Ibrutinib Boosts the Activity of Second CD19-Directed CAR T-Cell Therapy in Refractory Non-Hodgkin Lymphoma

A second treatment with CD19-directed CAR T-cell therapy plus ibrutinib (Imbruvica) following failed prior CD19-directed CAR T-cell therapy and salvage treatment with ibrutinib led to greater efficiency and anti-CD19 CAR T-cell amplification, but also higher grades of cytokine release syndrome (CRS) and more serious hematologic toxicity in patients with refractory B-cell non-Hodgkin lymphoma (B-NHL), according to findings from a study published in Cancer Science.

The results indicated that in the first round of treatment, 2 patients with follicular lymphoma achieved partial response (PR), 2 patients with mantle cell lymphoma (MCL) achieved stable disease (SD), and 1 patient with MCL and 2 patients with follicular lymphoma experienced progressive disease (PD). All 7 patients with refractory B‐NHL who achieved PR, SD, or PD from the first CD19‐directed CAR T‐cell therapy received ibrutinib as a salvage therapy during the following 7 to 16 months. During ibrutinib therapy, 0 patients discontinued or withdrew from treatment because of ibrutinib-related toxicity. However, the disease progressed again during ibrutinib therapy in all 7 patients.

All 7 patients received a second treatment with CD19-directed CAR T-cell therapy. In the second round of treatment, ibrutinib treatment was continued during the second‐time CD19‐directed CAR T‐cell therapy. Three patients with refractory MCL and 3 patients with follicular lymphoma achieved CR with the second‐time CD19‐directed CAR T‐cell therapy plus ibrutinib; 1 patient with follicular lymphoma achieved PR. The tumors in 2 patients disappeared after second‐time CD19‐directed CAR T‐cell therapy.

“The successful outcome of the second‐time anti‐CD19‐CAR T‐cell therapy compared with the first‐time anti‐CD19‐CAR T‐cell therapy before ibrutinib salvage therapy might confirm the role of ibrutinib in improving the activity of anti‐CD19‐CAR T cells in our study,” co-lead study authors, Meijing Liu, and Haobin Deng, both of The First Central Clinical College of Tianjin Medical University, Tianjin, China, wrote in the study publication.

The 7 patients with refractory B‐cell non-Hodgkin lymphoma (B-NHL) included in the observational case series were admitted to the Department of Hematology in Tianjin First Central Hospital between January 2017 and January 2019. Three patients had refractory MCL during which time ibrutinib was not yet available in China. Four patients had refractory follicular lymphoma.

Prior to receiving a diagnosis of refractory B‐NHL, all patients had received at least third‐line treatment, including rituximab (Rituxan)-based combination regimens. The cutoff date was September 30, 2020.

Efficacy was evaluated in all patients at 1 and 2 months after the first‐time and second‐time administrations of the CD19‐directed CAR T‐cell therapy. CR, PR, SD, and PD were defined in accordance with the Lugano Revised Criteria for Response assessment.

In the first round of treatment, all patients received ibrutinib as salvage treatment 1 month after all adverse effects (AEs) of CAR T‐cell therapy had resolved. Patients 2, 3, 4, 5, 6, and 7 received 420 mg of ibrutinib per day, taking into account their body weight of 60 kg to 80 kg, whereas patient 1 received 560 mg of ibrutinib per day because their weight was 115 kg. The treatment duration in patients 1, 2, 3, 4, 5, 6, and 7 was 14, 8, 16, 7, 9, 15, and 13 months, respectively.

Because disease progression occurred without stopping ibrutinib therapy, patients received the same CD19‐directed CAR T‐cell therapy combined with ibrutinib in the second round of treatment.

After the second‐time CD19-directed CAR T‐cell therapy, all 7 patients received ibrutinib as a maintenance treatment until death or intolerable AEs.

Patients had a median age of 55 years (range, 37‐67). No patients received hematopoietic stem‐cell transplantation prior to entry on the study.

Maintenance therapy with ibrutinib was continued after the second‐time CD19‐directed CAR T‐cell therapy. Ibrutinib treatment was continued for a median duration of 13 months (range, 7‐16) at a daily dose of 420 mg or 560 mg.

Additional findings demonstrated that the CR status was maintained for 12, 17, 13, 12, 11, and 6 months in patients 1, 2, 3, 4, and 5, and patient 7 until September 30, 2020. The disease in patient 6 who had obtained PR with the second‐time CD19‐directed CAR T‐cell therapy, progressed again and died 6 months after the second‐time CD19‐directed CAR T‐cell therapy.

With the first‐time CD19‐directed CAR T‐cell therapy, the mean efficiency of CD19‐directed CAR transduction in all patients was 42.27% ± 15.63%. With the second‐time CD19‐directed CAR T‐cell therapy, the mean efficiency of CD19‐directed CAR transduction in all patients was 63.41% ± 14.85%.

Moreover, the median peaks of the CD19‐directed CAR T cells and CD19‐directed CAR gene copy of the 7 patients were higher with the second‐time therapy than with the first‐time therapy (P = .0245 and P = .0335, respectively).

No differences in the transduction efficiency and proliferation between the 2 administrations of CD19-directed CAR T-cell therapy were reported.

Regarding AEs, patients experienced pyrexia with or without chills, fatigue, nausea, decreased appetite, edema, and hypoalbuminemia after the CD19‐directed CAR T‐cell infusion. Cases of

CRS were grades 0 to 2 in the first round and grades 2 to 4 in the second round of treatment with CD19‐directed CAR T‐cell therapy.

No patients were diagnosed with immune effector cell–associated neurotoxicity syndrome (ICANS) with the first‐time CD19‐directed CAR T‐cell therapy, but 1 patient with MCL was diagnosed with grade 2 ICANS with the second-time CD19‐directed CAR T‐cell therapy.

Hematologic toxicity was graded as 1 to 3 with the first‐time treatment and graded 3 and 4 with the second‐time treatment of CD19‐directed CAR T‐cell therapy.

“Although the CRS grades and hematological toxicity grades were greater than in the first‐time anti‐CD19‐CAR T‐cell therapy, the second‐time anti‐CD19‐CAR T‐cell therapy was relatively safe and practicable,” wrote the study authors.

AEs occurred 5 to 7 days after CD19‐directed CAR T‐cell infusion; patients recovered 14 to 16 days after the CD19‐directed CAR T‐cell infusion. Two patients were diagnosed with Gram‐negative bacterial infections with the second‐time CD19‐directed CAR T‐cell therapy. These patients were cured with antibiotics and supportive treatment. No patients were diagnosed with invasive fungal disease.

“The number of cases in our study was relatively small, so more cases are needed to confirm this conclusion. The period of ibrutinib therapy might play an important role in the success of the second‐time anti‐CD19‐CAR T‐cell therapy. Moreover, the mechanisms of the combination of anti‐CD19‐CAR T cells with ibrutinib and how to manage the more serious AEs need further research,” concluded the study authors.

Reference

1. Liu M, Deng H, Mu J, et al. Ibrutinib improves the efficacy of anti‐CD19‐CAR T‐cell therapy in patients with refractory non‐Hodgkin lymphoma. Cancer Science. Published online May 1, 2021. Accessed May 11, 2021. doi:10.1111/cas.14915