Diffuse large cell lymphoma (DLBCL), a highly aggressive malignancy, is the most common type of non-Hodgkin lymphoma worldwide, with an annual incidence of 5.6 cases for every 100,000 men and women. Since 2006, the standard of care (Soc ) in the first-line setting has been the chemoimmunotherapy regimen R-CHOP, consisting of rituximab, three chemotherapy drugs (cyclophosphamide, doxorubicin and vincristine), and a glucocorticoid (either prednisone or prednisolone). While this therapy is curative for around 60% of patients, the remaining 40% experience disease that is refractory to or relapses after the initial therapy.

Historically, the outlook for these patients was poor, with the only chance of cure being intensive salvage immunochemotherapy, followed by high-dose chemotherapy and an autologous stem cell transplant (ASCT) in those that respond to the salvage chemotherapy. Due to age and comorbidities, only about half of relapsed/refractory (R/R) patients are eligible for transplant, and of those who do have a transplant, only an estimated 25% derive any long-term clinical benefit.

Big changes in this disease landscape began in 2017 with the US FDA’s approval of the first CD19-targeting CAR-T cell therapy, Gilead’s Yescarta (axicabtagene ciloleucel), for R/R disease in patients who had received at least two lines of prior therapy. This was followed by the approval of two further CD19-targeting CAR-Ts in the same patient population, Novartis’ Kymriah (tisagenlecleucel) in 2018 and Bristol-Myers Squibb’s Breyanzi (lisocabtagene maraleucel) last year. With the limitations of salvage chemotherapy and ASCT, Phase III trials were set up to evaluate CAR-Ts in R/R patients who had only received a single line of chemoimmunotherapy.

In April this year, the landmark ZUMA-7 study led to the approval of Yescarta as a second-line therapy, with the CAR-T demonstrating a four-fold increase in event-free survival (EFS) compared with SOC salvage chemotherapy and ASCT (8.3 months versus two months). This was followed by the approval of Breyanzi for second-line treatment in June, based on the Transform study, which also demonstrated a greater than four-fold improvement in EFS compared with the SOC (10.1 months against 2.3 months). Unfortunately, the BELINDA study investigating Kymriah as a second-line therapeutic did not report positive results.

Despite these recent approvals, there remains a high level of unmet need. CAR-Ts are prohibitively expensive and require expert medical centres for treatment; furthermore, around 50% of patients who receive CAR-T therapy for DLBCL relapse. The POLARIX study comparing a CD19-targeting antibody-drug conjugate (ADC), Roche’s Polivy (polatuzumab vedotin), in combination with R-CHP (rituximab plus cyclophosphamide, doxorubicin and prednisone) demonstrated a progression-free survival (PFS) advantage over the SOC, R-CHOP in the first line setting. Once approved, this could increase the number of patients cured with first-line therapy.

The Phase II L-MIND study, together with the follow-up RE-MIND2 study, reported that the combination of MorphoSys’ Minjuvi (tafasitamab), an anti-CD19 monoclonal antibody (mAb), and lenalidomide in R/R patients gave a median overall survival of around 35 months. The RE-MIND2 study compared Minjuvi with multiple therapies, including CAR-Ts, and while the number of patients receiving CAR-Ts was small, their OS was comparable, making this combination a significant contender in the R/R setting. In the LOTIS-2 study, ADC Therapeutics’ Zynlonta (loncastuximab tesirine) showed an almost 50% response rate in the third-line setting, with responses observed in patients who had relapsed post-anti-CD19 CAR-T therapy, making this ADC another therapeutic option.

In addition to the exciting changes to the DLBCL paradigm, there is a plethora of novel agents in the pipeline. Another exciting class is the bispecific T-cell engagers (BiTEs), which direct cytotoxic T-cells to CD20-expressing tumour cells. With CD20 as the target, there is potential for use after CAR-T therapy has failed. CAR-NK products are also in development, including Takeda’s allogeneic anti-CD19 CAR-NK, TAK007, which has demonstrated efficacy in a Phase I/II study.

Advances are also being made in CAR-T technology, which aims to increase accessibility and efficacy. These include Novartis’ YTB323 CAR-T, which is entering a Phase III trial; the product is manufactured using the T-Charge platform, cutting manufacture time to less than two days, thereby increasing capacity and reducing the need for bridging therapies. Allogene’s ALL0-501A is an allogeneic CAR-T therapy currently in Phase II development, with a lack of personalised manufacture aimed at making CAR-T therapy more accessible and cheaper.

With multiple highly effective agents already approved for DLBCL and a pipeline crowded with promising novel agents, there is expected to be very stiff competition between therapeutics in this disease setting. Innovation and investment are expected to continue to transform the patient outlook in a disease setting that has historically offered limited treatment options.