Wednesday, 13 April 2016

LLNI & Lymphoid Cancer Research

This month you are going to get an insight into a different type of research supported by LLNI. In addition to the team here at the CCRCB we also work closely with consultants and other clinical staff in the hospitals. This blog will explain more information on a project ran by Dr Mark Catherwood from the Belfast City Hospital.

 Dr Catherwood has been in the haematology diagnostic laboratories in BCH trying to  develop methods of screening patients for the spectrum of mutations that occur in a specific gene in chronic lymphocyctic leukaemia.    

Poor prognosis in chronic lymphocytic leukemia (CLL) patients is linked to deletion of parts of the chromosome 17. Often with these patients, a deletion will remove one copy of an important gene called TP53 whilst a mutation will deactivate in the other copy of TP53.  TP53 is tumour suppressor gene that stops the development of cancers.  These abnormalities are associated with patients who have a poor response to chemotherapy and immunotherapeutic regimens.  

The deletion and/or mutation of the TP53 gene occurs on average in 10-15% of untreated CLL patients, and the incidence rises to 40-50% in fludarabine-refractory cases.  This has created a clinical need to reassess TP53 status as the disease progresses.  This is of importance as it has been shown that TP53 mutations without deletions of chromosome 17 occur in a sizeable proportion of CLL patients (~5% in first line treatment situation) and are also associated with significantly worse outcome.

Until recently, no effective treatments were available for these patients, as current therapeutic regimens could only achieve limited and short-lasting responses again with a dismal prognosis despite additional lines of treatments.  The only potentially curative approach is that of an allogeneic transplant.

Notably, the outcome of CLL patients with deletion of chromosome 17 and/or TP53 gene mutation appears to be dramatically improved by treatment with novel, non-chemotherapeutic agents such as the B-cell receptor signaling inhibitors Ibrutinib and Idelalisib in combination with Rituximab.

Idelaisib has been approved by the FDA in the US and the EMA in Europe and endorsed by UK NICE in adult patients for the first-line treatment of cases harbouring deletion of chromosome 17 and/or TP53 mutations or in treatment of CLL cases refractory to chemo(immuno)therapeutic regimens.

However, the availability of these new drugs has created the need for practicing haematologists to carefully screen all CLL patients for deletion of chromosome 17 and TP53 gene mutations before the implementation of both first and subsequent lines of treatment.   This is so the most appropriate treatment is selected whilst avoiding potentially ineffective regimens and the related unnecessary toxicity – a process of personalized or stratified medicine. 

Dr Catherwood has been working with Professor Ken Mills in the Centre for Cancer Research and Cell Biology (CCRCB) at Queen’s University Belfast on a project funded by a development grant from the Leukaemia and Lymphoma NI to use next-generation sequencing (NGS) approaches to rapidly screen and identify mutations in CLL patients, even those that are present in a very low percentage of cells.    

This method can also be developed for detecting TP53 mutations in other types of lymphoid malignancies such as lymphoma and eventually adapted to screen for several mutations in other types of blood cancer.

This project is an example of how the funding by LLNI is being used to translate research studies, such as this one using NGS to identify TP53 mutations, into a diagnostic clinical environment to improve patient outcomes for a variety of cancers.