Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CART constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CART therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CART cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CART therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CART cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CART cell therapy.

Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma

“…Management of these adverse events was carried out according to the institutional guidelines in each center. Infectious complications were managed homogenously according to the Spanish consensus guidelines 16 …”

Invasive Fungal Infections after Anti-CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy: State of the Evidence and Future Directions

“…Another guideline from the European Society for Blood and Marrow Transplantation recommends mold-active azole prophylaxis in patients with prior allogenic HCT, prior invasive aspergillosis, and those receiving corticosteroids [ 29 ]. Other groups have suggested that ≥4 prior anti-tumor treatment lines, CAR-T-cell dose of >2 × 10 7 /kg, prolonged neutropenia (≥3 weeks), and use of >1 dose of tocilizumab or the administration of other immunosuppressive agents (such as anakinra and siltuximab) for the management of CRS and ICANS should also warrant the use of mold-active antifungal prophylaxis [ 30 , 31 ].…”

“…It is standard practice to administer trimethoprim-sulfamethoxazole (or alternatives, such as dapsone, atovaquone, and monthly intravenous pentamidine) for 3–6 months after CAR-T-cell therapy to prevent PCP [ 6 , 30 , 31 ]. Given that many CAR-T-cell patients are expected to experience prolonged lymphopenia due to “on-target, off-tumor” effects of CAR-T-cells, these patients may be at risk for PCP beyond 6 months.…”

“…Given that many CAR-T-cell patients are expected to experience prolonged lymphopenia due to “on-target, off-tumor” effects of CAR-T-cells, these patients may be at risk for PCP beyond 6 months. Some authors have suggested that PCP prophylaxis be continued until the CD4 + T-cell count is greater than 200 cells/µL [ 30 ]. Indeed, cases of PCP have been reported over 6 months after CAR-T-cell therapy in lymphopenic patients whose PCP prophylaxis had been discontinued [ 8 , 9 , 13 ].…”

Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies

“…Strict recommendation for antifungal prophylaxis applies in limited cases (prior mold infection, ≥3 weeks of neutropenia before and after CAR T-cell therapy, dexamethasone use > 0.1 mg/Kg/day for at least a week) [ 175 , 176 ]. A recent position paper from Spain stated that PJP prophylaxis along with fluconazole should be standard for children under CAR T-cell therapy, while prophylaxis against filamentous fungi (posaconazole, nebulized liposomal amphotericin B or micafungin) should be added when two or more criteria are met: ≥four prior treatment lines, neutropenia prior to the infusion, CAR-T doses > 2 × 10 7 cells/Kg, previous IFD, tocilizumab and/or steroids use [ 177 ]. Tocilizumab use alone is a risk factor for IFDs and patients should be closely monitored [ 178 ].…”