Beijing GoBroad Boren Hospital: What You Need to Know About CAR-T for Relapsed/Refractory DLBCL

For patients with diffuse large B-cell lymphoma (DLBCL) resistant to the R-CHOP regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone), long-term survival remains poor regardless of clinical stage or genetic risk. Novel therapies are urgently needed to improve outcomes for these relapsed/refractory patients.

1. Clinical Trials of CAR-T for R/R DLBCL

CAR-T therapy has achieved remarkable success in relapsed/refractory acute lymphoblastic leukemia and delivers promising efficacy for DLBCL. Key global landmark trials:

ZUMA Trial

The earliest pivotal CAR-T trial for R/R DLBCL, using CD19-targeted CAR-T with a CD28 costimulatory domain. The ZUMA series has advanced to ZUMA 9 and real-world research, enrolling over 295 patients. Key findings: CD28-based CAR-T triggers rapid, severe cytokine release syndrome (CRS); 32% of patients required ICU admission for CRS. Re-administering identical CAR-T cells to partial-response (PR) patients failed to boost efficacy.

JULIET Trial

A global multicenter trial using CAR-T with a 4-1BB costimulatory domain, which showed milder adverse reactions than CD28-based constructs.

Outstanding challenges remain for CAR-T in R/R DLBCL: optimal timing of intervention, higher complete remission (CR) rates, long-term disease control after remission, and standardized management of CRS toxicity.

2. CAR-T Outcomes for Lymphoma and Myeloma at Our Adult Lymphoma Department

Our team runs multiple immunotherapy programs: CD19 CAR-T for R/R B-cell malignancies, sequential CD19/CD22 CAR-T for R/R DLBCL, and BCMA CAR-T for relapsed/refractory multiple myeloma.

Patient Profile

Treated patients include DLBCL, Burkitt lymphoma, follicular lymphoma and multiple myeloma, mostly stage III/IV and heavily pretreated (average 10 chemotherapy cycles). Many relapsed after autologous stem cell transplantation or prior CAR-T elsewhere, presenting with progressive disease and high clinical difficulty at admission.

Therapeutic Efficacy

Early CR rate reaches 64%, with an overall response rate around 70%. Multiple myeloma achieves superior outcomes; heavily pretreated, rapidly progressive DLBCL and Burkitt lymphoma show suboptimal responses.

Safety Profile

Overall CRS incidence around 80%; 70% grade I-II, only 13.20% severe grade III-IV. Median CRS onset at day 5 (range 1-11).

Representative Case Reports

Case 1: Diffuse Large B-Cell Lymphoma

Non-germinal-center DLBCL, stage IVB. The patient achieved PR after 4 cycles of R-CHOP, then complete remission after R2-CHOP and autologous stem cell transplant, maintained with lenalidomide consolidation. Three months before admission, a recurrent abdominal mass (6.7 x 8.4 x 7.1 cm), bilateral pulmonary and left renal nodules developed. GDP chemotherapy failed to control progression, accompanied by fever, emaciation, jaundice, partial intestinal obstruction and gastrointestinal hemorrhage.

Direct CAR-T infusion carried high risks of massive GI bleeding and severe pulmonary CRS. We first controlled hemorrhage and obstruction with debulking conditioning chemotherapy, then administered murine CD19 CAR-T with standardized CRS supportive care. All symptoms resolved after infusion; PET-CT at day 60 confirmed full clearance of the primary lesions.

Case 2: Multiple Myeloma

An elderly man with a 10-year history of IgG-Kappa multiple myeloma. He attained CR after PAD/VAD chemotherapy and autologous transplant, maintained with lenalidomide plus 8 cycles of CIK cell therapy. The disease later progressed despite multiple lines (PCD, PRD, chidamide, carfilzomib, anti-CD38 monoclonal antibody, pomalidomide). A lumbar extramedullary plasmacytoma developed, complicated by pulmonary fungal infection and coronary stent implantation. Admission tests revealed 52% abnormal plasma cells in bone marrow, 14.85% BCMA-positive plasma cells, plus TP53/KRAS mutations.

We administered reduced-dose conditioning chemotherapy and split BCMA CAR-T infusion on day 1 and day 14 to mitigate toxicity. Only grade 1 fever occurred as CRS. At day 30 and 46 after infusion, IgG levels normalized, bone marrow plasma cells turned negative, and PET-CT showed full resolution of the extramedullary lesions.

Key principles from our practice:

• Individualized debulking regimens for patients with high tumor burden before CAR-T infusion.
• Combined and sequential multi-target CAR-T strategies to enhance efficacy.
• Standardized minimal residual disease (MRD) monitoring to guide post-remission maintenance.