Relapsed Diffuse Large B-Cell Lymphoma after Allogeneic CAR T-Cell Therapy Successfully Treated with PD1 Inhibition

Abstract

Introduction Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) post-chimeric antigen receptor therapy (CAR-T) are limited. Here, we report the successful treatment of R/R DLBCL with programmed cell death 1 (PD1) inhibition post-allogeneic CAR-T. Case Report A previously healthy 26-year-old Caucasian man developed B-symptoms and cervical lymphadenopathy. Biopsy revealed DLBCL, activated B-cell subtype, double expressor and Ki-67 >80%. PET/CT scan revealed disease above and below the diaphragm. He achieved a partial response (PR) after R-CHOP, progressive disease (PD) after R-ICE, stable disease (SD) after R-ESHAP, and PD one month after autologous CD19-targeted CAR-T with CTL019 (CD3ζ/4-1BB). He then received R-lenalidomide (len) with radiation (24 Gy) to his mediastinal mass achieving a PR, followed by a myeloablative (Cy/TBI-12 Gy) allogeneic stem cell transplant (aSCT) from his 10/10 HLAmatched brother. He achieved 100% donor chimerism 30 days post-aSCT (D+30). Despite persistent full donor chimerism, D+60 PET/CT showed PD with confirmed relapse upon biopsy. Immunosuppression was discontinued, and ibrutinib with len was started, followed by donor lymphocyte infusion (DLI) which led to a mixed response. He then continued on ibrutinib with weekly temsirolimus and received a second DLI achieving a PR, with PD shortly thereafter. He next proceeded to allogeneic CAR-T with axicabtagene-ciloleucel (CD3ζ/CD28), complicated by grade 1 cytokine release syndrome without neurotoxicity. Three weeks post-CAR-T, he developed diplopia due to a cranial nerve palsy. Brain MRI showed new pontine T2 changes. Cerebrospinal fluid (CSF) was negative for lymphoma and infection, but notable for T-cell predominance. One month postCAR-T, PET/CT showed a complete metabolic response (CMR). Repeat brain MRI was unchanged. Two months later, he developed dizziness and intractable nausea, and repeat brain MRI showed a new lesion in the inferior cerebellar vermis, with resolution of previous pontine change. Evaluation of the CSF and peripheral blood revealed no CAR T-cell persistence, and PET/CT confirmed disease relapse in the cerebellum and mediastinum. Patient then received focal radiation (24 Gy) to his cerebellar lesion along with pembrolizumab 200 mg IV every 3 weeks, after which his neurologic symptoms resolved. MRI one day after radiation showed near-complete resolution of enhancing vermis lesion. After 3 cycles of pembrolizumab, PET/CT showed a CMR, with no active disease on brain MRI. Three months into PD1-inhibition therapy, his disease remains in CMR, without GVHD nor treatment-related toxicities. Conclusion This case illustrates the efficacy of allogeneic CAR-T after failure of autologous CAR-T and aSCT. Furthermore, PD1 inhibition can be used safely after allogeneic CAR-T, underscoring the need for prospective clinical studies.