Updated Follow-up of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated with Lisocabtagene Maraleucel in the Phase 1 Monotherapy Cohort of Transcend CLL 004, Including High-Risk and Ibrutinib-Treated Patients

Background: Lisocabtagene maraleucel (liso-cel) is an investigational, CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T cell product administered at equal target doses of CD8⁺ and CD4⁺ CAR⁺ T cells. Liso-cel is being studied in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the ongoing, open-label, phase 1/2 TRANSCEND CLL 004 study (NCT03331198). Here, we report outcomes of patients in the phase 1 monotherapy cohort after a median follow-up of 18 months (mo).

Methods: Eligible patients had received ≥3 (standard-risk disease) or ≥2 (high-risk disease: del[17p], TP53 mutation, unmutated IGHV, or complex karyotype) lines of prior therapy, including a Bruton tyrosine kinase inhibitor (BTKi) unless contraindicated. Patients with active untreated central nervous system disease, Eastern Cooperative Oncology Group performance status >1, or Richter transformation were excluded. After 3 days of lymphodepletion with fludarabine and cyclophosphamide, patients received liso-cel infusion at 1 of 2 dose levels (DLs): 50 × 10⁶ (DL1) or 100 × 10⁶ (DL2) CAR⁺ T cells. Dose-limiting toxicities were evaluated for 28 days postinfusion. Responses were assessed using 2018 International Workshop on CLL criteria. Minimal residual disease (MRD) was assessed in blood by flow cytometry and/or in bone marrow (BM) by next-generation sequencing (both with a sensitivity of ≤10^-4). Persistence of liso-cel was monitored by quantitative polymerase chain reaction.

Results: Overall, 23 and 22 patients were evaluable for safety and efficacy, respectively. Median age was 66 (range, 49‒79) years, median number of prior therapies was 6 (range, 3‒13), and 83% of patients (n=19/23) had high-risk disease. All patients (N=23) had received prior ibrutinib, with 91% (n=21) refractory to, or who relapsed on, ibrutinib and 9% (n=2) who were intolerant to ibrutinib; overall, 48% (n=11) were refractory to both a prior BTKi and venetoclax. The safety profile was similar to that previously reported; no late or delayed adverse events of concern have emerged with the longer follow-up (Table). Among the 22 efficacy-evaluable patients, overall response rate (ORR; complete response [CR]/CR with incomplete blood count recovery [CRi] + partial response) was 82% (n=18); the CR/CRi rate was 45% (n=10). By Day 30, 68% of patients (n=15) achieved an overall response. At 15 mo and 18 mo, 53% (n=10/19; 6 CRs) and 50% (n=7/14; 5 CRs) of patients maintained their responses, respectively. At a median follow-up of 18 mo, the median duration of response was not reached (NR) in patients who had achieved a response to liso-cel (n=18), and median progression-free survival was 18 mo (95% CI, 3.0-NR) in all efficacy-evaluable patients. Two patients who completed the study maintained their response through 24 mo on study and have enrolled in a long-term follow-up study. Five of 8 patients who progressed had Richter transformation. The subgroup of patients refractory to both a prior BTKi and venetoclax had a similar ORR compared with the total evaluable population, with a CR rate of 60% (n=6/10; Table). Of 20 MRD-evaluable patients, 15 (75%) had undetectable MRD (uMRD) in the blood, 13 (87%) of whom also had uMRD in the BM, with most (60%) achieving uMRD in the BM by Day 30. Preliminary data show that liso-cel was detectable in the blood for up to 18 mo postinfusion in 4 (36%) of 11 patients.

Conclusions: Liso-cel treatment resulted in a high rate of uMRD in this heavily pretreated, high-risk population of patients with R/R CLL/SLL, including those refractory to both a BTKi and venetoclax. Responses were rapid and durable, with liso-cel detectable for up to 18 mo postinfusion. No late or delayed adverse events of concern emerged with longer follow-up. The phase 2 monotherapy expansion of the study is currently enrolling at DL2.

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