Novel Agents Replace CAR T-Cell Therapy in Later-Line, Relapsed/Refractory DLBCL

New treatments are emerging for patients with relapsed/refractory diffuse large B-cell lymphoma in addition to chimeric antigen receptor T-cell therapy, which has moved up into the second line.

New treatments are emerging for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in addition to chimeric antigen receptor (CAR) T-cell therapy, which has moved up into the second line. These advances come in the form of alternative CD19-directed antibodies, antibody-drug conjugates (ADCs), and bispecific antibodies, explained Andrew D. Zelenetz, MD, PhD, who provided an overview of available treatments in large cell lymphoma in a presentation during the 40th Annual CFS®.1

Weighing Concerns With Available CAR T-Cell Therapies

Three CD19-directed CAR T-cell products are approved for use in patients with DLBCL following at least 2 prior therapies: axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi).

The 2 acute toxicities that require close monitoring following infusion are cytokine release syndrome (CRS) and immune cell–associated neurologic syndrome (ICANS). The former can present as high fever, hypotension, tachycardia, decrease in protein/albumin, and weight gain; coagulopathy and increased transfusion requirements; elevated aspartate or alanine aminotransferase, bilirubin, alkaline phosphatase, and creatinine; cardiac arrhythmias; and elevated serum cytokines, elevated serum C-reactive protein, and ferritin. The latter often presents with word finding difficulties that can progress to coma and cerebral edema or seizures. Although tocilizumab (Actemra) and corticosteroids can be used to treat CRS, it is not clear whether their activity extends to treatment of ICANS.

Persistent adverse effects (AEs) may include cytopenia, B-cell aplasia, risk of infection, and decline in neurocognitive performance.

“B-cell aplasia is an on-target effect and can result in significant immunosuppression and contributes to the risk of severe COVID-19 in these patients,” said Zelenetz, medical director of quality informatics at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York.

Recognition and early intervention of these toxicities are especially important as these treatments are moved into earlier lines of therapy. All 3 products have been evaluated in the second-line setting, but only axi-cel and liso-cel demonstrated positive results against standard of care (SOC) in the phase 3 ZUMA-7 (NCT03391466) and TRANSFORM (NCT03575351) trials, respectively. Both trials enrolled patients with relapsed or refractory disease within 12 months of frontline therapy.

At a median follow-up of 25 months in ZUMA-7, the median event-free survival (EFS) was 8.3 months with axi-cel vs 2 months with SOC; the median progression-free survival (PFS) was 14.7 months vs 3.7 months, and the overall survival (OS) was not reached vs 35.1 months, respectively.2 With limited follow-up of 6 months in TRANSFORM, the median EFS was 10.1 months with liso-cel vs 2.3 months with SOC; the median PFS was 14.8 months vs 5.7 months, and the OS was NR vs 16.4 months, respectively.3 Notably, grade 3 or higher CRS and ICANS were significantly higher with axi-cel compared with liso-cel, at 6% vs 1% and 21% vs 4%.

“Tisagenlecleucel and liso-cel are better-tolerated drugs than axi-cel; however, with experience we’ve been able to reduce the toxicity of axi-cel,” Zelenetz said.

Both agents received FDA approval for the treatment of patients with LBCL that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy. However, limited access, long-term toxicity, and expense may be prohibitive, Zelenetz explained. He added that high-dose therapy and autologous stem cell transplant, although typically reserved for patients in a PET complete response, could be a suitable option for patients with PET partial response (PR). In a case-matched Center for International Blood and Marrow Transplant Research analysis of CAR T-cell therapy and autologous stem cell transplant, patients in PET PR demonstrated comparable outcomes.4

Alternative CD19-Directed Therapy

For patients who are ineligible for high-dose therapy and transplant, tafasitamab-cxix (Monjuvi) plus lenalidomide (Revlimid) may represent a potential option. The combination was evaluated in the L-MIND trial (NCT02399085) in patients who received 1 to 3 prior treatment regimens.

At a follow-up of at least 35 months, the objective response rate (ORR) was 57.5% (95% CI, 45.9%-68.5%), the median PFS was 11.6 months (95% CI, 6.3-45.7), and the median OS was 33.5 months (95% CI, 18.3-NR).5

“The PFS curve looks a lot like a CAR T-cell curve; however, there is some selection bias in this study for favorable patients and we are awaiting further data with respect to this antibody,” Zelenetz said.

Another available option is loncastuximab tesirine-lpyl (Zynlonta). The agent was approved in April 2021 based on findings from the phase 2 LOTIS-2 trial (NCT03589469). To be eligible for enrollment in the study, patients had to have at least 2 prior lines of therapy. Notably, patients with primary refractory disease were eligible for enrollment, as were patients who received autologous and allogeneic transplant as long as it was more than 30 and 60 days from enrollment, respectively, whereas this population was excluded in L-MIND. 

The ORR was 48.3% (95% CI, 39.9%-56.7%), the median PFS was 4.9 months, and the median OS was 9.9 months.6

“The median PFS is short, though there are some patients who have durable responses. But given the relatively high response rate, it’s not a bad option, potentially, for bridging therapy,” Zelenetz said.

Despite limited experience, data have shown that CAR T-cell therapy following treatment with loncastuximab tesirine may be viable. In a small experience, 10 of 10 tested patients retained CD19 expression following treatment with loncastuximab tesirine and experienced an ORR of 50% (n = 7) with CAR T-cell therapy.7

Another ADC that has been evaluated and approved in the relapsed/refractory setting is polatuzumab vedotin-piiq (Polivy). In the ROMULUS trial (NCT01691898), the agent was combined with rituximab (Rituxan) and displayed a best overall response rate of 56% and a median PFS of 5.5 months (95% CI, 4.3-12.8).8 This trial served as the basis for the randomized phase 2 trial (NCT02257567) evaluating bendamustine plus rituximab (BR) vs polatuzumab vedotin plus BR (pola-BR).

The best overall response rate was 70% with pola-BR vs 33% with BR alone, and the median PFS (HR, 0.31; 95% CI, 0.18-0.55; P < .0001) and OS (HR, 0.35; 95% CI, 0.19-0.67; P = .0008) favored the use of the triplet, at 6.7 months (95% CI, 4.9-11.1) vs 2.0 months (95% CI, 1.5-3.7) and 11.8 months (95% CI, 9.5-NE) vs 4.7 months (95% CI, 3.7-8.3).9 

“If you overlay the results of the ROMULUS trial on the PFS curve from this trial, I would argue that they are completely identical. We simply do not know what’s happening with the bendamustine in this setting. We at MSK pretty much exclusively use polatuzumab vedotin plus rituximab without bendamustine because of the reduced toxicity and retained activity, particularly if you’re using polatuzumab vedotin to position someone to see if they’re going to be eligible for CAR T-cell therapy or even as bridging therapy after you’ve collected CAR T cells,” Zelenetz said.

Bispecific Antibodies in Development

Bispecific antibodies in development include mosunetuzumab, glofitamab, epcoritamab, odronextamab, and IGM-2323. Furthest along in development are glofitamab and epcoritamab, which have shown comparable activity in heavily pretreated patients in phase 1/2 (NCT03075696; NCT03625037) trials.

At a median follow-up of 12.6 months with glofitamab, the ORR was 51.6%, the median PFS was 4.9 months, and the median OS was 11.5 months.10 At a median follow-up of 10.7 months with epcoritamab, the ORR was 63.1%, the median PFS was 4.4 months, and the median OS was not reached.11

In both trials, patients had received a median of 3 prior lines of therapy and 33.1% and 39% of patients received prior CAR T-cell therapy, respectively.

In terms of safety, the rate of grade 3 or greater treatment-related adverse effects was 41.6% with glofitamab; this rate was not reached with epcoritamab. Grade 3 or higher CRS and neurotoxicity was higher with glofitamab and tocilizumab use was more than doubled with glofitamab. However, less than 10% of patients in both trials discontinued treatment because of AEs.

“The overall results seem to be quite similar. The drugs are given in a stepped-up manner to reduce the risk of CRS and ICANS. These drugs are not yet approved for treatment but certainly are promising agents,” Zelenetz concluded.


  1. Zelenetz AD, New landscape for relapsed or refractory (R/R) diffuse large B-cell lymphoma: 2L and beyond. Presented at: 40th Annual CFS®; November 9-11, 2022; New York, NY.
  2. Locke FL, Miklos DB, Jacobson CA, et al; ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
  3. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6
  4. Shadman M, Pasquini M, Ahn KW, et al. Autologous transplant vs chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission. Blood. 2022;139(9):1330-1339. doi:10.1182/blood.2021013289
  5. Duell J, Maddocks KJ, Gonzalez-Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2417-2426. doi:10.3324/haematol.2020.275958
  6. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X
  7. Thapa B, Caimi PF, Ardeshna KM, et al. CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy. Blood Adv. 2020;4(16):3850-3852. doi:10.1182/bloodadvances.2020002587
  8. Palanca-Wessels MCA, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol. 2015;16(6):704-715. doi:10.1016/S1470-2045(15)70128-2
  9. Sehn LH, Kamdar M, Herrera AF, et al. Randomized phase 2 trial of polatuzumab vedotin (pola) with bendamustine and rituximab (BR) in relapsed/refractory (r/r) FL and DLBCL. J Clin Oncol. 2018;36(suppl 15):7507. doi:10.1200/JCO.2018.36.15_suppl.7507
  10. Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥ 2 prior therapies: Pivotal phase II expansion results. J Clin Oncol. 2022;40(suppl 16):7500. doi:10.1200/JCO.2022.40.16_suppl.7500
  11. Thieblemont C, Phillips T, Ghesquieres H, et al. Primary results of subcutaneous epcoritamab dose expansion in patients with relapsed or refractory large B-cell lymphoma: a phase 2 study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract LB2364.