Dr Leonard Highlights Crucial New Data, Practice Changing Therapies in DLBCL

John Leonard, MD, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, presented novel data in upfront and second line aggressive B-cell lymphoma during the virtual Great Debates & Updates in Hematologic Malignancies.

“Diffuse large B-cell lymphoma (DLBCL) has a lot of action from recent meetings and important new data. This is the most common lymphoma, and tends to present in advanced stage disease. We typically cure two-thirds of patients, and we have reasonably good prognostic tools,” explained Dr Leonard.

In the last few decades, the standard care for most patients involves R-CHOP in 6 cycles, and if patients relapse, a second line treatment is introduced. Patients with chemosensitive relapsed disease receive autologous stem cell transplant (AutoSCT). In the relapsed and refractory (R/R) setting, chimeric antigen receptor (CAR) T-cells and novel agents are recommended.

Dr Leonard highlighted several controversial regimens for patients who do not respond to R-CHOP. Etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, also known as EPOCH, is a regimen used to treat double hit, primary mediastinal, and HIV associated lymphomas. Testicular lymphoma often receives radiation. Additionally, limited stage disease has abbreviated durations of cycles and elderly patients receive mini-R-CHOP for a tolerable treatment experience.

In the POLARIX study of R-CHOP versus polatuzumab-R-CHP in DLBCL, also presented at the 2021 American Society of Hematology (ASH) Annual Meeting, the difference of neuropathy in previously untreated patients was examined. Over half of patients in both arms had predominantly grade 1 or 2 peripheral neuropathy with generally comparable toxicity profiles.

The primary endpoint of the trial was progression-free survival (PFS) with a 6.5% difference benefitting polatuzumab-R-CHP (76.7%) versus R-CHOP (70.2%). Notably, there was no difference in overall survival (OS).

“Older patients, male patients, those with a higher risk IPI score, and those with an absence of bulky disease seemed to benefit more from polatuzumab. Perhaps this subset analysis is hypothesis generating,” elaborated Dr Leonard.

In the relapsed setting, several different approved CD19-directed CAR T-cell products used in R/R DLBCL and follicular lymphoma (FL) after 2 more lines of therapy include axicabtagene citoleucel, tisagenlecleucel, and lisocabtagene maraleucel, Dr Leonard noted that although there are some differences in these regimens, in some ways they are quite similar.

“The ZUMA-7, TRANSFORM, and BELINDA studies have important takeaways and practice changing findings for the future,” emphasized Dr Leonard.

In the ZUMA-7 study of axicabtagene citoleucel versus standard of care in the second line setting for patients with R/R LBCL, over 90% of patients experienced a cytokine release syndrome (CRS) event, which was expected, according to Dr Leonard. The primary endpoint of event-free survival (EFS) was met with 8.3 months versus 2 with the standard of care regimen. There was not a significant difference in OS.

“All of the subgroups seemed to benefit regardless of age, response to previous therapy, disease subtype, and other parameters,” confirmed Dr Leonard.

In the TRANSFORM study of lisocabtagene maraleucel for second line relapsed DLBCL, the primary endpoint of EFS was met with a 6-month survival difference to standard of care. The OS favored lisocabtagene maraleucel, demonstrating support for CAR T-cell therapy.

In the BELINDA study of tisagenlecleucel for second line relapsed DLBCL, bridging chemotherapy was permitted for patients prior to AutoSCT. The primary endpoint of EFS was the same between both arms at 3.0 months.

“There were some differences between these 3 trials. The ZUMA-7 and TRANSFORM trials had positive findings, BELINDA being a negative trial. The EFS definitions were different with new therapies started as an event. The complete response rates of 65% in ZUMA-7 and 66% in TRANSFORM differ from 28% in BELINDA,” noted Dr Leonard.

Dr Leonard confirmed the second line CAR-T studies imply that in patients with chemoresistant disease, more chemo and AutoSCT is ineffective. The differential outcome between the BELINDA study and tisagenlecleucel pointed to chemotherapy bridging involving patients with a heavier disease burden, additional chemo cycles, a longer period to receive CAR-T, a different regimen, less lymphodepletion, and event definitions, according to Dr Leonard.

“The takeaway here is that CAR-T cells will be a standard of care for patients with disease progression after 1 year. For practical reasons, many patients will get some chemo before CAR-T cell therapy. For those who relapse later, AutoSCT will remain as the standard of care,” concluded Dr Leonard.