Merging immune and molecular signals in HCL for improved prognosis and treatment decision making
David Ritchie
PhDUniversity of Melbourne
Project Term: October 1, 2021 - September 30, 2023
Our research consortium of diagnostic, translational and clinical researchers will undertake an integrated and novel exploration of the immune and genomic landscape in hairy cell leukemia (HCL) and correlate those data with response to both conventional and newly emerging therapies. We will apply our innovative platforms of digital spatial profiling, whole genome sequencing and circulating tumor DNA to provide highly novel data from our already collected sample bank from over 60 patients with HCL.
Hairy cell leukaemia (HCL) is a rare and slowly growing cancer of B lymphocytes. It has unique features and is often defined by the presence of a specific genetic change known as the BRAF V600E mutation. In some rare cases BRAF V600E mutations are not present and different genetic causes have been identified including our recently reported novel observation of an alternative type of BRAF alteration. For those patients with HCL that does not contain the BRAF V600E mutation there is a need to understand the precise genomic drivers of these atypical cases as those discoveries may critically inform personalized targeted treatment strategies.
Patients with HCL are commonly treated with cladribine (chemotherapy) and rituximab (an antibody targeting B cells) and often achieve complete and durable remission, however as many as 50% of patients experience disease relapse, requiring further treatment. Why some patients require recurrent therapy and others have long term remissions is unknown. We believe that understanding the genetics of the hairy cells and how the immune system responds to them may help answer this question. Our initial findings in the analysis of bone marrow samples taken before and after cladribine treatment has shown that patients with durable remissions have greater rates of immune recovery indicating that treatments that enhance immune recovery may allow long term remissions to be achieved. New molecularly-targeted therapies such as BRAF, MEK and BTK inhibitors provide non-chemotherapy options in HCL. The genomic mechanisms of resistance and the immune impact of these novel agents in HCL are largely unknown and may be of value for guiding subsequent therapy decisions.
This study proposes to further define the genomic and immune landscape of HCL as it relates to diagnosis, therapeutic decisions and disease monitoring in patients. Through this study we will develop and consolidate new discoveries via state-of-the-art genomic profiling and cutting edge immune profiling to help inform personalized treatment and optimize health outcomes.
The Hairy Cell Leukemia Foundation (HCLF) and The Leukemia & Lymphoma Society (LLS) have joined forces to create the HCL2025 program to support targeted research to build a more comprehensive foundational understanding of the molecular basis of hairy cell leukemia (HCL), develop additional therapies, and optimize outcomes for patients with this disease.