Liso-Cel Demonstrates Durable Responses in Heavily Pretreated, High-Risk CLL

Tanya Siddiqi, MD

Lisocabtagene maraleucel (liso-cel; JCAR017) appeared tolerable and induced an 81.3% best overall response rate (ORR) and 43.8% complete response (CR) rate in heavily pretreated, high-risk patients with chronic lymphocytic leukemia (CLL) who previously received ibrutinib (Imbruvica), according to dose-finding results of a small phase I/II trial presented at the 2018 ASH Annual Meeting.

The CD19-directed 4-1BB chimeric antigen receptor (CAR) T-cell therapy also showed low rates of grade 3 cytokine release syndrome (CRS) and neurotoxicity, explained lead study author Tanya Siddiqi, MD, an assistant clinical professor in the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope in Duarte, California, in a presentation during the meeting.

“Liso-cel demonstrated promising activity in a heavily pretreated patient population in high-risk CLL, all of whom had received prior ibrutinib,” she added of the preliminary findings. “These responses seem to be deepening over time.”

Patients who progress on B-cell receptor inhibitors have poor prognosis, Siddiqi explained, adding that CR and undetectable minimal residual disease (uMRD) rates with this class of agents remain inadequate—creating an unmet need for this patient population.

Liso-cel consists of a defined CD4 and CD8 composition and 4-1BB costimulatory domain; its defined composition allows administration of a precise dose of treatment. The CAR T-cell therapy was granted a breakthrough therapy designation by the FDA for patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, grade 3b follicular lymphoma, or not otherwise specified disease that is de novo or transformed from indolent lymphoma in December 2016.

The phase I TRANSCEND CLL 004 study (NCT03331198) investigated 16 patients with relapsed/refractory CLL or small lymphocytic lymphoma who failed on or were ineligible to receive a BTK inhibitor. Patients with high-risk disease must have failed on ≥2 prior therapies, while those with standard-risk disease must have progressed on ≥3 prior treatments. Their ECOG performance status was 0 or 1.

The median age was 64.5, and 50% of patients were male. Rai stage III/IV and Binet stage C were both detected in 10 patients. Additional high-risk features were reported, including TP53 mutation (n = 10), complex karyotype (n = 8), and 17p deletion (n = 7). All 16 patients received prior ibrutinib, most received the BTK inhibitor in the relapsed/refractory setting (n = 13), and 8 patients had ibrutinib progression and prior venetoclax (Venclexta).

The dose-escalation modified toxicity probability-interval-2 trial comprised a 28-day dose-limiting toxicity (DLT) period. The dose levels were —1 (2.5 x 10⁷; n = 0), 1 (5 x 10⁷; n = 6), and 2 (1 x 10⁸; n = 10). Following enrollment and apheresis, liso-cel was manufactured and bridging therapy was allowed. This was followed by lymphodepletion with fludarabine at 30 mg/m² and cyclophosphamide at 300 mg/m² for 3 days, then 2 to 7 days later, liso-cel was administered. On-study follow-up was 24 months, with a long-term follow-up planned for up to 15 years after last liso-cel infusion.

The primary endpoint was to determine the recommended dose and safety, while exploratory objectives were antitumor activity and pharmacokinetics.

Grade ≥3 treatment-emergent adverse events (TRAEs) were reported in all patients; the most frequently reported were thrombocytopenia (75%), anemia (68.8%), neutropenia (62.5%), and leukopenia (56.3%). Grade ≥3 TRAEs were observed in 9 patients (56.3%), the most notable being neutropenia (37.5%), leukopenia (31.3%), lymphopenia (31.3%), and anemia (25.0%). There was one DLT of grade 4 hypertension, which was reported in dose level 2.

All serious AEs were grade ≥3 and were observed in 7 patients (43.8%): lung infection (18.8%), and aphasia, decreased blood fibrinogen, encephalopathy, febrile neutropenia, hypertension, and hyponatremia in 1 patient each (6.3%).

Overall and grade 3 AEs of special interest were CRS (75% and 6.3%, respectively), neurologic events (37.5% and 18.8%), and tumor lysis syndrome (12.5% and 12.5%). CRS was more common in the dose level 1 cohort than dose level 2 (100% vs 60%) but neurologic events were lower (33.3% vs 40.0%). Grade 3 tumor lysis syndrome occurred in 1 patient in each dose level cohort. The percentage of patients who experienced CRS and neurologic events was comparable in dose level 1 and 2 (33.3% vs 30.0%).

Aside from the 81.3% (n = 13) best ORR and 43.8% (n = 7) CR rate, results showed that the partial response (PR) or nodular PR rate was 37.5% (n = 6), the stable disease (SD) rate was 12.5% (n = 2), and there was 1 case of progressive disease (PD; 6.3%).

In the dose level 1 cohort, the ORR was 100%; the CR rate was 83.3% (n = 5), and the PR rate was 16.7% (n = 1). There were no cases of SD or PD.

In the dose level 2 cohort, the ORR was 70%; the CR rate was 20% (n = 2), the PR rate was 50% (n = 5), the SD rate was 20% (n = 2), and the PD rate was 10% (n = 1).

Response was assessed at 30 days following treatment with liso-cel. Across both cohorts, the ORR was 75% (n = 12) with a 31.3% CR rate (n = 5) and a 43.8% PR rate (n = 7). In the dose level 1 cohort, the ORR was still 100% with a 50% CR and PR rate (n = 3 each). The ORR, CR rate, and PR rate were 60% (n = 6), 20% (n = 2), and 40% (n = 4), respectively, in the dose level 2 cohort.

Efficacy was again evaluated at 3 months posttreatment with liso-cel. Overall, the ORR was 80% (n = 8), the CR rate was 50% (n = 5), and the PR rate was 30% (n = 3). The ORR was 83.3% (n = 5), the CR rate was 50% (n = 3), and 33.3% (n = 2) in the dose level 1 cohort. In the dose level 2 group, the ORR was 75% (n = 3), followed by a 50% CR rate (n = 2) and 25% PR rate (n = 1).

“I think it is a little bit too early and short to say that there is a dose-response correlation at this point; this is certainly something we will be following over time,” said Siddiqi.

Minimal residual disease was evaluated at 10-4 sensitivity via 6-color flow cytometry using peripheral blood and at 10-6 sensitivity by clonoSEQ deep sequencing of bone marrow aspirates. Eleven patients (73.3%) had uMRD sensitivity 10-4 (uMRD4) via flow cytometry at day 30, all of whom continue to remain undetectable at the most recent follow-up, Siddiqi noted. All 5 patients with a post-dose follow-up at 6 months continue to maintain uMRD4 response.

The pharmacokinetic/pharmacodynamic profile showed that the median time to peak expansion for all patients was 16 days (range, 4-30). Results of a correlative biomarker analysis, in which 38 cytokines were analyzed in 13 patients within the first 30 days of treatment, showed that interleukin-16 and tumor necrosis factor were elevated before onset in 3 of 4 patients who experienced grade 2/3 neurologic events.

Siddiqi noted that following an analysis of dose-escalation data and determining the recommended phase II dose, the phase II portion of the trial will likely open for accrual in the first half of 2019.

Siddiqi T, Soumerai JD, Wierda WG, et al. Rapid MRD-negative responses in patients with relapsed/refractory CLL treated with liso-cel, a CD19-directed CAR T-cell product: preliminary results from TRANSCEND CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. Presented at: 2018 ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego. Abstract 300.

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