Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL

Abstract

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.

Graphical abstract

Figure 1

Patient flow diagram. *Liso-cel is composed of an equal target dose of CD8⁺ and CD4⁺ CAR⁺ T cells. While CAR⁺ T cells could be manufactured for all patients, 1 patient received nonconforming product. ^†This patient was discovered to have Richter transformation after leukapheresis and prior to receiving liso-cel and was included in the safety population but not the efficacy population, as Richter transformation was an exclusion criterion.

Figure 2

Responses and uMRD. (A) Best overall response. Response-evaluable patients were defined as having had a pretreatment assessment and ≥1 postbaseline assessment. One patient in the safety population was not evaluable for response. (B) uMRD. MRD-evaluable patients were defined as those with detectable MRD at baseline. Two patients in the response-evaluable population were not evaluable for MRD. nPR, nodular partial response; PR, partial response; uMRD, undetectable minimal residual disease.

Figure 3

Swim lane plot, duration of response, and progression-free survival. (A) Individual patient response assessments, (B) duration of response, and (C) progression-free survival. *BTKi progression/venetoclax failure subgroup, defined as patient(s) whose disease progressed on BTKi and had failed venetoclax due to progression, intolerance, or failure to respond after ≥3 months of therapy. ^‡MRD nonevaluable patients. No patient who achieved uMRD and was tested subsequently had detectable disease at a later time point. Testing for MRD was not required after month 12. EOS, end of study; ND/unk, not done/unknown; NR, not reached; RT, Richter transformation.

Figure 4

Progression-free survival according to detectable disease status by flow cytometry and NGS. Patients were grouped according to whether MRD was detectable (MRD positive) or undetectable (uMRD; <10⁻⁴) in peripheral blood as analyzed by flow cytometry and by response (A) or detectable (MRD positive) or undetectable (uMRD; <10⁻⁴) in bone marrow as analyzed by NGS and by response (B). Response was classified as CR or PR.