In TRANSCEND CLL 004 study, lisocabtagene maraleucel induced durable complete response or remission in patients with difficult-to-treat relapsed or refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), including patients with Bruton tyrosine kinase (BTK) inhibitor progression and venetoclax failure, with a manageable safety profile.
The depth and durability of the responses and manageable safety profile indicate that lisocabtagene maraleucel is a potentially effective treatment for this population with a high unmet medical need. The findings are presented at 2023 ASCO Annual Meeting on 6 June in Chicago, IL, US along with a simultaneous publication in The Lancet by Dr. Tanya Siddiqi of the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center in Duarte, CA, US, and colleagues.
Targeted therapies, including BTK inhibitors, PI3K inhibitors, and BCL2 inhibitors, alone or combined with CD20 monoclonal antibody, have shown efficacy in patients with CLL or SLL. However, patients with relapsed or refractory disease who experience intolerance to or progression after BTK inhibitor and BCL2 inhibitor have no established standard of care and the outcomes are poor.
The authors wrote in the background that specifically, heavily pretreated patients with high-risk cytogenetic features have low complete response or remission rates including with incomplete marrow recovery of 0–5% and short median overall survival (OS). Real-world evidence indicates progressively worse outcomes as treatment options become exhausted. In later lines of treatment, CLL no longer appears to behave as an indolent or chronic disease. Safe and effective treatment options in this population are scarce. In previous studies, CD19-directed, chimeric antigen receptor (CAR) T-cell therapies showed promise as a potential treatment modality for relapsed or refractory CLL or SLL, but were not investigated further.
Lisocabtagene maraleucel is an autologous, CD19-directed, CAR T-cell product administered at equal target doses of CD8-positive and CD4-positive CAR T cells. The phase I dose-escalation portion of TRANSCEND CLL 004 established a lisocabtagene maraleucel target dose of 100 × 106 CAR-positive T cells as the recommended phase 2 dose. The study team reported the findings from a primary analysis of the monotherapy portion of TRANSCEND CLL 004.
TRANSCEND CLL 004 is an open-label, single-arm, phase I-II study conducted in the US. Patients aged 18 years or older with relapsed or refractory CLL or SLL and at least two previous lines of treatment, including a BTK inhibitor, received an intravenous infusion of lisocabtagene maraleucel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) CAR-positive T cells.
The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL 2018) criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%).
Between 2 January 2018 and 16 June 2022, 137 enroled patients underwent leukapheresis at 27 sites in the US. In total, 117 patients received lisocabtagene maraleucel; median age was 65 years (IQR 59–70), 37 patients (32%) were female, and 80 patients (68%) were male, 99 patients (85%) were White, 5 patients (4%) Black or African American, 2 patients (2%) of other races, and 11 patients (9%) of unknown race. Included patients received median of 5 previous lines of treatment and all 117 patients had received and had treatment failure on a previous BTK inhibitor. A subset of 70 patients had also experienced venetoclax failure.
In the primary efficacy analysis set at DL2 comprising 49 patients, the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (95% confidence interval [CI] 9–32; p = 0.0006). Responses were durable after a one-time infusion with lisocabtagene maraleucel, with a median duration of response of 35.3 months overall and not reached in patients with complete response or remission (including with incomplete marrow recovery). Efficacy outcomes were similar in the full population (relapsed or refractory CLL or SLL after progression on BTK inhibitor), showing a clinical benefit of lisocabtagene maraleucel in this broader population.
Lisocabtagene maraleucel generated complete response or remission (including with incomplete marrow recovery) and induced high undetectable minimal residual disease (MRD) rates in both blood and marrow with > 95% concordance. The study team also showed that undetectable MRD versus detectable MRD was associated with longer progression-free survival (PFS), irrespective of best overall response.
Undetectable MRD was reached by day 30 post infusion in most patients. All MRD-evaluable patients with complete response or remission (including with incomplete marrow recovery) or partial response or remission (including nodular partial response or remission) reached undetectable MRD in both blood and marrow. About half of MRD-evaluable patients with stable disease reached undetectable MRD status in blood, marrow, or both. Among patients with stable disease, those who achieved undetectable MRD in blood had higher lisocabtagene maraleucel expansion with longer median PFS compared with those who had detectable MRD, suggesting that these patients derive clinical benefit from lisocabtagene maraleucel even without meeting response criteria by iwCLL 2018.
In patients treated with lisocabtagene maraleucel, grade 3 cytokine release syndrome was reported in 10 patients (9%) with no grade 4 or 5 events and grade 3 neurological events were reported in 21 patients (18%) of which 1 was grade 4 and there were no grade 5 events. Among 51 deaths on the study, 43 occurred after lisocabtagene maraleucel infusion, of which 5 were due to treatment-emergent adverse events within 90 days of lisocabtagene maraleucel infusion. One death was related to lisocabtagene maraleucel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis).
The authors commented that lisocabtagene maraleucel has the potential to fill a gap in the treatment landscape for patients with relapsed or refractory CLL or SLL who have experienced disease progression on previous BTK inhibitor and venetoclax failure. Whereas most current and emerging therapies target BTK, BCL2, PI3K, or anti-CD20 with continuous treatment, lisocabtagene maraleucel represents a new mechanism of action with a single dose of treatment. Even with investigational non-covalent BTK inhibitors, risk of mutations that cause resistance to these therapies are emerging. Moreover, unlike current therapies, lisocabtagene maraleucel is a one-time infusion that does not require continuous treatment.
This study is limited by the single-arm design. In addition, the study enroled patients with heavily pretreated disease. In this patient population, the dropout rate after leukapheresis was 15%, despite a high manufacturing success rate of 96% and optional bridging therapy for disease control during lisocabtagene maraleucel manufacturing. Among the reasons for dropout were accelerated disease progression, which led to patient death or no longer meeting eligibility criteria.
The follow-up period for duration of response and survival outcomes is still short, with more than 50% of responders ongoing and about 60% of efficacy-evaluable patients censored for OS. Longer follow-up will provide further insight into the durability of response and long-term survival benefits of lisocabtagene maraleucel in relapsed or refractory CLL or SLL, because single-dose treatment with a long treatment-free interval is an important benefit to patients. To further understand the potential association between CD19-positive cell levels and disease relapse, additional investigation is needed, because the assay used in this study does not distinguish between malignant and normal CD19-positive cells.
This is the first multicentre clinical study of CD19-directed CAR T-cell therapy for patients with relapsed or refractory CLL or SLL and the first study to report efficacy for CAR T-cell therapy in relapsed or refractory CLL after progression on BTK inhibitor and venetoclax failure. The authors concluded that they demonstrated the feasibility of CAR T-cell therapy as a treatment option in relapsed or refractory CLL.
The study was funded by Juno Therapeutics, a Bristol-Myers Squibb Company.
References
- Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study. The Lancet; Published online 6 June 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01052-8
- Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel (liso-cel) in R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of TRANSCEND CLL 004. J Clin Oncol 41, 2023 (suppl 16; abstr 7501).