Historically, patients with high-risk variants of aggressive B-cell lymphoma had limited treatment options, resulting in a poor prognosis. Those who relapsed did not respond well to second-line chemotherapy and autologous stem cell transplantation, and this is still true today. However, with the advent of CAR T-cell therapy, such patients who do not have chemotherapy-sensitive disease in the second-line setting can receive CAR T-cell therapy in the third line.

Commercially available CAR T-cell products are US Food and Drug Administration approved for use in relapsed/refractory B-cell lymphoma, including relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma. At this time, available CAR T-cell therapies include axicabtagene ciloleucel and tisagenlecleucel, and the approval of lisocabtagene maraleucel is expected imminently as well. Data from 3 pivotal trials using these products (ZUMA-1, JULIET, and TRANSCEND) suggest that patients with DHL and triple-hit lymphoma (THL) have responses and response durability that are consistent with those of the overall population. So, although DHL is considered an adverse prognostic feature with conventional therapy, it appears that the same may not be true in the context of anti-CD19 CAR T-cell therapies.

How do these patients fare in the real-world setting? Well, abstract 1213 reported on a single-center retrospective analysis of 75 consecutive patients treated with commercially available CAR T-cell therapy at the University of Pennsylvania. A total of 18 patients with double-expressing lymphoma (DEL) and 10 patients with DHL were identified. At a median follow-up for the entire cohort of approximately 16 months, the best overall response rate was 56% for patients with DEL, 50% for patients with DHL, and 55% for patients with non-DEL/DHL. The authors also reported that, at 16 months, 69% of responding DEL continued in complete response, 72% of non-DEL/DHL continued in complete response, and 100% of DHL continued in complete response. Thus, in patients receiving either axicabtagene ciloleucel or tisagenlecleucel, we have seen consistently that the overall and complete response rates, as well as the durability of those responses, have replicated what was observed in the pivotal trials that included patients with DHL, which is encouraging.

For those with DHL or THL, advancements are also being pursued in the frontline setting. Dose-adjusted EPOCH-R has emerged as a preferred treatment based on retrospective analyses showing improved progression-free survival with this regimen compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone). Further, if you look at 3 different abstracts from this meeting that specifically focused on a dose-adjusted EPOCH-R regimen as first-line treatment of aggressive B-cell lymphomas (ie, abstracts 2126, 2131, and 1190), you will find fairly remarkable consistency with a 2-year progression-free survival of approximately 66%, meaning that, at 2 years, two-thirds of these patients are alive and progression free. I also think that we are beginning to recognize that, the more cases of diffuse large B-cell lymphoma in which we actually check for rearrangements of MYC, BCL2, and BCL6, the more DHLs we actually find. This may result in the inclusion of some lower-risk DHLs, which could also lift the overall prognosis of the DHL category.

Overall, these abstracts highlight the evolving treatment landscape for patients with DHL or THL. It is important to check the cytogenetics and see if patients have a DHL or a THL, and I think that we should make sure to no longer counsel patients that this is a disease that carries a uniformly grave prognosis. Further, patients with chemotherapy-insensitive disease in the second-line setting now have the option of CAR T-cell therapy. So, with improved treatment options in the upfront and relapsed settings, we may be able to change the natural history of DHL and improve the prognosis for these high-risk patients.