Checkpoint Inhibition before Axicabtagene Ciloleucel Cell Therapy in Primary Mediastinal B-Cell Lymphoma (PMBCL) Treated in Real Life Setting

Background: Eighty-five percent of PMBCL are cured by standard therapy, but the outcome of refractory/relapsed (R/R) PMBCL is very poor. Checkpoint inhibitors (CPIs) have shown promising activity in relapsed PMBCL. Axibactagene ciloleucel (axi-cel) CAR-T cell therapy, can induce durable responses and is currently approved for the treatment of adult patients with R/R PMBCL.

Aims of this analysis were:

1. to register all Italian PMBCL patients candidate to CAR-T in the 6 active centers;

2. to evaluate the intention to treat overall response rate (ORR, complete [CR] and partial response [PR]) in patients treated with axi-cel and CPIs for salvage or bridging before CAR-T and for relapse after CAR-T;

3. to evaluate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

Methods: In August 2019 the Italian Drug Agency (AIFA) approved axi-cel; before the reimbursement by AIFA, an expanded access program supported by Kite/Gilead started. One patient slot per month per qualified center was available. Patients were included in a large national CAR-T prospective observational study approved by ethics committees.

Results: Since April 2019 to March 2020, 20 R/R PMBCL were evaluated and 18 were apheresized in order to receive axi-cel; 2 were excluded because active CNS disease in one, and eligibility to transplant, while in CR, in the second one. Their clinical characteristics were: median age 38 years (range 22-50), male 8 (44%), stage II 6 (33%), advanced stage III/IV 12 (66%), bulky disease 6 (33%); LDH upper than normal 3 (2%). Median number of prior lines was 3 (2-6); 5 patients (28%) had a previous autologous stem cell transplant and 12 (66%) received a prior radiotherapy. The majority of patients, 16 (89%) were refractory to the last treatment when they were evaluated for CAR-T eligibility; 9 of 18 patients had CPI exposure before leukoapheresis: 6 pembrolizumab and 3 nivolumab in combination with brentuximab-vedotin. No manufacturing failures were reported. Bridging therapy was performed in 16 of 18 patients (88%). Seventeen patients (94%) received lymphodepleting Flu-Cy chemotherapy and only 16 pts received CAR-T for central nervous system (CNS) progression during bridging therapy (n=1) and respiratory failure due to pneumonia (n=1); the 2 patient not infused were exposed to CPIs. Median vein to vein time was 40 days (30-79). Median follow-up time for infused patients was 209 days (9-444). CRS was observed in 12 of 16 infused patients: 5 grade 2 and 7 grade 1. ICANS (2 grade 1, 2 grade 2, 1 grade 3) was recorded in 5 patients. No differences regarding CRS and ICANS occurrence were observed in patients exposed or not to CPIs. At 30-days after the infusion, all the 16 infused patients were evaluable for response: 7 (44%) CR, 5 (31%) PR, with ORR 75%, 3 (19%) stable disease (SD) and 1 (6%) progressive disease (PD). Two patients in PR at 30 days converted to CR at 90 days, with continuous CR at 180 days; all the 3 patients in SD and 1 out of 5 in PR at 30 days progressed at 90 days. Considering the 9 patients exposed to CPIs before CAR-T, 7 out of 9 were infused and all the 7 infused were evaluable for response: 2 (29%) CR, 4 (57%) PR, with ORR 86%, and 1 (14%) died because of a rapid CNS progression after infusion. Two patients in PR at 30-days converted to CR at 90-days, one with continuous CR at 180 days after CAR-T.

Conclusions: In our series of 16 infused patients, axi-cel was effective with an ORR of 75% (CR 44%) at 30-days after CAR-T infusion and ORR of 54% (CR 46%) in the 13 patients evaluable at the median follow-up time (180-days after CAR-T infusion). It is important to note the 4 patients from the original real life cohort never received axi-cel. It is noteworthy that ORR was 86% in patients receiving CPIs before CAR-T and 75% in those not exposed to CPIs. With the limitation of small number, the exposure of immune-checkpoint inhibitors seems not to affect negatively response rate and adverse events.