Lead Investigator: Florencia Tettamanti, AstraZeneca
Title of Proposal Research: Predicting survival in chronic lymphocytic leukaemia from measurable residual disease (MRD) kinetics
Vivli Data Request: 8839
Funding Source: Both researchers in this application are full-time employees of AstraZeneca.
Potential Conflicts of Interest: Dr Florencia Tettamanti is an AstraZeneca employee and may hold stock. These interests will be disclosed in all relevant presentations and publications in which the research is published.
Dr. Giovanni Di Veroli is an AstraZeneca employee and may hold stock. These interests will be disclosed in all relevant presentations and publications in which the research is published.
Summary of the Proposed Research:
Chronic lymphocytic leukaemia (CLL) is the most common type of chronic leukaemia, with around 3,800 individuals diagnosed with CLL per year in the UK. Chemoimmunotherapy is a primary form of treatment for CLL. This form of treatment combines chemotherapy, which uses drugs to kill or slow the cancer cells, with immunotherapy, which stimulates the immune system to fight the cancer. Although chemoimmunotherapy treatment of patients with CLL results in high response rates, CLL remains an incurable disease. There were a reported 976 deaths from CLL in the UK between 2017-2019. Identifying how early markers predict an individual’s clinical outcome can help inform the best course of treatment and improve patient prognosis.
The lack of sustained response observed in CLL can be attributed to measurable residual disease (MRD) following treatment. MRD are remnant cancer cells which are detected in patients considered to be in complete/partial remission, with no or little evidence of clinical disease. Several studies have shown an association between undetectable MRD (uMRD) and improved clinical prognosis following treatment in CLL. Consequently, the international working group of CLL (iwCLL) currently recommends the evaluation of MRD following treatment as an early predictor of progression. However, not all patients with uMRD at this timepoint remain disease free nor do all patients without uMRD progress. The level of MRD has also been found to be important. A limited number of studies have shown that low, but detectable MRD levels are associated with improved outcomes compared to higher MRD levels. Moreover, MRD levels have been observed to vary over time, therefore it is likely that a single observation of MRD is insufficient to infer prognosis. Indeed, a study which modelled changes in MRD levels over time posttreatment, found that patients with low-risk clinical features of severity had lower MRD growth rates than patients with high-risk clinical features of severity whilst the proportion of uMRD after end of treatment was comparable between the two groups.
This project aims to identify and validate new MRD derived biomarkers (e.g MRD level and change in MRD level over time) that can predict an individual patient’s prognosis to better inform their treatment. The aim is to build a mathematical model of MRD changes over time which also predicts risks of progression and overall survival. Such models have successfully been developed to estimate the ability of using prostate specific antigen to predict prostate cancer resurgence. The model we will construct may also be useful in the design of future clinical studies with a lower number of patients. Such a model for CLL could also later be expanded to other blood cancers.
Requested Studies:
A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab
Data Contributor: Roche
Study ID: NCT02005471
Sponsor ID: GO28667
A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions
Data Contributor: Roche
Study ID: NCT02242942
Sponsor ID: BO25323