Single-Center Experience with Axicabtagene-Ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel) for Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Comparable Response Rates and Manageable Toxicity
Authors: Buecklein Veit , Blumenberg Viktoria , Ackermann Josephine , Schmidt Christian , Rejeski Kai , Mueller Niklas , Reischer Anna , von Baumgarten Louisa , Schoeberl Florian , Humpe Andreas , von Bergwelt Michael , Subklewe Marion 
Published: November 2020

The CD19 CAR T-cell products Axi-cel and Tisa-cel induce complete responses (CR) in 40-58% of patients (pts) with relapsed/refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL). However, treatment can be associated with significant toxicity, with Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) as the most prominent and specific adverse events of CAR T-cell therapy. Toxicity profiles differ between both commercially available products, mainly due to their divergent co-stimulatory domain (4-1BB in Tisa-cel vs. CD28 in Axi-cel).

Here, we report our single-center experience of DLBCL patients treated with Axi-cel or Tisa-cel at the LMU Munich University Hospital between January 2019 and June 2020. Toxicities, response rates and survival of DLBCL patients were retrospectively assessed.

As of June 2020, 48 patients were enrolled for CD19-CAR T-cell therapies at our centre, and 37 DLBCL patients (pts) were apheresed. Median time interval between apheresis and CAR T-cell treatment was 39 days. So far, 31 DLBCL pts were transfused (Axi-cel: 18, Tisa-cel: 13). Median age of transfused pts was 60 years (range 19-74, Axi-cel: 60 years, Tisa-cel: 60 years). ECOG was 0-1 in 19 and 2-3 in 12 pts at time of CAR T-cell transfusion (Axi-cel: 0-1 in 13 and 2-3 in 5 pts, Tisa-cel: 0-1 in 6 and 2-3 in 7 pts). 13 pts had undergone prior stem cell transplant (9 autologous, 3 allogeneic, Axi-cel: 4 auto, 2 allo; Tisa-cel: 5 auto, 1 allo). Median number of prior DLBCL therapy lines was four (range 2-9, Axi-cel: 4, Tisa-cel: 4). Only 9/31 pts (29%) met the inclusion criteria of the pivotal clinical trials (due to e.g. infection, CNS disease, thrombocytopenia) at time of enrolment into our CAR T-cell treatment program. 23 pts (74%) received bridging chemotherapy (Axi-cel: 13/18 pts [72%]; Tisa-cel: 10/13 [77%]).

Further details on radiographic response and the incidence of toxicities for all treated pts are summarized in the accompanying table. Response assessment after three months using PET/CT was available for 28 pts. Objective response rate (ORR) was 46%, with CR in eight (28%) and partial remission (PR) in five pts (18%). CRS occurred in 29/31 pts (84% CRS °1-2, 10% °3). Tocilizumab was applied in all CRS pts, with a median of four total infusions (range 1-4). 16 pts (52%) developed ICANS (33% °1-2, 16% °3-4, and 3% °5), which was managed with steroids in 9/16 pts. With a median follow-up of seven months, median progression-free survival (PFS) was 2.4 months for all pts. PFS was significantly longer for pts with normal vs. elevated LDH at time of apheresis (not reached vs. 1.5 mo, p=0.031). PFS of patients with two prior lines of therapy (n=7) was comparable with pts with three (n=5) or more (n=15) lines (2 lines: 3.1 mo, ≥3 lines: 1.9 mo, p=0.520). The time interval of ≤ 12 months (n=8 pts) from initial diagnosis of DLBCL to CAR T-cell transfusion was not prognostic and did not identify patients with worse PFS (≤12 mo: 1.7 months, &gt;12 mo: 2.8 mo, p=0.569).

In summary, in our cohort of heavily pretreated patients with a median of four prior DLBCL therapy lines, we observed an ORR of 46% (28% CR) at 3 months after CAR T-cell therapy, with no significant differences between patients treated with Axi-cel and Tisa-cel. In line with results of the pivotal clinical trials, treatment with Axi-cel was associated with a moderately higher incidence of ICANS. Overall, CAR T-cell toxicities were well manageable.

Normal LDH levels at time of apheresis identified patients with high probability of sustained remission. In contrast, the number of prior therapy lines or the time interval from initial diagnosis of DLBCL to CAR T-cell transfusion had no impact on PFS. These hypothesis-generating findings might be helpful for future clinical decision-making, but need to be confirmed in a larger cohort. Therefore, we have set up a comprehensive patient monitoring program to identify predictive clinical and immunological markers of response and survival in CAR T-cell treated DLBCL patients. We will present updated results with longer follow-up at the annual meeting.

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Disclosures

Buecklein: Celgene: Research Funding; Pfizer: Consultancy; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy. Blumenberg:Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding. Subklewe:Seattle Genetics: Research Funding; Morphosys: Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding; AMGEN: Consultancy, Honoraria, Research Funding.