In this issue of Blood, Neelapu and coinvestigators have shown that older patients with advanced B-cell non-Hodgkin lymphoma (NHL) did just as well as younger patients receiving chimeric antigen receptor (CAR) T cells on the ZUMA-1 trial.1,2  Common perceptions, although not necessarily well founded, among oncologists and hematologists treating older patients with advanced NHL, such as diffuse large B-cell lymphoma (DLBCL), are that these patients are not fit enough to receive, do not want to receive, and will not derive any significant benefit if they do receive more aggressive therapies, such as hematopoietic stem cell transplantation (HSCT) or CAR T-cell therapy. The definition of an “older patient” is generally defined as patients >65 years of age, even though it has been argued that the more clinically relevant delineation is closer to 75 years, at which time comorbidities, physical dependency, and symptoms associated with aging become more prevalent.3  Such perceptions are also based on some fact, as age >60 years has been demonstrated to be an independent negative prognostic factor in patients with NHL.4  However, this observation from the early 1990s may not hold as great of significance today, as both therapy and supportive care have significantly improved over time. Indeed, the outcomes for older DLBCL patients to initial therapy with modern immunochemotherapy regimens are quite good, with 5-year overall survival rates approaching ∼70%.5 

The more significant challenge that arises is how to treat older patients with relapsed and refractory (R/R) disease. The treatment of choice in this situation would be some form of HSCT, either autologous or allogeneic. Outcomes for older DLBCL following autologous HSCT are actually similar to their younger counterparts.6  Unfortunately, only a small minority of older patients over the age of 65 years is actually eligible for transplant because of lack of disease chemosensitivity. Trials utilizing CAR T cells targeting CD19 have resulted in relatively high response rates that are sustained in a significant minority of patients with R/R B-cell NHL.2,7  In univariate analyses from these trials, CAR T cells appear to be equally efficacious among older patients receiving this treatment.

Despite these encouraging results, there may be similar perceptions and concerns that the use of CAR T cells may result in increased toxicities and have lower or limited efficacy in older patients with R/R DLBCL. To address these concerns, Neelapu and his fellow investigators from the ZUMA-1 trial performed a post hoc subgroup analysis of efficacy and safety of the autologous anti-CD19 CAR T-cell product axicabtagene ciloleucel (axi-cel) in patients ≥65 years as compared with patients <65 years of age with R/R aggressive B-cell NHL, the majority of which were DLBCL. Their analyses demonstrated most importantly that outcomes were nearly identical between the 2 age groups with slight trends favoring the 65 years and older age cohort, which comprised approximately a quarter of the study population, in regard to complete responses, duration of response, progression-free survival, and 24-month overall survival rate, which was 54%. These results were observed in the context of the 2 groups being relatively matched in regard to disease stage, tumor burden, and number of prior therapies. Of biologic interest, the axi-cel products in the older age cohort were noted to have similar peak and 28-day area-under-the-curve expansion to the younger cohort. In regard to toxicity, the overall incidences of cytokine release syndrome (CRS) and neurologic toxicities were not reported. The incidence of grade ≥3 CRS was similar and relatively low (7% vs 12%) between the 2 groups. However, the incidence of any grade ≥3 neurologic toxicities was notably higher (44% vs 28%) in the older age cohort, particularly in rgard to encephalopathy, to which the investigators attributed age as a risk factor. There was minimal discussion in regard to long-term side effects, other than hypogammaglobulinemia, but they are assumed to have been minimal as the majority of studies on CAR T cells report resolution of most symptoms by 6 weeks after infusion.

As the options and outcomes for most older patients with R/R DLBCL and other advanced B-cell NHL are very limited, these are highly encouraging results. The immediate criticism is that these are highly selected patients, as is the case for all aggressive therapies, which require relatively normal organ functions and a good performance status. However, as has been clearly demonstrated with HSCT, there is no absolute upper age cutoff for CAR T-cell therapy, and similar to HSCT, even more fragile patients may potentially benefit from this therapy after undergoing an individualized optimization program.8  Toxicities, particularly neurologic toxicities, remain a concern, but they appear to be manageable and will likely improve over time. The clinical benefits of CAR T cells have been clearly demonstrated in older patients, and it is imperative that this option should, at a minimum, be considered and offered to this patient population.

Conflict-of-interest disclosure: M.R.B. serves as a consultant for and receives honoraria from Novartis, Celgene, CRISPR Therapeutics, and Kite/Gilead.

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