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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Final draft guidance for the treatment, which has been available through the NHS Cancer Drugs Fund (CDF) since December 2018, recommends tisagenlecleucel for children and young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The recommendation and final draft guidance from NICE for the routine rollout of this CAR T-cell therapy is based on data collected from its use in the NHS as well as additional clinical trial evidence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
7th July 2022
CAR T cells (CTC) which can be manufactured in a single day have been shown to be effective and with an acceptable safety profile, for the treatment of patients with relapsed or refractory B cell acute lymphoblastic leukaemia according to a first-in-human clinical study by a group of Chinese researchers.
In CTC therapy, the patient’s own T cells are genetically engineered and then re-infused in an effort to eliminate their tumour cells. The T cells contain an extracellular ligand binding domain which is able to recognise antigens displayed on the surface of tumour cells (normally CD19).
Nevertheless, as more clinical trials have been undertaken, it has become evident that 30-60% patients relapse after treatment, probably due to persistence of CAR T-cells and escape or down-regulation of CD19 antigen. A further problem is that the T-cell engineering process can take 9 to 14 days and up to four weeks before infusion back into the patient.
For the present study, the Chinese team developed a type of CAR T cells that were manufactured using a novel process completed in 24 hours. The final product CTC product, GC007F, was tested in patients with relapsed or refractory B cell acute lymphoblastic leukaemia and for comparative purposes, the researchers also manufactured CTCs by conventional methods.
CAR T cells and patient outcomes
A total of 21 patients with CD19+ relapsed or refractory B cell acute lymphoblastic leukaemia were enrolled and given a single infusion of GC007F cells although only 18 were included in the final analysis after the others withdrew due to adverse effects. The median peak of CAR T cells was on day 10 and the median persistence was 56 days. The GC007F cells also showed better proliferation and tumour killing than conventional CTCs.
After 28 days, all patients had achieved complete remission (CR), with 17 achieving CR and maintaining minimal residual disease negative, MRD (i.e., no disease was detected after treatment) after 3 months. Additionally, at 6 months, 16 patients maintained CR with 14 maintaining MRD negative and the longest duration at the time of writing was 29 months without the need for transplant.
In terms of safety, 95.2% (n = 20) of patients experienced cytokine release syndrome (a recognised adverse effect) and which was greater than grade 3 (i.e., severe) in 52.4% (11) of patients. Neurotoxicity developed in 6 patients and was greater than grade 3 severity in 3 patients.
Overall, eight patients underwent allogeneic haematopoietic stem cell transplantation after GC007F treatment.
The authors concluded that these preliminary data suggested that their next day GC007F cells appeared to be effective and with a manageable toxicity profile.
Citation
Zhang C et al. Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia Blood Cancer J 2022
16th December 2021
Ethic and socioeconomic disparities in survival outcomes have been highlighted in an analysis of newly diagnosed children and young adults with acute lymphoblastic leukaemia (ALL). This was the main finding from a study by researchers from Institute for Health Policy, Evaluation and Management, University of Toronto, Canada, presented at ASH 2021.
Health disparities are major issue for racial, ethnic, and socioeconomically disadvantaged groups and although outcomes in childhood ALL have steadily improved, disparities based on ethnicity and socioeconomic (SES) factors appear to persist.
For the present study, the Canadian team sought to identify the presence of any persistent inequities by race/ethnicity and SES in childhood ALL in the largest cohort ever assembled for this purpose. They identified a cohort of newly-diagnosed patients with ALL, ranging in age from 0 to 40 years enrolled in trials between 2004-2019. Race/ethnicity was categorised as non-Hispanic white vs. Hispanic vs. non-Hispanic Black vs. non-Hispanic Asian vs. Non-Hispanic other.
SES was proxied by insurance status: United States (US) Medicaid (public health insurance for low-income individuals) vs. US other (predominantly private insurance) vs. non-US patients (mainly jurisdictions with universal health insurance). Event-free and overall survival (EFS, OS) were compared across race/ethnicity and SES. The relative contribution of disease prognosticators (age, sex, white blood cell count, lineage, central nervous system status, cytogenetics, end Induction minimal residual disease) were examined with Cox proportional hazard multivariable models of different combinations of the three constructs of interest (race/ethnicity, SES, disease prognosticators) and examining hazard ratio (HR) attenuation between models.
Findings
The study cohort included 24,979 children, adolescents, and young adults with ALL. A total of 13,872 (65.6%) of the whole cohort were Non-Hispanic White patients, followed by 4354 (20.6%) Hispanic patients and 1517 (7.2%) non-Hispanic Black patients. Those insured with US Medicaid were 6944 (27.8%).
The 5-year EFS was 87.4% among non-Hispanic White patients vs. 82.8% among Hispanic patients (hazard ratio, HR = 1.37, 95% CI 1.26 – 1.49; p<0.0001] and 81.9% among non-Hispanic Black patients. The outcomes for non-Hispanic Asian patients were similar to those of non-Hispanic White patients.
US patients on Medicaid had inferior 5-year EFS as compared to other US patients (83.2% vs. 86.3%, HR = 1.21, 95% CI 1.12 – 1.30, p<0.0001) while non-US patients had the best outcomes, with a 5-year EFS of 89%.
There was substantial imbalance in traditional disease prognosticators (e.g. T-cell lineage) across both race/ethnicity and SES, and of race/ethnicity by SES. For example, T-lineage ALL accounted for 17.6%, 9.4%, and 6.6% of Non-Hispanic Black, Non-Hispanic White, and Hispanic patients respectively (p<0.0001).
Multivariable analysis showed how EFS among Hispanic patients was substantially attenuated by the addition of disease prognosticators and the hazard ratio reduced from HR 1.37 to 1.17 and was further (but not fully) attenuated by the subsequent addition of SES (HR 1.11).
In contrast, the increased risk among non-Hispanic Black children was minimally attenuated by both the addition of disease prognosticators and subsequent addition of SES (HR reduction of 1.45 to 1.38 to 1.32). Similarly, while the superior EFS of non-US insured patients was substantially attenuated by the addition of race/ethnicity and disease prognosticators (HR 0.79 to 0.94), increased risk among US Medicaid patients was minimally attenuated by the addition of race/ethnicity or disease prognosticators (HR 1.21 to 1.16).
OS disparities followed similar patterns but were consistently worse than in EFS, particularly among patients grouped as non-Hispanic other.
The authors concluded that there were substantial disparities in survival outcomes by race/ethnicity and SES and that these disparities varied between specific disadvantaged groups., adding that future studies are required to identify specific drivers of survival disparities that may be mitigated by targeted interventions.
Citation
Gupta S et al. Racial, Ethnic, and Socioeconomic Factors Result in Disparities in Outcome Among Children with Acute Lymphoblastic Leukemia Not Fully Attenuated By Disease Prognosticators: A Children’s Oncology Group (COG) Study. ASH Conference 2021
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