Dr Sujith Samarasinghe, Great Ormond Street Hospital

01 March 2013
Developing a model for personalised dosing of vincristine

Childhood acute lymphoblastic leukaemia has an excellent outcome with modern treatment, including a drug called vincristine. Unfortunately, however, vincristine can cause nerve damage, leading to pain, numbness, difficulties with walking and handwriting and impact on long-term dexterity. In this project Dr Samarasinghe sets out to obtain a better understanding of how to optimise the dosing of this important drug.

Amount of award: £61,973  │ Date of award: March 2013

Overview
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Although we have achieved a survival rate of more than 90 per cent, this requires two to three years of toxic chemotherapy for each child. Some patients also require radiotherapy and stem cell transplant.

One of the key components of chemotherapy is a drug called vincristine. Vincristine is an essential tool in the treatment of leukaemia but, like most chemotherapy drugs, it has side effects. Vincristine can cause nerve damage, also known as peripheral neuropathy. This can lead to pain, numbness, difficulties with walking and handwriting and impact on long-term dexterity. If significant neuropathy arises during treatment, the dose may have to be reduced or treatment suspended, placing the child at risk of relapse.

Despite the widespread use of vincristine in the treatment of childhood ALL, and other childhood cancers, little is known about the prevalence and incidence of vincristine-induced peripheral neuropathy (VIPN). This is largely due to the lack of specific and sensitive measurement tools for use in children. Taking advantage of the current national childhood ALL clinical trial (UKALL 2011) in which some patients are receiving vincristine and some not, the team will use an adapted version of a scale developed to assess neuropathy in adult patients to establish the frequency of neuropathy in childhood ALL patients and determine its severity after vincristine treatment.

The team will also explore the impact of genetic variations in vincristine-pathways. Genetic variation means that some children metabolise the drug faster and are less likely to develop neuropathy. However, because they break down the drug faster this might increase the risk of relapse. Conversely, other children who metabolise the drug more slowly have higher exposure and are potentially at greater risk of neuropathy. By examining the relationship between genetic variants, vincristine exposure and outcome (in terms of both neuropathy and response to therapy) the team expect to provide important new information on how to dose vincristine optimally in children.

About the research team
Dr Sujith Samarasinghe is a Consultant Paediatric Haematologist at Great Ormond Street Hospital in London. He is a key member of the national leukaemia toxicity group and has worked on defining toxicities for UKALL 2011, with a view to developing strategies to reduce their incidence.

The project team also includes Dr Nick Goulden, Dr Gareth Veal and Dr Jamie Renbarger, some of the most experienced clinical triallists in childhood ALL, lending additional expertise in genetics, pharmacology and paediatrics.

What difference will this project make?
This study will significantly improve our understanding of the variables that influence both the effectiveness and the side-effects of vincristine therapy for children with ALL and certain other cancers. This will help to enable personalised dosing, so that each child can be given an optimal dose to derive maximum benefit with minimal risk of side-effects.

Read more: About acute lymphoblastic leukaemia


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