CD19 CAR T Cells Plus Acalabrutinib Shows Early Activity in Relapsed/Refractory MCL

CD19 CAR T cells paired with acalabrutinib (Calquence) was found to be well tolerated and to elicit responses in patients with relapsed/refractory mantle cell lymphoma (MCL), according to data from a phase 1 study (NCT04484012) shared during the 2023 ASH Annual Meeting.

In evaluable patients (n = 8), the overall response rate (ORR) was 88%, with a complete response rate (CR) of 75%; 50% of patients achieved a CR with minimal residual disease (MRD) negativity (< 10-4), and 25% had a CR with MRD positivity. Moreover, the partial response (PR) rate was 12.5% and 12.5% of patients had stable disease (SD).

In those who received the CD19 product at 200 x 106 CAR-positive cells, which was dose level 1, the ORR achieved with the combination was 75%, which was comprised of a CR with MRD negativity rate of 50% and a PR rate of 25%; 25% of patients achieved SD. In those who received the product at dose level 2, which was 500 x 106 CAR-positive cells, the ORR with the combination was 100%; 50% of patients experienced a CR with MRD negativity and 50% had a CR with MRD positivity.

The median follow-up following CAR T infusion was 20.3 months (range, 12.0-32.2). The median progression-free survival (PFS) was 14.7 months (95% CI, 9-not estimable [NE]) and the median overall survival (OS) was not reached (95% CI, 22%-NE). The median duration of response was 13.8 months (95% CI, 8.1-NE). A total of 5 patients had initiated new therapy, 4 patients experienced progressive disease (PD), and 1 patient died because of PD.

“CD19 CAR T plus acalabrutinib showed encouraging clinical activity in a high-risk relapsed/refractory MCL population,” John H. Baird, MD, an assistant professor in the Division of Lymphoma, Department of Hematology and HCT, at City of Hope National Medical Center in Duarte, California, and colleagues, wrote in a poster. “In patients who achieved CR, responses were durable beyond cessation of acalabrutinib. The 1-year PFS and duration of CR [was] 55% [95% CI, 29%-41%].”

Although targeted therapies have helped to improve outcomes in MCL, the disease remains incurable. For those with relapsed or refractory disease, CD19-targeted CAR T-cell therapies have provided durable disease control but at the cost of severe immune-related toxicities. Acalabrutinib has been found to have synergistic effects with CD19-targeted CAR T-cell therapy.

“We hypothesized that combining a naive and memory phenotype–enriched CD19 CAR T product with acalabrutinib would attenuate the incidence of severe immune-related toxicities post-CD19 CAR T infusion [and] improve the durable CR rate compared [with] reported monotherapy rates,” the study authors wrote in the poster. Investigators also hypothesized that this approach would allow for fixed-duration BTK inhibition without sacrificing durable disease control.

The single-center, dose-escalation trial enrolled patients with MCL who had received at least 1 prior line of therapy, including 3 to 7 months of a BTK inhibitor, without evidence of PD prior to leukapheresis.

Patients received a single intravenous infusion of TN/MEM-enriched CD19.28.z.EGFRt-CAR T cells at a flat dose plus acalabrutinib at 100 mg twice daily.

The median patient age was 63 years (range, 38-70) and the majority were male (75%). More than half of patients had a simplified Mantle Cell Lymphoma International Prognostic index of intermediate or high-risk disease (62.5%), 50% had a Ki-67 proliferation index of 30% or higher, 75% had a TP53 mutation, 12.5% had a complex karyotype, and 75% had bone marrow involvement of 10% or higher at the time of enrollment.

The median number of prior lines of therapy received was 2 (range, 2-3). Seventy-five percent of patients experienced early relapse following frontline therapy, 25% had prior autologous stem cell transplantation, 62.5% of patients received prior bendamustine (Bendeka), and 50% had received bendamustine within 1 year before leukapheresis. The median duration of BTK inhibitor therapy before leukapheresis was 6.1 months (range, 4.5-7.3) and the ORR achieved with BTK inhibitors at the time of enrollment was 75%.

Additional data indicated that peak CAR T levels occurred at a median of 11 and 8 days for those in dose levels 1 and 2, respectively. Notably, peak CAR T levels were 20-fold higher in those treated at dose level 1 vs those in dose level 2. CAR T cells persisted in 75% of evaluable patients (n = 8) at 6 months or longer following infusion. No differences were observed in CAR T product phenotype by dose level or previous exposure to bendamustine.

Regarding safety, 62.5% of patients experienced cytokine release syndrome (CRS). The median time to onset after infusion was 3 days (range, 1-4) and the median duration was 4 days (range, 2-5). These patients received tocilizumab (Actemra; 25%) or intravenous immunoglobulin (37.5%).

The most common treatment-emergent adverse effects (TEAEs) in all patients (n = 8) included anemia (any grade, 100%; grade ≥3, 38%), neutropenia (88%; 88%), thrombocytopenia (88%; 25%), lymphopenia (100%; 100%), fatigue (88%; 0%), pain (50%; 0%), nausea (100%; 0%), vomiting (63%; 0%), hypoalbuminemia (88%; 0%), hypophosphatemia (50%; 0%), hypertension (75%; 25%), and anorexia (63%; 0%).

At dose level 2, accrual of patients is ongoing.

Reference

Baird JH, Del Real MD, Song JY, et al. CD19-directed CAR T-cells (CD19-CAR) combined with acalabrutinib achieves durable remissions in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL). Blood. 2023;142(suppl 1):4840. doi:10.1182/blood-2023-182456