PD-1 Inhibitors Plus Anti-CD19-CAR T Cells May Be Safe for R/R DLBCL

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Maintenance therapy with a PD-1 inhibitor appears to be an effective and safe treatment for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who achieved a complete response (CR) and a partial response (PR) with previous anti-CD19-CAR T-cell therapy.¹

Patients with R/R DLBCL with a high tumor load did not benefit from PD-1 inhibitors combined with anti-CD19-CAR T cells vs the anti-CD19-CAR T-cell therapy alone. However, patients who had an objective response rate (ORR) in the combination therapy may derive benefit from PD-1 inhibitor maintenance therapy receiving this combination therapy.

These findings come from a case-control study which evaluated 44 patients with R/R DLBCL who had more than 1 evaluable lymphoma lesion larger than 7.5 cm in diameter. These patients were divided into combination and control groups based on preference. A total of 26 patients with R/R DLBCL were assigned to the combination group and given combined treatment with PD-1 inhibitors and anti-CD19-CAR T cells. Then, the other 18 patients with R/R DLBCL were put in the control group where they received anti-CD19-CAR T-cell therapy alone.

Fludarabine at 30 mg/m2/day was given to patients along with cyclophosphamide at 400 mg/m2/day from days −4 to −2 as lymphodepleting chemotherapy. In the combination group, patients were given PD-1 inhibitors, including sintilimab (Tyvyt) at 200 mg on day −1. Additionally, the anti-CD19-CAR T-cell infusion dose was 2 × 106 cells/kg on day 0 in among all 44 patients with R/R DLBCL.

Prior to the study, no patients had undergone hematopoietic stem cell transplant. Investigators evaluated the primary end points of ORR, progression-free survival (PFS), and overall survival (OS). Follow-up took place between the date of anti-CD19 CAR T-cell infusion to the data cut-off date of December 31, 2020, or the date of death.

Among the 44 patients enrolled, all patients had high tumor bulk and at least 1 tumor with a maximum diameter of ≥ 7.5 cm. No differences were noted regarding age, sex, stage, International Prognostic Index scores, or primary line of chemotherapy between the combination and control groups. Further, there was no significant difference in the number of CAR T-cell infusions between the 2 groups (P =.9090).

Eleven patients (42.31%) in the combination group achieved CR, 6 patients (23.08%) achieved PR, and 5 patients (19.23%) maintained stable disease (SD). The other 4 (15.38%) patients had progression of disease (PD). In this group, the ORR was 65.39%.

Then, 7 patients (38.89%) achieved CR, 4 (22.22%) achieved PR, 4 (22.22%) maintained SD, and the 3 (16.67%) achieved PD in the control group. The ORR in this group was 61.11%, noting that there was no significant difference in the ORR between the 2 groups of patients with R/R DLBCL with a high tumor burden (P =.7720).

All 17 patients given the combination who achieved CR and PR received PD-1 inhibitor maintenance therapy after the data of combined treatment with PD-1 inhibitors and anti-CD19-CAR T cells was evaluated. With the following PD-1 inhibitor maintenance therapy, 9 patients who had a CR in their previous combination therapy lived in CR up to the data cut-off date while 2 patients who achieved CR relapsed again and maintained SD after their maintenance therapy up to this date. In 1 of these patients, their disease progressed again 4 months after CR, and progressed 5 months after CR in the other patient.

In the combination therapy group, 2 of the 6 patients who achieved PR survived until the data cut-off date with continued PR. The tumor volume of 1 patient was further reduced by PD-1 inhibitor maintenance therapy, 2 patients relapsed again and maintained SD, and the other 2 patients died of progressive disease.

No patients discontinued maintenance therapy due to grade 3/4 adverse events associated with PD-1 inhibitors. All patients administered the anti-CD19-CAR T-cell therapy recovered from the symptoms of AEs 14-25 days post-infusion.

There were no significant differences in the symptoms between the 2 groups. Two patients in the combination group with grade 3 hematological toxicity and 2 patients with grade 2 hematological toxicity were diagnosed with bacterial infections during their combination therapy. For those in the control group, 2 patients with grade 2 hematological toxicity were diagnosed with bacterial infections during the anti-CD19-CAR T-cell therapy, but none of the patients died due to bacterial infections.

In addition to 4 patients (15.38%) who were diagnosed with grade 3/4 cytokine release syndrome (CRS) in the combination group, another 18 patients were diagnosed with grade 1/2 CRS while receiving combination therapy. In the combination therapy group, immune effector cell–associated neurotoxicity syndrome (ICANS) of any grade was reported in 3 patients (11.54%), including 1 (3.85%) with grade 2 ICANS and the other 2 (7.69%) with grade 1 ICANS.

One patient (5.56%) was diagnosed with grade 3 CRS in the control group, and the other 12 patients were diagnosed with grade 1/2 CRS while receiving the anti-CD19-CAR T-cell therapy. There were 2 patients (11.11%) who had grade 1 ICANS with anti-CD19-CAR T-cell therapy. However, there was no difference in the CRS or ICANS grades between the combination and control groups and none of the patients died of any level of CRS or ICANS during therapy.

While receiving PD-1 inhibitor maintenance therapy, 8 patients reported grade 1 CTCAE, and 3 patients had grade 2 CTCAE. None of the patients discontinued PD-1 inhibitor maintenance therapy due to their AEs.

Further research with a large sample size and continued observation is warranted.

_REFERENCES:

_{Mu J, Deng H, Lyu C, et al. Efficacy of programmed cell death 1 inhibitor maintenance therapy after combined treatment with programmed cell death 1 inhibitors and anti-CD19-chimeric antigen receptor T cells in patients with relapsed/refractory diffuse large B-cell lymphoma and high tumor burden. Hematol Oncol. 2023;41(2):275-284. doi:10.1002/hon.2981}