After decades of essentially unchanged treatment paradigms in large B-cell lymphomas (LBCL), the past few years have challenged our dogma. Is there a better way? The standard treatment for relapsed/refractory (R/R) aggressive B-cell lymphomas has been salvage chemotherapy followed by autologous stem cell transplant (SCT) for those deemed eligible. Remarkable durable responses have now been seen in R/R aggressive non-Hodgkin lymphoma (NHL) after two lines of treatment in the ZUMA-1, JULIET, and TRANSCEND trials with the use of anti-CD19 chimeric antigen receptor T cell (CAR-T) therapies. This has led many to wonder if CAR-T therapy should be used in earlier lines of treatment. Dr. Frederick Locke (pictured) presented the results of ZUMA-7, a phase III randomized trial of axicabtagene ciloleucel (axi-cel) versus standard-of-care (SOC) in the second-line in patients with R/R LBCL, at the Plenary Scientific session. The abstract was introduced by Alex Herrera, MD, who described CAR-T therapy as a “revolutionary advance in the treatment of hematologic malignancies being the first therapy to receive regulatory approval for the treatment of aggressive B cell NHL since rituximab.”
While most patients with diffuse large B-cell lymphoma (DLBCL) respond to first-line chemo-immunotherapy (CIT), 10 to 15 percent will have primary refractory disease and another 20 to 35 percent will eventually relapse.1 Dr. Herrera reminded the audience of the CORAL study, which showed no difference in outcomes with different rituximab-chemotherapy–based salvage regimens. Patients with early relapse or who were refractory to frontline therapy had particularly poor responses and prognosis; those who required third-line treatment had an overall response rate (ORR) of 39 percent, with 27 percent achieving a complete response (CR) and 12 percent a partial response (PR). Only 31.5 percent proceeded to transplant and the median overall survival (OS) in this population was 4.4 months.2,3 In the commonly referenced SCHOLAR-1 data, patients with refractory DLBCL had an ORR to second-line treatment of 26 percent (CR, 7%) with a median OS of 6.3 months.4 Given these poor outcomes in R/R aggressive NHL, new approaches are clearly needed.
Patients eligible for ZUMA-7 had disease that progressed within 12 months of initial therapy that included an anti-CD20 antibody and anthracycline. Those in the axi-cel arm received standard lymphodepletion with three days of cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day. The only bridging therapy allowed was corticosteroids. In the SOC arm, patients received investigator’s choice of CIT with platinum-based treatment, and those with PR or CR proceeded to autologous SCT. If patients did not respond to SOC CIT, they could receive CAR-T therapy off protocol.
ZUMA-7 enrolled 359 patients globally with a median age of 59 years; 74 percent had primary refractory disease and 46 percent had a high second-line age-adjusted international prognostic index (sAAIPI; 2-3). Ninety-four percent of patients assigned to axi-cel were infused. Only thirty-six percent of patients on the SOC arm were able to proceed to autologous transplant after second-line CIT. The study met its primary endpoint of a 50 percent improvement in event-free survival (EFS) compared to SOC. On the axi-cel arm, 178 patients were pheresed, and 170 received the infusion. The median time from pheresis to infusion was 29 days, and corticosteroid only could be used as bridging during this manufacturing time. With 24.9 months of median follow-up, median EFS was longer with axi-cel versus SOC (8.3 months vs. 2 months). Secondary endpoints of ORR/CR rates were higher with axi-cel compared to SOC (83/65% vs. 50/32%). Patients with higher tumor burden had decreased likelihood of CR in the SOC arm but not in the axi-cel arm. There was not a clear OS benefit in the axi-cel arm, but this may be because 56 percent of patients randomized to the SOC arm received commercial or investigational CAR-T therapy off protocol. Treatment-related deaths occurred in one patient in the axi-cel arm and two patients in SOC arm. Six percent of those receiving axi-cel had grade 3 or higher cytokine release syndrome (CRS), and grade 3 or higher neurologic events occurred in 21 percent of patients. There were no grade 5 CRS or neurologic events with axi-cel. Dr. Locke and colleagues noted that axi-cel had more than four-fold greater median EFS and 2.5-fold greater EFS at two years, and that the safety profile of axi-cel was comparable to what has been seen in the third-line setting.
The BELINDA study and TRANSFORM trial (both also presented at this year’s annual meeting, abstracts LBA-6 and 91, respectively) are similar phase III studies evaluating the CAR-T constructs tiso-cel and liso-cel, respectively, in similar patient cohorts. Dr. Herrera pointed out a key difference in these studies – BELINDA and TRANSFORM allowed bridging chemotherapy after aphaeresis while ZUMA-7 only allowed corticosteroids. ZUMA-7 and TRANSFORM also included need for third-line lymphoma therapy as an event, whereas BELINDA did not, which is arguably a very important event. The variability in bridging and definition of events could account for some difference in outcomes among these studies. Nonetheless, it seems likely that CAR-T therapy will be used in earlier lines of therapy, bringing new questions for us to study. Dr. Herrera suggested that “Old areas of research may become new again,” and we may soon be asking questions like “What is safety and efficacy of salvage therapy and autologous transplant after CAR-T?
During the Q&A after the presentation, Dr. Ruemu Birhiray from Indianapolis asked Dr. Locke to describe the ethnic/racial breakdown of the patients enrolled on ZUMA-7. The patients were primarily white, highlighting the need to diversify clinical trials to better represent the population who are actually being treated for these diseases, and to generate equality in the availability of these treatments. Even in a scientific plenary, the topic of diversity and inclusion remains front and center at this year’s annual meeting.
- Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22-32.
- Hagberg H, Gisselbrecht C, CORAL study group. Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study. Ann Oncol. 2006;17 Suppl 4:iv31-iv32.
- Van Den Neste E, Schmitz N, Mounier N, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regiments in the International CORAL study. Bone Marrow Transplant. 2016;51(1):51-57.
- Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808.
Dr. Blackmon and Dr. Brem indicated no relevant conflicts of interest.
