Implementation of CAR T-cell therapy in the real world - A round table discussion

The Multiple Myeloma Hub is pleased to report a summary of real-world experiences of chimeric antigen receptor (CAR) T-cell implementation as discussed at the 2^nd European CAR T-Cell Meeting. Contributors included Stephan Mielke, Karolinska Institute, Stockholm, SE, Gilles Salles, South Lyon University Hospital, Lyon, FR, and Marcelo C. Pasquini, Medical College of Wisconsin, Wisconsin, US.

To begin, Professor Stephan Mielke focused on the progression of CAR T implementation in Sweden. He explained that there are four CAR T-cell treatment centers, only two of which offer CAR T therapy as standard of care (SOC). The centers, Lund, Gothenburg, Stockholm and Uppsala, have formed the basis for Sweden’s CAR T-cell competence network (SWECARNET). SWECARNET stands as a cooperative network between academia, healthcare providers and the industry aiming to deliver education and quality assurance through meetings and lectures. Professor Mielke made it clear that access to CAR T-cell therapy is not equally distributed throughout Europe and hopes that SWECARNET will assist in overcoming the complexities of CAR T-cell implementation.¹

We were also pleased to speak to Professor Gilles Salles, who discussed real-world data from the French cohort study previously presented by Catherine Thieblemont at the 24^th Congress of the European Hematology Association (EHA).² An interview with Professor Thieblemont at EHA 2019 is available here.

French cohort study design²

• Retrospective data from five centers across France: Lille, Lyon, Montpellier, Nantes and Paris (Saint-Louis), were collected from July 17^th – December 31^st, 2018
• Patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) were treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel
• Objectives:
  • Organization of CAR T-cell implementation in France
• • Measure the outcome of CAR T-cell therapy in the real world

Results

• Characteristics of patients receiving ‘real world’ CAR T therapy and those involved in the clinical trials, ZUMA 1 and JULIET, are compared in Table 1

Table 1. Patient characteristics from real world, ZUMA and JULIET studies

• At a three-month follow-up (n= 53):
  • Progression free survival (PFS) was 53.7% (95% CI, 41.6—69.2)
  • Overall survival (OS) was 82.2% (95% CI, 72.3—93.5)
• Prognostic factors found to have a significant impact on OS following CAR T infusion were:
  • Number of prior lines of therapy, hazard ratio (HR)= 1.80 (95%CI, 1.26—2.58) p= 0.001
  • Eastern Cooperative Oncology Group performance status (ECOG PS) at screening, HR= 3.69 (95%CI, 1.51—9.03) p= 0.004
  • Absence of infection, HR= 0.10 (95%CI, 0.01—0.89) p= 0.039

Professor Salles also presented data from studies reporting CAR T-cell therapy experiences in the UK, Spain and Germany (Tables 2 and 3).

Table 2. Reported experience of tisagenlecleucel and axi-cel treatment in the UK

Table 3. Reported experience of tisagenlecleucel and axi-cel treatment in Spain and Germany

Aside from delivering valuable data from a number of European studies, the key message from Professor Salles was the urgent need for a uniformed system worldwide, particularly between Europe and the US. As shown by the studies presented, CAR T-cell data remain incomplete, with countries using different readout measures for clinical efficacy, prognosis and toxicities. Availability of patient data through collaboration is required to provide a greater picture regarding factors contributing to CAR T-cell therapy outcome. A summary of novel routine guidelines was presented by Ibrahim Yakoub-Agha, Lille University Hospital, Lille, FR, at the 2^nd CAR T meeting and was recently covered by the Multiple Myeloma Hub, see more here. 

Finally, Professor Marcelo C. Pasquini emphasized the need for an efficient CAR T-cell registry (CT registry) to maximize the utilization and coordination of CAR T-cell therapy worldwide. Not only is the CT registry important in managing regulatory requirements, such as long-term follow-up and post approval safety studies (PASS), but also in developing a uniform grading system for CAR T-cell toxicities like cytokine release syndrome (CRS) and neurological events (NE). It has been extremely difficult to compare safety data across clinical trials due to the variations between toxicity grading systems. Professor Pasquini hopes that the CT registry and implementation of the novel American Society for Blood and Marrow Transplantation (ASTCT) consensus grading system will help to lower the incidences of serious toxicities through correct evaluation and treatment approach.⁶ Toxicity grading systems reported during the 45^th Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in Frankfurt, DE, can be accessed here.

Professor Pasquini also highlighted how the rapid increase in CAR T-cell therapy is already impacting worldwide practices. Since 2016, 2058 patients have received CAR T-cell therapy across 123 CAR T centers worldwide, over half of which taking place in 2019. It was made very apparent that the level of hematopoietic cell transplantation (HCT) is declining in line with a rise in CAR T-cell therapy. To date, the primary indication for CAR T therapy in the US, comprising 71% of applications, is non-Hodgkin lymphoma (NHL), followed by acute lymphocytic leukemia (ALL; 22%) and multiple myeloma (MM; 6%).⁶

Take home message

All three contributors highlighted the demand for European and worldwide collaboration to increase the availability, effectiveness and quality of CAR T-cell therapy. Introducing regulatory bodies will allow CAR T-cell therapy to reach its full potential.