How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies

Abstract

Adoptive immunotherapy using B-cell-targeted chimeric antigen receptor (CAR)-modified T cells to treat hematologic malignancies is transforming cancer care for patients with refractory or relapsed diseases. Recent and anticipated regulatory approval for products targeting acute lymphoblastic leukemia, lymphomas, and multiple myeloma have led to global implementation of these novel treatments. The rapidity of commercial utilization of CAR-T-cell therapy has created a largely unexplored gap in patient supportive-care approaches. Such approaches are critical in these complex patients given their high net state of immunosuppression prior to CAR-T-cell infusion coupled with unique acute and persistent insults to their immune function after CAR-T-cell infusion. In this "How I Treat" article, we focus on key questions that arise during 3 phases of management for patients receiving CD19-targeted CAR-T cells: pre CAR-T-cell infusion, immediate post CAR-T-cell infusion, and long-term follow-up. A longitudinal patient case is presented for each phase to highlight fundamental issues including infectious diseases screening, antimicrobial prophylaxis, immunoglobulin supplementation, risk factors for infection, 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 the paucity of data specific to this treatment modality.

Graphical abstract

Figure 1.

On-target, off-tumor side effects of CD19-targeted CAR–T-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, naïve B cells, and memory B cells but not on antibody-producing plasma cells.

Figure 2.

Timeline for antimicrobial prophylaxis in patients receiving CD19-targeted CAR–T-cell therapy. In patients meeting high-risk criteria, refer to Table 2 for additional recommendations for antimicrobial management and infection monitoring. Monitoring absolute CD4 T-cell counts can be considered for guidance regarding when to stop prophylaxis for herpesviruses and Pneumocystis jirovecii pneumonia (PCP), although the utility of this approach in cancer treatment–induced cytopenias is unclear. ^aDuring periods of severe neutropenia (ANC <0.5 × 10⁹/L).

Figure 3.

Indications for immunoglobulin replacement immediately prior to and for the first 3 months after CD19-targeted CAR–T-cell therapy. We suggest consideration of prophylactic immunoglobulin treatment prior to and after CD19-targeted CAR–T-cell therapy in patients with severe hypogammaglobulinemia (serum IgG <400 mg/dL). Higher thresholds can be considered in patients with serious or recurrent infections. Beyond the first 3 months after CD19-targeted CAR–T-cell infusion, we recommend consideration of prophylactic immunoglobulin treatment in patients with IgG ≤400 mg/dL and serious, persistent, or recurrent bacterial infections. Additionally, continuation of immunoglobulins could be considered in patients with IgG ≤400 mg/dL and persistent B-cell aplasia (≤20 cells per mm³ of CD19⁺ or CD20⁺ normal B cells in peripheral blood leukocytes). Reproduced from Hill et al with permission from Elsevier.

Figure 4.

Phases of opportunistic infections in CD19-targeted CAR–T-cell therapy recipients. ^aApproximately 50% of bacteremia episodes are due to gram-positive organisms and 50% are due to gram-negative organisms. The conceptual model for this figure was adapted from Tomblyn et al.

Figure 5.

Possible approaches to vaccination strategies after CD19-targeted CAR–T-cell therapy. (A) Possible vaccination approach in CD19-targeted CAR–T-cell therapy recipients who have no history of prior HCT or who completed post-HCT vaccines. (B) Possible vaccination approach in CD19-targeted CAR–T-cell therapy recipients who have a history of prior HCT and did not complete post-HCT vaccines. ^aCheck serum IgG titers to S pneumoniae (23 serotypes), tetanus toxoid, hepatitis A virus, and HBVsAg. ^bA response is defined as achieving the following for all administered vaccines: for non–S pneumoniae vaccines: at least twofold increase in IgG from prevaccination to 1 to 2 months postvaccination or achieving a seroprotective IgG level at 1 to 2 months postvaccination; for the S pneumoniae vaccine (Prevnar 13): at least twofold increase in IgG from prevaccination to 1 month postvaccination, achieving an IgG >1.3 µg/mL for ≥50% of the Prevnar 13 serotypes, or as defined by the testing laboratory. Ab, antibody. This figure was adapted from the Fred Hutchinson Cancer Research Center Standard Practice Manual.