Multi-Centre Real-World Outcomes of Large B-Cell Lymphoma Patients Treated with 2L Axicabtagene Ciloleucel in the UK

Background
After approval of axicabtagene ciloleucel (axi-cel) as second-line (2L) treatment for large B-cell lymphoma (LBCL) relapsed or refractory within 12 months of first-line (1L) chemoimmunotherapy (CIT), access to 2L axi-cel in the UK was granted in May 2023. Here, we present outcomes of patients intended to be treated with axi-cel in the 2L setting through the National UK CAR T programme.

Methods
Consecutive patients approved for standard-of-care axi-cel by the UK National CAR T Clinical panel (NCCP) between May 2023-March 2024 across 15 commissioned CAR T centres were included. 221 patients were approved for 3L axi-cel, 210 were approved for 2L treatment and are the focus of this analysis.

Results
Of 210 patients approved for 2L axi-cel (intent-to-treat (ITT) cohort), data were available for 181 at the time of abstract submission (results of the full cohort will be provided at the meeting). Of 181 approved patients, 175 (97%) underwent leukapheresis, 164 (91%) were infused. Median time from approval to infusion was 49 days (IQR 42-58), with a median vein-to-vein time of 35 days (IQR 33-44.5).

In the ITT cohort, median age was 61 years (range 22-76), 11.2% were from ethnic minority background. LBCL subtypes were de novo diffuse large B-cell lymphoma NOS in 71.3%, high-grade B-cell lymphoma in 9.3%, and transformed follicular lymphoma in 11.6%. At the time of CAR T approval, 74.7% had advanced stage disease, 33.0% extranodal involvement of ≥2 sites, 61.7% elevated LDH and 25.7% bulky disease. 1L CIT was R-CHOP in 70.7% and polatuzumab-R-CHP in 16.0%. 12.7% of patients had received consolidation radiotherapy (RT).

Disease status after 1L CIT was complete metabolic response (CMR) in 28.7%, partial response (PR) including those with biopsy-proven disease persistence in 28.1%, stable disease in 0.6% and progressive disease (PD) in 42.7% (20.8% primary progression, 21.9% PD vs interim PET scan). The time interval from 1L CIT to axi-cel approval was at the end of 1L treatment in 57.2%, within 3 months in 18.3%, between 3-6 months in 10% and 6-12 months in 14.4%.

Pre-apheresis holding therapy was required in 42% of approved patients with majority receiving systemic CIT. Post-apheresis bridging therapy (BT) was given in 97% (systemic BT 67.4%, RT 21.4% and combined modality treatment 8.1%). The most common BT regimens were R-GDP (48.1%) and R- bendamustine/polatuzumab (32.6%). Overall response rate (ORR) to BT was 50.7% (14.2% CMR). Pre-lymphodepletion (LD), 50% had elevated LDH and 34.6% had a CAR-HEMATOTOX score of ≥2. Visually assessed pre-LD total metabolic tumour volume (TMTV) was <100 ml in 56.8%, 100-300 ml in 27.7% and >300 ml in 15.5%.

The best ORR after CAR T infusion was 85.2% (57.8% CMR). With a median follow-up of 6.9 months from approval in the ITT population, median overall survival (OS) has not been reached, with a 6-month OS of 86.7% (95%CI: 79.5 – 91.5) for infused patients and 20.0% (95%CI: 3.8 – 45.2) for patients not infused. Median progression-free survival (PFS) of infused patients was 8.4 months (IQR: 2.9 – NR) with a 6-months PFS of 57.9% (95%CI: 48.2 - 66.4%). Factors associated with inferior PFS included requirement of holding therapy, lack BT response, pre-LD elevated LDH and visually assessed TMTV of >100 ml.

Any grade CRS and ICANS were seen in 97.6% and 44.5% with grade ≥3 in 4.3% and 17.1%, respectively. 90.2% of patients received tocilizumab, 60.4% corticosteroids and 18.4% anakinra. 19.9% required ICU admission. Grade ≥3 ICAHT (Immune Effector Cell-Associated Hematotoxicity) was seen in 29% of patients at 1 month. The non-relapse mortality rate at 6 months was 4.0%.

Conclusion

This large national real-world cohort of LBCL patients intended to be treated with 2L axi-cel provides valuable insights into patient selection, management and outcomes for this new standard-of-care indication in daily practice. Response rates observed in our cohort are comparable to those reported in the ZUMA-7 trial. With limited follow-up at the current time, PFS and OS are encouraging despite 42% patients requiring urgent pre-apheresis holding therapy and 97% receiving post-apheresis bridging therapy, neither of which were permitted in the ZUMA-7 trial. Updated survival analyses will be provided at the meeting.