Standard first-line therapy for aggressive B-cell lymphoma includes upfront R-CHOP, which achieves a cure in approximately 60% of patients. For the remaining 40% who relapse or who have progressive disease, if they are fit, the treatment algorithm is to give salvage second-line therapy with the intent of autologous stem cell transplantation. If they are not fit, our treatments are more limited; thus, one of the continuing needs is to further improve available effective therapies for individuals who, prior to chimeric antigen receptor (CAR) T-cell therapy, had incurable, relapsed, aggressive B-cell lymphoma. In addition, we continue to explore different ways to improve upfront therapy without increasing toxicity.

With regard to high-risk disease, there is the ongoing question of how to optimize the approach to double-hit and triple-hit lymphoma treatment. Historically, this has been a challenging group to treat, as many of these patients respond dramatically to initial chemoimmunotherapy, only to relapse with their disease, with its intact antiapoptotic pathway. Retrospective studies have shown that there is little value in going back to high-dose chemotherapy for these patients, nor is there great value in high-dose chemotherapy consolidation with the use of autologous stem cell transplantation if they have already received intensified chemotherapy (eg, hyper-CVAD or EPOCH-R). So, the focus switched for the double-hit lymphomas to immune therapy such as allogeneic transplantation. And, with the advent of CAR T-cell therapy, the following question arises: What is the value of such cellular immunotherapy in double-hit lymphoma?

The approval of one such therapy, axicabtagene ciloleucel (axi-cel), was based on the pivotal ZUMA-1 study, which included adults with relapsed/refractory large B-cell lymphoma who received 2 or more lines of systemic therapy. While this study had a limited number of patients with double-hit lymphoma, the real-world analysis by Nastoupil et al published in the Journal of Clinical Oncology included 64 patients with double-/triple-hit lymphoma, confirming the feasibility of axi-cel outside of clinical trials. The overall safety and efficacy were comparable to that of ZUMA-1. 

Here at ASH 2020, in abstract 405, Neelapu and colleagues presented the interim analysis of ZUMA-12, a phase 2 study of axi-cel as part of a first-line approach in patients with high-risk large B-cell lymphoma. High-risk disease was defined as an International Prognostic Index score of 3 or higher or double- or triple-hit lymphoma by fluorescent in situ hybridization and positive interim positron emission tomography (ie, Deauville positron emission tomography score of 4 or 5) after 2 cycles of chemoimmunotherapy. As of August 25, 2020, 32 patients were treated with axi-cel, 53% of whom had double-hit or triple-hit status. The best objective response rate was 85% and the best complete response (CR) rate was 74%. At data cutoff, 70% of patients had an ongoing response. The findings from this study contribute to our understanding that, in patients with high-risk recurrent lymphoma or persistent disease after induction, consideration for CAR T-cell therapy is supported. 

Another need is that of less toxic regimens for patients who are frail and/or older and with treatment-limiting comorbidities. Currently, we may offer them rituximab with lenalidomide, or mini-CHOP, or a reduced-dose upfront induction treatment. And so, there is interest in whether immune therapies such as CAR T-cell therapy or perhaps bispecific antibodies in combination with CHOP might offer higher rates of response in these patients. 

What is the potential downside of T-cell–engaging bispecific antibodies? Well, one cannot predetermine or select which T-cell population will be engaged inside the body. And then, there are circulating protective polyclonal antibodies already in the body that may interfere with this type of interaction, including, potentially, persistent rituximab. 

Mosunetuzumab is a novel CD20/CD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells. As reported in abstract 1184, a total of 36 patients with newly diagnosed diffuse large B-cell lymphoma were treated with mosunetuzumab combined with CHOP, and the overall response rate (ORR) was 96% among the 27 patients who received the M-CHOP (mosunetuzumab plus CHOP) regimen, with 85% of patients achieving a CR. Historically, ORR with CHOP induction was approximately 50%, and ORR improved to approximately 60% by adding rituximab. A second related phase 1/2 study was reported in abstract 401, where single-agent mosunetuzumab was tested in 29 elderly patients (most of whom were >80 years of age), showing manageable toxicities and 63.5% ORR and 45.5% CR. So, based on these preliminary data, this novel concept of replacing rituximab with mosunetuzumab appears to be a reasonable approach; however, the long-term benefits of this approach remain to be seen.

As we look to improve upon 60% CR rates with upfront induction therapy for aggressive large cell lymphoma, I believe an important goal is to achieve this without increasing toxicity. In the phase 3 PHOENIX study, patients younger than 60 years who received ibrutinib with R-CHOP had improved progression-free survival and overall survival compared with those receiving R‐CHOP alone; however, the addition of ibrutinib increased toxicity and compromised the delivery of R‐CHOP in those older than 60 years. Previously published data indicate that acalabrutinib, a second-generation Bruton tyrosine kinase inhibitor, may be associated with a lower risk for atrial fibrillation and major bleeding adverse events. In abstract 1185, 24 patients with diffuse large B-cell lymphoma received the phase 2 dose for acalabrutinib of 100 mg twice daily, and age did not compromise the delivery of full-dose R-CHOP in combination with acalabrutinib. At 12-month follow-up, the ORR in 22 evaluable patients receiving the phase 2 recommended dose was 95%, with 82% of patients achieving a metabolic CR. Progression-free survival and overall survival for the patients who received the recommended dose was 100%. The most common adverse events were low blood counts, which is expected with R-CHOP chemotherapy, with febrile neutropenia reported in 13% of patients. The authors concluded that the combination of acalabrutinib and R-CHOP did not increase toxicity and may be associated with improved efficacy. I look forward to the results of a randomized clinical trial that explores the effectiveness of these novel induction combination therapies.