Little is known about the long-term effects of CAR-T cell therapy. Although medium-term complications, such as cytopenia and hypogammaglobulinaemia, may persist and require ongoing treatment, there do not appear to be other durable toxicities specific to this new immunotherapeutic class (Fried et al. 2019; Cordeiro et al. 2020; Cappell et al. 2020). However, to date, CAR-T therapy has been evaluated in patients with multiple relapsed diseases following several lines of treatment, including allogeneic stem cell transplantation, making it difficult to identify which effects may be directly attributable to this novel treatment. Nonetheless, as the use of CAR-T cell therapy increases, structured models for survivorship care will need to be established. The factors that will affect care requirements include the primary malignancy, prior treatment, the specific CAR-T therapy and patient age and frailty.

The main late effects identified to date are shown in Table 36.1. Hypogammaglobulinaemia and prolonged cytopenias appear to be more common in patients with ALL than in patients with B-NHL. In the ELIANA trial, which tested tisagenlecleucel (Kymriah™) in ALL, the median time to B-cell recovery was not reached at a median follow-up time of 13 months (Maude et al. 2018). Prolonged cytopenias in all three cell lines have also been commonly reported. In an Israeli study of 29 patients with either ALL or B-NHL responding after treatment with CTL109 with a CD28 costimulatory domain, factors associated with late cytopenias were prior allo-HCT and higher-grade CRS (Fried et al. 2019).

Table 36.1 Main late effects after CAR-T cell therapy
Full size table

Apart from one patient in the ZUMA-1 trial who developed MDS at 19 months, there were no secondary malignancies reported in the three clinical trials that led to licensing of CD-19-directed therapy in B-ALL and B-NHL. In addition, some late cancers are to be expected in such heavily pretreated patients. Although there is one report of unintended insertion of the CAR gene into leukaemic B cells, thus far, there have been no reports of insertional oncogenesis during CAR-T cell production.

The role of vaccinations following CAR-T cell therapy remains unclear. Until evidence-based specific CAR-T vaccination programmes are produced, protocols similar to HSCT should be considered (Majhail et al. 2012).

Follow-Up and Programmes

As a specialized service, CAR-T therapy in Europe is generally provided based on a hub-and-spoke model: patients are referred from local hospitals to regional cellular therapy centres. One option is to provide follow-up in JACIE-accredited allo-HCT late effects clinics alongside transplant recipients. They operate on a checklist model to ensure that survivors are systematically and longitudinally assessed for late toxicities. Over time, dedicated CAR-T late effects clinics can be developed if the growing pool of survivors reaches a critical mass. Service-level agreements (SLAs) between CAR-T centres and referral centres should cover shared care and outreach arrangements.

Such clinics require multidisciplinary team (MDT) input, including physicians involved in CAR-T administration, clinical nurse specialists, clinical psychologists, data managers, and clinical trial staff. All CAR-T recipients will have been heavily pretreated. Therefore, a cumulative burden of broader physical and psychological late effects will need to be considered. Areas to cover in the clinic include CAR-T persistence; secondary malignancies; autoimmune disease; endocrine, reproductive and bone health; psychological health; and patient-reported outcomes, including quality of life (Buitrago et al. 2019; Ruark et al. 2020). Importantly, the patient-reported quality-of-life studies performed thus far indicate levels of physical and mental health comparable to that in the normal population.

Initial follow-up will be determined by the status of the underlying disease. Patients should be seen monthly for the first year, when the focus will be on remission status alongside any short-term complications. Subsequent follow-up can focus on longer-term effects, 6 months for the following 2 years, annually until the 15 year, and potentially indefinitely. Patients who proceed to subsequent HSCT, cytotoxic therapy and/or immune effector cell therapy should be followed as recommended by Majhail et al. (2012).

Post-authorisation Safety Surveillance (PASS)

As both tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™) are based on genetic modification of autologous T-cells using viral vectors, the EMA and FDA made marketing approval conditional on a 15-year PASS. In 2019, the cellular therapy module of the EBMT registry was found by the EMA to be fit-for-purpose for regulatory oversight of such pharmacoepidemiological studies. The MED-A cell therapy form has been modified for use with CAR-T cells and other academic- or industry-manufactured cell therapies. In November 2020, the German health insurance regulator directed centres to report commercial CAR-T cell treatments to the EBMT Registry and confirmed that reporting such data will be a condition for reimbursement of the costs of CAR-T cell therapy.

JACIE

FACT-JACIE standards were initially developed for the accreditation of HCT programmes (Snowden et al. 2017; Saccardi et al. 2019). The current seventh edition of the standards also covers immune effector cells (IECs) to accommodate cellular therapy, including CAR-T cells. In addition to clauses addressing the need for policies on the management of acute toxicities, standard B.7.12 specifies the need for “policies and Standard Operating Procedures for monitoring by appropriate specialists of recipients for post-cellular therapy late effects”. Inspection of IEC standards is incorporated within standard JACIE site visits.

For centres that undertake CAR-T cell therapy outside of an accredited allo-HCT programme, there are a number of options. Given that most CAR-T cell therapies are currently used to treat lymphoma, compliance with the IEC standards can be achieved as part of the accreditation covering autologous HCT (auto-HCT). The same considerations could apply to myeloma specialists working outside of allo-HCT programmes. In the event of CAR-T cells or related therapies becoming applicable more broadly to nonhaematological cancers, an alternative strategy already adopted by FACT is to undertake independent IEC accreditation specifically for CAR-T cells and other IECs. JACIE also provides a robust method to ensure that programmes meet the requirements for mandatory long-term data submission to the EBMT Registry, as well as potential benchmarking of survival outcomes.

The eighth edition of the FACT-JACIE standards will be published in 2021 with more detail on immune effector cells to help provide a framework for centres to establish and assure the quality and safe practice of treatment administration and short- and long-term follow-up of CAR-T therapy.

Key Points

  • To date, few durable toxicities have been directly attributable to CAR-T cell therapy.

  • The principal late effects identified to date include hypogammaglobulinaemia, cytopenias, and infections.

  • Structured models for survivorship care include JACIE-accredited allo-HCT late effects clinics.

  • Areas to monitor in the clinic include CAR-T persistence; secondary malignancies; autoimmune disease; endocrine, reproductive and bone health; psychological health; and patient-reported outcomes, including quality of life.

  • EMA has mandated 15-year postauthorization safety surveillance (PASS) of all CAR-T cell therapies, and the cellular therapy module of the EBMT registry has been approved for this purpose.

  • The current seventh edition of the FACT-JACIE transplant standards also covers immune effector cells (IECs) to accommodate cellular therapy, including CAR-T cells.