The effects observed with concurrent ibrutinib and lisocabtagene maraleucel in the relapsed or refractory chronic lymphocytic leukeima population included changes in gene signatures related to proliferation, inflammation, and T cell exhaustion.
Measurable effects were induced in the chimeric antigen receptor (CAR)-positive and endogenous T cells of patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) treated with concurrent ibrutinib (Imbruvica), according to results presented during the Society for Immunotherapy of Cancer 2021 Annual Meeting.1
The effects observed with concurrent ibrutinib in the r/r CLL population included changes in gene signatures related to proliferation, inflammation, and T cell exhaustion, the data show.
Occurrences of inherent T-cell dysfunction in CLL have significantly curbed the development of new CAR T-cell therapies. Ibrutinib has demonstrated the ability to modulate CAR T cells directly to enhance their function in a way that does not impact anti-tumor effects. The potential benefit of concurrent ibrutinib was therefore explored in the phase 2, open-label, multicenter TRANSCEND CLL 004 study (NCT03331198).1,2
In the study, the FDA-approved CAR T-cell agent lisocabtagene maraleucel (liso-cel; Breyanzi) was administered alone or with concurrent ibrutinib for the treatment of patients with r/r CLL.3 An analysis as to how the concurrent therapy affected patients was carried out on post-infusion CAR-positive and endogenous T cells using a novel cell-sorting, low-input RNA sequencing method. Patients' cells were evaluated beyond peak expansion which include 1 month and 2 months post CAR T-cell infusion.1
Overall, 16 patients were treated with liso-cel alone and 19 received the CAR T-cell agent with concurrent ibrutinib. In addition to the post-infusion effect, investigators also assessed CAR-positive T cell pharmacokinetics by flow cytometry, serum interleukin-6 measured by electrochemiluminescent multiplex immunoassay, and minimal residual disease in peripheral blood and bone marrow measured using flow cytometry and next-generation sequencing, respectively.
With concurrent ibrutinib added to liso-cel, patients had positive enrichment of cell proliferation-associated gene sets as well as negative enrichment of inflammation-associated gene sets at peak expansion in CAR-positive T cells. In endogenous T cells, these same effects were shown but were less marked.
In terms of the secondary study outcomes, the combination of liso-cel and concurrent ibrutinib achieved increased CAR-positive T cell expansion and reduced serum interleukin-6. Expression was increased and sustained in CAR-positive and endogenous T cell od independently acquired CLL genes with the combination compared with no expression with liso-cel monotherapy.
The addition of concurrent ibrutinib also resulted in a higher undetectable minimal residual disease as well as prolonged progression-free survival and duration of response. In terms of the T cell exhaustion-related gene signature, treatment with liso-cel and concurrent ibrutinib greatly improved CAR-positive T cells leading to improved progression-free survival compared with liso-cel monotherapy.
TRANSCEND CLL 004 is ongoing with a target enrollment of 200 patients with CLL or small lymphocytic lymphoma. Patients will receive the FDA-recommended dose of liso-cel, which is a single dose containing 50 to 110 x 106 CAR-positive viable T cells with a 1:1 ratio of CD4 and CD8 components. The CAR T treatment must be administered by intravenous infusion and alone or with concurrent ibrutinib and must be followed with preceded by fludarabine and cyclophosphamide for lymphodepletion, per the FDA’s recccomendation.2,3
To be eligible for enrollment, patients with CLL or SLL must have received and failed Bruton tyrosine kinase (BTK) inhibitor treatment or have been deemed ineligible for BTK inhibitor therapy. All patients are required to have an ECOG performance status of ≤ 1 as well as adequate bone marrow and organ function to be eligible for enrollment.2
Patients with CLL or SLL and high-risk features must have failed at least 2 lines of prior therapy and those with standard-risk features must have failed at least 3 prior lines of therapy in order to enter into the monotherapy arm.
For inclusion in the combination arm, patients are required to be receiving ibrutinib and progressing at the time of study enrollment, be receiving ibrutinib for at least 6 months with a response less than complete response and have high-risk features, have BTK or PLCgamma2 mutations per local laboratory assessment, and have previously received ibrutinib and have no issues to restarting ibrutinib therapy. The study is actively recruiting patients who meet these requirements across the United States.
1. Thorpe J, Rytlewski J, Gillenwater H, et al. 449 Concurrent ibrutinib enhances T cell function in patients with chronic lymphocytic leukemia (CLL) treated with lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T cell therapy. J Immunother Cancer. 2021; 9(suppl 2). doi: 10.1136/jitc-2021-SITC2021.449
2. Study evaluating safety and efficacy of jcar017 in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Clinicaltrials.gov. Accessed November 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03331198
3. FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. FDA. News release. February 5, 2021. Accessed November 16, 2021. https://bit.ly/3Dnmlzd