# Presentation: 916613

## Naomi Winick, M.D.

- Arthritis Advisory Committee
- on July 15, 2003
- by

## TPMT Assessment, 6-MP Dosing and Childhood ALL

**Years From Study Entry**

**Estimated Survival Percentage**

- Improved Survival in Childhood ALL
-  by Study Era

## 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

## Gene for TPMT has

- Relling & Dervieux Nature Ca
- Rev 2001;1:99-108

- A common variant that
- Causes low activity,
- High levels of 6MP
- Metabolites

- Inherited differences
- in Metabolism

- Inherited differences
- In 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

## ALLInduction 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

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

## Slide 17

## 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

## Summary

- The availability of TPMT, TGN assessment improves the care of children with ALL
- Prospective testing of all children will limit, not eliminate, severe myelosuppression and the risk of second malignancy

## Summary

- Rare pts require dramatic dose mod
- Children with intermediate activity require std or near std doses to maximize the likelihood of cure
- Risks of inadvertent delays in therapy and/or over-interpretation of a result must be considered

## Dosing based on toxicity and thiopurine pcol results: 

- Pts with serious toxicity,
- or suspected noncompliance
- Adjust doses based on thiopurine pcol results

- Pts with no
- Toxicity and
- WBC in target:
- NO CHANGE