Experts Debate CAR T-cell Therapy vs. Transplant for Relapsed Diffuse Large B-cell Lymphoma

NEW YORK — Chimeric antigen receptor T-cell therapy confers better outcomes than autologous stem cell transplant to some patients with relapsed diffuse large B-cell lymphoma, but it may be premature to declare transplant obsolete in this setting, according to a debate at HemOnc Today New York.

Autologous stem cell transplantation has been the standard of care for patients with relapsed and primary refractory DLBCL since 1995.

That year, The New England Journal of Medicine published a paper by Philip and colleagues that compared autologous transplant with conventional treatment for 109 patients (median age, 43 years). All patients had chemotherapy-sensitive disease, and no patient had received rituximab (Rituxan; Genentech, Biogen) as induction or as part of salvage therapy.

Results showed transplant significantly improved EFS and OS.

“However, more than half of patients we’d even consider for autologous stem cell transplant can’t get there because they don’t have chemosensitive disease,” Michael R. Bishop, MD, professor of medicine at University of Chicago, said during his portion of the debate. “If you have chemosensitive disease, you would expect long-term EFS right around 40%.”

Several new therapies — specifically CAR T-cell therapy — have emerged.

The two FDA-approved CAR T-cell therapies — axicabtagene ciloleucel (Yescarta, Kite) and tisagenlecleucel (Kymriah, Novartis) — are indicated for treatment of certain patients with large B-cell lymphoma.

The ZUMA-1 trial — results of which served as the basis of FDA approval for axicabtagene ciloleucel — enrolled 101 patients (median age, 58 years; range, 23-76) with DLBCL (n = 77), primary mediastinal large B-cell lymphoma or transformed follicular non-Hodgkin lymphoma.

Nearly a quarter of patients had undergone prior autologous stem cell transplant and 77% had been refractory to their last line of therapy.

Two-thirds of patients had progressive disease after their last chemotherapy regimen, and 13% had stable disease.

“Chemosensitivity was not important, and CAR T-cell therapy is relatively agnostic to chemosensitivity,” Bishop said.

In the DLBCL subset, at 6 months, researchers reported a 36% overall response rate and a 31% complete response rate. One-third of patients had ongoing responses at 6 months, and 1-year OS for this group was 90%.

The phase 2 JULIET trial — which evaluated tisagenlecleucel for 93 heavily pretreated adults with relapsed or refractory DLBCL — yielded similar results.

“CAR T cells have a lower 1-year treatment-related mortality rate than autologous stem cell transplant — 3% vs. 7% in the high-risk group, and 3% vs. 4% in the standard-risk group ,” Bishop said. “It does not require patients to have chemosensitive disease. It results in similar EFS and PFS in older patients and patients who have primarily refractory disease or early relapse.”

Early results suggest complete remissions are sustained, he added.

“CAR T cells should now be the treatment of choice in high-risk relapsed/refractory diffuse large B-cell lymphoma,” Bishop said. “I think eventually CAR T cells will replace autologous stem cell transplantation for all patients with relapsed or refractory disease.”

In the second half of the debate, Nirav N. Shah, MD, MSHP, assistant professor at Medical College of Wisconsin, argued autologous stem cell transplant remains a viable option for certain patients with relapsed DLBCL.

He contended the data from the 1995 NEJM paper by Philip and colleagues was biased toward chemosensitive patients.

He also disputed the argument that autologous stem cell transplant has no role for patients with early relapse.

A Center for International Blood and Marrow Transplant Research study included chemosensitive patients who achieved complete response or partial response who underwent autologous transplant for DLBCL.

Researchers stratified patients based on early relapse — defined as primary refractory and relapse less than 12 months after initial diagnosis — or late relapse.

Results showed 3-year PFS rates of 44% for those with early relapse vs. 52% for those with late relapse, and 3-year OS rates of 50% in the early relapse group and 67% in the late relapse group.

Shah also reviewed data from ZUMA-1 , which showed 39% of patients remained in remission at 27 months — and the JULIET trial, in which only 67% of enrolled patients were infused, ORR at 3 months was 38% and the 3-month complete response rate was 32%.

“If you achieve a complete response to CAR T therapy, you do well, and that’s true for a lot of modalities,” Shah said. “But when you look at median PFS for all treated patients, it is only 3 months. What happens if you get CAR T and you fail?”

A retrospective study of 51 patients with progressive large cell lymphoma after anti-CD19 CAR T-cell therapy showed median OS of 13.6 months for those with delayed progression but only 5.1 months for those with primary progressive disease. Only eight of 51 patients who progressed were alive without lymphoma beyond 12 months.

“When you say, ‘I’m not going to bother with salvage chemotherapy. I’m going to take you right to CAR T because that is the best modality we have,’ if it doesn’t work, you’re in trouble,” Shah said. “Patients who undergo autologous transplant can be rescued by CAR T, but the majority of patients who fail CAR T treatment will die.”

In addition, long-term outcomes and toxicity profile data are still immature, and the long-term risks of genetically modified therapies remain unknown, Shah said.

“We haven’t treated enough patients with CAR T-cell therapy to compare the treatment-related mortality of these different modalities,” Shah said. “For autologous transplant, we have reliable data going back to 1995 that show 3-year PFS is 40% to 50% if you have chemosensitive disease. For this patient group, I believe autologous transplant still is the standard of care. We know the short-term and long-term toxicity profile because we have been doing this for 30 years.”

Among chemorefractory patients, available data show a 1-year PFS of 30% to 40% for those who undergo CAR T-cell therapy. However, follow-up data are limited and results are limited by trial design, Shah said. – by Mark Leiser

Reference:

Bishop MR and Shah NN. CAR T cells vs. autologous SCT for relapsed DLBCL. Presented at: HemOnc Today New York; March 21-23, 2019; New York.

Disclosure : Bishop reports honoraria from Celgene, Kite/Gilead and OptumHealth; speakers bureau roles with Agios, Celgene and Kite/Gilead; and advisory board or consultant roles with CRISPR Therapeutics, Juno Therapeutics, Kite/Gilead, Novartis and OptumHealth. Shah reports consultant fees from Juno Therapeutics, contracted research with Miltenyi Biotech, and ownership interests in Exelixis, Geron and OncoSec.