titration less feasible
• Some long-term adverse effects (2nd tumors) have
  been associated with defective TPMT activityso
  acute myelosuppression is not the only problem

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Low TPMT also Associated with Risk of t-AML
Low TPMT associated with second Cancers among pts
treated with thiopurines

• Higher risk of irradiation-induced brain tumor
  (Relling et al, Lancet, 35434-39, 1999)
• Higher frequency t-AML in pts with low TPMT
  (Relling et al Leukemia, 12346-52, 1998 Thomsen
  et al, Cancer 86 1080-86, 1999)
• Higher frequency of skin cancer in renal trx pts
  with high TGNs (? Low TPMT) (Lennard et al, Br J
  Derm 113723-9, 1982)

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Is there loss of efficacy after 6-MP dose
reduction?
NO!
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SJCRH Protocol Total XII Outcome not worse among
pts with TPMT defect despite 6MP dose decreases
in patients with TPMT defect and toxicity
N19
N161
P 0.096
Blood 93 2817-2823, 1999
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Total 13B 1994-1998

• Included vcr/steroid monthly pulses
• MTX/6MP backbone
• Doses based on combination of toxicity
  thiopurine measures
• N250

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SJCRH Protocol Total XIIIB Cumulative Incidence
of Relapse is not Higher Among TPMT Heterozygotes
than Wild type Patientsdespite 6MP dose
decreases in pts with TPMT defect and toxicity
P 0.43
N231
N15
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How should we use TPMT genotyping?

• Part of the informed patient process
• Pretreatment in intensive protocols
• Early in toxicity evaluation for all patients

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Optimal dose for each child differs by TPMT
genotype
Relling et al JNCI, 1999
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Doses adjusted based on toxicity and thiopurine
pcol results, with Testing done prospectively in
all pts
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How should we use TPMT genotyping?

• Part of the informed patient process
• Pretreatment in intensive protocols
• Early in toxicity evaluation for all patients

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Doses adjusted based on toxicity Adjustments
Driven by testing plus toxicity
Pts with serious toxicity Adjust doses based on
TPMT results
Pts with no Toxicity and WBC in target NO CHANGE
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• Emphasis should not be focused on population
  averages, but rather on providing prescribers
  with the tools to determine the most effective
  and safest drug dosage for individual patients
  with a minimum of trial and error.
• Gerhard Levy, Clin Pharmacokin 34323-33, 1998