Lisocabtagene Maraleucel Continues to Show Promise in Relapsed/Refractory CLL

Tanya Siddiqi, MD

The CAR T-cell therapy lisocabtagene maraleucel (liso‐cel; JCAR017) demonstrated high rates of response, including minimum residual disease (MRD) in blood and marrow in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), according to the latest results from the TRANSCEND CLL 004 study presented at the 2019 International Conference on Malignant Lymphoma.

The best overall response rate (ORR) in 22 evaluable patients was 81.8% (95% CI, 56.7-94.8). Ten patients (45.5%) achieved complete remission with/without complete blood count recovery (CR/CRi), and 36.4% achieved a partial response. Progressive disease occurred in 17.8% of patients.

Undetectable MRD (uMRD) was achieved in blood by 75% of patients and in marrow by 65% of patients by day 30.

By day 30, most (68%) patients achieved early objective response and 60% had uMRD. The responses have deepened with time in 27% of patients. The responses were durable and maintained for 6 months: ORR in 67% and uMRD in 64% of patients. CR was maintained for 9 months in 83% of patients achieving CR, and 3 patients continue in CR for 12 months.

Median time to peak blood CAR T-cell level was 16 days (range, 4-30).

“Achieving deep and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia, which is considered incurable, may depend on eradication of minimal residual disease,” said Tanya Siddiqi, MD, City of Hope. “Patients who progress on therapy have poor outcomes,” she added.

“Lisocabtagene maraleucel is an investigational, anti‐CD19 CAR T cell product that is administered as a defined composition of CD4+/CD8+ CAR T cells; in the ongoing phase I/II TRANSCEND CLL 004 study, we assessed safety, pharmacokinetics, and efficacy of lisocabtagene maraleucel,” she explained.

To produce this construct, peripheral blood mononuclear cells (PBMCs) are harvested from the patients and transformed using a Lentiviral vector with separately formatted CD4, which targets the tumor, and CD8, which binds a major histocompatibility complex molecule.

TRANSCEND CLL 004 (NCT03331198) enrolled patients with relapsed/refractory CLL or SLL. Patients were required to have failed or be ineligible for treatment with a BTK inhibitor, have received ≥2 prior lines of therapy, and have an ECOG performance status of ≤1. The median patient age was 66 years (range, 49-79), 47.8% were male, and 34.8% of patients had bulky disease. Siddiqi pointed out that 73.9% of the patients received bridging treatment and 82.6% had high-risk features, including a complex karyotype (47.8%), del(17p; 34.8%), and/or TP53 mutation (60.9%). The patients had received a median of 5 (range, 2-11) prior lines of therapy, including ibrutinib (100%).

After undergoing lymphodepleting chemotherapy, 9 patients received liso‐cel infusion at 50 × 106 total CAR+ T cells and 14 patients received 100 × 106 total CAR+ T cells. Patients were monitored for dose‐limiting toxicities (DLTs). Response was assessed by International Workshop on CLL 2008 criteria. MRD was assessed by flow cytometry in blood and by Next‐Generation Sequencing in bone marrow.

At the data cutoff, 16 patients had been transfused with liso‐cel; of these, 6 received the lower dose level and 10 received the higher dose level.

“MRD‐negative CRs were seen in patients who had failed both BTK inhibitors and venetoclax,” Siddiqi said.

At the low dose, the ORR was 77.8% (95% CI, 40.0-97.2); 66.7% of patients had CR/CRi, and 11.15% achieved partial response. At the higher dose, the ORR was 84.6% (95% CI, 54.6-98.1); 30.8% of patients had CR/CRi, and 53.8% achieved partial response. In the respective dose levels, 27.2% and 7.7% of patients experienced PD.

“Adverse events were manageable at both dose levels and the rates of grade 3 neurological events and cytokine release syndrome were low,” Siddiqi noted.

Treatment-emergent adverse events (TEAEs) at either dose level of any cause occurred in all patients; grade ≥3 occurred in 95.7% of patients, including 88.9 and 100% at the low and high doses, respectively.

The most common grade 3/4 TEAEs were anemia, (78.3%), cytokine release syndrome (CRS; 8.7%), thrombocytopenia (69.6%), neutropenia (56.5%), and leukopenia (43.5%). Two patients in the high-dose arm had DLTs; 1 had grade 4 hypertension and 1 patient had grade 3 encephalopathy, grade 3 muscle weakness, and grade 4 tumor lysis syndrome (TLS).

Six on-study deaths occurred; 4 deaths were due to disease progression, 1 due to grade 5 respiratory failure and the cause of 1 death was unknown.

No grade 5 TEAEs of special interest occurred. Grade 3 CRS occurred in 8.7% of patients and grade ≥3 neurological events (NE) occurred in 21.7% of patients. Any grade CRS or NE occurred in 78.3% of patients, with 34.8% experiencing CRS and NE. Grade ≥3 TLS occurred in 17.4% of patients.

“In this study of heavily pretreated patients with standard risk and high‐risk CLL or SLL and previous ibrutinib treatment, patients rapidly achieved CR/CRi and undetectable MRD,” Siddiqi summarized. “These findings justify the conduct of the phase II component of the study, which is currently enrolling patients for treatment at dose level 2,” said Siddiqi.

Siddiqi T. TRANSCEND CLL 004: minimal residual disease after lisocabtagene maraleucel in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 065.

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