The discussion is organized into frequently asked questions (FAQs) to facilitate good clinical practice. and vaccination. We hope this discussion will provide a framework for institutions and health care providers to formulate their own approach to preventing infections in light of SGI-7079 the paucity of data specific to this treatment modality. Visual Abstract Open in a separate window Introduction Adoptive immunotherapy using B-cellCtargeted chimeric antigen receptor (CAR)-modified T (CAR-T) cells to treat hematologic malignancies has fundamentally transformed cancer treatment paradigms. This novel therapy for patients with B-cell malignancies, including acute lymphoblastic leukemia (ALL) and large SGI-7079 B-cell lymphomas, has had unprecedented success.1-6 There has been rapid and wide-scale utilization of these treatments since the commercial approval of the first 2 CD19-targeted CARCT-cell products by the US Food and Drug Administration in 2017: (1) tisagenlecleucel (Kymriah; Novartis) for refractory or relapsed (R/R) B-cell ALL in patients aged 0 to 25 years and R/R lymphomas in adults and (2) axicabtagene ciloleucel (Yescarta; Kite/Gilead) for R/R lymphomas in adults. Additionally, there are SGI-7079 hundreds of ongoing clinical trials around the world. Although CD19-targeted CARCT-cell therapies are promising treatment options, the currently approved products have serious toxicities including cytokine release syndrome (CRS) and immune effector cellCassociated neurotoxicity syndrome (ICANS).4,6-14 These acute toxicities and their treatment add to the already high net state of immunosuppression and infection risk due to patients underlying malignancy, prior cytotoxic treatments, and pre CARCT-cell infusion lymphodepletion chemotherapy. Prolonged cytopenias, especially due to the on-target, off-tumor depletion of normal CD19-expressing B cells (Figure 1), may result in profound and prolonged immune deficits given that CAR-T cells are a living drug that may persist for years.4,11,15-21 Thus, CARCT-cell immunotherapies pose unique challenges for acute and long-term infection prevention. The rapidity of commercialization and implementation of CD19-targeted CARCT-cell immunotherapies has created a largely unexplored gap in the supportive-care approaches to maintaining not only cancer-free, but also infection-free, survival. Open in a separate window Figure 1. On-target, off-tumor side effects of CD19-targeted CARCT-cell therapy. (A) Depiction of a CD19-targeted CAR-T cell that has both on-target, on-tumor and on-target, off-tumor activity. (B) The lineage of B cells from early to fully differentiated cells depicting expression of the CD19 cell surface antigen on pre-B cells, na?ve B cells, and memory B cells but not on antibody-producing plasma cells. This How I Treat article arose from a need for pragmatic standards for infection prevention in patients treated with CD19-targeted CAR-T cells, while recognizing the dearth of data specific to this treatment modality. We present a longitudinal patient case to facilitate a discussion of how we approach infection screening, monitoring, prophylaxis, and vaccination in CD19-targeted CARCT-cell recipients. The discussion is organized into frequently asked questions (FAQs) to facilitate good clinical practice. Suggested medication doses are based on adults. Supplemental FAQs (sFAQs) are available on the Web site. None of the recommendations are based on randomized, controlled clinical trials in this patient population; instead, they are based on our expert opinion, opinions of others in the field, and approaches used in other relevant contexts. Many of these recommendations align with generally accepted infection-prevention strategies in patients with leukemias or lymphomas receiving high-dose corticosteroids, B-cellCtargeted therapies like rituximab, or hematopoietic cell transplantation (HCT). The MGC24983 recommendations are intended as general guidance for management of patients receiving CD19-targeted CAR-T cells. Infectious diseases screening prior to CARCT-cell therapy Clinical case A 52-year-old woman diagnosed with diffuse large B-cell lymphoma had persistent disease despite 4 prior treatment regimens including an anti-CD20 antibody, alkylating agents, and an anthracycline. She had no other notable past medical history and had high performance status (Eastern Cooperative Oncology Group [ECOG] score of 1 1) and normal organ function including normal left-ventricular ejection fraction. She was not a suitable candidate for an HCT due to refractory disease and was referred for treatment with CD19-targeted CARCT-cell therapy using axicabtagene ciloleucel. FAQs FAQ 1: What screening tests should be performed for infectious diseases prior to CD19-targeted CARCT-cell therapy? At a minimum, we recommend screening all patients for HIV antibodies, hepatitis B virus (HBV) surface antigen (HBsAg), HBV surface antibody (anti-HBs), HBV core antibody (anti-HBc), and hepatitis C virus (HCV) antibody with reflex nucleic acid testing if any of these tests are positive (Table 1). Additional serologic screening can be considered for herpes simplex virus 1/2 (HSV1/2) and varicella-zoster virus (VZV), especially for patients not receiving acyclovir prophylaxis; cytomegalovirus (CMV); human T-cell lymphotropic virus type 1 (HTLV-1); (syphilis); and should be considered in patients with risk factors for exposure; testing may be indeterminate in.
