Association of CD19⁺-targeted chimeric antigen receptor (CAR) T-cell therapy with hypogammaglobulinemia, infection, and mortality - 23/11/24

Doi : 10.1016/j.jaci.2024.10.021

Natalia M. Sutherland, MD ^a, Baijun Zhou, MHS ^b, Lingxiao Zhang, MPH ^b, Mei-Sing Ong, PhD ^c,^d, Joseph S. Hong, BS ^b, Andrew Pak, BS ^b, Katherine J. Liu, BA ^b, Matthew J. Frigault, MD ^e,^f, Marcela V. Maus, MD, PhD ^e,^g, Joshua A. Hill, MD ^h,^i,^j,^k, Kerry Reynolds, MD ^e,^f, Jolan E. Walter, MD, PhD ^l,^m,^n,^o, Carlos A. Camargo, MD, DrPH ^e,^p, Sara Barmettler, MD, MPH ^b,^e,^⁎
^a Department of Medicine, Massachusetts General Hospital, Boston, Mass
^b Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, Mass
^c Department of Population Medicine, Harvard Medical School, Boston, Mass
^d Harvard Pilgrim Health Care Institute, Boston, Mass
^e Harvard Medical School, Boston, Mass
^f Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Mass
^g Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, Mass
^h Department of Medicine, University of Washington, Seattle, Wash
ⁱ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Wash
^j Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Wash
^k Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, Wash
^l Department of Pediatrics, University of South Florida, St Petersburg, Fla
^m Department of Medicine, University of South Florida, St Petersburg, Fla
ⁿ Division of Pediatric Allergy/Immunology, Johns Hopkins-All Children's Hospital, St Petersburg, Fla
^o Division of Pediatric Allergy Immunology, Massachusetts General Hospital, Boston, Mass
^p Department of Emergency Medicine, Massachusetts General Hospital, Boston, Mass

^∗Corresponding author: Sara Barmettler, MD, MPH, Massachusetts General Hospital, 55 Fruit Street, MGH Allergy Associates, Yawkey 4B, Boston, MA 02114.Massachusetts General Hospital55 Fruit StreetMGH Allergy AssociatesYawkey 4BBostonMA02114

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Graphical abstract

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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.

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Key words : Hypogammaglobulinemia, CD19, CAR-T therapy, infection, secondary immune deficiency, immunoglobulin replacement therapy, risk factors

Abbreviations used : ALC, ANC, BCMA, CAR-T therapy, EMR, HCT, ICD, IgRT