Kinetics of humoral deficiency in CART19-treated children and young adults with acute lymphoblastic leukaemia

A Deyà-Martínez,M Torrebadell,L Alsina,A Català,A Vlagea,A Esteve-Solé,A P García,A Alonso-Saladrigues,M Juan,S Rives,A Faura

doi:10.1038/s41409-020-01027-6

Abstract

CD19-CAR T-cell therapy (CART19) causes B-cell aplasia (BCA) and dysgammaglobulinemia but there is a lack of information about the degree of its secondary immunodeficiency. We conducted a prospective study in children and young adults with acute lymphoblastic leukaemia treated with CART19, analysing the kinetics of BCA and dysgammaglobulinemia during therapy, as well as the B-cell reconstitution in those with CART19 loss. Thirty-four patients were included (14 female) with a median age at CART19 infusion of 8.7 years (2.9–24.9). Median follow-up after infusion was 7.1 months (0.5–42). BCA was observed 7 days after infusion (3–8), with persistence at 24 months in 60% of patients. All patients developed a progressive decrease in IgM and IgA: 71% had undetectable IgM levels at 71 days (41–99) and 13% undetectable IgA levels at 185 days (11–308). Three of 12 patients had protective levels of IgA in saliva. In two of three patients who lost CART19, persistent B-cell dysfunction was observed. No severe infections occurred. In conclusion, BCA occurs soon after CART19 infusion, with a progressive decrease in IgM and IgA, and with less impairment of IgA, suggesting the possibility of an immune reservoir. A persistent B-cell dysfunction might persist after CART19 loss in this population.

Highlights

Chimeric antigen receptor (CAR) T-cell therapy uses genetic engineering to express a surface receptor against a tumour antigen on T-cells, combining, in a chimeric molecule, the antigen specificity of an antibody, with signalling domains allowing cytotoxic antitumoral function [1, 2].The most extensively investigated of these receptors is CAR19 T-cell therapy (CART19), used in B-cell malignancy treatment [1,2,3] with very promising results
CART19 therapies have revolutionised the treatment of B-cell malignancies, but the short follow-up experience with this therapy precludes defining the degree of secondary immunodeficiency and recommendations for its management
Our descriptive study first analysed the kinetics of B-cell aplasia (BCA) and dysgammaglobulinemia in a paediatric cohort treated with two different CART19 constructs, exploring the possibility of an immune reservoir for immunoglobulin synthesis

Summary

Introduction

Chimeric antigen receptor (CAR) T-cell therapy uses genetic engineering to express a surface receptor against a tumour antigen on T-cells, combining, in a chimeric molecule, the antigen specificity of an antibody, with signalling domains allowing cytotoxic antitumoral function [1, 2]. The most extensively investigated of these receptors is CAR19 T-cell therapy (CART19), used in B-cell malignancy treatment [1,2,3] with very promising results. CART19 therapy causes B-cell aplasia (BCA) of variable duration. CD19 is expressed on the surface of B-cells during all maturation stages (from pro-B cell in bone marrow to memory B cell and plasmablasts).

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Conclusion