Tisagenlecleucel, formerly CTL019, has been approved by the European Commission for the treatment of paediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse; and for the treatment of adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

Tisagenlecleucel, developed by Novartis in collaboration with the University of Pennsylvania, is a one-time treatment that uses a patient's own T cells to fight cancer, and the only chimeric antigen receptor T cell (CAR-T) therapy to receive regulatory approval in the EU for these two distinct B-cell malignancies.

Tisagenlecleucel was also the first CAR-T cell therapy ever approved by the US Food and Drug Administration (FDA).

"The [tisagenlecleucel] approval is a transformational milestone for patients in Europe in need of new treatment options," said Liz Barrett, CEO, Novartis Oncology.

Tisagenlecleucel, a cell dispersion for infusion with doses varying between 1.2 x 10⁶ and 6 x 10⁸ CAR- positive viable T cells, is a living medicinal product, manufactured individually for each patient by reprogramming the patient's own immune system cells.

Tisagenlecleucel is the only approved CAR-T cell therapy built using the 4-1BB costimulatory domain, which is critical for full activation of the therapy, enhancement of cellular expansion and durable persistence of the cancer-fighting cells.

This approval was based on the review of the only two global registration CAR-T clinical trials, JULIET and ELIANA, which included patients from eight European countries.

In these trials, it demonstrated strong and durable response rates and a consistent safety profile in two difficult-to-treat patient populations.

Tisagenlecleucel was designated as an orphan medicinal product and is one of the first PRIME-designated therapies to receive EU approval; PRIME (PRIority MEdicines) is a program launched by the European Medicines Agency (EMA) to enhance support for the development of medicines that target an unmet medical need and help patients benefit as early as possible from therapies that may significantly improve their quality of life.

"Bringing tisagenlecleucel to patients in the EU advances the treatment paradigm in an unprecedented way and delivers a lifesaving therapy to young patients with ALL who have not been successfully treated with existing therapies, and who have limited options left," said Prof. Peter Bader, Head of the Division for Stem Cell Transplantation and Immunology and Principal Investigator of the ELIANA study at the University Hospital for Children and Adolescents in Frankfurt/Main.

Both B-cell ALL and DLBCL are aggressive malignancies with significant treatment gaps for patients.

In Europe, ALL accounts for approximately 80% of leukaemia cases among children, and for patients who relapse from standard of care therapies, the outlook is poor.

This low survival rate is in spite of patients having to undergo multiple treatments, including chemotherapy, radiation, targeted therapy or stem cell transplant, and further highlights the need for new treatment options.

DLBCL is the most common form of non-Hodgkin lymphoma, accounting for up to 40% of all cases globally.

For patients who relapse or don't respond to initial therapy, there are limited treatment options that provide durable responses, and survival rates are low for the majority of patients due to ineligibility for autologous stem cell transplant (ASCT) or because salvage chemotherapy or ASCT have failed.

Novartis expects to launch initially in the paediatric ALL indication, as we continue to ramp up capacity.

Moreover, timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centres for the appropriate indications, as well as the completion of national reimbursement procedures.

Training is already underway at key qualified treatment centres to facilitate safe and seamless delivery to patients.

The EC approval of tisagenlecleucel in paediatric and young adult patients with r/r B-cell ALL is based on the pivotal Phase II ELIANA clinical trial, the first paediatric global CAR-T cell therapy registration study for tisagenlecleucel in children and young adults with r/r B-cell ALL.

ELIANA was conducted in collaboration with the University of Pennsylvania and Children's Hospital of Philadelphia, evaluating tisagenlecleucel in patients in 25 centres in the US, Canada, Australia, Japan, and in Europe, in Austria, Belgium, France, Germany, Italy, Norway and Spain.

75 patients infused with tisagenlecleucel with three or more months of follow-up, 81% of patients achieved overall remission (95% CI: 71% - 89%) with 80% of responders still in remission at 6 months.

Sixty percent of patients achieved complete response (CR) and 21% of patients achieved CR with incomplete blood count recovery (CRi).

Of those patients in remission, 100% had no minimal residual disease (MRD) detected in the bone marrow.

Overall survival (OS) was 90% at six months, and 76% at 12 months. Median OS was 19.1 months (95% CI: 15.2 - NE) in this difficult-to-treat patient population.

In ELIANA, 47% percent of patients experienced Grade 3 or 4 CRS.

There were two deaths within 30 days of infusion: one due to progressive disease with CRS and one death with resolving CRS from intracranial haemorrhage.

Within eight weeks of treatment, 13% of patients experienced Grade 3 or 4 neurological events.

The most common severe (Grade 3 or 4) neurological events were encephalopathy and/or delirium.

Severe (Grade 3 or 4) febrile neutropenia and infection occurred in 36% and 44% of patients, respectively.

The EC approval of tisagenlecleucel in adult patients with r/r DLBCL is based on the pivotal Phase II JULIET clinical trial.

JULIET was conducted in collaboration with the University of Pennsylvania, and is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan, and Europe in Austria, France, Germany, Italy, Norway and the Netherlands.

In the JULIET trial, patients were infused in the inpatient and outpatient setting.

93 evaluable patients were followed for at least three months or discontinued earlier, tisagenlecleucel demonstrated an overall response rate (ORR) of 52% (95% confidence interval [CI], 41% - 62%), with 40% achieving a complete response (CR) and 12% achieving a partial response (PR).

The relapse-free probability at 6 and 12 months was 68% and 65%, respectively; and the median duration of response was not reached at the time of data cut-off, indicating sustainability of response.

The OS rate at 12 months was 49% and median OS was 11.7 months among all infused patients (n=111) (95% CI, 6.6-NE).

In JULIET, 22% of all treated patients experienced Grade 3 or 4 CRS within eight weeks of infusion with tisagenlecleucel, as defined by the Penn Grading Scale, a rigorous scale for grading CRS.

CRS was successfully managed globally using site education on implementation of the CRS treatment protocol.

Twelve percent of patients had Grade 3 or 4 neurologic adverse events, which were managed with supportive care.

Grade 3 or 4 cytopenias lasting more than 28 days were reported based on laboratory findings and included thrombocytopenia (41%), lymphopenia (28%), neutropenia (24%), leukopenia (21%) and anaemia (14%), Grade 3 or 4 infections and Grade 3 or 4 febrile neutropenia occurred in 32% and 15% of patients, respectively.

Source: Novartis