Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL 2003

Summary The influence of thiopurine methyltransferase ( TPMT ) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL 2003, a trial in which treatment intensity was adjusted based on minimal residual disease ( MRD ). TPMT genotype was measured in 2387 patients (76% of trial entrants): 2190 were homozygous wild‐type, 189 were heterozygous for low activity TPMT alleles (166 TPMT *1/*3A , 19 TPMT *1/*3C , 3 TPMT *1/*2 and 1 TPMT *1/*9 ) and 8 were TPMT deficient. In contrast to the preceding trial ALL 97, there was no difference in event‐free survival ( EFS ) between the TPMT genotypes. The 5‐year EFS for heterozygous TPMT *1/*3A patients was the same in both trials (88%), but for the homozygous wild‐type TPMT *1/*1 patients, EFS improved from 80% in ALL 97% to 88% in ALL 2003. Importantly, the unexplained worse outcome for heterozygous TPMT *1/*3C patients observed in ALL 97 (5‐year EFS 53%) was not seen in ALL 2003 (5‐year EFS 94%). In a multivariate Cox regression analysis the only significant factor affecting EFS was MRD status (hazard ratio for high‐risk MRD patients 4·22, 95% confidence interval 2·97–5·99, P  <   0·0001). In conclusion, refinements in risk stratification and treatment have reduced the influence of TPMT genotype on treatment outcome in a contemporary protocol.