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. 2025 Feb;155(2):605-615.
doi: 10.1016/j.jaci.2024.10.021. Epub 2024 Nov 4.

Association of CD19+-targeted chimeric antigen receptor (CAR) T-cell therapy with hypogammaglobulinemia, infection, and mortality

Natalia M Sutherland  1 , Baijun Zhou  2 , Lingxiao Zhang  2 , Mei-Sing Ong  3 , Joseph S Hong  2 , Andrew Pak  2 , Katherine J Liu  2 , Matthew J Frigault  4 , Marcela V Maus  5 , Joshua A Hill  6 , Kerry Reynolds  4 , Jolan E Walter  7 , Carlos A Camargo Jr  8 , Sara Barmettler  9
Affiliations

Association of CD19+-targeted chimeric antigen receptor (CAR) T-cell therapy with hypogammaglobulinemia, infection, and mortality

Natalia M Sutherland et al. J Allergy Clin Immunol. 2025 Feb.

Abstract

Background: CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19+ receptors on B cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse.

Objectives: We sought to evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality.

Methods: We performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (IgG ≤600 mg/dL), infections prior to and after CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality.

Results: Patients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy levels (587 to 362 mg/dL; P < .0001). Thirty-seven percent of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia prior to CAR-T therapy was associated with worsening hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia post CAR-T therapy was associated with an increased risk of serious infection following CAR-T therapy (incidence rate ratio: 2.7; 95% CI: 1.5-5.2; P = .002). Risk factors for mortality included mild hypogammaglobulinemia (400 mg/dL < IgG ≤ 600 mg/dL), infections ≤100 days post-CAR-T therapy, and hospitalizations for infections. Immunoglobulin replacement was associated with a decreased risk of mortality.

Conclusions: We identified ∼90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia before CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia after CAR-T therapy, which was associated with an increased risk of serious infection and mortality post CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.

Keywords: CAR-T therapy; CD19; Hypogammaglobulinemia; immunoglobulin replacement therapy; infection; risk factors; secondary immune deficiency.

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Conflict of interest statement

Disclosure statement S. Barmettler is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number K23AI163350 and a Faculty Development Award from the American Academy of Allergy Asthma & Immunology (AAAAI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Disclosure of potential conflict of interest: M.V. Maus is an inventor on patents related to adoptive cell therapies held by University of Pennsylvania and MGH (some licensed to Novartis and Luminary, respectively); holds equity in 2SeventyBio, A2Bio, Affyimmune, Cargo, Century Therapeutics, Neximmune, Oncternal, and TCR2; serves on the Board of Directors of 2Seventy Bio; has served as a consultant for multiple companies involved in cell therapies; and receives sponsored research support from KitePharma and Moderna. J. A. Hill has served as a consultant for Moderna, Allovir, Gilead, SentiBio, Modulus, Karius, CSL Behring, Takeda, and Geovax; and received research funding from Allovir, Gilead, Takeda, and Merck. The rest of the authors declare that they have no relevant conflicts of interest.

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