scholarly journals Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL2003

2015 ◽  
Vol 170 (4) ◽  
pp. 550-558 ◽  
Author(s):  
Lynne Lennard ◽  
Cher S. Cartwright ◽  
Rachel Wade ◽  
Ajay Vora
Keyword(s):  
Treatment Outcome ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Thiopurine Methyltransferase ◽  
The Uk

Acute Lymphoblastic Leukaemia Has a Poor Outcome in Children with Down Syndrome Due to Infective Death in Remission (Results of UK MRC ALL 97 Trial).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 873-873 ◽  
Author(s):  
Josu de la Fuente ◽  
Sue Richards ◽  
David K. Webb ◽  
Ian M. Hann ◽  
Christopher D. Mitchell ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
High Rate ◽  
Childhood All ◽  
Free Survival ◽  
Children With Down Syndrome ◽  
Medical Research Council Trial ◽  
The Uk

Abstract Acute lymphoblastic leukaemia (ALL) has a poorer outcome in children with Down syndrome (DS) which has been attributed in the past to a higher incidence of infective death in remission and late relapses. We report on the outcome of children with DS enrolled on the UK Medical Research Council trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Thirty seven children had DS (2%), of whom three were treated on the high risk protocol (HR1). Thirty-three (89%) achieved complete remission at the end of induction, 3 died during induction (8%), and one died later without remission. The median follow up was 4.9 years (2.4–7.8). The 5-year event free survival (EFS: 48.0%, SD 8.9) was not an improvement on the previous MRC UKALL XI trial (57.9%, SD 8.0, p=0.2) and was significantly worse than for children without DS (p<0.00005). At the time of follow up, 46% of the children had died (n=17). Five patients suffered relapse, and the relapse rate was not significantly different from those without DS. One patient known to have cardiac disease died during maintenance due to arrhythmia and 8 died of infection, resulting in a significantly higher rate of death in remission (28%) than in children without DS (3%, p<0.00005). Infective deaths were associated with intensification therapy, except in one child who died during interim maintenance. It was possible to isolate a microorganism in 50% of the cases (two cases of Pseudomonas, one Staphylococcus aureus, one Staphylococcus epidermidis and yeast) plus Rhinovirus was found in a nasopharyngeal aspirate of a fifth case with clinical evidence of bacterial sepsis. For the randomised comparisons (prednisolone versus dexamethasone n=30, mercaptopurine versus thioguanine n=23), results within the DS patients were not significantly different from those in all patients, with benefit for dexamethasone. The increase in remission deaths with DS was greater with prednisolone, and with mercaptopurine (p for interaction = 0.0002, <0.00005, respectively). The revision of the trial in 1999 which adopted the template of CCG 1952 which improved EFS, did so for DS patients also, with no change in the DS remission death rate. In conclusion, children with DS may benefit from increased treatment intensity but still have an unacceptably high rate of infective death in remission.

Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular biological aspects

2005 ◽  
Vol 41 (4) ◽  
pp. 613-623 ◽  
Author(s):  
Connie Brouwer ◽  
Ronney A. De Abreu ◽  
Jenneke J. Keizer-Garritsen ◽  
Lambert H.J. Lambooy ◽  
Kai Ament ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Thiopurine Methyltransferase ◽  
Biological Aspects

Barriers To Clinical Trial Enrolment For Teenagers and Young Adults With Acute Lymphoblastic Leukaemia: The Impact of Age Eligibility Criteria

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1401-1401
Author(s):  
Lorna Anne Fern ◽  
Clare Rowntree ◽  
Rachael E Hough ◽  
Ajay J Vora ◽  
Adele Fielding ◽  
...  
Keyword(s):  
Young Adults ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Eligibility Criteria ◽  
Incidence Data ◽  
Paediatric Trial ◽  
Time Period ◽  
Teenagers And Young Adults ◽  
The Uk ◽  
The Impact

Abstract Background Overall survival (OS) for teenagers and young adults (TYA) aged 15-24 years (yrs) with acute lymphoblastic leukaemia (ALL) is inferior to OS for children. In the UK, five-year OS for children up to 14 years with ALL is 89%, falling to 69% for 15-19 yr olds and 52% for 20-24 yr olds (O'Hara et al, National Cancer Intelligence Network, 2013). Both disease biology and choice of protocol are likely to be important in explaining these differences. However, lower rates of inclusion into clinical trials with increasing age may also be a significant factor. In the UK 3 national paediatric and adult ALL trials were open to recruitment between 1997-2006 (table 1). In 2006 the upper age eligibility criteria for UKALL2003 was increased from 18 to 24 yrs and the lower age limit of UKALL XII was correspondingly increased to reflect emerging evidence that TYA have improved outcomes when treated on paediatric protocols. Aims 1. To examine trial accrual rates (AR) by age over a ten year period (1997-2006) to three UK national ALL trials. 2. To determine the influence of amending the age eligibility criteria for UKALL2003 on TYA accrual Methods ALL incidence figures for patients aged 1-39 yrs during the study period of 1997-2006 were obtained from a national cancer registry. Incidence data was classified according to the morphology-based coding specifically for TYA (Birch et al, BJC, 2002). Accrual rates (AR) were expressed as the ratio of patients entered onto trials during the same time period compared to incidence cases. Descriptive statistics were applied for an observational dataset where sample size or incidence cases cannot be controlled (Fern et al. BJC, 2008). We obtained a further incidence data set for cases diagnosed in 2007 and 2008 to examine the impact of age eligibility amendments in 2006 and 2008 to UKALL2003. Results ALL was diagnosed in 4,579 patients aged 1-39 yrs between 1997-2006, 2,767 were under 10 yrs. The figure shows the proportion of newly diagnosed ALL patients entering trials 1997-2006. Red arrows show age eligibility criteria of the trials. 65% of all patients were enrolled onto one of the 3 trials. AR were highest for under 10's (71.5%), declining to 55.2% for 15-16 yr olds, 43.4% for 17-18 yr olds and 40% for those aged 21-24 yrs. The amendments to age inclusion criteria for UKALL2003 and UKALL XII improved AR for 17-18 yr olds to a level equivalent to AR for 15-16 yr olds. AR for 19-20 yr olds also improved to 62.5%. However, recruitment of 21-24 year olds did not change. During 1997-2006 three quarters of 17-18 yr olds recruited to trials were enrolled onto UKALLXII. After protocol amendments, three quarters of 17-18 yrs were recruited to the paediatric trial. Conclusions We have shown a decline in trial accrual with increasing age for teenagers and young adults with ALL despite the availability of national trials spanning the age range being available during the time period studied. Due to close cooperation between adult and paediatric trial management groups, major changes were made to age eligibility criteria for both paediatric and adult trials, following increasing evidence that TYA have better outcomes when treated on paediatric protocols. We have shown an increased accrual of older teenagers to ALL trials in the UK following these changes. No improvements were observed for 21-24 year olds. However, this age group were only eligible for UKALL 2003 during the last year of our analysis. This approach to trial eligibility design may serve as a model for future trials, both in ALL and other cancers. Disclosures: No relevant conflicts of interest to declare.

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