Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study

Abstract

Background: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma.

Methods: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 10⁶ (dose level 1) or 100 × 10⁶ (dose level 2, DL2) chimeric antigen receptor-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 criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198.

Findings: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis).

Interpretation: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable.

Funding: Juno Therapeutics, a Bristol-Myers Squibb Company.

Figure 1:. Trial profile

BTK=Bruton tyrosine kinase. CAR=chimeric antigen receptor. DL1=dose level 1, 50 × 10⁶ CAR⁺ T cells. DL2=dose level 2, 100 × 10⁶ CAR⁺ T cells. Liso-cel=lisocabtagene maraleucel. *At data cutoff (Sept 29, 2022), the conforming status of CAR T-cell product for one patient was not available in the dataset; therefore, the product for this patient was considered non-conforming and the patient was not included in the efficacy and safety analyses that required the receipt of conforming product; after data cutoff, it was confirmed that the patient received conforming product, so this patient will be included in future safety and efficacy analyses. †Safety analyses included all patients who received liso-cel; patients were not included in the safety analyses if they received non-conforming product, defined as any product wherein one of the CD8 or CD4 cell components did not meet one of the requirements to be considered liso-cel but was considered appropriate for infusion. ‡Data from the long-term follow-up study were included for the analyses of study duration, overall survival, and deaths. §Efficacy analyses included patients who received liso-cel and had measurable disease before liso-cel infusion based on independent review committee assessment; patients were excluded if they did not have baseline disease assessment completed or no longer had measurable disease on baseline disease assessment after anticancer therapy for disease control and before liso-cel infusion, or if they developed Richter transformation or mantle cell lymphoma before liso-cel infusion; patients were not included in the efficacy analyses if they received non-conforming product; retreatment with liso-cel was allowed for patients who had a complete response or remission (including with incomplete marrow recovery) with the first liso-cel treatment and subsequently progressed, including with Richter transformation; no independent review committee assessments were performed after retreatment; two patients received liso-cel retreatment in the full population. ¶Venetoclax failure was defined as discontinuation of venetoclax due to disease progression or intolerability and met indications for further therapy per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, or no objective response within 3 months of initiating venetoclax. ||The number of patients screened is unavailable for this subset because the patients’ disease characteristic was not necessarily recorded if they did not meet eligibility criteria.

Figure 2:. Kaplan-Meier curves in the primary efficacy analysis set at DL2

Kaplan-Meier curves are shown for duration of response by best overall response (A), progression-free survival by best overall response (B), overall survival by best overall response (C), and progression-free survival by MRD status in blood (D). Data are expressed as median (95% CI). CAR⁺=chimeric antigen receptor-positive. CR=complete response or remission. CRi=complete response or remission with incomplete marrow recovery. DL2=dose level 2, 100 × 10⁶ CAR⁺ T cells. Liso-cel=lisocabtagene maraleucel. MRD=minimal residual disease. nPR=nodular partial response or remission. NR=not reached. PR=partial response or remission. *Patients were not evaluable for MRD (eg, calibration failure).

Figure 3:. Cellular kinetics and total CD19⁺ cells in the full population at DL2

Relationship between liso-cel cellular kinetic parameter AUC_(0–28d) and efficacy by response (A) and by best overall response and MRD status in blood (B). Total CD19⁺ cells versus liso-cel expansion in responders (C), patients with stable disease (D, E), and patients with progressive disease (F). In parts A and B, the cellular kinetic parameter AUC_(0–28d) values from individual patients are shown as circles, with the median of each subgroup shown by lines. Patients with unknown MRD status were excluded. Patients with progressive disease who also had detectable MRD are not shown because the sample size was small (n=2). AUC_(0–28d)=area under the curve from 0 to 28 days after infusion. CAR⁺=chimeric antigen receptor-positive. CR=complete response or remission. CRi=complete response or remission with incomplete marrow recovery. DL2=dose level 2, 100 × 10⁶ CAR⁺ T cells. Liso-cel=lisocabtagene maraleucel. MRD=minimal residual disease. nPR=nodular partial response or remission. PR=partial response or remission. uMRD=undetectable minimal residual disease.