Key updates on CAR-T therapies for the treatment of B-ALL
Here we review recent updates on chimeric antigen receptor T-cell (CAR-T) therapies for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) from the 2021 European Hematology Association (EHA) and American Society of Clinical Oncology (ASCO) meetings.
Despite advances in the treatment of adult B-ALL, the standard of care remains multi-agent chemotherapy and allogeneic stem cell transplant for eligible patients. This approach accomplishes high complete remission rates; however, long-term disease-free survival is only achieved in about 40% of patients. Recently, data from multiple studies has demonstrated the potential benefits of CAR T-cell therapy for patients with R/R B-ALL, in particular with regards to achieving durable remissions.1
The study reported brexucabtagene autoleucel therapy achieved complete remissions (CRs) or CRs with incomplete hematological recovery in 71% of patients. Of the 56% of patients who achieved a CR, 97% were measurable residual disease (MRD)-negative. The median duration of remission was approximately 12.8 months with a median relapse-free survival of 11.6 months. The median overall survival (OS) was 18.2 months overall, with patients who achieved a CR yet to reach their median OS.2
The safety profile of brexucabtagene autoleucel among this patient group appears to be relatively favourable, although two deaths have been directly attributed to the therapy. 24% and 25% of patients experienced cytokine release syndrome (CRS) or neurotoxicity of grade III and IV, respectively; however, CRS and neurotoxicity events were generally reversible.
“We were able to treat patients safely and we were able to do so with a really high efficacy. Again, extended remission duration, extended overall survival. And so, when we think about this population, again, this heavily pre-treated population with high tumor burden, I really think that these results are unparalleled,” said Dr Shah.
Dr Shah also suggested that incorporating brexucabtagene autoleucel earlier on in the treatment of patients may result in more favorable outcomes.
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Although outcomes for pediatric B-ALL have significantly improved over the last few years, overall survival rates remain notably lower for infant patients (under 12 months) with B-ALL. As such, novel treatment approaches are required in order to improve outcomes for this subgroup of patients.4
In this video, Sara Ghorashian of the Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK, presents the findings of a study which collected standardized data from patients aged under three years through the I-BFM Resistant Diseases Committee. 30 patients across 15 centers met the eligibility criteria for the study upon screening. Kaplan-Meier estimates were utilized to assess survival outcomes, and this consisted of overall survival (OS), event-free survival (EFS), and an additional stricter composite EFS.
Dr Ghorashian reports that, despite the traditional concerns regarding manufacturing in infants, it was found that there was a low manufacturing failure rate of 7%, and that only one patient out of 30 could not receive the CAR T-cell product due to disease progression.
The outcomes of the retrospective study were synonymous with data from the older patient population investigated in the ELIANA trial, which was restricted to pediatric patients above the age of three. The study reported a measurable residual disease (MRD)-negative complete response rate of 92%, compared to 77% observed in the ELIANA Study.3 Dr Ghorashian elaborated: “Our event-free survival and our overall survival outcome data were very similar to patients of an older age range receiving treatment on the ELIANA study. So, for example, the six-month event-free survival was 67 versus 73%”.
The toxicity profile for the infant age range was also documented as favourable, again mirroring data from the ELIANA trial. Overall, it was found that severe cytokine release syndrome incidence, as well as the rate of severe neurotoxicity, was significantly reduced with the aid of multiple grading systems.
Although the use of tisagenlecleucel appears to be effective in younger children, there is still a need for longer follow-up to determine whether this therapy is a feasible and accessible line of treatment for this patient sub-group.
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STAR was developed with the aim of improving on the safety profile and efficacy rates which have been observed with the use of existing anti-CD19 CAR T-cell therapies. Although various types of CAR-T treatments have been shown to produce complete remission rates as high as 68-93%, there are many outstanding challenges for CAR-T therapy which need to be addressed. For example, treatment-related adverse events such as cytokine release syndrome (CRS) and neurotoxicity can be lethal, relapse rates remain a problem, and around 10-30% of patients with B-ALL do not respond to CAR-T therapy.6
Preclinical data demonstrated that the STAR-T’s ability to eliminate cancerous cells was comparable to that of anti-CD19 CAR-T therapies. In this video, Dr Lu discusses the results of an ongoing Phase I study (NCT04260945) of STAR T-cell therapy for patients with R/R B-ALL. Ten patients were enrolled into the open-label study, nine of whom received a single infusion of STAR-T which was preceded by standard conditioning treatment with fludarabine and cyclophosphamide.
Dr Lu reports that 14 days after infusion, eight out of nine patients had achieved a measurable residual disease (MRD)-negative complete remission (CR). After treatment, 6/8 patients proceeded to undergo allogeneic hematopoietic stem cell transplantation, of whom four continued to be in CR for a median period of 258 days. Although the occurrence of CRS was high (77.8%), all incidences were of grade I and only three patients suffered from neurotoxicity. “It’s clinically feasible, and we were able to manufacture with almost 100% success and show the high efficacy and the low toxicity, so we’re very happy about these results,” said Dr Lu.5
Both preclinical and Phase I trial data show encouraging results from the dual STAR therapy, however, there is much work yet to be done to reciprocate such data on a larger scale to truly reflect its efficacy.