Despite the promising results of chimeric antigen receptor (CAR) T-cell therapies in patients with acute lymphoblastic leukemia, lymphoma, and multiple myeloma (MM), not all eligible patients have the opportunity to benefit from this treatment, due to long waiting lists and (inter)national variation in availability of this therapy. In this issue of Blood, Bell et al discuss a framework to help make difficult decisions in prioritizing patients receiving CAR T-cell therapy when limited CAR T-cell production slots are available.1
Many clinicians face the ethical challenges of limited CAR T-cell treatment availability due to limited or no access to CAR T cells, which is unfortunately still true in a considerable number of countries worldwide due to manufacturing limitations, regional access problems with only a few sites offering the treatment, staffing shortage at the CAR T-cell center, or reimbursement issues. Due to limited availability, patients may have to spend a long time on a waiting list for a manufacturing and/or treatment slot. Recently, the experience in CAR T-cell slot allocation of leading CAR T-cell centers in the United States was studied.2 For patients with MM, the median time spent on a waiting list was 6 months, and about a quarter of these patients did not make it to CAR T-cell treatment. Most centers use a form of prioritization and ranking, but criteria varied.2 Maximizing medical benefit by weighing the chances of patients most likely to make it to leukapheresis and/or dosing and/or achieving a clinical response was the most heavily weighted criterion.2 In most centers the prioritization criteria were not transparent to patients, and in almost half of the centers physician-only teams determined patient selection and slot allocation.
Prioritizing is very complex clinical decision-making process. CAR T-cell therapy can be highly effective but may also cause severe side effects. Moreover, it is an intensive treatment strategy, requiring commitment and understanding from patients and their caregivers. Currently, there are no established guidelines to assist clinicians to prioritize CAR T-cell-eligible patients. With the input of a diverse working group, including clinicians, researchers, patients, and others working in operational, quality control, or bioethics roles in the CAR T-cell process, Bell et al produced a framework based on broad criteria for prioritization of CAR T-cell-eligible patients. In multiple sessions, criteria with potential impact on the prioritizing process were discussed and judged, resulting in a transparent 3-step prioritization process. In the first step (form A), medical benefit is assessed by a disease-specific team. Patients proceed to step 2 (form B) when any degree of benefit is established. In step 2, a multidisciplinary team including a social worker, nurse, and psychologist, among others, evaluates for functional and psychological challenges and arranges additional support when needed. In the last step (step 3), all patients with medical benefit, reasonable toxicity profile, and adequate, or at least optimized, psychosocial support are discussed in the weekly Cell Therapy Review Committee meetings.
The authors have to be commended for their commitment to ensuring equal access for all patient populations when therapy slots are scarce. In step 2 of the process they help to optimize the situation for those with a marginalized socioeconomic status, geographic limitations, financial constraints, and insurance coverage limitations. However, psychosocial factors are still part of form B and may interfere with final decision-making. Ideally, these psychosocial factors should not count against a patient in an ethical framework. In addition, predictive markers for poor response at baseline, such as bulky disease, poor performance status, and increased C-reactive protein (CRP) and lactate dehydrogenase, may change if successful bridging strategies are used.3 In step 3 clinicians still advocate for their patients, but it is thought that the process and the transparency of forms A and B will lead to a more structured discussion to promote procedural justice. The authors have addressed a very important topic, and their description of the process for developing this ethical framework of prioritizing treatment may inspire other medical centers. However, the usability and acceptability of this framework still needs to be studied in the real world.
CAR T-cell therapy can also bring other moral dilemmas, even when sufficient CAR T-cell slots are available.4 Clinicians may, for example, experience moral stress when patients do not completely fit the eligibility criteria, when there is a high risk for toxicity, and also in situations in which patients or family members have unrealistic expectations of CAR T-cell therapy (eg, when the disease is rapidly progressive).4 Important questions can then arise, such as whether infusion should be continued. Acknowledging and dealing with these moral conflicts is important to be able to provide good medical care for patients, but it is also important for the well-being of the team of health care professionals.5 In our institution, we offer moral case deliberation, which is a methodically structured joint reflection among health care professionals when a case that is perceived as morally or ethically troublesome.
In time, hopefully more products and alternative manufacturing approaches like point of care production and decreased costs may improve access to CAR T-cell therapies worldwide. Also, alternative effective therapies such as bispecific antibodies may in part replace CAR T-cell therapy as they are available “off the shelf.” In addition, evidence-based algorithms to predict individual efficacy, outcome, and toxicity risk would help in prioritizing patients. Unfortunately, such an algorithm is not yet available, and algorithms do have limitations. Currently patient prioritization depends on multidisciplinary decision-making, and the results of the study by Bell et al help by offering a well-described ethical framework, highlighting transparency and equity, which is an important first step toward uniformity in prioritizing patients for CAR T-cell therapy.
Conflict-of-interest disclosure: M.T.K. reports honoraria from and consulting/advisory role for Galapagos NV, CAR-T Point of Care. M.J.K. reports honoraria from and consulting/advisory role for BMS/Celgene; Kite, a Gilead company; Miltenyi Biotec; Novartis; and Roche; research funding from Kite, a Gilead company; and travel support from Kite, a Gilead company; Miltenyi Biotec; Novartis; and Roche.