Challenging DLBCL Cases: Early Relapse and Follicular Lymphoma Transformation

CAR T-Cell Therapy and Bispecific Antibodies in DLBCL

Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with lymphoma experts Matthew Lunning, DO, FACP, of the University of Nebraska Medical Center, and Gilles Salles, MD, PhD, of Memorial Sloan Kettering Cancer Center, for the Oncology Brothers podcast Challenging Cases series. The doctors discussed management of a case of early relapse after frontline therapy and a case of follicular lymphoma transformation to DLBCL. 

CAR T-Cell Therapy for Early DLBCL Relapse

The doctors first discussed the case of a 58-year-old man with no significant comorbidities who was diagnosed with stage IIIA de novo germinal center B-cell-like (GCB) DLBCL. In the frontline setting, he received 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and achieved a complete metabolic response on PET/CT scans at the end of treatment. However, 8 months later, he presented with night sweats, weight loss, and rising lactate dehydrogenase. Repeat imaging identified widespread disease, and repeat biopsy confirmed recurrent GCB subtype DLBCL without MYC/BCL2 alterations or bone marrow involvement.

In patients who relapse within 1 year of completing frontline induction therapy, CAR T-cell therapy is a preferred second-line treatment, Dr. Lunning said. Two CAR T-cell therapies are approved in this setting: axicabtagene ciloleucel (axi-cel), based on the ZUMA-7 trial, and lisocabtagene maraleucel (liso-cel), based on the TRANSFORM trial. Between these agents, Dr. Salles’ group largely uses liso-cel because of its slightly better tolerability compared with axi-cel. If pursuing CAR T-cell therapy for this patient, next steps would be to proceed with leukapheresis and initiate secondary therapies until the CAR T-cell product is ready. 

The goal of secondary therapies is to achieve disease control and debulk the tumor prior to CAR T-cell infusion. Treatment given between leukapheresis and CAR T-cell infusion is called bridging therapy, whereas treatment given before leukapheresis is called holding therapy. Generally, Drs. Salles and Lunning favor polatuzumab vedotin plus rituximab for holding and bridging therapy. If this approach doesn’t achieve a satisfactory response, they may escalate to stronger chemotherapy or incorporate radiation, ideally after leukapheresis is completed. Notably, bendamustine-based regimens should not be used as holding therapy because they may impair T-cell fitness, although they can be used for bridging therapy. 

Follicular Lymphoma Transformation to DLBCL

The second case described a 67-year-old woman who was initially diagnosed with grade 1-2 follicular lymphoma 6 years ago. She first received 6 cycles of bendamustine plus rituximab followed by 2 years of rituximab maintenance, and she achieved a complete response and stayed in remission for 3 years. Four years after her diagnosis, she relapsed with grade 3A follicular lymphoma and received 6 cycles of R-CHOP, which yielded a partial response. At this point, repeat biopsy confirmed a transformation to MYC/BCL2 double-hit, non-GCB DLBCL with TP53 mutation. 

Although this patient may still be a candidate for CAR T-cell therapies, her aggressive transformation calls for rapid, potent intervention, which may complicate the CAR T-cell process, Dr. Salles said. He typically avoids using bispecific antibodies as holding therapy, but this patient requires immediate management to determine if she is even eligible for leukapheresis and CAR T-cell manufacturing. To that end, Dr. Salles suggested starting a bispecific antibody–based regimen with glofitamab or mosunetuzumab.

Outside of this case, emerging data support the use of bispecific antibodies as bridging therapy. Broadly, experience using bispecific antibodies in other diseases, along with improved management of adverse effects, has facilitated greater adoption of bispecific antibodies in community settings. In addition, ongoing trials will help clarify the optimal sequencing of CAR T-cell therapies and bispecific antibodies, Dr. Lunning said.