Managing hypogammaglobulinemia in patients treated with CAR-T-cell therapy: key points for clinicians

ABSTRACT

Introduction

The unprecedented success of chimeric antigen receptor (CAR)-T-cell therapy in the management of B-cell malignancies comes with a price of specific side effects. Healthy B-cell depletion is an anticipated ‘on-target’ ‘off-tumor’ side effect and can contribute to severe and prolonged hypogammaglobulinemia. Evidence-based guidelines for the use of immunoglobulin replacement therapy (IGRT) for infection prevention are lacking in this population.

Areas Covered

This article reviews the mechanisms and epidemiology of hypogammaglobulinemia and antibody deficiency, association with infections, and strategies to address these issues in CD19- and BCMA-CAR-T-cell recipients.

Expert Opinion

CD19 and BCMA CAR-T-cell therapy result in unique immune deficits due to depletion of specific B-lineage cells and may require different infection prevention strategies. Hypogammaglobulinemia before and after CAR-T-cell therapy is frequent, but data on the efficacy and cost-effectiveness of IGRT are lacking. Monthly IGRT should be prioritized for patients with severe or recurrent bacterial infections. IGRT may be more broadly necessary to prevent infections in BCMA-CAR-T-cell recipients and children with severe hypogammaglobulinemia irrespective of infection history. Vaccinations are indicated to augment humoral immunity and can be immunogenic despite cytopenias; re-vaccination(s) may be required. Controlled trials are needed to better understand the role of IGRT and vaccines in this population.

KEYWORDS:

• CAR-T-cell therapy
• CD19
• BCMA
• infection
• IgG replacement therapy
• IVIG
• hypogammaglobulinemia
• B-cell aplasia
• vaccination
• COVID-19

Article highlights

• Prolonged B-cell aplasia and hypogammaglobulinemia are commonly reported following CAR-T-cell therapy, but the clinical impact of hypogammaglobulinemia on infection risk is not well elucidated.

• CD19 and BCMA CAR-T-cell therapies induce distinct humoral immune deficits due to the expression of their targets in distinct stages of differentiation of normal B-lineage cells and could require different clinical approaches for infection prevention that should stem from prospective studies and clinical trials.

• There is growing evidence of at least partially maintained pathogen-specific IgG levels following CD19 CAR-T-cell therapy. In contrast, there is evidence for poor maintenance of pathogen-specific IgG levels prior to and after BCMA-targeted CAR-T-cell therapy, which may be attributable to the depletion of long-lived plasma cells. Memory B-cell pools may need to be re-established independent of CAR-T-cell type.

• Infection risk is high in CAR-T-cell recipients due to a plethora of host- and treatment-related factors. Infection density is higher within the first month following CAR-T-cell infusion and decreases subsequently. Bacterial infections are more frequent in the early period while viral infections predominate later.

• There is limited evidence supporting prophylactic IgG replacement in CAR-T-cell recipients. In light of the adverse events, costs and limited access, routine IgG replacement should be carefully evaluated and prioritized in patients with severe or recurrent bacterial infections. More intensive IgG replacement strategies should be considered in pediatric patients and BCMA-targeted CAR-T-cell recipients.

• IgG levels may not be an adequate biomarker of humoral immunodeficiency, and multiple aspects of the clinical condition of a patient should be used to guide the decision of whether and when to initiate IgG replacement. More sophisticated tools for risk stratification and clinical decision making are needed.

• Hypogammaglobulinemia does not preclude adequate vaccine responses, but vaccine immunogenicity generally is low in CAR-T-cell recipients.

• Current vaccine recommendations are extrapolated from other immunocompromised populations and future studies are needed to define the need and timing for revaccination and to identify factors associated with vaccine immunogenicity in CAR-T-cell therapy recipients.

• As CAR-T-cell therapies continue to expand, infection prevention and management strategies are becoming increasingly crucial to optimize outcomes in a growing population of CAR-T-cell recipients.

Declaration of Interest

E Kampouri has received grants from the Swiss National Science Foundation (SNSF grant no. P500PM_202961) and SICPA Foundation. JA Hill received consulting fees or honoraria from Gilead Sciences. Amplyx, Allovir, Allogene therapeutics, CRISPR therapeutics, CSL Behring, OptumHealth, Octapharma, and Takeda and research funding from Takeda, Allovir, Karius, and Gilead Sciences. J Gauthier reports serving as a consultant for Eusapharma, JMP, Larvol, Multerra Bio, being in the advisory board of Legend Biotech and Janssen and receiving research support from Sobi, Juno Therapeutics, and Celgene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.