Presented at the Arthritis Advisory Committee

on July 15, 2003by

Naomi Winick, M.D.

TPMT Assessment, 6-MP Dosing and Childhood ALL

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

Pts with > 1 defective TPMT allele- lower risk ALL relapse, higher risk brain tumor

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