Radiotherapy as a bridging strategy for patients with relapsed or refractory large B‐cell lymphoma undergoing CAR T‐cell therapy

CAR T-cell therapy has significantly improved survival for relapsed/refractory large B cell lymphoma (LBCL), but bridging therapy may be required as patients await CAR T infusion.1 Bridging radiation therapy (RT) can control locally progressive disease, alleviate symptomatic disease, and debulk tumors with high metabolic volume without increasing the toxicities of subsequent CAR T-infusion.1 Our group has previously presented the outcomes of bridging therapy in LBCL patients undergoing CD19-targeted CAR T-cell therapy.2 As a continuation, we now present our multi-institutional experience in assessing the impact of bridging RT in comparison to other systemic regimens. Following Institutional Review Board approval, a retrospective study was conducted for consecutive LBCL patients who received either tisagenlecleucel (tisa-cel) or axicabtagene ciloleucel (axi-cel) CAR T-cell therapy between 2017 and 2021. Methodology details are provided in the Supplementary Data. Patient characteristics are summarized in Table 1S. One hundred twenty five patients received bridging therapy: 28 patients received RT alone, 11 patients received combined modality therapy (CMT), and 86 patients received systemic therapy (ST) alone—Table 2S provides a summary of the systemic regimens. There was a greater proportion of patients with advanced age (≥60 years) in the RT group (p = .02). Following CAR T-cell therapy infusion, the best overall response rate (ORR) was 77% (n = 96), with a complete response (CR) in 51% (n = 64) and a partial response (PR) in 26% (n = 32). No significant difference was detected in ORR between axi-cel versus tisa-cel patients, but CR was better in patients who received axi-cel (OR = 2.3, p = .02). Cytokine release syndrome (CRS) and immune effector cell neurotoxicity syndrome (ICANS) occurred in 80% (n = 100) and 51% (n = 64), respectively, with grade 3 or higher CRS and ICANS reported in 5% (n = 6) and 24% (n = 30), respectively. No statistically significant differences were observed based on type of bridging therapy. The median follow-up after CAR T-cell therapy infusion was 9.2 months (IQR: 2.7–26.8 months). The median event-free survival (EFS) was 5.4 months for the axi-cel group, compared to 2.9 months for those who received tisa-cel (p = .03). The median overall survival (OS) was not significantly different between axi-cel and tiso-cel groups (20.6 months vs. 42.2 months; p = .9) (Figure 1SA,B). Based on the type of bridging regimen, the median OS was 14 months for the RT group, not reached for the CMT group, and not reached for the ST group (p = .01), while the median EFS was 3.5 months for the RT group, 3.0 months for the CMT group, and 4.0 months for the ST group (p = .9) (Figure 2SA,B). No statistically significant difference was detected in the duration of response (DOR) based on the type of bridging therapy (p = .6). Furthermore, for patients with stage I disease, no significant difference was observed in OS or EFS based on the type of bridging therapy. We then identified 37 patients (30%) who had response data based on the PET scan conducted after bridging therapy before CAR T-cell infusion. The median OS among responders (n = 15) was not reached, compared to 18.8 months for non-responders (n = 22) (p = .3), while the median EFS among responders was not reached, compared to 4.0 months for non-responders (p = .03) (Figure 3SA,B). There was no difference in response to therapy based on the class of bridging therapy (p = 1.0). Among the 39 patients who underwent bridging RT (including RT and CMT cohorts), a total of 45 sites were irradiated. The median dose/fractionation was 24 Gy (range, 10–37.5 Gy) and 8 fractions (range, 4–15 fractions). Thirty-seven sites (82%) were irradiated for symptom palliation, and 8 sites (18%) were irradiated to control asymptomatic disease. Sites of RT include head and neck (n = 13, 29%), CNS (n = 10, 20%), chest (n = 7, 16%), pelvis (n = 6, 13%), abdomen (n = 3, 6%), extremities (n = 3, 6%), and paraspinal area (n = 3, 6%) (Table 3S). Out of the 35 sites evaluated, 21 sites (60%) were bulky (≥5 cm) at the time of RT. The 1-year in-field PFS rate was 82% (Figure 1A). Seven sites experienced local recurrence, with median time to in-field progression of 5.3 months (range, 1.8–12.1 months), and 4 of these sites were bulky at time of RT. No significant difference in in-field response was detected between axi-cel and tisa-cel recipients. The 1-year out-of-field PFS rate was 35% (Figure 1B). Twenty-three patients experienced out-of-field progression, with a median time to progression of 3.5 months (range, 1.4–14.7 months); 9 of these sites were bulky at time of RT. There was no significant difference in in-field or out-of-field recurrence between bulky sites and those that were not. No significant difference was detected in ORR, CR, or DOR post-CAR T infusion in patients with bulky lesions between those who received only ST regimens (n = 40) and those who received RT alone or CMT (n = 21). Sixteen patients underwent bridging RT prior to apheresis due to clinical urgency. On univariate analysis, patients receiving RT due to clinical urgency prior to apheresis had a lower likelihood of achieving overall response post-CAR T compared to those receiving bridging RT post-apheresis (OR = 0.2, p = .04). This finding is most likely confounded by the high tumor burden and unfavorable baseline characteristics pre-CAR T infusion leading to rapidly progressive disease necessitating an urgent bridging RT before apheresis. There was no statistically significant difference in in-field response between patients who received bridging RT before apheresis and those who received it after apheresis. The mean ± SD of pre-RT ALC was 0.46 ± 0.51/μL, and for post-RT/apheresis, it was 0.39 ± 0.41 K/μL. The absolute ALC Δ RT/apheresis was 0.44 ± 0.51 K/μL. We found no statistically significant difference in ALC count pre-RT and post-RT/apheresis (p = .8). Post-RT/apheresis ALC showed no significant association with post-CAR T ORR or in-field response post-RT. No significant association was also found between the drop in ALC Δ RT/apheresis and ORR post-CAR T-cell therapy. Among the 39 patients who were treated with bridging RT, 21 patients were treated with comprehensive RT field to 25 sites with a median dose of 24.5 Gy (range, 18–36 Gy), while 18 patients received focal RT to 20 sites with a median dose of 22 Gy (range, 10–37.5 Gy) (p = .5). No significant difference in OS was found between high-dose RT (BED10 >30 Gy) and low-dose RT (BED10 ≤30 Gy) groups. There was also no statistically significant difference in BED10 in sites that experienced local failure and sites that remained locally controlled. Patients who received focal RT were more likely to have an IPI of ≥3 (p = .006), and advanced-stage disease (p < .001). No significant difference was detected among patients with elevated LDH, poor ECOG PS, CNS disease, age (≥60 years), double/triple hit or expressor status, type of CAR T product, and bulky disease. The median survival among patients who received comprehensive RT was 21.5 months, and for focal RT was 13.1 months (p = .1) (Figure 4S). We found that the patients who receiving bridging RT had lower median OS compared to the CMT and ST groups (p = .01), despite having comparable baseline characteristics at the time of apheresis, including International Prognostic Index (IPI) risk factors and bulky disease, except for advanced age (≥60 years) (p = .02). Previously reported series of patients who received bridging RT had similarly unfavorable baseline characteristics—for example, our study had high IPI in 18/28 compared to Pinnix et al.3 who reported 6/11 with high IPI. The majority of the patients who received bridging RT in our cohort were referred for RT primarily for palliative purposes to alleviate symptomatic disease, including 36% of patients in the CMT group who received RT for progression of systemic therapy. On the other hand, Roddie et al.4 have reported that 44% (25/62) of patients with high IPI in the RT-only group, translating to superior outcomes in overall response rates and survival rates post-CAR T compared to the CMT and ST groups. Since the initial reports on bridging RT, there has been significant improvement in systemic therapy bridging options, which may help explain the results as RT cannot be expected to improve OS in patients with advanced stage disease as its role in these patients is restricted to local control. Indeed, no significant difference was detected in OS or EFS among patients with stage I disease based on the type of bridging therapy, which argues against RT being an inferior bridging modality for patients with limited disease burden. Within the RT group, comprehensive bridging RT patients trended towards improved long-term outcomes compared to focal bridging RT patients, particularly for limited-stage disease. We show that RT continues to offer high rates of in-field response in this highly refractory population. However, patients with more than one site of disease may be better served with CMT or ST bridging rather than RT bridging alone in terms of OS outcomes. Currently, no established consensus exists for dose/fractionation for the purposes of bridging RT. Therefore, we are conducting a pilot trial, the first of its kind, to investigate once-weekly RT using artificial intelligence-driven adaptive technology to optimize bridging RT dose and field in terms of logistics, time, cost, and toxicities (NCT06004167). Furthermore, our results from the sensitivity analysis showed that RT is a reasonable bridging strategy in both CNS and non-CNS sites (See Supplement). Due to the theoretical concern that RT might impact adequate T-cell collection and CAR T-cells' efficacy, it has been recommended that bridging RT be administered after apheresis. However, in the present study, we report 16 patients who received bridging RT prior to apheresis due to clinical urgency. To the best of our knowledge, this study is the first to investigate the impact of bridging RT prior to apheresis, which underscores the successful T-cell collection in those patients; however, conclusive statements regarding whether bridging RT affects CAR T levels and T-cell fitness cannot be drawn. We acknowledge the potential limitations in this study, including the retrospective aspect; variability in RT dose/fractionation; lack of PET quantitative parameters; and selection of bridging therapy, which was determined at the discretion of the physician; and the heterogeneity of the patient population, which encompassed patients with CNS lymphoma and those who received two distinct CAR T-cell products. Furthermore, in contrast to our findings in the salvage setting post-CAR T failure,5 we didn't observe a dose–response relationship favoring higher doses for improved OS, similar to a previously reported series,6 possibly due to the small sample size and the small number of local failures. In conclusion, our findings support that ST and CMT bridging may be better than RT for the vast majority of patients given their advanced stage disease. While RT demonstrates high in-field response rates in this highly refractory population, patients with multiple disease sites may benefit more from CMT or ST bridging strategies than from RT alone for improved OS outcomes. Nonetheless, bridging RT, whether alone or in combination with ST, is safe and effective for patients with locally progressive LBCL prior to CAR T-cell therapy. Patients who are suitable for comprehensive RT trend towards superior OS compared to focal RT, and those patients who are not would likely better be served by adding systemic therapy. Exploring the use of bridging RT prior to apheresis for clinical urgency and its impact on CAR T-cells' efficacy requires further research considering factors such as the volume of irradiated bone marrow and the irradiated tumor size. Despite improved outcomes with systemic bridging options in our retrospective study, further investigation is warranted to optimize RT dose, fractionation, field size, and concurrent therapies to enhance its effectiveness for a broader patient population. HSA, CGP, and CAJ conceived and designed the study and wrote the manuscript. CGP and CAJ provided supervision. All authors interpreted data and contributed to revising the manuscript, and approved the submitted version. HSA has no conflicts of interest to disclose. AKN reports honoraria from Elsevier and UpToDate; served on the Board of Trustee for the American Board of Radiology. MJF reports a consultancy role for Celgene, Novartis, Arcellx, and Gilead/Kite; research funding from Novartis and Gilead/Kite. CAJ reports honoraria from Kite, Gilead Company, Novartis, BMS/Celgene, Instil Bio, ImmPACT Bio, Lonza, Ipsen, Epizyme, bluebird bio, and Daiichi Sankyo; reports consulting or advisory role for Kite, Gilead Company, Novartis, BMS/Celgene, Instil Bio, ImmPACT Bio, Lonza, Ipsen, Epizyme, bluebird bio, and Daiichi Sankyo; and research funding from Kite, a GileadCompany, and Pfizer. CGP reports research grant from Varian. All patients provided informed consent for CAR T-cell therapy. The data generated in this study are not publicly available due to information that could compromise patient privacy or consent. Data S1. Supporting Information. 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