Real world CAR T cell data in diffuse large B-cell lymphoma: hitting a moving target

The landscape of CAR T cell therapy for diffuse large B-cell lymphomas (DLBCL) in the last few years has been evolving at the speed of light and making sense of real-world CAR T data can often feel like the early twentieth century physicists attempting to define the properties of light itself. The Heisenberg Uncertainty Principle teaches us that the better we can define a photon’s speed, the less precisely we can define its position [1]. So too, in interpreting real world CAR T data it often feels that by the time we have gathered a large enough sample to make meaningful observations in the real world, the treatment paradigm has already shifted enough to muddy those observations and sometimes even make them obsolete. In this issue of Leukemia & Lymphoma, Maziarz et al. report a realworld comparison of healthcare resource utilization and costs of two of the three FDA-approved CAR T cell therapies in 3rd line or later for patients with DLBCL: tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) [2]. Using Premier Healthcare data from 2017 to 2020, they compared non-CAR T cell costs as well as length of hospital stay, intensive care unit (ICU) stays, and readmission rates within 30 and 60 days after discharge between the two products. The study demonstrated a significant difference in cost between the two products, with an average nonCAR T cost of $27,594 versus $51,378 during the infusion encounter and $28,777 versus $46,575 during follow-up for tisa-cel and axi-cel respectively. This difference was primarily driven by differential cost of inpatient versus outpatient administration and treatment related toxicities. While twenty five percent of patients received tisa-cel infusion as an outpatient, all of the patients receiving axi-cel were admitted for inpatient treatment. Most of the cost differences between the two products were a consequence of this contrast during the initial infusion encounter: length of hospitalization, percentage ICU admission and length of ICU stay, tocilizumab utilization, and readmission rates. Outside of the initial CAR T infusion, rates of inpatient admission, day 30 and 60 re-admission were similar between the two cohorts, as were rates of ICU admission and rates of grade 3þ cytokine release syndrome (CRS) and neurotoxicity. The above findings are indeed consistent with earlier real-world studies which show that tisa-cel is much more likely to be given as an outpatient than axi-cel [3,4]. The difference in practice is in part driven by the conduct of the pivotal studies leading to approval of these two products: the JULIET trial allowed select patients to be treated as outpatients at investigator’s discretion [5], while the ZUMA-1 trial mandated inpatient hospitalization for all patients [6], This was also true for patients enrolled in the BELINDA [7] and ZUMA-7 [8] studies of CAR T second line therapy for DLBCL. Results of primary studies and real world data have both demonstrated an earlier onset and greater severity of CRS for patients receiving axicel when compared to tisa-cel, thereby providing a justification for the difference in utilization. Outpatient CAR T infusion is a lower cost endeavor than hospitalizing patients, so it is not surprising that tisa-cel given outpatient is cheaper than administration of axi-cel that requires hospitalization. The same is true for the cost of treating patients with more severe CRS/ICANs. However, this gap may well be narrowing, as data demonstrating the feasibility of outpatient administration of axi-cel has recently been presented [9,10] and results from a large Phase IV study of axi-cel administration are forthcoming (NCT05108805) soon. It is of interest that the use of prophylactic corticosteroids and/or tocilizumab, prior to infusion of axi-cel, was associated with reduced incidence of severe CRS which did not appear to impair disease control or result in increased rates of neurologic toxicity [11,12]. It appears likely that outpatient administration of axi-