CNS bridging radiotherapy achieves rapid cytoreduction before CAR T-cell therapy for aggressive B-cell lymphomas

Abstract

Chimeric antigen receptor (CAR) T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extracranial lymphoma in which it can improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that BRT would achieve similar, significant cytoreduction before CART for CNSL (CNS-BRT). We identified patients with CNSL with non-Hodgkin B-cell lymphoma who received CNS-BRT before commercial CART. Cytoreduction from CNS-BRT was calculated as change in lesion size before CART. Twelve patients received CNS-BRT, and the median follow-up among survivors is 11.8 months (interquartile range, 8.5-21.9). Ten patients had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All 10 patients with CNSL had progressive disease at the time of CNS-BRT. Of 12 patients, 1 experienced grade ≥3 cytokine release syndrome, and 3 of 12 patients experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome. CNS-BRT achieved a 74.0% (95% confidence interval, 62.0-86.0) mean reduction in lesion size from baseline (P = .014) at a median of 12 days from BRT completion and before CART infusion. Best CNS response included 8 complete responses, 1 partial response, and 1 progressive disease. Three patients experienced CNS relapse outside the BRT field. Preliminary data suggest CNS-BRT achieves rapid cytoreduction and is associated with a favorable CNS response and safety profile. These data support further study of BRT as a bridging modality for CNSL CART.

Graphical abstract

Figure 1.

CNS-BRT response. (A) Paired lesion-size analysis shows a significant decrease in lesion size after CNS-BRT, before CAR T-cell infusion (P = .014). The mean decrease in lesion size was 74.8%. (B) Baseline imaging and CNS-BRT response for patients with leptomeningeal lesions. Patient 1: coronal T1 postcontrast MRI through orbits shows disease centered in bilateral superolateral extraconal fat (asterisks) and infiltrating the bilateral infraorbital nerves (arrowheads); 55 days after radiotherapy (RT) completion there is near complete resolution of orbital masses and decreased prominence of the infraorbital nerves. Patient 3: sagittal T1 postcontrast MRI of the lumbar spine demonstrating enhancing soft tissue mass filling much of the thecal sac from T12-L2; 19 days after RT completion there is marked decrease in intrathecal contrast enhancement (arrowheads). Patient 10: sagittal T1 postcontrast MRI of the lumbar spine showing enhancing soft tissue mass filling much of the thecal sac from T12 to superior extent of L2; 43 days after RT completion there is near complete resolution of the mass (arrowheads). Patient 3 and 10 had bulky spinal leptomeningeal lesions. (C) Baseline imaging and CNS-BRT response for patients with parenchymal brain lesions. All images show axial T1 postcontrast MRIs of the brain. Patient 5: enhancing lesion centered in the right occipital lobe shows significant reduction in size 2 days after RT completion. Patient 6: enhancing right frontal/operculum lesion shows significant reduction in size, 3 days after RT completion. Patient 9: enhancing paramedian lesion at the right frontoparietal convexity shows marked reduction in size, 42 days after RT completion. Patient 11: enhancing lesion centered in the left thalamus shows significant contraction, 4 days after RT completion. Patient 12: enhancing right gangliocapsular lesion shows near complete resolution, 5 days after RT completion.

Figure 2.

CNS response. (A) Swimmers plot of treatment, response, and relapse time for 10 patients with CNSL. Status and events are coded in the legend. Response times on the plot correspond to the time when the best response was achieved. (B). Waterfall plot showing the best overall CNS response as measured by change in lesion size (sum of product diameters) from baseline. All 10 patients exhibited a response. The mean best response was a decrease in lesion size by 94.8% (95% CI, −89.4 to −100.1). Overall, there were 8 CRs and 2 PRs.

Figure 3.

CNS relapse. (A) The 12-month cumulative risk of CNS relapse after CNS-BRT and CART was 25.0% (95% CI, 6-52). (B) Images showing the CNS-BRT treatment plans to the 50% isodose line. Patient 1: sagittal postcontrast computed tomography (CT) of the head with RT field targeting the orbits. Patient 3: sagittal noncontrast CT of the spine with RT field targeting T11 through L3. Patient 12: axial noncontrast CT of the head with RT field targeting the right gangliocapsular area. (C) Images show sites of post-CART CNS relapse. Patient 1: sagittal positron emission tomography (PET)/CT showing [¹⁸F]fluorodeoxyglucose (FDG)-avid relapse in the brain, 1 month after CAR T-cell infusion (white arrow). Patient 3: sagittal PET/CT showing 2 FDG-avid sites of relapse at the margins of prior RT field, 1 month after CAR T-cell infusion (white arrows). Patient 12: axial postcontrast T1 MRI showing a left periventricular relapse, 5 months after CAR T-cell infusion (white arrows).