Access offsets poverty in quest for CAR T cells

In this issue of Blood, Newman et al¹ examined the influence of household poverty and neighborhood on access and outcomes of young patients treated with commercial (tisagenlecleucel) or investigational CD19 chimeric antigen receptor (CAR) T cells for relapsed/refractory B-acute lymphoblastic leukemia (B-ALL)/lymphoma. As a proxy for poverty, investigators used Medicaid-only insurance and the Childhood Opportunity Index, a multidimensional quality measure of US neighborhood metrics with scores across 3 domains of opportunity (education, health/environment, and social/economic).¹ On the basis of nearly a decade of data from 206 patients (aged 1-29 years) treated at Children’s Hospital of Philadelphia, the authors found that patients unexposed to household poverty were more likely to receive CAR T-cell therapy despite higher disease burden. As high disease burden is an independent prognosticator of worse outcome, it is notable that overall survival outcomes appeared the same between groups. Furthermore, despite similar rates of complete remission (CR), patients from low-opportunity neighborhoods experienced increased hazard of relapse but were less likely to proceed to salvage therapies.¹ 

Five years after US Food and Drug Administration approval of the first CAR T-cell targeting B-ALL (tisagenlecleucel), research collaboratives and real-world consortia have identified predictors of toxicity, response, and remission following tisagenlecleucel beyond those detected in clinical trials.^2,3 This timely article explores the impact of social determinants of health (SDOH) on outcomes. Nevertheless, it is tricky to extrapolate the conclusions of this study to broader populations treated in the real world, given the robust resources available to the cohort of patients evaluated in this report. These patients were predominantly treated on clinical trials with closely regulated follow-up that may have protected against the adverse impact of household poverty or neighborhood resources. In addition, housing and travel support provided directly by the institution likely protected from the true impact of household or neighborhood poverty, while also protecting against the (often unconscious) referral bias that oncologists face when making clinical decisions about patients with limited resources. Despite the wide catchment area representing a broad referral base from 38 states, Black/African American patients were underrepresented, comprising only 7.28%, similar to other large studies of CAR T cells targeting hematologic malignancies.^4,5 In contrast to recent real-world reports showing worse outcomes of African Americans treated with tisagenlecleucel,⁶ in this study, Black/African American and Hispanic/Latino patients had similarly high rates of CR. These findings reflect recent adult data in patients treated with axicabtagene ciloleucel,⁷ highlighting the outsized contribution of delayed referral and SDOH to worse outcomes in Black/African Americans treated with CAR-T.

As the authors note, use of insurance at time of CAR T-cell infusion as a proxy for household poverty can lead to misclassification, as patients may lose private insurance or switch to public insurance during their leukemia journey. Classification of children from higher-income homes as publicly insured can lead to an unrealistically optimistic picture of how poverty and other SDOH impact patients seeking CAR-T therapy. The authors appropriately underscore the need for future multi-institutional studies that examine the impact of more granular area–based and household-level exposures and specifically explore family-reported poverty to bypass the limitations of proxied SDOH. Notably, most patients in this report had private insurance and were treated on clinical trials, raising the question of how results would differ in populations who are largely publicly insured. Delayed or denied insurance approval is another determinant of outcome, and investigating those who do and do not go on to receive this therapy, whether commercially or on a clinical trial, merits elucidation in a similar study.

Every aspect of CAR T-cell therapy challenges access for vulnerable populations: treatment must be given at a specialized center of excellence, and patients are required to remain within that vicinity for at least 1 month; there is a limited window of opportunity for referral that may exacerbate existing biases; therapy is expensive, with resource-intensive logistics; and insurance challenges remain despite existing guidelines. In the clinical trial setting, even more barriers for poverty-exposed and racial/ethnic minorities can contribute to underrepresentation, especially for complex, personalized therapies, such as CAR T cells. Obtaining insurance coverage for routine costs related to the trial can be difficult, especially for patients seeking treatment outside their coverage network, not to mention the limited referral center resources to address logistical challenges not covered by patient assistance programs.

What would Hippocrates think? Are we doing no harm by creating targeted therapeutic options intended for all, but treating patients within health care systems that unintentionally systematically exclude the most vulnerable? Perhaps this point is made most saliently by recognizing the population not represented within this study: patients who were not referred, excluded, or unable to travel for CAR T cells. We routinely consider these patients as we work to address the clinical obstacles that bar them from potentially life-saving therapies, while paying less attention to sociodemographic barriers. By definition, patients who “made it” to a clinical trial at a large institution despite having public insurance, living in a lower-resource neighborhood, or having household poverty are unlikely to truly represent the most vulnerable patients.

This report supports the hypothesis that predictors of response to CD19 CAR T cells may rely as much on access to treatment as on any underlying disease determinant. When patients with household poverty do receive treatment with CAR T cells, whether commercial or on a clinical trial, they have similar outcomes to patients without household poverty. As with pre-CAR T-cell disease burden and antigen load, neighborhood poverty level is not easily modifiable. However, this article highlights the importance of a robust and accessible financial infrastructure equipped to offset costs and diminish logistical burdens in providing equitable care,⁸ leading to equitable outcomes regardless of socioeconomic status and neighborhood opportunity.

Conflict-of-interest disclosure: R.H.R. has received honoraria from Novartis and Medical Learning Institute, a consultant fee from Pfizer, and research funding from Tessa Therapeutics and is on the Board of Directors for the American Society of Gene and Cell Therapy and Be The Match/National Marrow Donor Program. E.N. has received honoraria from Novartis, Atara Bio, and Medexus/Medac GmbH for serving as a consultant.