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12th April 2024
Tisagenlecleucel (brand name Kymriah) has been recommended for routine rollout on the NHS by the National Institute for Health and Care Excellence (NICE), its manufacturer Novartis has announced.
Final draft guidance for the treatment, which has been available through the NHS Cancer Drugs Fund (CDF) since December 2018, recommends tisagenlecleucel for children and young adults up to and including 25 years of age who have B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse.
A chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel is administered as a one-off infusion into the blood stream.
Dr Sara Ghorashian, consultant in paediatric haematology at Great Ormond Street Hospital for Children NHS Foundation Trust, said: ‘During its time in the CDF, tisagenlecleucel has changed the way in which people with relapsed or refractory B-ALL have treatment.
‘It offers a chance of durable remissions and prolonged overall survival for people who often have no other option. The CDF has enabled us to build robust real-world evidence and I’m delighted that NICE has recommended that children and young adults should continue to have access to this treatment.’
The recommendation and final draft guidance from NICE for the routine rollout of this CAR T-cell therapy is based on data collected from its use in the NHS as well as additional clinical trial evidence from three studies.
Presented to NICE as a pooled dataset, the ELIANA, ENSIGN and B2101J trials showed people treated with tisagenlecleucel lived for longer and without experiencing relapse or progression, and improved overall survival for people compared with standard treatment.
For example, the median overall survival was 48 months, compared with a median overall survival for two other standard treatments of 7.5 months for blinatumomab and a median overall survival of three months for salvage chemotherapy.
Data collected from ELIANA have been published in the Journal of Clinical Oncology.
NHS use data found that the 24-month overall survival was 72% following treatment.
According to Novartis, tisagenlecleucel was used to treat 133 children and young adults while in the CDF between 2018 and September 2023.
12th December 2022
Tisagenlecleucel appears to remain effective for more than 3 years in paediatric and young adults who had relapsed or refractory acute lymphoblastic leukaemia according to the results of a follow-up study by an international research group.
B-cell acute lymphoblastic leukaemia (ALL) is a clonal malignant disease originated in a single cell and characterised by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B-cell differentiation. Moreover, ALL is the most common childhood cancer and has a high survival rate when properly managed. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and in the ELIANA trial, after a single infusion, the drug provided durable remission with long-term (12 month) persistence in paediatric and young adult patients with relapsed or refractory B-cell ALL. Moreover, the trial reported an overall remission rate within 3 months of 81% and improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after the infusion. However, what remains uncertain is the durability of the response to treatment observed in the ELIANA trial and in the present study, researchers provided an update on the efficacy of the drug.
Tisagenlecleucel longer-term efficacy
In the follow-up arm, 79 patients with a median age of 11 years (57% male), 92% of whom had experienced a treatment relapse, provided on-going data for a median follow-up of 38.8 months. Overall, participants had received a median of 3 previous lines of therapy.
In the updated analysis, the overall remission rate was 82% and the median event-free survival was 24 months. In addition, event-free survival was 44% (95% CI 31 – 57) and overall survival was 63% (95% CI 51 – 73) at 3 years with most events having occurred with the first two years. Researchers estimated the 3-year relapse-free survival with and without censoring for subsequent therapy to be 52% and 48% respectively. The estimated overall survival rate was 63% (95% CI 51 – 73%).
A total of 24 relapses were recorded and of which 6 had occurred 12 months after the Tisagenlecleucel infusion. Interestingly, there were no new or unexpected long-term adverse events reported although grade 3/4 adverse events were seen in 29% of patients more than 12 months after the infusion. However, grade 3/4 infection rates did not increase longer than 1 year after infusion. Patients also reported improvements in quality-of-life up to 36 months after infusion.
The authors concluded that these data demonstrated favourable long-term safety and suggested that tisagenlecleucel is a potentially curative treatment option for heavily pretreated paediatric and young adult patients with either relapsed or refractory acute lymphoblastic leukaemia.
Citation
Laetsch TW et al. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial J Clin Oncol 2022
5th September 2022
Higher doses of the CAR T cell therapy tisagenlecleucel lead to better overall, event-free and relapse-free survival in children with relapsed or refractory acute lymphoblastic leukaemia, according to the findings of a retrospective study by US researchers.
Acute lymphoblastic leukaemia (ALL) is a malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood and extra-medullary sites and 80% of cases occur in children. While chemotherapy is used first line, in cases where this initial treatment is either refractory or if patients relapse, chimeric antigen receptor-modified T cells (CAR T-cells) against CD19, have been shown to be effective.
The target dose of transfused cells was 2.0 to 5.0 x 106 CAR transduced viable T-cells per kg, for those weighing less than 50 kg and 1.0 to 2.5 x 108 T-cells for those weighing over 50 kg. However, whilst it is an effective therapy, what remains unclear is whether the dose of tisagenlecleucel impacts on disease-related outcomes such as overall survival.
As a result, in the present study, the US researchers decided to retrospectively examine the impact of dose using data from the Pediatric Real World CAR Consortium which collects data from 15 paediatric oncology centres that are using commercial tisagenlecleucel.
The team included patients with relapsed or refractory ALL and divided the infused cell doses into quartiles, D1 (0.1341.300 x 106), D2 (1.301-1.700 x 106), D3 (1.701- 2.400 x 106) and D4 (2.401-5.100 x 106).
Overall survival (OS) was defined as the time from infusion to death from any cause, event-free survival (EFS), the time to the earliest non-response, relapse or death.
Patients who did not respond were considered to have had a EFS event on day 28. Relapse-free survival (RFS) was only defined among responders, as the time from day 28 to relapse.
Tisagenlecleucel and disease outcomes
A total of 180 children with a mean age of 12.6 years (40.3% female) were included in the analysis and the median cell dose was 1.7 x 106 cells/kg and overall, 82.8% of patients had a treatment relapse and 51% described as having a high disease burden.
Overall survival for the entire cohort after 3 years was 58.9% (95% CI 47.6 – 72.9%) and the median follow-up time was 402.5 days. In multivariable regression, those on the highest dose (D4) had a significantly improved survival compared to those in D1, the lowest dose (hazard ratio, HR = 0.22, 95% CI 0.08 – 0.61, p = 0.008).
For EFS, multivariable regression showed that again, those receiving the highest compared to the lowest dose, had improved survival (HR = 0.24, 95% CI 0.12 – 0.49, p < 0.001). Finally, RFS was also greater among those receiving the highest dose (HR = 0.18, 95% CI 0.07 – 0.49, p = 0.002). There were also no differences in toxicity across the different dose ranges.
The authors concluded that as higher doses were associated with superior survival in a real world setting, further work was required to examine the value of using higher tisagenlecleucel dosing.
Citation
Stefanski HE et al. Higher doses of tisagenlecleucel associate with improved outcomes: a report from the pediatric real-world CAR consortium Blood Ave 2022
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