Liso-cel Plus Ibrutinib Demonstrates Tolerable Safety Profile in Relapsed/Refractory CLL/SLL

William G. Wierda, MD, PhD

Lisocabtagene maraleucel (liso-cel; Breyanzi) in combination with ibrutinib (Imbruvica) was associated with manageable safety for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to updated data from the phase 1 TRANSCEND-CLL-004 trial (NCT03331198) presented at the International Workshop on CLL.¹

At a median follow-up of 17 months no grade 5 adverse events (AEs) or grade 4 or 5 cytokine release syndrome (CRS) or neurological events were reported. Of the 23 evaluable patients, all-grade CNS events were reported for 18 patients (78%), with only 1 (4%) having grade 3 CRS. All-grade neurologic events were reported for 7 patients (30%), 4 of whom (17%) had grade 3 events. Eleven of these patients (48%) required tocilizumab (Actemra) and/or corticosteroids to manage CRS and/or neurologic events.

“The treatment landscape for CLL and SLL has remarkably improved of the past several years,” said William G. Wierda, MD, PhD, in a presentation of the data. “However, unmet needs exist [for] the treatment of patients with relapsed or refractory CLL and SLL, especially [for] those with high-risk features [such as] alterations in the TP53 gene.” Wierda is the D.B. Lane Cancer Research Distinguished Professor in the department of leukemia in the division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston.

Investigators of the TRANSCEND CLL-004 study evaluated the safety and efficacy of liso-cel, an autologous CD-19-directed, chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed or refractory CLL or SLL who had progressed on ibrutinib, had high-risk features and received ibrutinib for at least 6 months achieving less than a complete response on therapy, had a BTK or PLCγ2 mutation, or had received prior ibrutinib with no contraindication to reinitiating ibrutinib.

Of the 23 patients enrolled in the combination cohort, 4 were in the dose level 1 group and received liso-cel infusion at 50 x 10⁶ CAR T cells; 19 were in the dose level 2 group and received 100 x 10⁶ CAR T cells. Both cohorts first underwent 3 days of lymphodepletion with fludarabine (30 mg/m²)/cyclophosphamide (300 mg/m²).

At baseline, the median number prior therapies was 4 (range, 1-10) and over half of all patients (52%) previously received a Bruton tyrosine kinase inhibitor and venetoclax (Venclexta). Further, 39% of patients received additional bridging therapy.

In a detailed analysis of the safety data, the median time to CRS onset was 7 days (range, 1-13), and the median duration of CRS was 5.5 days (range, 3-13). For neurologic events, the median time to onset was 9 days (range, 5-13) and the median duration was 7 days (range, 1-10).

Nineteen patients (83%) experienced ibrutinib-related treatment-emergent AEs (TRAEs). Nine patients (39%) experienced grade 3/4 ibrutinib-related TRAEs, which included neutropenia/neutrophil count disease (n = 6), anemia (n = 4), thrombocytopenia (n = 2), atrial fibrillation (n = 1), hypertension (n = 1), lung infection (n = 1), and staphylococcal infection (n = 1). Ibrutinib-related TRAEs infrequently resulted in dose reduction (n = 2) or discontinuation (n = 4) and were all resolved.

There was no clear difference in safety observed between the 2 dose level cohorts.

“Dose level 2 was selected as the recommended dose expansion of liso-cel and ibrutinib in patients with relapsed/refractory CLL/SLL,” Wierda said.

Investigators showed that overall response rate (ORR), an exploratory end point, had promising efficacy data. The ORR was 95% (n = 21/22), which included a 59% (n = 13) complete response (CR) rate and a 36% (n = 8) partial response (PR) rate. Deepening of response was later observed in 4 patients who initially had a PR and improved to a CR in subsequent assessment.

Those who received liso-cel 100 x 10⁶ CAR T cells, had a more pronounced CR. Specifically, 61% (n=11/18) had a CR and 29% (n = 7/11) had a PR compared with 50% (n = 2/4) and 25% (n = 1), respectively, for patients who received 50 x 10⁶ CAR T cells.

No patients had progressive disease during the first month after lisocabtagene maraleucel. One patient in the dose level 1 group had stable disease for 6 months but later progressed.

Additionally, undetectable MRD accessed in blood flow cytometry or in bone marrow by next generation sequencing was achieved in 86% of patients (n = 18/21 and n = 19/22, respectively) at any time point.

All responders (n = 21/22) achieved a response by day 30 after lisocabtagene maraleucel. Among 18 patients with at least 6 months of follow-up, 83% (n = 15) maintained or improved response by day 30. Two patients achieved a response, but later progressed due to Richter transformation.

Both median duration of response and progression-free survival were not reached (NR; 95% CI, NR-NR) at a median follow-up of 17 months.

“[Because of these] encouraging preliminary results, we continue to evaluate the [effect] of liso-cel combined with ibrutinib on efficacy and safety in this actively enrolling clinical trial,” Wierda said.

Reference

1. Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory CLL/SLL. Presented at: 2021 International Workshop on Chronic Lymphocytic Leukemia; September 17-20, 2021; virtual. Abstract 1084088.