Premium
Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL 2003
Author(s) -
Lennard Lynne,
Cartwright Cher S.,
Wade Rachel,
Vora Ajay
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13469
Subject(s) - thiopurine methyltransferase , hazard ratio , medicine , genotype , oncology , confidence interval , gastroenterology , immunology , disease , azathioprine , biology , genetics , gene
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.