Retrospective Analysis Supports Utilization of Auto-HCT in Relapsed LBCL Achieving a CR

Mazyar Shadman, MD, MPH

Autologous hematopoietic cell transplantation (auto-HCT) lowered relapse and progression rates and improved survival outcomes vs CAR T-cell therapy in patients with relapsed large B-cell lymphoma (LBCL) who experienced complete remission (CR) with interim treatment, according to findings from a real-world, retrospective study that were presented during the 2023 ASH Annual Meeting.¹

“The message here is that this data could be practice informing and also confirming,” Mazyar Shadman, MD, MPH, associate professor in the Clinical Research Division and Innovators Network Endowed Chair at Fred Hutch Cancer Center in Seattle, said during a presentation of the data. “Patients who relapse after first-line therapy after 12 months, the current standard of care is to receive salvage therapy with [autologous] transplant, and this data confirmed that.”

Shadman added that currently there are no data suggesting that patients who are in complete remission should receive CAR T-cell therapy in the setting of relapse after 12 months. Although, he said, in patients with primary refractory disease, the goal of therapy should be CAR T-cell therapy.

“All the efforts should be done to improve access to CAR T,” he said. “But until then, for patients who achieve a good clinical response, namely complete response, an [autologous] transplant strategy could be a reasonable option to discuss with the patient and could add another potential curative therapy for these patients, knowing that CAR T could still be utilized in the later line of therapy if [autologous] transplant fails the patient.”

Improved PFS and Relapse Rates

In the analysis, the 2-year PFS rate was 66.2% (95% CI, 60.4%-71.8%) in patients who underwent auto-HCT compared with 47.8% (95% CI, 26.4%-59.4%; P < .001) in those who received CAR T-cell therapy across the entire cohort.

The auto-HCT group also had a lower relapse rate at 2 years compared with the CAR T-cell therapy group (27.8% [95% CI, 22.6%-33.4%] vs 48% [95% CI, 36.4%-59.7%]; P < .001).

In addition, patients who underwent auto-HCT demonstrated a higher overall survival (OS) rate at 2 years compared with those treated with CAR T-cell therapy (78.9% [95% CI, 73.9%-83.6%] vs 65.6% [95% CI, 53.6%-76.6%]; P = .037).

Researchers also focused on outcomes in patients who had relapsed disease within the first 12 months of frontline therapy, in which auto-HCT was also associated with improved PFS (68.2% [95% CI, 61.1%-74.9%)] vs 48.4% [95% CI, 35.7%-61.3%]; P = .001) and a lower rate of relapse (25% [95% CI, 18.8%-31.7%] vs 46.3% [95% CI, 33.5%-59.3%] P < .001), compared with CAR T-cell therapy. Of note, the OS superiority seen in the entire cohort was not sustained with auto-HCT among those who relapsed within the first 12 months.

In the multivariable analysis, treatment with auto-HCT, when compared with CAR T-cell therapy, was associated with a lower risk of relapse/progression (HR, 2.18; 95% CI, 1.48-3.20; P < .0001) and of disease progression (HR, 1.83; 95% CI, 1.27-2.63; P = .0011). There was no significant difference in treatment-related mortality (HR, 0.59; 95% CI, 0.19-1.83; P = .3632) and in OS (HR, 1.44; 95% CI, 0.91-2.28; P = .123).

The most common cause of death in the auto-HCT and CAR T-cell therapy groups was lymphoma (60% vs 68%, respectively), followed by infections (16.5% vs 12%). In the auto-HCT group, second malignancies were the third most common cause of death, occurring in 3.5% of the cohort, “as expected with high-dose chemotherapy,” Shadman said. In contrast, the third most common cause of death in patients who received CAR T-cell therapy was pulmonary failure at 8%.

Shadman did note some limitations of this current study, including the fact that it was a retrospective analysis.

“By nature, it’s subject to a number of limitations including potential confounders that, despite our efforts, were not accounted for,” he added. “Ideally, a randomized trial would give us the answer in patients who are chemo-sensitive regardless of the timing of relapse [after] receiving [auto-HCT] vs CAR-T.”

The other limitation may be that more than half of the patients in this study were treated with the CAR T-cell therapy tisagenlecleucel (tisa-cel; Kymriah).

“Among the 3 FDA-approved CAR-T products, [tisa-cel] seemed to have the efficacy that is not as good as [axicabtagene ciloleucel (Yescarta); axi-cel] and [lisocabtagene maraleucel (Breyanzi); liso-cel],” Shadman said. “I should say that in this cohort, we compared the efficacy of tisa-cel to axi-cel, and we did not find a significant difference in the efficacy. But ideally, this analysis should be repeated when we have more patients with lisa-cel and axi-cel therapy in the analysis.”

CAR T-Cell Therapy Vs Auto-HCT

CAR T-cell therapy is the standard of care for relapsed LBCL and can be used as early as the second-line setting, which was determined by findings from the ZUMA-7 (NCT03391466) and TRANSFORM (NCT03575351) trials. Despite these findings, their application in clinical practice sometimes lends to a different experience.

“In practice, however, access to CAR T-[cell therapy] is not easy, and there is, most of the time, delay between the time that the decision is made to refer a patient to CAR T therapy until patients, in fact, receive treatment or even undergo leukapheresis,” Shadman said. “So many of these patients end up receiving chemotherapy while waiting for referral for the CAR T center. And some of these patients achieve a response to chemotherapy in the form of either a partial response or complete response.”

Researchers conducting this study aimed to compare outcomes of patients with LBCL who received auto-HCT with those treated with CAR T-cell therapy while in a complete response. Shadman noted that he and his team have previously shown superior efficacy of auto-HCT vs CAR T-cell therapy in patients with LBLC who were in partial remission.

Shadman emphasized the importance of knowing that he and his team aimed to answer a different question than what the ZUMA-7 and TRANSFORM trials answered. In particular, the ZUMA-7 and TRANSFORM trials compared CAR T-cell therapy with salvage therapy plus auto-HCT, and most patients had an event, defined as either failing salvage therapy to provide a remission for that patient or when the disease did not respond to auto-HCT.

“We’re looking at patients who already underwent salvage therapy and achieved not only a chemo-sensitive response but complete remission,” Shadman said. “So we are comparing CAR T vs transplant in patients who have already shown that they’re chemo-sensitive.”

The current study was a retrospective analysis of data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry of patients aged 18 to 75 years who received auto-HCT or CAR T-cell therapy while in a complete remission.

“These are patients who could at least, by age criteria, be potential candidates for [autologous] transplant even if they received CAR T,” Shadman said.

Patients were excluded if they received CAR T-cell therapy or auto-HCT previously.

The primary end points of the study were PFS and OS. Secondary endpoints included relapse/progression rate, non-relapse mortality, and cause of death. Researchers also performed a subgroup analysis of patients with progressive disease 12 months after finishing first-line treatment.

Due to the retrospective nature of the study, there were differences at baseline between the CAR T-cell therapy and auto-HCT groups. For example, patients treated with CAR T-cell therapy had a higher Karnofsky score that was less than 90% compared with those who underwent auto-HCT (P < .01). The CAR T-cell therapy group also received more prior lines of therapy compared with the auto-HCT group (3 vs 2, respectively; P < .01). Patients who underwent auto-HCT also had a longer median follow-up vs those who received CAR T-cell therapy (49.7 months vs 24.7 months, respectively). In the CAR T-cell therapy group, most patients received tisa-cel (53.2%), followed by axi-cel (45.6%) and liso-cel (1.3%).

Reference

Shadman M, Wooahn K, Kaur M, et al. Autologous transplant (auto-HCT) Is associated with improved clinical outcomes compared to CAR-T therapy in patients (pts) with large B-cell lymphoma (LBCL) achieving a complete remission. Blood. 2023;142(1):781. doi:10.1182/blood-2023-173536