Part 3: Reporting on hypogammaglobulinemia and B-cell aplasia
Peter Bader, Ibrahim-Yakoub-Agha & Christian Chabannon
The two approved / licensed CAR-T Cells in Europe are autologous CAR-T Cells that target CD19, a membrane antigen expressed at all stages of normal B-Cell differentiation and on a wide variety of B-Cell malignancies. tisagenlecleucel and axicabtagene ciloleucel are indicated for the treatment of specific subtypes of relapsed or refractory B-Cell non-Hodgkin’s lymphoma. Additionally, tisagenlecleucel is indicated for the treatment of Acute Lymphoblastic Leukemia (ALL) of the B-Cell subtype in children and young adults, up to the age of 25.
An expected “on-target / off tumor” effect associated with the administration of these two medicinal products is B-cell aplasia and hypogammaglobulinemia. B-cell aplasia or lymphopenia can be considered a surrogate marker for persistent CAR-T Cell activity.
Both EBMT and CIBMTR collect data on B-cell aplasia and hypogammaglobulinemia following treatment with tisagenlecleucel and axicabtagene ciloleucel. This is important to further evaluate the incidence of such complications in real-world conditions, to refine specific treatment strategies, and for healthcare providers and healthcare authorities including Health Technology Assessment (HTA) agencies to measure the necessary resource needed to care for these complications.
Information is to be reported at each follow-up (D100, 6 months, 1 year and then annually). In the absence of a grading system for hypogammaglobulinemia, and because of variability across biological assays used by laboratory medicine departments, it is left to the investigator judgement to decide whether hypogammaglulinemia is present, worsened or improved since last follow-up. Decision to substitute is based on a combination of biological and clinical criteria (including occurrence of infections) that are likely to be different across programs, and whether the program treats adult or pediatric patients. So far, there is no specific recommendation for Ig substitution of patients treated with CAR-T Cells as compared to other etiological conditions. Immunoglobulin substitution must be reported in a binary manner (“Yes” or “No”). Detailed reporting on the nature of Immunoglobulins used, dosage, start and finish-time is expected in the relevant section of the form
Diagnosis of B-Cell aplasia relies on the detection of B-Cells in peripheral blood samples using flow cytometry assays that may differ from one program to another. It is thus left to the investigator to decide whether B-Cell aplasia is present or not. Presence or absence of B-Cell aplasia must be reported at the time of treatment and patient registration, as well as at follow-up times. Additionally, it is requested to report on the % of B-Cells; please, enter the lowest value that appears on consecutive laboratory reports during the period covered by the follow-up form.
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3. Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Ciceri F, et al. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2020;105(2):297-316.
CAR-T cells activities in Europe