A recent study conducted by TFRI-funded researchers at BC Cancer sheds light on the cause behind the different outcomes of patients with diffuse large B cell lymphoma (DLBCL) who experienced a relapse in their disease. The study confirmed that patients whose cancer relapses shortly after treatment typically have poor responses to additional chemotherapy-based treatment. However, when the relapse occurs more than two years from the time of diagnosis, the outcomes to chemotherapy are significantly better.

The project, led by Dr. David Scott, clinical director of BC Cancer’s Centre for Lymphoid Cancer (CLC) and associate professor at University of British Columbia, and Dr. Laura Hilton, staff scientist at the CLC, began as part of a Terry Fox Program Project Grant and recently received additional funding as part of the Marathon of Hope Cancer Centres Network. With this, the team aimed to understand the molecular characteristics of both the initial diagnostic and relapse tumour samples of DLBCL patients being treated at BC Cancer and across Canada.

“For some time, we have known that patients who experience early relapse have had very poor outcomes when we used our traditional approach that essentially relies on providing more chemotherapy,” says Dr. Scott. “With chemotherapy resistance baked into the tumour from the start, we require new tools for these patients. New strategies, such as CAR-T cell therapy and bispecific antibodies, have emerged and the task now is to deliver these to our patients. Meanwhile, patients with late relapses have what we consider to be new lymphomas that can likely be cured with chemotherapy.”

DLBCL is a relatively common type of lymphoma, with approximately 300 cases diagnosed each year in British Columbia; around 100 patients experience relapse annually. The study findings offer this group improved chances of long-term remission.

“In 2012, I was diagnosed with DLBCL and treated successfully," said Johanna J, a BC Cancer patient. "After more than eight years, thinking I had been cured, I had a recurrence which left me feeling very anxious.  My oncologist elected to treat my late relapse with the same chemo regimen as was used the first time. I responded effectively once again. This recurrence happened two years ago and I continue to be cancer-free to this day."

The findings in this study explain why Johanna’s relapsed lymphoma responded so well to chemotherapy again and provides crucial insights into the underlying biological reasons for these differences in response in early compared to late relapse. Traditionally, chemotherapy-based treatments have been the standard of care for DLBCL patients who relapse. However, recent studies have shown that CAR-T cell therapy can significantly improve outcomes for patients with early relapse. Understanding what causes resistance and the differences between patient subgroups can help tailor treatment approaches and ultimately improve outcomes.

“We compared the genetic make up of pairs of tumours and found that in patients with late relapses, the relapsed tumour was very different from their first lymphoma tumour,” said Dr. Hilton. “On the other hand, patients with earlier relapses showed greater similarities between their first and relapsed tumours. This suggests that resistance to treatment in early relapses is already present at the time of diagnosis, which explains why these patients have limited benefit from further chemotherapy after relapse.”

The research team plans to focus on patients with early relapse to further understand treatment resistance and identify more effective therapies. Additionally, they aim to explore the common precursor cells that contribute to the development of DLBCL and their role in determining how patients will respond to a range of different treatments.

The study's insights have far-reaching implications, influencing the design of clinical trials and the development of targeted therapies. By distinguishing between different patient populations, researchers can better assess treatment efficacy and develop personalized approaches for improved outcomes. 

Sequencing of patient samples for this study was partially funded by the Marathon of Hope Cancer Centres Network. These samples are now a part of the MOHCCN Gold Cohort, which means that in the future, other researchers may use this data to further their precision medicine studies. Further funding was also provided by the Terry Fox Research Institute, through the Terry Fox New Frontiers Program Project Grant in Modeling Lymphoma Evolution and Clinical Trajectory Using Multiomics. Other funders include Genome Canada, Genome BC, Michael Smith Health Research BC, Canadian Institutes of Health Research, National Institutes of Health, the Provisional Health Services Authority and the BC Cancer Foundation in partnership with Princess Margaret Cancer Centre and Canadian Clinical Trials Group.

Read the original article here.

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