CAR T cells in chronic lymphocytic leukemia: a long unusual journey?

The treatment landscape of patients with chronic lymphocytic leukemia (CLL) has dramatically changed over the last decade with the advent of highly selective targeted therapies such as Bruton’s tyrosine kinase (BTK) and B-cell lymphoma-2 (Bcl-2) inhibitors (1). Ibrutinib was the first oral BTK inhibitor approved for the management of CLL followed by second-generation BTK inhibitors such as acalabrutinib and zanubrutinib (2-4). Venetoclax is the first Bcl-2 inhibitor approved for the management of CLL (5). It has been demonstrated that patients with disease progression after both BTK and Bcl-2 inhibitors, so-called double-refractory disease, have few remaining therapeutic options. Recently, pirtobrutinib—a selective, non-covalent, reversible BTK inhibitor—was approved by the Food and Drug Administration (FDA) for the treatment of relapsed and/or refractory (R/R) CLL that progressed after prior treatment with BTK inhibitor and Bcl-2 inhibitor. This approval was based on the data of the BRUIN phase I–II trial with an objective response rate (ORR) of 82% and median progression-free survival (PFS) of 19.6 months (6). These data was confirmed in the BRUIN CLL-321 phase III trial that compared pirtobrutinib with the combination of idelalisib and rituximab or bendamustine and rituximab with a median overall survival (OS) of less than 3 years (7). These results highlighted an urgent unmet need in the double-refractory disease. The introduction of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the management of patients with B-cell malignancies and significantly improved the survival rates of patients treated with CD19-targeting CAR T-cells. The development of CAR T-cell in CLL has been limited by several challenges such as antigen heterogeneity, interactions within the tumor microenvironment, T-cell lymphopenia and exhaustion, and the enrichment of high-risk mutations due to previous therapies (8). Lisocabtagene maraleucel (liso-cel) is a CD19-targeting autologous CAR T-cell, and is the only one approved by the FDA in patients with heavily pretreated double-refractory CLL. This approval was granted based on the data of the TRANSCEND CLL 004 phase II trial without requiring a phase III trial due to the urgent need in this subgroup of patients (the trial will be discussed later) (9).

Recently, Davids et al. reported in Blood the results of the ZUMA-8 phase I trial evaluating brexucabtagene autoleucel (brexu-cel), another CD19-targeting CAR T-cell in patients R/R CLL (10). Brexu-cel is already approved by the FDA for the management of adult patients with R/R B-cell acute lymphoblastic leukemia, and adult patients with R/R mantle cell lymphoma (11,12). The ZUMA-8 enrolled patients who failed at least two prior lines of treatment including a BTK inhibitor and were divided into four cohorts. The cohort 1 of patients received an infusion of 1×10⁶ CD19-targerting CAR T-cells per kg while patients in cohort 2 received 2×10⁶ CAR T-cells per kg. Patients in cohort 3 (low tumor burden), and cohort 4A (post-ibrutinib) received 1×10⁶ cells per kg. The study enrolled fifteen patients with a median age of 63 years (range, 52–79 years). Brexu-cel was successfully manufactured for 100% of patients. Twelve patients (80%) received more than three prior lines of treatment. Only four patients (27%) had a 17p deletion, and seven patients (47%) had complex karyotype. At a median follow-up of 24.3 months, the ORR was 47% (7/15 patients), and only 1 patient (7%) achieved complete response (CR). All three patients in the cohort 3 with low tumor burden showed a response with one patient achieving CR and two patients with partial response (PR) according to the International Workshop on CLL 2018 criteria (13). These patients were the only ones who presented durable response including two patients with ongoing responses at 23 months at data cutoff. The authors reported that the median overall peak CAR T-cell level was 1.71 cells per µL (range, 0–679.38 cells per µL) and the appreciable CAR T-cell expansion only occurred in 4 of 15 patients (27%). Due to this suboptimal CAR T-cell expansion, the ZUMA-8 trial was discontinued early (10).

The ORR in the ZUMA-8 trial was comparable to that observed in the TRANSCEND CLL 004 (47% vs. 43%) while the CR was lower (7% vs. 18% of CR or remission with incomplete marrow recovery). In fact, in the TRANSCEND CLL 004 trial, 137 patients underwent leukapheresis, and 117 patients received liso-cel at two different doses 50×10⁶ (dose level 1) or 100×10⁶ (dose level 2; DL2). The most common reason for not receiving liso-cel was death or disease progression seen in eight patients. All patients had failed a previous BTK inhibitor and 60% of patients (70/117 patients) had treatment failure on previous venetoclax. The primary endpoint was the CR (including with incomplete marrow recovery) in efficacy-evaluable patients with previous BTK inhibitor and venetoclax failure at DL2. The median age was 65 years [interquartile range (IQR), 59–70] years comparable to the ZUMA-8 trial. Interestingly, 85% of patients enrolled in the study had high-risk cytogenetics, and nearly half of patients had TP53 aberrations vs. 27% in the ZUMA-8 trial. The study met its primary endpoint with a rate of CR or remission with incomplete marrow recovery rate of 18% [95% confidence interval (CI): 9–32%; P=0.0006] according to the International Workshop on CLL 2018 criteria (13). The ORR was 43% that was not statistically significant in comparison with the null hypothesis. At a median follow-up of 21.1 months for all patients, the median PFS, and the median duration of response (DOR) were 11.9 and 35.3 months, respectively. Interestingly, the median PFS and DOR of patients with CR or remission including those with incomplete marrow recovery were not reached underlying the potential of durable responses (9). However, the median PFS and DOR were not reported in the ZUMA-8 trial.

Both trials included selected fitter patients with younger age in comparison with the broader CLL population with older age and comorbidities. There was no demographic difference between the two trials conducted in the USA for TRANSCEND CLL 004 and USA and Italy for ZUMA-8 (9,10). Huang et al. presented at the 2025 American Society of Hematology annual meeting a multicenter retrospective analysis of real-world evidence of liso-cel in patients with R/R CLL and received commercial liso-cel in the United States. Thirty patients with double-refractory disease were enrolled, with a median age of 67 years. Approximately, two-third of patients presenting del17p and/or mutated TP53, and 27 patients (90%) previously received pirtobrutinib among them eighteen patients (60%) received pirtobrutinib as last treatment before liso-cel. The results were widely different from those found in the ZUMA-8 trial. The ORR was 83.3% (25/30 patients), and the CR/unconfirmed CR (CRu) was 60% (17/30 patients) with median time to best response of 30 days (14). These findings should be confirmed with larger sample size and longer follow-up.

Brexu-cel has no new safety signals in the ZUMA-8 trial in patients with R/R CLL. Grade 3 or higher adverse events (AEs) were reported in all patients (100%), and treatment-related AEs (TRAEs) emerged in 9 patients (60%). Furthermore, grade 3 or higher serious AEs were observed in 6 patients (40%). All-grade cytokine release syndrome (CRS) occurred in 12 patients (80%) with only one grade 4 CRS (7%) in the cohort 3 and considered as the only dose-limiting toxicity observed. Furthermore, all-grade neurotoxicity was observed in 11 patients (73%), and grade 3 neurotoxicity was reported in 20% of patients. No grade 5 AE was reported (10). Moreover, infections and infestations were reported in 6 patients (40%). The safety profile was also comparable to that observed with liso-cel in the TRANSCEND CLL 004. Liso-cel was associated with 92% of grade 3 or higher treatment-emergent AEs (108/117 patients). All-grade CRS was reported in 99 patients (85%) including 10 grade 3 CRS (9%). Moreover, all-grade neurological events occurred in 53 patients (45%) with 19% of grade 3 or higher neurological events. Grade 3 or higher infections occurred in 17% of patients treated with liso-cel while hypogammaglonunemia was reported in 15% of patients (9). The high incidence of CRS and neurotoxicity in comparison with toxicity reported in patients with large B cell lymphoma could be in part related to the biology of the disease.

One of the limitations of the ZUMA-8 trial is the absence of published data regarding minimal residual disease (MRD), which is an important biomarker of response, in patients treated with brexu-cel. However, data published from the TRANSCEND CLL 004 regarding MRD are very encouraging. The rate of undetectable MRD in blood using next-generation sequencing with a sensitivity of 10⁻⁴ was 63.3% with a high concordance with marrow results (>95%). Interestingly, all patients with double-refractory disease, evaluable for MRD and who achieved PR or CR according to International Workshop on CLL 2018 criteria, reached undetectable MRD. The authors also found that undetectable MRD was associated with longer PFS vs. detectable MRD irrespective of best overall response. Furthermore, 60% of patients evaluable for MRD with stable disease achieved undetectable MRD in blood, marrow, or both. The authors also reported that among patients with stable disease according to the International Workshop on CLL 2018 criteria, patients with undetectable MRD in blood had higher liso-cel expansion and longer median PFS in comparison with those with detectable MRD (9). These data suggest that patients could derive clinical benefit from liso-cel even without meeting response criteria with International Workshop on CLL 2018 criteria, and raise the questions about these criteria of response highlighting the need for a timely revision to include other criteria such as MRD.

In both clinical trials, ZUMA-8 and TRANSCEND CLL 004, durable clinical benefit and CAR T-cell expansion were mainly observed in patients with low tumor burden, highlighting tumor burden as a key determinant of CAR T-cell efficacy. To be noted that ZUMA-8 trial was stopped due to suboptimal CAR T-cell expansion. In an exploratory analysis from TRANSCEND CLL 004, the authors found that patients with low burden disease at baseline were correlated with increased likelihood of achieving response in patients with R/R CLL (15). In fact, it has been demonstrated that high tumor burden in patients with CLL creates a highly immunosuppressive niche that impairs the CAR T-cell expansion and persistence (16). One of the strategies that could be used is a tumor debulking approach before leukapheresis using BCL-2 antagonists, anti-CD20 based therapy or BTK inhibitors in order to reduce disease load and to ameliorate the composition of T cells collected. In the ZUMA-8, short-course ibrutinib before the leukapheresis did not improve outcomes suggesting that longer exposure is needed to reverse chronic T-cell dysfunction. Interestingly in the Huang et al. presentation, the CR/CRu rate in patients who received prior pirtobrutinib as last treatment before liso-cel was 72% (13/18 patients) versus 28% (5/12 patients) in patients who did not receive pirtobrutinib as last line of treatment (14).

In conclusion, CAR T-cell therapy could be promising in patients with R/R CLL, but its efficacy depends on specific parameters. Available data suggest that durable responses require low tumor load and improved T-cell function. Overcoming the immunosuppressive effect of the tumor microenvironment of CLL will demand multiple approaches leading to disease control, immune restoration and refined CAR design.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-179/coif). The authors have no conflicts of interest to declare.

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