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Irreversible, covalent Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib, have demonstrated impressive outcomes in the treatment of multiple B-cell malignancies; however, the emergence of clinical resistance due to BTK cysteine 481 (C481) mutations means that patients often discontinue therapy.1
Pirtobrutinib (formerly LOXO-305), is a highly selective and reversible BTK inhibitor, which is currently being investigated as an alternative treatment for multiple B-cell malignancies. Pirtobrutinib retains the ability to block BTK in the presence of C481 mutations, as it does not require the C481 site for binding to the ATP binding domain of BTK, thus reducing the risk of acquiring resistance and providing a potential alternative therapeutic option for patients with resistance to covalent BTK inhibitors.2
In this video, Nirav N. Shah, MD, from the Medical College of Wisconsin, WI, provides an update on the Phase I/II BRUIN study (NCT03740529), which is investigating the efficacy and safety profile of pirtobrutinib in patients with previously treated chronic lymphocytic leukemia (CLL), small cell lymphocytic leukemia (SLL) or non-Hodgkin lymphoma (NHL).
Dr Shah reports that efficacy was seen in a range of NHL subtypes, including mantle cell lymphoma (MCL), Richter’s syndrome, follicular lymphoma, and diffuse large B-cell lymphoma.
In patients with MCL, an overall response rate of 52% was observed, with 25% of patients achieving a complete response. The data also supported a favorable safety profile, with no grade 3 atrial fibrillation.3
In particular, Dr Shah highlights that pirtobrutinib demonstrated efficacy in patients who had previously failed treatment with covalent BTK inhibitors.
AUTO1 is a fast off-rate chimeric antigen receptor (CAR) currently used in the treatment of adult and pediatric acute lymphoblastic leukemia (ALL). The low toxicity and high persistence of the construct makes it an attractive potential therapy for many subtypes of non-Hodgkin lymphoma, such as indolent lymphoma, diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). Patients suffering from these diseases are often older with many comorbidities and may benefit from a low-toxicity CAR treatment.
At the 26th Congress of the European Hematology Association (EHA 2021), Claire Roddie, MD, PhD, of the University College London Hospitals NHS Foundation Trust, London, UK, discussed the early safety and efficacy data from the ALLCAR19 trial, investigating AUTO1 in patients with relapsed/refractory indolent B-cell lymphoma (NCT02935257).
As of February 18th, 2021, 10 patients had been recruited to the trial, and at the time of presenting, nine patients with indolent non-Hodgkin lymphoma had been treated with AUTO1. These patients had a median age of 56. All patients had stage 3 or 4 disease and had been heavily pre-treated, with a median of three prior lines of therapy. Furthermore, approximately 50% of the patients had previously received an autograft.4
Despite the poor prognosis for this cohort of patients, CAR T-cell products were successfully manufactured for all nine patients using a semi-automated, closed process. All products met the release criteria and were enriched with central memory populations, which are associated with long persistence and limited T-cell exhaustion.
Dr Roddie reports that AUTO1 behaved as expected, with minimal immunotoxicity, commenting that considering the patient profile, the presence of only one grade 2 cytokine release syndrome (CRS) and no grade 3 CRS is particularly promising. All infused patients demonstrated complete metabolic response within three months.
Dr Roddie concludes that these promising findings encourage the recruitment of patients with DLBCL and CLL, in order to assess whether AUTO1 can achieve comparable outcomes in these cohorts.
The pivotal ELIANA study (NCT02435849) investigated the efficacy and safety of tisagenlecleucel in pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL); however, this study excluded patients under the age of three.
In this video, Sara Ghorashian, PhD, of the Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK, talks on the findings of a retrospective analysis of the outcomes of children under the age of three with B-ALL who received tisagenlecleucel chimeric antigen receptor (CAR) T-cell therapy.
Dr Ghorashian reports that tisagenlecleucel was found to have good manufacturing feasibility, with a manufacturing failure rate of around 7% and only 1/30 patients unable to receive the CAR-T cell product due to disease progression.5
Dr Ghorashian gives an overview of the key efficacy findings, highlighting that the complete response, incomplete hematologic recovery, and overall survival data at 6 and 12 months were very similar to the ELIANA study. The measurable residual disease (MRD)-negativity rate was 92% in the retrospective study versus 77% in the ELIANA study, the 6-month event-free survival was 67% vs 73% and the 12-month event-free survival was 58% vs 50%. The toxicity profile of tisagenlecleucel for this age range was found to be favorable.
Dr Ghorashian concludes that tisagenlecleucel is a feasible treatment for patients with B-ALL under the age of three; however, the median follow-up time is relatively short, and a longer follow-up time is required.
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