In a retrospective cohort study reported in a research letter in Blood Advances, Jennifer L. Crombie, MD, and colleagues found that axicabtagene ciloleucel produced high overall and complete response rates in patients with primary mediastinal B-cell lymphoma. They also observed some evidence to indicate that the activity of immune checkpoint inhibitors may be increased following treatment with the agent.
Jennifer L. Crombie, MD
As stated by the investigators, axicabtagene ciloleucel is approved for relapsed aggressive B-cell non-Hodgkin lymphoma, although the pivotal phase II trial included very few patients with primary mediastinal B-cell lymphoma. Thus, outcomes of treatment in this patient population are not well understood.
They further noted that primary mediastinal B-cell lymphoma, unlike other aggressive B-cell non-Hodgkin lymphoma subtypes, often harbors alterations resulting in increased expression of PD-1 ligands (PD-L1/2). Pembrolizumab is approved for the treatment of relapsed or refractory primary mediastinal B-cell lymphoma, and the combination of nivolumab and brentuximab has shown activity in the disease.
Study Details
The study included 33 previously treated patients (median of three prior lines of therapy) who received an infusion of axicabtagene ciloleucel outside a clinical trial setting between January 2018 and July 2019 at five U.S. academic medical centers. A total of 19 patients received immune checkpoint inhibitor treatment before (n = 14), after (n = 4), or before and after (n = 1) axicabtagene ciloleucel. The median duration of follow-up was 13.8 months.
Key Findings
Among 32 evaluable patients, 25 (78%) had an objective response, with 22 (69%) experiencing a complete response. The median time to best response was 29 days (range = 20–492 days).
Among all patients, progression-free survival at 12 and 24 months was 64% (95% CI = 49%–84%) and 64% (95% CI = 49%–84%). Overall survival at 12 and 24 months was 83% (95% CI = 70%–98%) and 78% (95% CI = 64%–96%).
Cytokine-release syndrome of any grade was observed in 88% of patients and was grade ≥ 3 in 6%. Neurologic toxicity of any grade was observed in 39% of patients and was grade ≥ 3 in 27%.
Among the 15 patients who received immune checkpoint inhibitor treatment prior to axicabtagene ciloleucel, 6 (40%) had an objective response to immune checkpoint inhibitor treatment, with a complete response in 4 (27%). Among the four patients who received immune checkpoint inhibitor treatment after axicabtagene ciloleucel, an objective response was observed in three (75%), all complete responses; among these four patients, immune checkpoint inhibitor treatment was given within 100 days after axicabtagene ciloleucel in three and at approximately 1 year in one.
One patient with no response to nivolumab prior to axicabtagene ciloleucel achieved a complete response with pembrolizumab given within 100 days after treatment with axicabtagene ciloleucel. Another patient had no response to pembrolizumab after axicabtagene ciloleucel but subsequently achieved a response with brentuximab plus nivolumab after allogeneic stem cell transplantation.
Rates of overall and complete response after axicabtagene ciloleucel were 80% and 73% among patients who received prior immune checkpoint inhibitor treatment and 72% and 61% among those who did not receive prior immune checkpoint inhibitor treatment, respectively.
No significant differences between patients with vs without prior immune checkpoint inhibitor treatment were observed in progression-free survival (hazard ratio [HR] = 0.9, 95% CI = 0.22–3.73, P = .88) or overall survival (HR = 1.17, 95% CI = 0.25–5.41, P = .84). Rates of cytokine-release syndrome and neurotoxicity associated with axicabtagene ciloleucel were similar for patients with vs without prior immune checkpoint inhibitor treatment.
Axicabtagene ciloleucel is an active therapy for patients with relapsed/refractory primary mediastinal B-cell lymphoma with an efficacy toxicity profile similar to that seen in prior studies in large B-cell lymphomas…. Additional prospective studies exploring the combination of checkpoint blockade and CAR T-cell therapy are warranted.— Jennifer L. Crombie, MD, and colleagues
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The investigators stated, “Although our findings are limited by their retrospective nature and small sample size, they raise the question of whether checkpoint blockade can result in enhanced activity following treatment with axicabtagene ciloleucel. Studies have demonstrated increased PD-1 expression following CAR T-cell therapy, suggesting a potential mechanism of immune escape. The combination of checkpoint blockade and CAR T-cell therapy, however, has not been examined in lymphomas known to have increased sensitivity to PD-1 inhibition, where the synergistic potential might be greatest.”
They concluded, “Axicabtagene ciloleucel is an active therapy for patients with relapsed/refractory primary mediastinal B-cell lymphoma with an efficacy toxicity profile similar to that seen in prior studies in large B-cell lymphomas…. Additional prospective studies exploring the combination of checkpoint blockade and CAR T-cell therapy are warranted.”
Dr. Crombie, of Dana-Farber Cancer Institute, is the corresponding author for the Blood Advances article.
Disclosure: For full disclosures of the study authors, visit ashpublications.org/bloodadvances.
