Maintaining a fit T‐cell compartment: lymphoma treatment sequencing in the era of chimeric antigen receptor T‐cell therapies

Abstract

We welcome the recent publication by Trotman et al. presenting approaches to front-line treatment of follicular lymphoma (FL) in Australia. Trotman et al. highlight the potential application of bendamustine combinations for FL front-line and in relapsed disease. In the absence of an overall survival (OS) benefit favouring a particular chemotherapy backbone, both bendamustine and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) are recommended by the authors, in combination with an anti-CD20 antibody. There are benefits of bendamustine in terms of lower early toxicity and longer progression-free survival, at the potential cost of increased late infection and second malignancy rates. We highlight an additional factor of emerging importance in treatment selection for non-Hodgkin lymphoma: the potential impact on subsequent chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapies directed against CD19 are licensed for relapsed and refractory aggressive B-cell lymphoma treatment internationally, including in Australia. Early phase trials indicate CD19 CAR T cells are similarly able to induce durable remissions in other B-cell lymphomas, including FL. If the apparent plateau of relapses seen in aggressive B-cell lymphomas holds true in larger FL trials, CAR T cells have the potential to compete with allogeneic stem cell transplantation to deliver long-term remission. Trotman et al. note the prolonged T-cell lymphopenia associated with bendamustine use. Production of CAR T cells requires an adequate T-cell harvest, circulating Tlymphocyte levels <350/μL being strongly associated with CAR T-cell production failure. Treatments that cause prolonged T-cell lymphopenia therefore have the potential to preclude subsequent CAR T-cell therapy. Units across Australia are already delivering CAR Tcell therapies. This includes a trial in high-risk, relapsed FL (NCT03568461). Until results of this and similar trials are available, the role of CAR T cells for FL remains uncertain. However, we believe that, as OS is similar between the front-line treatment options, avoiding T-cell depleting chemotherapy regimens should be a consideration when discussing treatment options with younger patients who are potential future CAR T-cell therapy candidates. In summary, because chemotherapy is not curative for advanced FL, it is critical to maintain a long-term perspective of treatment options. Maintaining a ‘fit’ T-cell compartment may be an increasingly important consideration in the era of CAR T cells.