Defining ctDNA monitoring and immune modulation in a novel, risk stratified clinical trial for PTLD
Jennifer Amengual
MDColumbia University Medical Center
Project Term: February 1, 2025 - January 31, 2028
Posttransplant lymphoproliferative disorders (PTLD) are a group of lymphomas that arise during immunosuppression following organ transplantation and are a significant source of morbidity and mortality. PTLD remains challenging to treat due to disease heterogeneity, patient comorbidities, the risk of infectious complications, and organ rejection. The goals of this proposal are to (1) study the therapeutic efficacy and safety of dose modified R-EPOCH in High-Risk PTLD patients; (2) determine the utility of ctDNA defined molecular response as a novel risk-stratification biomarker in PTLD; (3) understand the impact of immune-suppression on T cell function, T cell receptor diversity, and the detection of oncoviruses. The overall goal is to reduce morbidity and identify novel biomarkers for personalized precision treatment decisions to improve survival in this devastating disease.
Posttransplant lymphoproliferative disorders (PTLD) are a group of lymphomas that arise during immunosuppression (medicine to prevent organ rejection) following solid organ or stem cell transplantation. Lymphoma is a cancer of the white blood cells found in the lymph nodes. Though rare, PTLD is becoming more common as more transplants are performed and it is a major source of suffering and early death. Because the behavior of PTLD varies between patients, current guidelines support a sequential and risk stratified treatment approach. This strategy divides patients between low- and high-risk based on simple clinical factors rather than the biology of their disease. Overall survival in high-risk patients is only 59% after 2 years and treatment is associated with excess toxicity.
Unfortunately, there has been no improvement in survival even in the modern era of novel medicines, making PTLD an area of unmet need. Treatment with the R-EPOCH regimen has improved outcomes in aggressive lymphomas related to HIV, another high-risk lymphoma related to a poor functioning immune system. Based on these observations, we reviewed patients at our hospital who received R-EPOCH for PTLD and found that outcomes were improved without the addition of excess toxicity. Our goal is to use R-EPOCH as a foundation to improve outcomes for patients with PTLD. We believe that if R-EPOCH is better tolerated and more effective than other chemotherapy strategies, then high-risk patients may have improved survival while limiting side effects. We will conduct a clinical trial examining a risk-stratified approach for untreated PTLD.
We will also measure circulating viral and tumor DNA (ctDNA) from simple blood draws throughout the study. ctDNA refers fragments of DNA that are shed into the blood as tumor cells die. This advanced technology has refined non-invasive detection of measurable residual disease (MRD), and helped to guide decisions in other lymphoma subtypes, but has not been well studied in PTLD. Given the varied biology of PTLD and the presence of viral DNA as a unique biomarker, we aim to validate this breakthrough technology in PTLD to precisely define and stratify which patients truly require chemotherapy. In addition, as transplant patients are on chronic immunosuppression which may impact infectious complications and risk of relapse, we will measure the impact of treatment and immunosuppression on T cell immune function and emergence of viruses that drive cancer.
These results will directly improve the lives of patients suffering from PTLD. It will help us learn if treatment with R-EPOCH is better than other strategies. It will define a new precision medicine approach to measure the effects of treatments in PTLD. It will inform how treatment effects immune function and risk of infection and disease relapse throughout the treatment spectrum. We hope to be able to make better informed decisions on how to treat this understudied rare lymphoma.