Cytokine Release Syndrome and Neurotoxicity after Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory B-Cell Lymphoma: Is There an Association with Bridging Radiotherapy?

Abstract

<h3>Purpose/Objective(s)</h3> CD19-targeting chimeric antigen receptor T-cell (CART) therapy is an effective treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL). However, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may limit applicability and typically require hospitalization for toxicity management. Bridging radiotherapy (RT) may be used to debulk tumor burden or maintain performance status prior to CART therapy infusion, but associations with CRS and ICANS remain unclear. We assessed associations of bridging RT with CRS and ICANS among a cohort of patients (pts) receiving commercial CART therapy. <h3>Materials/Methods</h3> 94 pts receiving tisagenlecleucel (n=66) or axicabtagene ciloleucel (n=28) for r/rABL between April 2018 and June 2020 at a single institution were retrospectively identified. 22 pts (23%) received bridging RT (B-RT group) and 72 (77%) did not (NB-RT group). CRS was graded with ASTCT and ICANS with CTCAE v5.0. Grade ≥2 CRS (CRS2) and grade ≥2 ICANS (ICANS2) were compared between B-RT and NB-RT groups using Fisher exact test. Logistic regression was used to assess associations of patient characteristics, tumor bulk metrics (metabolic tumor volume [MTV], largest lesion max diameter [LLMD], and total lesion glycolysis [TLG]), and bridging therapy with CRS2 and ICANS2. <h3>Results</h3> B-RT group had better performance status (ECOG ≥1 41% vs 68%, p=0.027) and numerically but not significantly higher MTV (median 42.6mL vs 15.2, p=0.38), LLMD (median 5.8cm vs 3.5, p=0.12), and TLG (median 298.3 mL*SUV vs 60.8, p=0.22). Median B-RT dose was 31 Gy (IQR 20-40), most commonly in 2-2.5 Gy/fraction (n=17, 77%). Grade 1, 2, and 3 CRS occurred in 27 (29%), 19 (20%), and 5 (5%) pts, respectively. Grade ≥2 CRS occurred in 4/22 pts (18%) in B-RT group vs 20/72 pts (28%) in NB-RT group (p=0.16). Univariate analysis revealed associations between the following and CRS2: MTV (odds ratio [OR] 1.02 per 10 mL, p=0.025), LLMD (OR 1.12, p=0.01), largest lesion ≥5 cm (OR 2.98, p=0.046) and TLG (OR 1.02 per 100 mL*SUV, p=0.014), but not B-RT (OR 0.58, p=0.37), bridging systemic therapy (B-ST) (OR 1.33, p=0.56) or ECOG ≥1 (OR 1.33, p=0.56). Grade 1, 2, 3, and 4 ICANS occurred in 11 (12%), 6 (6%), 5 (5%), and 2 (2%) pts, respectively. Grade ≥2 ICANS occurred in 1/22 pts (5%) in B-RT group vs 12/72 pts (17%) in NB-RT group (p=0.29). Univariate analysis revealed associations between the following and ICANS2: MTV (OR 1.02 per 10 mL, p=0.048), TLG (OR 1.02 per 100 mL*SUV, p=0.017), and a trend for ECOG ≥1 (OR 3.98, p=0.085), but not B-RT (OR 0.24, p=0.18) or B-ST (OR 1.22, p=0.75). <h3>Conclusion</h3> In this single-institution study, bridging RT was used for good performance status pts with bulky tumors and was associated with low rates of CRS and ICANS. An ongoing multi-institutional effort will help refine predictive models for these toxicity endpoints and further elucidate the role of bridging RT.