CAR T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most frequently occurring subtype of non-Hodgkin lymphoma. Although curability is high following first-line immunochemotherapy, around 40 percent of patients will relapse or exhibit refractory disease, which dramatically reduces life expectancy. [Best Pract Res Clin Haematol 2018;31:209-216] Despite salvage chemo-immunotherapy and stem cell transplantation, patients with relapsed/refractory (R/R) DLBCL have a dismal prognosis. In the SCHOLAR-1 study, the median overall survival (OS) for refractory DLBCL was 6.3 months, the complete response rate was 7 percent, and the 1-year OS rate was 28 percent. [Blood 2017;130:1800-1808]

CAR T-cell therapies revolutionized the therapeutic landscape
Chimeric antigen receptor (CAR) T-cell therapy is a novel approach to genetically modify a patient’s own T cells to better target and eliminate cancer cells. [Transplant Cell Ther 2023;29:440-448]

“Currently, CAR T-cell therapies approved by the US FDA in the third-line R/R DLBCL setting include axicabtagene ciloleucel (axi-cel), tisagenlecleucel and lisocabtagene maraleucel, which were extensively studied in the ZUMA-1, JULIET, and TRANSCEND trials, respectively,” said Dr Joshua Sasine, a haematology and oncology specialist and co-director of the CAR T Programme at Cedars-Sinai Medical Centre, California, US.

“Overall response rates from these trials ranged from 52 to 82 percent, and complete response rates were from 40 to 54 percent, demonstrating how CAR T-cell therapies have altered the course of chemorefractory DLBCL compared with conventional treatments. [N Engl J Med 2017;377:2531-2544; Lancet Oncol 2019;20:31-42; N Engl J Med 2019;380:45-56; Lancet 2020;396:839-852],” he added.

Notably, axi-cel has the longest follow-up data of about 5 years. In patients treated with axi-cel (n=101), the objective response rate (ORR) was 83 percent, with 58 percent of patients achieving complete response. Median OS was 25.8 months, and the estimated 5-year OS rate was 42.6 percent. There was sustained overall and disease-specific survival, with no new safety signals. The findings support the curative potential of axi-cel in a subset of patients with aggressive BCL. [Blood 2023;141:2307-2315]

On-target effect of CAR T-cell therapies
Despite efficacy in treating R/R DLBCL, CAR T-cell therapies are associated with significant toxicities, primarily cytokine release syndrome (CRS) – which is a systemic inflammatory response that occurs as CAR T cells activate and expand. It is an “on-target effect” of CAR T-cell therapy which means that the T cells are working aggressively to fight the disease.

“CRS occurs days after infusion and is characterized by flu-like symptoms, such as fever, nausea, and fatigue. It can progress to life-threatening hypotension, hypoxia, and death. A high disease burden is associated with more severe CRS,” said Sasine. [Blood 2014;124:188-195; Biol Blood Marrow Transplant 2019;25:625-638]

The other side effect with CAR T-cell therapies is immune effector cell-associated neurotoxicity syndrome (ICANS). “The presentation of ICANS is varied and may manifest as confusion, dysarthria, aphasia, seizures and very rarely, cerebral oedema. The onset of ICANS is usually later than CRS and the symptoms usually last longer than the CRS symptoms,” explained Sasine. [Biol Blood Marrow Transplant 2019;25:625-638]

Mild forms of CRS and ICANS can be managed with appropriate supportive care, while serious adverse events can be effectively managed with established protocols. [Transplant Cell Ther 2023;29:440-448]

“To reduce or preempt treatment-related toxicity, several exploratory safety management cohorts were added to the ZUMA-1 trial,” shared Sasine. “Cohort 4 of the trial showed that earlier intervention with corticosteroids and/or tocilizumab reduced the incidence of grade ≥3 CRS and neurologic events (NEs) compared with later intervention. Cohort 6 showed that prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs, without affecting the efficacy outcomes for axi-cel patients.” [Br J Haematol 2021;195:388-398; Br J Haematol 2021;194:690-700]

Broader application of CAR T-cell therapy in the real world
Patient selection for CAR T-cell therapy is complex and requires consideration of overall fitness, existing comorbidities, organ function, and prior therapies (Table). While product labels and inclusion/exclusion criteria from pivotal clinical trials serve as a guide for patient selection, real-world data support the application of CAR T-cell therapy in broader groups of patients.

“Overall, patient referrals for CAR T therapy in the real-world setting have expanded beyond the strict criteria used in clinical trials and have maintained clinical efficacy while demonstrating improved safety,” Sasine said. “For instance, in the axi-cel commercial experience, >40 percent of the analysed patients would have been ineligible for clinical trial participation. Despite this, the efficacy and safety profile were comparable with ZUMA-1. [Leuk Lymphoma 2020;61:799-807] Notably, transplant-ineligible patients, or those who relapse after ASCT transplantation may be considered for CAR T-cell therapy,” he added.

Early referral of patients if they meet the criteria for CAR T-cell therapy is particularly important, Sasine emphasized. “If patients are referred too late in their disease following multiple lines of therapy, they may no longer be eligible for treatment and enrolment for clinical trials,” he pointed out.

Early referral allows sufficient processing time for approval of treatment, manufacturing time of CAR T cells, and may prevent exposure to additional treatment-related toxicities that may pose challenges to successful delivery of cellular therapy. [Biol Blood Marrow Transplant 2019;25:2305; Leuk Lymphoma 2020;61:799-807]

Case-sharing
Sasine shared a case of a typical CAR T-cell patient in his institution. A 74-year-old man presented with stage IVA DLBCL characterized as double-expresser lymphomas (DEL)/double-hit lymphomas (DHL), high lactate dehydrogenase (LDH), with ECOG performance status 1. He had no CNS involvement but extensive extranodal involvement. His past medical history included stage III chronic kidney disease from hypertension.

Initial treatment included three cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), to which he had a partial response. After relapse, he had one cycle of R-ICE (rituximab plus ifosfamide, carboplatin, and etoposide), leading to a stable disease.

He received CAR T-cell therapy. Grade III CRS occurred on Day +3, and 5 to 6 days later, he developed Grade III ICANS. Both adverse events resolved with treatment. On Day +35, the PET-CT scan showed a complete response, and he remains in remission at Day +155. Though he has prolonged cytopenias, he received appropriate antimicrobial prophylaxis and did not get any infections.