Lenalidomide Enhance CAR T-Cells Response in Patients with Refractory/Relapsed Large B Cell Lymphoma Experiencing Progression after Infusion

Background. Anti-CD19 Chimeric Antigen Receptor (CAR) T-cells is a major therapeutic advance in the management of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, some patients will experience progression or relapse after infusion. Treatment of these relapses or progressions is not standardized and is usually based on strategies that will avoid the destruction of the CAR T-cells, such as immuno-oncology drugs. Lenalidomide is reported to activate CD8 T cells, inhibit regulatory T cells and restore T-cell immune synapse. We report here our experience of Lenalidomide in the treatment of progression or relapse after CAR T-cells infusion.

Methods. Between June 2018 and July 2020, 111 patients with R/R DBLCL were treated with commercialized anti-CD19 CAR T-cells, axicabtagene ciloleucel (axi-cel yescarta) (n=60) or tisagenlecleucel (Tisa-cel kymriah) (n=51). Relapse and progression after CAR T-cells was defined based on the Cheson 2014 criteria. Efficacy of the treatment proposed at time of relapse post-CAR T-cells was assessed by CT scan and 18FDG-PET after the 1st cycle and at the end of treatment. CAR-T expansion was regularly monitored in blood by flow cytometry.

Results. In the whole cohort, the clinical characteristic was a median age at 61.9 (range 23 to 77), male n=73 (66%). Histology subtypes were DLBCL (n=90) (including GC n=39 and non-GC n=37), PMBL (n=6), Tr FL (n=15). 85 (76.6%) patients presented a primary refractory lymphoma. IPI included 30 low risk, 23 low-intermediate, 23 high-intermediate and 14 high risk. The median number of lines of treatment before CAR T cells infusion was 3 (IQR, 2 to 4) ranging from 1 to 9. At time of infusion, median total metabolic tumor volume (TMTV) was 52.4 (IQR, 12.1 to 170.1), ranging from 1.44 to 4247.

Fifty-nine patients failed after Tisa-cel (n=33) of Axi-cel (n=26) infusion. Failure occurred after CAR T-cell within a median time of 6 months; 16 (27%) of the failures occurred before day 15 (D15), 27 (45.8%) during the first month after infusion (<M1), and 45 (76.3%) during the first-3 months after infusion (<M3). At failure, the patients received lenalidomide (LEN) (n=41, 69.5%) with (n=30) or without (n= 10) rituximab (R) or Obinutuzumab (O) (n=1); immune-checkpoint inhibitor including Pembrolizumab (n=2); BTK inhibitor (n=1); BET inhibitor (n=1); chemotherapy or immune-chemotherapy (n=3); radiotherapy (n=2). Six (10.2%) patients received palliative care only and three (5.1%) patients died before receiving further treatment. The best overall response rate was observed in 16 (27.1%) of the patients, including best complete response in 9 and best partial response in 7; 35 progressed. The median progression-free survival was 101 days, and the median overall survival 225 days. Considering the cohort of patients who received LEN, the 11 patients who started LEN+/-R or O before D15 post-CAR T-cell infusion (group ≤D15) experienced a higher ORR (7/11, 63.6% vs 9/48, 18.8%, p=0.006), and a higher CR rate (4/11, 36.4% vs 5/48, 10.4%, p=0.05). In univariate analysis, the 6 evaluable patients with early LEN (≤D15) had a higher CART expansion in blood during the first 28 days (median AUC D0-D28=1363 days*CART Cells number/µL of total blood) than other relapsing patients (median=97, p=0.042), including those treated with LEN after D15 (median=56, p=0.033), or even than patients without relapse (median=277, p=0.069).

Conclusion. LEN used at time of relapse post-CAR T-cell may provide high response rate, particularly in patients receiving LEN early after infusion. Comprehensive analyses of the anti-tumoral effect, but also an immunomodulatory effect mechanisms using tumor transcriptomic and single cell analyses will be presented.