Advancing into the era of CAR T-cell therapies: Tisagenlecleucel in the treatment of B-cell acute lymphoblastic leukaemia and diffuse large B-cell lymphoma

Prof. Franco Locatelli
Dr. Udo Holtick
Dr. Francesca Lim
21 May 2021

Tisagenlecleucel is the first therapy to be approved by the Singapore Health Sciences Authority under the Cell Tissue and Gene Therapy Product Regulations enacted on 1 March 2021. On 4 March 2021, Novartis organized a launch symposium for tisagenlecleucel, a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of paediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukaemia (ALL) and adults with r/r diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. The invited speakers were Prof Franco Locatelli from the Sapienza University of Rome, Italy, Dr Udo Holtick from the University Hospital of Cologne, Germany, and Dr Francesca Lim from Singapore General Hospital, Singapore. Prof William Hwang from National Cancer Centre, Singapore, chaired the symposium.

CAR-T cell therapy for r/r B-cell ALL in paediatric and young adult patients
ALL is the most common cancer among children and the most frequent cause of cancer death in people younger than age 20. Approximately 15–20 percent of children with ALL relapse after standard treatment. [N Engl J Med 2015;373:1541-1552]

“ELIANA is the first global, multicentre CAR T-cell trial, evaluating tisagenlecleucel in paediatric and young adult patients with CD19+ r/r B-cell ALL,” said Locatelli. [N Engl J Med 2018;378:439-48] 

“In an updated analysis of the trial, the ORR [overall remission rate] within 3 months was 82 percent (65/79; 95 percent confidence interval [CI], 72–90) and 98 percent achieved MRD [minimal residual disease] negativity. Moreover, the RFS [relapse-free survival] rate among responders was stable at 66 percent at 1 year and 62 percent at 2 years (Figure 1). The median duration of remission and overall survival (OS) were not reached,” added Locatelli. [Blood 2018;132(Supplement 1):895]

Kymriah Fig01

“In terms of safety, the majority of adverse events occurred within the first 8 weeks after infusion, with cytokine release syndrome (CRS) being the most common,” reported Locatelli. “CRS was manageable at sites with appropriately trained staff and no cases of cerebral oedema were observed. There were no new safety findings in this longer-term follow-up. These results suggest that tisagenlecleucel offers a new valuable therapeutic option for paediatric and young adult patients with r/r B-cell ALL.” [Blood 2018;132(Supplement 1):895]

Meanwhile, a cellular therapy registry recorded experience with tisagenlecleucel in a real-world setting. The analysis included 255 paediatric and young adult patients with ALL. Median follow-up was 13.4 months. Tisagenlecleucel demonstrated an efficacy similar to the ELIANA trial, with an initial complete remission (CR) rate of 85.5 percent. Twelve-month duration of response (DOR) was 60.9 percent, event-free survival was 52.4 percent, and OS rate was 77.2 percent. The overall rate and the incidence of grade ≥3 CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were lower compared with the ELIANA trial, and this could be due to lower disease burden in the real-world study patients. [Blood Adv 2020;4:5414-5424]

CAR-T cell therapy for r/r diffuse large B-cell lymphoma in adults
“Diffuse large B-cell lymphoma (DLBCL) is the most common of the aggressive lymphomas. Patients who do not respond to first-line treatment of R-CHOP (immune-chemotherapy) have a poor prognosis with median OS <6 months. Around 75 percent of all relapses occur within 1 year,” said Holtick. [Ann Oncol 2017;28:3058-3064]

“Evidence from the SCHOLAR-1 study has shown that achieving a complete remission is absolutely critical for survival. [Blood 2017;130:1800-1808] CAR T-cells are the most promising therapy to help achieve remission,” added Holtick.

JULIET is a global, phase II trial of tisagenlecleucel for r/r DLBCL in adult patients. After a median follow-up of 40.3 months, 115 patients received tisagenlecleucel infusion. “Progression-free survival (PFS) was 33 percent at 24 months and 31 percent at 36 months. Among all responders, 60 percent were estimated to maintain their response at 24 and 36 months. No new adverse events were detected with long-term follow-up,” reported Holtick. [ASH Annual Meeting 2020, abstract 1194]

A multicentre retrospective analysis of outcomes and toxicities conducted with two commercial CAR-T cell therapies (axicabtagene ciloleucel and tisagenlecleucel) for r/r aggressive B-cell lymphomas demonstrated that efficacy outcomes were similar to the responses in the pivotal clinical trials, and in terms of safety, tisagenlecleucel appeared to be associated with less CRS and neurological events (NEs) (Figure 2). [Blood 2019;134(Supplement 1):1599]

Kymriah Fig02

“The long-term follow-up and real-world data confirm both the safety and efficacy of tisagenlecleucel. Adverse events are manageable even in high-risk patients with large tumour masses,” emphasized Holtick.

“Are there reliable patient selection criteria for CAR-T cell therapy? To date, no risk factors allow the identification of patients who will not respond to CAR-T cell therapy. However, LDH level exceeding two times the upper limit of normal indicates a relevant risk for failure. In the JULIET trial, Myc-negativity and normal LDH level at baseline are associated with a longer PFS,” explained Holtick. [ASH Annual Meeting 2020, abstract 1194]

“In our experience, early identification of patients at risk for second-line treatment failure is highly recommended,” advised Holtick.

CAR-T cell therapy in Singapore
Sharing the experience of setting up the CAR-T cell programme at Singapore General Hospital (SGH), Lim said, “The key considerations for a successful CAR-T cell programme include patient demographics and population, clinical and research teams, a supportive multidisciplinary team, country regulations, costs, and institutional infrastructure. These will determine whether the investment in such a programme is viable and sustainable. The in-house apheresis unit at SGH is JACIE accredited, ensuring that it adheres to international standards.”

“At SGH, we have one commercially available industry-led CAR-T cell therapy, tisagenlecleucel, and two IRB-approved academic autologous CAR-T cell therapies for patients with r/r acute B-cell ALL and B-cell non-Hodgkin lymphomas. Thus far, we have treated eight patients with CAR-T cell therapy since the end of 2020, with another patient to receive tisagenlecleucel infusion by end of March 2021,” said Lim. “A longer follow-up is needed to evaluate patients’ responses,” concluded Lim.
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