Development of high throughput sequencing for MRD analysis in ALL
Research type
Research Study
Full title
Development of high throughput sequencing of peripheral blood for minimal residual disease analysis in acute lymphoblastic leukaemia
IRAS ID
129818
Contact name
Nicholas Goulden
Contact email
Sponsor organisation
Great Ormond Street Hospital / Institute of Child Health
Research summary
Minimal residual disease (MRD) measurement of acute lymphoblastic leukaemia (ALL) currently provides the most accurate test for balancing intensity of therapy with risk of disease relapse. In front line therapy MRD tested at day 28 of treatment allows reduction of treatment without increased risk of relapse for low risk cases whilst intensification of treatment improves prognosis in high risk. MRD also highlights cases that benefit from bone marrow transplant (BMT) after relapse and guides novel immune therapy after BMT.
Currently MRD is measured in mononuclear cell (MNC) DNA extracted from remission marrows. Bone marrows are performed under general anaesthesia limiting the frequency of testing. In the most recent ALL trial (UKALL 2003) 6.4% of 6,247 remission marrow samples provided inadequate amounts of DNA to define a negative MRD with a sensitivity of 1/10,000 - the low risk threshold at day 28 of treatment. Both these issues may be obviated through the study of DNA derived from blood mononuclear cells, however in 80% of cases the level of MRD in blood is one log lower than that seen in marrow -thus the low risk threshold at day 28 in blood is 0.001% i.e. beyond the sensitivity of the current method of MRD testing (allele specific oligonucleotide based real time PCR method). High throughput sequencing (HTS) has the potential to increase sensitivity of MRD testing from 1/10,000 to 1/1,000,000 cells thereby opening up the possibility that blood can be used instead of bone marrow.
Overall HTS would be a quicker, more widely applicable and more sensitive method of MRD testing. This will further improve accuracy of prediction of outcome thereby reducing burden of therapy and cost, as well as removing trauma associated with repeated bone marrow aspirates and associated risk of general anaesthetic.REC name
London - Camberwell St Giles Research Ethics Committee
REC reference
13/LO/1262
Date of REC Opinion
18 Sep 2013
REC opinion
Further Information Favourable Opinion