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The 2022 Tandem Meetings | Optimizing lymphodepletion chemotherapy in CAR-T therapy recipients

Whilst lymphodepletion chemotherapy enhances the efficacy of CAR-T therapy, it can also lead to an increased risk of infections, cytopenia, and chemotherapy-related toxicity. It is important to determine the optimal lymphodepletion regimen that preserves CAR-T efficacy while minimizing toxicity. In this video, Muhammad Bilal Abid, MD, MRCP, Medical College of Wisconsin, Milwaukee, WI, discusses the results of a study comparing the toxicity outcomes of patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) receiving two different intensities of fludarabine and cyclophosphamide-based lymphodepletion chemotherapy. Overall, it was found that patients treated with lower intensity lymphodepletion chemotherapy had a significantly lower incidence of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and neutropenic infections, as well as a shorter neutrophil and platelet engraftment as compared to patients treated with standard-dose lymphodepletion chemotherapy. These results need to be validated in a larger cohort. This interview took place at the Transplantation & Cellular Therapy (TCT) Meetings of ASTCT™ and CIBMTR® 2022 in Salt Lake City, Utah.

Transcript (edited for clarity)

Lymphodepletion chemotherapy increases treatment efficacy of CAR-T therapy by eliminating the regulatory T-cells and competing cytokine [inaudible] prior to CAR-T infusion. Now, while that primes the immune milieu for proliferation and persistence of CAR-T, lymphodepletion can also lead to toxicities, particularly related to cytopenia, related to immune reconstitution remain, related to infections...

Lymphodepletion chemotherapy increases treatment efficacy of CAR-T therapy by eliminating the regulatory T-cells and competing cytokine [inaudible] prior to CAR-T infusion. Now, while that primes the immune milieu for proliferation and persistence of CAR-T, lymphodepletion can also lead to toxicities, particularly related to cytopenia, related to immune reconstitution remain, related to infections. Hence, the optimal lymphodepletion regimen that prevents the associated toxicity without compromising CAR-T efficacy is not known.

So in this institutional study conducted at the American College of Wisconsin, we compared toxicity outcomes in adult patients with relapsed/refractory non-Hodgkin lymphoma between summer 2018 and fall 2020, who received two intensities of fludarabine and cyclophosphamide-based lymphodepletion chemotherapy.

We divided them into two cohorts. Such as patients in the standard dose lymphodepletion, a cohort received fludarabine 30 milligram per meter square per day for three days and cyclophosphamide 500 milligram per meter square per day, again for three days. Prior to a commercial FDA-approved CD19-directed CAR-T and to keep it homogenous, we used axi-cel only. Now in the low-dose lymphodepletion arm, patients received fludarabine 30 milligram per meter square for three days. However, they received cyclophosphamide 500 milligram per meter square for one day only prior to infusion of tandem bispecific CAR-T that targeted CD20 and CD19 treated on a Phase I clinical trial performed at the Medical College.

Some of the key results of our study included that there was a significantly lower incidence of early immune-mediated CAR-T related toxicities. Particularly, there were significantly lower cytokine release syndrome and ICANS among those patients who received lower dose lymphodepletion chemotherapy as compared to standard dose lymphodepletion chemotherapy. Accordingly, recipients of lower dose lymphodepletion chemotherapy also had lesser utilization of corticosteroids and tocilizumab. In addition to that, we also observed that recipients of lower dose lymphodepletion chemotherapy, prior to CAR T infusion, had a significantly shorter duration of lymphopenia. Median of five days as compared to 11 days in patients who received standard dose lymphodepletion chemotherapy. Also, there was a lower neutropenic fever episodes in the first 28 days among lower dose lymphodepletion chemotherapy recipients as compared to standard dose lymphodepletion chemotherapy recipients. Now while recipients of lower dose fluradarabine-cyclophosphamide lymphodepletion chemotherapy had lower incidence of overall bacterial and fungal infection, the results were not significant, likely a function of small size of the study. Lastly, some of the other outcomes such as neutrophil and platelet engraftment, length of hospital stay of the index admission, and readmission, 100 day readmission rates were also lower in recipients of lower dose lymphodepletion chemotherapy as compared to standard dose lymphodepletion chemotherapy.

There are two key takeaways from our study. Firstly, the findings of shorter duration of lymphopenia and lower incidence of neutropenic infections with lower dose lymphodepletion chemotherapy are promising and for obvious reasons need further validation in larger cohorts. The other is that optimal lymphodepletion strategy to maximize CAR efficacy and minimize toxicity needs further investigation.

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