https://orcid.org/0000-0001-8771-947X
In this issue of Blood Advances, Cederquist et al1 from the Memorial Sloan Kettering Cancer Center, New York, report their positive experiences using bridging radiotherapy (BRT) during the period between lymphapheresis and CD19 chimeric antigen receptor T-cell (CAR-T) infusion in patients with central nervous system (CNS) lymphoma.
The value of CAR-T therapy for the treatment of patients with extracranial relapsed/refractory B-cell malignancies has been diligently explored in numerous large prospective multicenter studies over the last decade. In contrast, the efficacy and safety of CAR-T therapy for patients with CNS manifestations of B-cell lymphomas have been less clear. Recent studies suggest that CAR-T therapy could be effective for the treatment of primary CNS lymphoma and secondary CNS manifestations of aggressive B-cell lymphomas.2,3 Specifically, 1 study reported 10 patients with advanced mantle cell lymphoma and secondary CNS involvement. The response rate after CD19 CAR- T therapy was 86% in the CNS, with a systemic response rate of 90% and 1-year progression-free survival (PFS) of 47%. There was some concern regarding a high rate of immune effector cell–associated neurotoxicity syndrome (ICANS) in 7 of 10 patients, including 5 patients with severe ICANS grade 3.4 A large meta-analysis summarizing patients with CNS large B-cell lymphoma (LBCL) described overall response rate (ORR) and complete response (CR) rate of 61% and 55%, respectively. The median overall survival was 8.8 months, and the median PFS was 4.4 months. Severe ICANS grade ≥3 was reported in 25% of the patients with severe cytokine release syndrome (CRS; ≥3) in 10%. Therefore, the authors concluded that the efficacy and safety of CAR-T therapy were comparable to those observed in patients treated with CAR-T therapy who did not have CNS involvement.2 In a limited number of patients with secondary CNS lymphoma, expansion and homing of CAR-Ts into the CNS could be demonstrated.5 Consequently, CAR-Ts directed against CD19 could be detected in the cerebrospinal fluid, demonstrating the potential of CAR-Ts to migrate through the blood-brain barrier.6
However, questions remain as to how to prepare patients optimally before CAR-T therapy, because standard treatment responses to CNS lymphomas are only short in many cases. Several studies have investigated BRT in the interval between apheresis and initiation of lymphodepleting chemotherapy in patients with LBCL. Pinnix et al reported an improved 1-year PFS (44% vs 25%) and ORR (100% vs 67%) in patients with LBCL who received BRT as compared with systemic therapy before axicabtagen ciloleucel CAR-T therapy. Strikingly, no mortalities were observed in the BRT cohort, in contrast to 7 deaths (mainly from septic shock) in the chemotherapy group.7
In this study, Cederquist et al performed a retrospective analysis of patients with B-cell lymphomas and CNS manifestations, who received CNS BRT before commercial CAR-T therapy. Cytoreduction from CNS BRT was exactly calculated with regard to the lesion size before CAR-T therapy.1 The authors reported a total of 12 patients undergoing CNS BRT before CAR-T therapies, with most patients diagnosed with secondary CNS lymphoma (n = 9), only 1 patient with primary CNS lymphoma, and 2 patients with epidural disease. At the time of CNS BRT, all patients with CNS lymphoma showed progressive disease. The response to BRT was evaluable in 10 patients. The authors found a mean reduction in lesion size from baseline of 74.0% before CAR-T infusion (median of 12 days from BRT completion to CAR-T infusion). The best CNS response was a CR in 8 patients with 1 partial response. One patient had a progressive disease. A favorable response to CNS BRT was also observed in leptomeningeal and brain parenchymal lesions. Three patients experienced CNS relapse outside of the BRT field. In summary, CNS BRT is associated with rapid cytoreduction and a favorable CNS response. It should be noted that 7 patients received systemic therapy in addition to CNS BRT. Regarding the safety of this approach, the overall rate of CRS in the study was 67%, with high-grade CRS at 8%. The overall rate of ICANS was 42%, with high-grade ICANS in 25%.1 The authors pointed out that all relapses in this study were associated with leptomeningeal manifestation of lymphoma (either at the time of the study or in the previous period). According to Cederquist et al, this was not surprising, because BRT is a local treatment, whereas leptomeningeal disease is a diffuse process that involves the complete neuroaxis.
As explained by Cederquist et al, the study shows several limitations, for example, the retrospective design, the limited number of patients with this rare disease, and the absence of patients without BRT. Despite these limitations, the study by Cederquist et al encourages clinicians to evaluate the options for CNS radiotherapy as a bridging treatment approach for patients with CNS lymphoma manifestations in the interval between lymphapheresis and CAR-T infusion. In their study, the response to CNS radiotherapy was rapid and favorable, and patients entered CAR-T infusion with a robust remission status. Moreover, bridging CNS radiotherapy did not seem to be associated with excess neurotoxicity,1 which is in line with past experiences using BRT for extracranial lymphomas.7 Larger and prospective studies are however required to evaluate the potential and safety of bridging CNS radiotherapy before CAR-T therapy to confirm the results of Cederquist et al.
In conclusion, the study by Cederquist et al paves the path to improve the outcomes of patients with CNS lymphoma manifestations undergoing CAR-T therapy. It serves as an important study ahead of the development of prospective studies to further investigate the optimal bridging strategies for patients with CNS lymphoma, which will ultimately influence the clinical management of patients with this rare and demanding lymphoma manifestation.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
