Point-Counterpoint
Chimeric Antigen Receptor T Cells: The Preferred Second-line Therapy for Relapsed/Refractory Large B-cell Lymphomas

Chimeric antigen receptor (CAR) T cells are the optimal second-line therapy for the vast majority of patients with relapsed/refractory (R/R) large B-cell lymphomas (LBCLs).

The preferred treatment for R/R diffuse LBCL, known by its acronym DLBCL, has long been second-line chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) for patients with chemosensitive disease. Unfortunately, this historic standard cures only a small fraction of patients in the modern era. Today, most patients who relapse or progress after frontline chemoimmunotherapy do so within one year of initial treatment, and the likelihood of a successful outcome with ASCT is extremely poor.^1,2  In fact, the majority of patients intended for ASCT never make it to transplant in the first place due to lack of chemosensitive disease. Stated another way, many are called, but few are chosen, and this is only considering transplant-eligible patients.

Given that the median age at DLCBL onset is in the late 60s, 50 to 60% of patients with R/R disease are not eligible for transplant and thus require alternate second-line and later therapies that offer curative intent. Considering transplant eligibility, chemosensitivity, and ASCT outcomes, the likely cure rate for ASCT in patients with second-line DLBCL today is less than 10%. What other option is there for both transplant-eligible and transplant-ineligible patients?

Two well-designed randomized trials evaluated the longstanding standard of care (SOC) compared with CAR T cells as second-line treatment for LBCL in patients with primary refractory disease or relapse within 12 months.^3,4  Both axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) proved substantially better than the SOC arms in terms of complete response rate, event-free survival, progression-free survival, quality of life, and even overall survival. In short, CAR T cells cured more patients than the historic standard of chemotherapy with or without ASCT.

What about transplant-ineligible patients, for whom curative options have been historically unavailable? Another phase II trial evaluated liso-cel as second-line therapy for transplant-ineligible patients with R/R LBCL, regardless of their duration of initial remission.⁵  Efficacy and cure rates were similar to those observed in the randomized trial, with an acceptable safety profile in an older, frailer patient population than included in the randomized trials. These data suggest that CAR T cells (either axi-cel or liso-cel) are the preferred second-line treatment for any patient with R/R LBCL within one year of initial chemoimmunotherapy, as well as for any transplant-ineligible patient who is eligible for CAR T-cell therapy (liso-cel preferred in this population). This leaves only a small minority of patients with R/R LBCL who should still be intended for second-line ASCT in the modern era: young/fit transplant-eligible patients who experience relapse more than one year after frontline chemoimmunotherapy. If patients in this small subgroup progress despite second-line chemotherapy with or without ASCT, then CAR T cells remain available as a third-line treatment option with curative intent.^6,7 

The data support the use of CAR T cells as the preferred second-line therapy for the vast majority of patients with R/R LBCL in the modern era, regardless of transplant eligibility. Access to care remains a major barrier given that CAR T cells are typically only available at large academic medical centers and are thus harder to access for patients in rural communities. This represents a huge limitation for much of the U.S. population. Bringing these transformational therapies closer to where patients live is therefore imperative.

Dr. Abramson has reported consulting activity for AbbVie, BMS, Genentech, Gilead, Novartis, and Roche.