ASCT Tops CAR T-Cell Therapy for Relapsed LBCL in Complete Remission

SAN DIEGO — Autologous stem-cell transplantation (ASCT) led to improved outcomes as compared with CAR T-cell therapy for patients with relapsed large B-cell lymphoma (LBCL) in complete remission, a retrospective analysis showed.

Patients who underwent ASCT had fewer relapses at 2 years (27.8% vs 48.0%) and better progression-free survival (PFS, 66.2% vs 47.8%), and overall survival (OS, 78.9% vs 65.6%). In the subgroup of patients with early treatment failure, ASCT was associated with a lower 2-year relapse rate (22.8% vs 45.9%). Treatment-related mortality did not differ between the two types of treatment.

By multivariate analysis, CAR T-cell therapy was associated with a higher risk of relapse and inferior PFS, reported Mazyar Shadman, MD, of the University of Washington and Fred Hutchinson Cancer Center in Seattle, at the American Society of Hematology (ASH) meeting.

“The message here is that this data could be practice informing and confirming,” Shadman said during an ASH press briefing. “In patients who relapse after first-line therapy after 12 months, the current standard of care is salvage therapy with autotransplant. This data confirms that. There’s currently no data suggesting that patients who are in CR [complete remission] should receive CAR-T therapy in that setting.”

“The goal of therapy should be CAR-T therapy, and all efforts should be made to improve access to CAR-T,” he continued. “Until then, for patients who achieve a good clinical response, an autotransplant [ASCT] strategy could be a reasonable option to discuss … and could add another potentially curative therapy for these patients, knowing that CAR-T could still be utilized in the later line of therapy if autotransplant fails the patient.”

LBCL in CR

During a discussion that followed the presentation, Shadman emphasized that the study involved patients who were in CR after initial relapse. Patients referred for CAR T-cell therapy often receive chemotherapy during the interval when cells are being processed for infusion.

“We don’t expect these patients to respond to subsequent chemotherapy because they have already shown that they don’t do well with chemotherapy,” he said. “However, some do. Sometimes we see after one or two cycles of chemotherapy, their disease goes away. They’re in complete remission.

“The [situation raises] a practical question. This patient has very chemo-sensitive disease. We know that they do well with autotransplant, so what do we do now? Still send them for CAR-T? Maybe try autotransplant because we know they can be cured with autotransplant, and if autotransplant doesn’t work, you still have CAR-T as your backup plan.”

For patients with primary refractory disease, CAR T-cell therapy is the treatment of choice in second line.

“We are not suggesting that these patients should be sent for autotransplant,” said Shadman.

The discussion led to comments about the FDA’s recent safety communication regarding a potential risk of secondary malignancies with CAR T-cell therapy.

“Do you think more of these CAR T-cell-related malignancies will emerge and is that further justification for pivoting toward autologous transplant in these patients?” asked press briefing moderator Mikkael Sekeres, MD, of the University of Miami Sylvester Comprehensive Cancer Center.

Shadman said he and other CAR T-cell investigators know little about the issue beyond what the FDA has communicated.

“The number of secondary cancers that may be directly related to CAR-T is extremely low compared to the benefit that CAR-T provides in curing a very high percentage of patients who have no other options,” said Shadman. “I don’t think that the signal — which is very important and should be followed and will be followed — will change anything in our practice in offering curative therapy for relapsed lymphoma.”

High-dose chemotherapy, often used in conjunction with ASCT, also is associated with secondary malignancies, he added.

Background, Key Findings

CAR T-cell therapy has become standard of care for relapsed LBCL as early as second line. In clinical practice, access to CAR T-cell therapy might be delayed because of logistical issues, and in the interim, patients may receive bridging chemotherapy. Some of the patients achieve a partial or complete response. Several reports have shown that CAR T-cell therapy is safety and active in patients who achieve a complete response with bridging therapy, said Shadman.

Additionally, Shadman and colleagues recently reported the superiority of ASCT over CAR T-cell therapy in patients with LBCL in partial remission.

The observations provided the basis for a retrospective comparison of outcomes with ASCT and CAR T-cell therapy in patients with LBCL in CR. Investigators hypothesized that transplant would be superior in that setting.

Data for the study came from the Center for International Blood & Marrow Transplant Research registry. The analysis included adults with diffuse LBCL in CR, treated with CAR T-cell therapy from 2018-2021 (n=79) or ASCT from 2015-2021 (n=281). Median follow-up was 24.7 months for CAR-T and 49.7 months for ASCT. The primary endpoints were PFS and OS.

The results favored ASCT for most outcomes:

• 2-year PFS: 66.2% vs 47.8% (P<0.001)
• 2-year OS: 78.9% vs 65.6% (P=0.037)
• Relapse/progression: 27.8% vs 48% (P<0.001)
• Nonrelapse mortality: 5.9% vs 4.1% (P=0.673)

An analysis of a subgroup of about 240 patients with early relapse (within 12 months) after first-line therapy also favored ASCT for PFS (68.2% vs 48.4%, P=0.001) and relapse/progression (25% vs 46.3%, P<0.001). Survival trended in favor of ASCT (79.6% vs 66.3%, P=0.131), and nonrelapse mortality did not differ significantly (6.8% vs 5.3%, P=0.771).

A multivariable analysis showed that CAR T-cell therapy was associated with significantly inferior PFS (HR 1.83, 95% CI 1.27-2.63, P=0.0011) and relapse/progression (HR 2.18, 95% CI 1.48-3.20, P<0.0001).

Shadman acknowledge several limitations of the analysis: inability to eliminate potential confounders; need for a randomized trial to compare CAR-T and ASCT in patients with LBCL in CR; and use of tisagenlecleucel (Kymriah) in a majority of patients, which could have led to underestimation of the efficacy of CAR T-cell therapy.