CAR T therapy drives sustained remission in refractory DLBCL
Longer-term follow-up of patients with refractory and relapsed diffuse large B-cell lymphoma (DLBCL) who received chimeric antigen receptor (CAR) T cell therapy showed sustained responses in about half of the patients, suggesting that CAR-T therapy may be an effective option for this hard-to-treat non-Hodgkin's lymphoma, according to the ZUMA-1* and JULIET** trials presented at ASH 2017.
“It is encouraging that the data continue to be so strong and suggest that CAR-T therapies for B-cell malignancies are here to stay,” said press briefing moderator Dr Renier Brentjens of Memorial Sloan Kettering Cancer Center in New York, New York, US.
In CAR-T therapy, a patient’s own T cells are harvested, genetically modified, and re-introduced back into the patient to target the CD-19 surface protein often expressed on malignant lymphoma cells.
Over 1-year durability in ZUMA-1
The multicentre pivotal phase II trial enrolled 111 patients with DLBCL, transformed follicular lymphoma, or primary mediastinal B-cell lymphoma who had refractory disease despite treatment with recommended prior therapy. After a conditioning regimen of low-dose cyclophosphamide and fludarabine, a target dose of 2×106 anti-CD19 CAR T cells/kg body weight (axicabtagene ciloleucel) was administered. [N Engl J Med 2017;doi:10.1056/NEJMoa1707447]
Of the 101 patients who received the CAR-T therapy axicabtagene ciloleucel, 54 percent had complete response after a median follow-up of 8.7 months. The objective response rate (ORR) ─ combined rates of complete response and partial response ─ was 82 percent (p<0.001 compared with a historical control rate of 20 percent).
After a median follow-up of 15.4 months in the updated analysis, 42 percent of patients remained in remission, with 40 percent having ongoing complete response after a single infusion of CAR T cells.
“Long-term follow-up of ZUMA-1 confirms that these responses can be durable and the ongoing responses at 24 months suggest that late relapses are uncommon. Patients who are in remission at 6 months tend to stay in remission,” said lead author Professor Sattva Neelapu from MD Anderson Cancer Center at University of Texas in Houston, Texas, US.
Nonetheless, the investigators noted that a complete response occurred at as late as 15 months in 23 patients even though most responses were expected within the first month.
“It would be reasonable to monitor patients who did not have a complete response at the first disease assessment and allow for an opportunity for an improved response, since consolidation with allogeneic stem-cell transplantation comes with a high rate of treatment-related death and would also ablate CAR T cells,” suggested Neelapu and co-authors.
The estimated overall survival (OS) rate at 18 months was 52 percent by Kaplan-Meier analysis, with the median OS not reached at the last follow-up before data cutoff.
“With existing therapy, the median survival for people with this disease is only 6 months. Here, we see more than half of patients ─ 59 percent ─ are still alive over a year after treatment,” he added.
Similar high response rate in JULIET
Another CAR T therapy making waves at ASH 2017 is tisagenlecleucel, which was recently approved for acute lymphoblastic leukaemia by the FDA, and is currently seeking approval for DLBCL with the pivotal phase II JULIET trial. The multinational, single-arm, open-label study enrolled 147 patients with relapsed/refractory DLBCL who had disease progression after ≥2 lines of chemotherapy and were ineligible for or had failed autologous stem cell transplant. [ASH 2017, abstract 577]
Among the 81 patients who received tisagenlecleucel, 32 percent achieved a complete response and 6 percent had a partial response. Furthermore, those who had remission at 3 months remained relapse-free at 6 months and beyond after a single infusion.
Of the 46 patients who were evaluable at 6 months, 30 percent achieved a complete response and 7 percent had a partial response (ORR, 37 percent). The probability of being relapse-free at 6 months was 73.5 percent.
The median OS had not been reached, and the probability of OS at 6 months was 64.5 percent.
Subgroup analyses showed consistent response rates across prognostic subgroups based on prior autologous stem cell transplant or double-hit lymphoma.
“About a third of patients who fail all current therapies, even transplant, could now have a form of therapy that may offer them durable remissions,” said lead author Professor Stephen Schuster from Abramson Cancer Center at the University of Pennsylvania in Philadelphia, Pennsylvania, US. “While we don’t completely understand why these remissions are so durable, it’s exciting and will change how this disease is treated when conventional therapies fail.”
More work ahead
Noting the short median 17-day turnaround time after leukapheresis, “ZUMA-1 thus provides a blueprint for treating a large number of patients with gene-engineered T cells … a rapidity that is critical, given the aggressive nature of refractory large B-cell lymphomas,” wrote Drs Eric Tran and Walter Urba from the Providence at Portland Medical Center in Portland, Oregon, US, and Dan Longo from Harvard Medical School in Boston, Massachusetts, US, in an editorial. [N Engl J Med 2017;doi:10.1056/NEJMe1714680]
While the studies demonstrated that the CAR-T approach is feasible in clinical settings beyond highly specialized academic centres, they added that “[these] studies reinforce the risks of unique and often serious toxic events that have been observed in earlier trials.”
Grade ≥3 adverse events occurred in 95 percent of patients in ZUMA-1 and 86 percent in JULIET, with neutropenia (78 percent), anaemia (43 percent), and thrombocytopenia (38 percent) being the most common in ZUMA-1. Grade ≥3 cytokine release syndrome (CRS; 13 percent in ZUMA-1 and 15 percent and 8 percent for grade 3 and 4 CRS, respectively in JULIET) and neurologic adverse events were also common (28 percent in ZUMA-1 and 12 percent in JULIET).
“There is still a lot we need to learn about toxicities,” said Brentjens.
The high cost of the therapy also poses financial challenge to patients.
“Despite the impressive clinical results, approximately half the patients … will not have a durable response after anti-CD19 CAR T-cell therapy … [for reasons] not completely understood,” noted the editorialists.
According to researchers of ZUMA-1, loss of CD19 and gain of PD-L1 expression in tumours were identified as potential mechanisms of resistance following CAR-T therapy, providing insights into ways to improve the therapy.