Treatment Outcomes in Patients with R/R CNSL in the Era of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Background:

The prognosis of refractory/relapsed central nervous system lymphoma (R/R CNSL)is extremely poor, especially for the patients who failed to High-dose(HD) MTX and/or BTK inhibitors in the chemotherapy(Chemo) era.Treatment outcomes in the Chimeric Antigen Receptor T-cell (CAR-T) therapy era are inconclusive.

Aims:

We comparatively analysed the efficacy and survival of R/R CNSL patients in subsequent regimen including Chemo,CAR-T,autologous transplantation(ASCT) or ASCT combined with CAR T-cell therapy.

Methods:

From September 2021 to March 2024, 131 patients from Beijing GoBroad Hospital were enrolled.The median age was 54(23-75)years old. The cohort included 66/131(50.4%) secondary CNS involvements such as 57 DLBCLs, 5 tFL, 4 PMBL, alongside 65/131(49.6%) primary CNS lymphomas (PCNSLs).95/131(72.5%) were parenchymal involved, 12/131(9.2%) were CNS involved, 24/131(18.3%) were both. According to the IELSG risk score, 43/65(66.2%)of patients with PCNSLs were at intermediate or high risk.The disease status was progressive disease in all patients who failed to multi-line therapies, including HD MTX(89/131,67.9%)and BTK inhibitors(73/131,55.7%).TP53 mutations was determined in 48/131 patients with 12/48 (25%) positive result by NGS.

In order to further reduce the tumor burden, all patients were treated with bridging therapy before subsequent regime.HD MTX-based remains the treatment for patients who have had effective prior MTX therapy and have been in remission for more than 6 months;MTX-resistant or in remission for less than 6 months with other chemotherapeutic agents including cytarabine, thiotepa,pemetrexed and BTKi (no previous BTKi exposing). Efficacy was assessed after 2 courses of bridging therapy, and subsequent treatment strategies were selected based on efficacy.

Results

The median follow-up time was 13.5 (range 1.55-50.2) months.The 2-year PFS was 0.40% and OS was 0.49% for the overall population, respectively.

There were 79/131(60.3%) patients achieve objective response rate (ORR)(CR=56;PR=23) from bridging therapy.2-year OS rates were 60% vs. 25% (P<0.001), and 2-year PFS rates were 55% vs. 12% (P<0.001) for bridging therapy effective and ineffective group, respectively.

Of the patients with effective bridging therapy, 16/79 (20.3%) received Chemo, 16/79 (20.3%) received CAR-T, 22/79 (27.8%)received ASCT and 25/79 (31.6%) received ASCT in combination with CAR-T therapy.

In the 77/79 (97.5%) patients evaluable for disease response after subsequent treatment,the ORR (CR) for Chemo was 40% (26.7%), the 2-year PFS was 0% and the 2-year OS was 13.5%.The ORR (CR) for CAR-T was 81.3% (75%), the 2-year PFS 30%,the 2-year OS 62%, and the ORR (CR) for ASCT was 85.7% (81%), the 2-year PFS 72%, and the 2-year OS 73%.The ORR (CR) was 92% (92%) for ASCT in combination with CAR-T therapy.The 2-year PFS was 66% and the 2-year OS was 69%.

In comparison, PFS was higher in the ASCT and ASCT combined with CAR-T than in the CAR-T cohort and significantly higher than in the Chemo group (p<0.001).

Patients with ineffective bridging therapy received subsequent therapy, including Chemo in 17/52 (32.7%) patients, CAR-T in 20/52 (38.5%), radiotherapy followed by CAR-T in 15/52 (28.8%).

In the 49/52 (94.2%) patients evaluable for disease response after subsequent treatment,the ORR(CR) for Chemo was 6.3% (6.3%), 2-year PFS 0%, 2-year OS 10%.The ORR(CR) for CAR-T was 40% (25%), the 2-year PFS 20%, the 2-year OS 27%.ORR(CR) was 73.3%(66.7%)for radiation followed by CAR-T, 2-year PFS was 39.0%, 2-year OS was 56%.

In comparison, PFS was higher in the cohort with radiation followed by CAR-T than in the other cohort (p=0.07).

In the MVA for all patients, significant factors for prolonged OS were low IELSG risk score(p=0.0328),effective bridging therapy (p=0.0161), CAR-T cell tharepy(p=0.0141),radiation therapy followed by CAR-T(P=0.0287) and ASCT combined with CAR -T (p=0.0222) .Significant factors for prolonged PFS were low IELSG risk score(p=0.0040),effective bridging therapy (p=0.0291), and ASCT combined with CAR-T (p=0.0129) .

Conclusion:

CAR-T cells therapy are an effective strategy for R/R CNSL.Consolidation with ASCT combined with CAR-T after effective bridging therapy significantly improves PFS in R/R CNSL.Radiation followed by CAR-T shows a promising remission rate and OS rate in patients with multi-drug resistant R/R CNSL and warranting further investigation.