Hope all is well this morning, I'm just hearing about your luggage....your abstract title for Cold S

1
Other Genes for ALL?
2
Finding new genes influencing ALL therapy

The Candidate Gene Strategy
3
Pharmacogenomics of Antileukemic Agents
Candidate Gene s (what we think we know)
Drugs
Genes

• CYP3A4, CYP3A5, PXR
• ABC transporters
• TPMT, GAPDH, HMGB1
• RFC, MTHFR, GGH, FPGS,TYMS,
• UGT1A1, UGT2B7
• GR, VDR
• GSTM1, GSTT1
• TOPOII

• Etop, Cyclo, Dex, Pred, Dauno, VCr
• above, MP, MTX
• MP, TG, AZA
• MTX
• Etop
• Pred, Dex
• Etop, Cyclo, Pred, Dauno
• Etop, Dauno

PI
4
ALL Risk-adjusted Chemotherapy SJCRH Total 13B
(N246)

• Lower Risk
• MTX/6MP
• MTX/6MP
• MTX/6MP
• Dex/VCR
• MTX/6MP
• MTX/6MP
• HDMTX/6MP
• Dex/VCR

• Intermed/High Risk
• VP/Cyclo
• MTX/6MP
• MTX/AraC
• Dex/VCR
• VP/Cyclo
• HDMTX/6MP
• VP/AraC
• Dex/VCR

5
Glucocorticoid group
Antimetabolite group
Phase II conjugating group
Candidate Genes for ALL chemotherapy 16
polymorphic loci in 13 genes
6
Visual genotype for 246 pts on Total XIIIB study
at 16 polymorphic loci
7
Do SNPs in candidate genes relate to efficacy
(EFS)?
Pharmacogenetics of ALL Chemotherapy SJCRH Total
13B (N246)
8
Pharmacogenetics (16 loci) of Hematologic
Relapse of Childhood ALL
TYMS (in GSTM1 null)
GSTM1
0.5
0.5
0.4
High TYMS
0.4
p0.03
P0.03
Cumulative incidence
0.3
0.3
High GST
Cumulative Incidence
0.2
0.2
0.1
0.1
0
0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
Time in Years
Time in Years
Null
Non Null
Rocha et al, Blood 2005
9
Pharmacogenetics of ALLExtended to COG Protocols

• Mary V. Relling, Pharm.D.
• Mini Devidas, Ph.D.
• Mike Borowitz, M.D.
• Stella Davies, M.D.
• Stephen Hunger, M.D.
• Bill Carroll, M.D.

10
Do SNPs in candidate genes relate to drug
toxicities?
Pharmacogenetics of ALL Chemotherapy SJCRH Total
13B (N246)