Paediatric, adolescent and young adult cancer: News
Outcome after Induction Failure in Childhood Acute Lymphoblastic Leukemia
Currently 80% of children with Acute Lymphoblastic Leukaemia (ALL) are being cured using current treatment methods. The biggest cause of treatment failure is due to relapse, with a small percentage (2-3%) of patients not acheiveing complete remission after 4-6 weeks of induction chemotherapy. Induction failure can be described as the persistence of leukaemic blasts in the bone marrow or extramedullary sites after induction therapy. These patients with initial induction failure are considered to be a very high risk patient subgroup.
In this study a retrospective analysis was performed on data from 14 cooperative study groups between 1985 and 2000. 44017 patients with ALL were treated of which induction failure occurred in 1041 patients (2.4%). These patients had a greater number of unfavourable characteristics such as high leukocyte count, age older than 6 years, positive for t(9;22)(BCR-ABL1), T cell phenotype, and 11q23 chromosomal rearrangement. These high risk presenting features were associated with a reduced rate of survival.
T-ALL patients who had a better outcome with allogeneic stem cell transplantation than with chemotherapy. The analysis also showed that patients younger than 6 years who had B cell ALL and with no high risk cytogenetic features have a better outcome with chemotherapy. This observation may have considerable clinical implications as transplantation is generally considered to be the standard of care for such patients. Published in the New England Journal of Medicine.
Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial
A clinical trial coordinated by Professor Vaskar Saha, Professor of Paediatric Oncology at the University of Manchester found that giving Mitoxantrone to children whose acute lymphoblastic leukaemia (ALL) had returned dramatically improved their survival.
216 children with relapsed ALL in the UK, Ireland, Australia and New Zealand took part in the study. 111 received the standard Idarubicin treatment and 105 were given Mitoxantrone. After 3years, 69% of those who had been given Mitoxantrone survived, compared to 45% of those who received Idarubicin. Fewer side effects were also seen in the children who received Mitoxantrone.
As a result, the randomisation part of the study closed early and all children now receive Mitoxantrone. This is the first time a trial in childhood ALL has closed early as a single drug has such clear benefit and is reported in The Lancet, Volume 376, Issue 9757, Pages 2009 - 2017.
Summary of the asparaginase work reported in Blood:
The Children's Cancer Group, led by Professor Vaskar Saha, in collaboration with Dr. Paul Bates and colleagues of the Biomolecular Modelling Laboratory at the Cancer Research UK London Research Institute, has designed improved versions of the anti-leukaemic drug, E. coli L-asparaginase (ASNase), a crucial drug in the treatment of childhood acute lymphoblastic leukaemia (Blood 2010, e-pub 24 Nov).
Using in-depth computational modelling predictions combined with experimental verifications, these candidate next-generation ASNase versions were designed to resist proteolytic degradation by the lysosomal enzyme AEP in lymphoblasts (Figure). Accelerated AEP-mediated degradation of ASNase represents a potential mechanism of lymphoblast drug resistance (J Clin Invest 2009; 119:1964-1973). Additionally, by modifying the drug's glutaminase activity, these new ASNase variants would potentially be associated with fewer clinical side effects without loss of anti-leukaemic activity.
Genome-wide study of chilhood leukaemia susceptibility
Dr Malcolm Taylor, Reader in Cancer Immunogenetics at the University of Manchester, in collaboration with scientists at the Institute for Cancer Research in London, used DNA samples collected in Manchester as part of the UK Childhood Cancer Study to report that children with normal inherited genetic variations in 3 genes are born with an increased risk of developing acute lymphoblastic leukaemia, the most common cancer of childhood.
The team identified a total of 10 common genetic variants implicating the Ikaros, (IKFZ1), ARID5B and CEBPE genes in childhood ALL and noted that all 3 genes are involved in the early differentiation of B lymphocytes, the cells transformed into leukaemia.
This is the first genome-wide study of childhood leukaemia susceptibility and confirms that normal genetic variations commonly present in the general population can influence leukaemia risk. (Nature Genetics 2009; 41(9):1006-10. Working with other colleagues, the group has now confirmed their findings on additional childhood leukaemia patients (Blood 2010; March 4;115(9):1765-7.)