Chimeric antigen receptor T‐cell therapy’s role in antiphospholipid syndrome: a case report

Chimeric antigen receptor (CAR) T-cell therapy is a novel cancer immunotherapy targeting cancer-specific cell surface antigens. Genetic modification of autologous T cells induces expression of a CAR specific for a tumour antigen (Miliotou & Papadopoulou, 2018). The CAR T cells initiate a sustained response against the targeted cells. In late 2017, the Food and Drug Administration (FDA) approved CD19 CAR T-cell therapy for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. CAR T-cell therapy has produced durable responses in refractory DLBCL; for instance, the ZUMA-1 trial evaluated axicabtagene ciloleucel, an autologous CD19 CAR T-cell therapy, in refractory DLBCL and established an overall response rate of 71% and a complete remission rate of 57% (Locke et al., 2017; Neelapu et al., 2017). CAR T-cell therapy is now gaining attention for its potential use as a targeted treatment for autoimmune disease. CAR T cells may be an alternative to current non-specific immunosuppressant agents, which require long-term monitoring and expose patients to the risk of multiple adverse reactions (Tahir, 2018). We report the case of a patient with DLBCL with a nearly 30-year history of autoimmune antiphospholipid syndrome (APLS) whose biomarkers for both diseases normalized after treatment with CAR T cells. We believe that the potential for treatment of autoimmune diseases such as APLS with CAR T cells warrants further investigation. The patient is a 67-year-old woman with a 29-year history of APLS. Although she was receiving anticoagulation therapy, she reportedly experienced multiple thromboembolic events, including eight confirmed deep venous thrombi and pulmonary emboli, since her APLS diagnosis. Most recently, her APLS had been treated with warfarin. In 2018, she presented to a primary care physician with a 2-month history of a pruritic erythematous rash covering her face and trunk. The results of a punch biopsy of the right malar cheek were diagnostic of DLBCL: immunohistochemistry was uniformly positive for CD20 and MUM1, strongly positive for BCL2, and negative for CD3, CD5, CD10, BCL1 and CD30. The patient was referred to The University of Texas MD Anderson Cancer Center, and the diagnosis was confirmed by skin and bone marrow biopsies, which showed DLBCL with nodular and trabecular patterns and a high proliferation rate (Ki-67 staining of 90%). Before chemotherapy, her APLS treatment was switched from warfarin to enoxaparin, since enoxaparin is shorter-acting and does not require monitoring. The patient completed three cycles of chemotherapy with rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (R-EPOCH); however, the dose of doxorubicin was reduced because the patient had an ejection fraction of 35%. Positron emission tomography/computed tomography (PET/CT) performed after three cycles of REPOCH showed new hypermetabolic subcutaneous nodules at the level of the thorax and upper extremities, with a Deauville score of 5. Biopsy of the PET-positive nodule confirmed refractory disease that was positive for CD20, BCL2, c-MYC and MUM1 with a Ki-67 of 90%. Salvage therapy with rituximab, dexamethasone, cytarabine and cisplatin (R-DHAP) was administered. The patient’s DLBCL was determined to be stable after one cycle. However, the patient developed acute renal injury and required renal replacement therapy. Thus, the strategy for salvage therapy was changed to CAR T cells due to the clear demonstration of chemorefractoriness and inability to tolerate standard of care platinum-based salvage therapy. Lymphodepleting chemotherapy with fludarabine and cyclophosphamide was given on days minus five to minus three, with infusion of axicabtagene ciloleucel CAR T cells on day zero, which was uneventful. The patient developed grade-I cytokine release syndrome with fever, which resolved with supportive care. During the patient’s CAR T-cell treatment, she received enoxaparin for anticoagulation, and no thrombotic events were reported. On day 30 after CAR T-cell infusion, PET/CT revealed no evidence of disease with a Deauville score of 2, as shown in Fig 1. The patient’s anticardiolipin levels were evaluated before and after CAR T-cell treatment. Her anticardiolipin levels were 97 3 immunoglobulin M phospholipid units (MPL) before CAR T cells, but normalized to <9 4 MPL after CAR T-cell treatment, as shown in Fig 2. Since completing CAR T-cell therapy, the patient has not required anticoagulation therapy and has not suffered any venous or arterial thromboembolic events, suggesting resolution of her APLS. At 1-year follow-up after CAR T-cell treatment, the patient’s DLBCL was in remission and her anticardiolipin antibody levels remained normal. Meanwhile, she has not recovered her CD19 B-cell population as measured by flow cytometry. We believe that the normalization of anticardiolipin levels may have been a positive effect of CAR T-cell therapy. This is the first reported case in which CAR T-cell therapy may have played a role in the suppression of APLS activity and in the normalization of autoantibody levels. APLS is an autoimmune disease characterized by venous or arterial Correspondence