{"entity":{"id":"rejuv-tx-b-cell-aplasia-and-immunoglobulin","kind":"technology","name":"B-cell aplasia and low antibodies after CAR-T and bispecifics, and immunoglobulin replacement","aka":["B-cell aplasia","hypogammaglobulinaemia after CAR-T","IVIg after CAR-T","immunoglobulin replacement after bispecifics"],"tldr":"Treatments aimed at a protein on B cells cannot tell a cancerous B cell from a healthy one, so they remove both, antibody levels fall and infections become more frequent. The fix is to give the antibodies back every few weeks. In one myeloma study, serious infections were ten times less frequent while people were receiving immunoglobulin.","summary":"The mechanism is on-target, off-tumour. A CD19-directed CAR-T cell kills every CD19-positive cell, which includes the entire normal B lineage from pro-B cell to memory B cell; a BCMA-directed bispecific antibody or CAR-T targets a protein expressed by normal plasma cells as well as myeloma cells. The result is B-cell aplasia, loss of the plasma cells that secrete antibody, and hypogammaglobulinaemia. OnCo already holds the glossary term `hypogammaglobulinaemia` and a treatment record for immunoglobulin replacement in lymphoma; this record is the quantitative and cross-disease account.\n\nAfter CD19 CAR-T. B-cell aplasia is expected and in many people persists as long as the CAR-T cells do, which in some is years. Immunoglobulin G falls over the months after infusion, and the degree varies: some patients maintain adequate levels from long-lived plasma cells that do not express CD19, which is the biological reason not everyone needs replacement.\n\nAfter BCMA-directed bispecific antibodies. The deficit is more complete, because BCMA is expressed by the long-lived plasma cells that CD19-directed therapy spares. A retrospective study of 37 patients treated with BCMA-targeted bispecific antibodies for relapsed or refractory myeloma characterised the problem precisely. Fifteen patients, 41 per cent, had a grade 3 to 5 infection, and there were two infection-related deaths during deep remissions. Eighty-four per cent of infections occurred during disease remission, which removes the usual explanation that infection reflects uncontrolled disease. The cumulative probability of grade 3 to 5 infection increased over time with no plateau. Among the 26 responders, profound hypogammaglobulinaemia occurred in 100 per cent and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin, the rate of grade 3 to 5 infections was 90 per cent lower than during observation, an incidence rate ratio of 0.10 (95 per cent CI 0.01 to 0.80, P = 0.0307). No other risk factor for infection was identified.\n\nThat is a retrospective within-patient comparison, not a randomised trial, and the grade here is moderate rather than strong for exactly that reason. The effect size is large, the mechanism is clear, the comparison is within the same patients across time, and the alternative explanation, that immunoglobulin was given to people who were doing better anyway, is weakened by the finding that most infections happened during remission. A pharmacovigilance analysis of reports to the FDA Adverse Event Reporting System found the hypogammaglobulinaemia signal strongest for BCMA-targeting bispecifics, with heterogeneity within the CD20 class; disproportionality analyses of spontaneous reports describe reporting patterns rather than incidence, and are included here as corroboration of the class effect rather than as a measurement of it.\n\nWhat replacement involves. Human normal immunoglobulin, pooled from thousands of donors, given intravenously every three to four weeks or subcutaneously weekly, dosed to keep the trough IgG above a threshold, commonly in the region of 4 to 6 g/L, with the threshold and the decision to start resting on the combination of the IgG level and the infection history rather than on the level alone. Subcutaneous administration can be given at home. Supply is finite and depends on plasma donation, which is a real constraint on practice in several countries.\n\nOne practical interaction that is easy to miss. Passively transferred antibody blocks the response to live vaccines and blunts the response to some inactivated ones. The CDC's guidance states that patients who have quantitative B-cell deficiencies and are receiving immunoglobulin therapy should not receive either non-live or live vaccines while receiving the immunoglobulin therapy because of concerns about the effectiveness of the vaccines, and that patients on chemotherapy with anti-B cell antibodies such as rituximab should wait at least six months. Anyone on replacement who is also due revaccination needs those two schedules planned together rather than separately.","status":"standard-of-care","asOf":"2026-10-02","wikipedia":"https://en.wikipedia.org/wiki/Hypogammaglobulinemia","links":[{"label":"Lancman et al., IVIg use associated with ten-fold reduction of serious infections in multiple myeloma patients treated with anti-BCMA bispecific antibodies (Blood Cancer Discov 2023)","url":"https://doi.org/10.1158/2643-3230.BCD-23-0049"},{"label":"Hill et al., Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy (Blood 2018)","url":"https://doi.org/10.1182/blood-2017-07-793760"},{"label":"CDC: altered immunocompetence, general best practice guidelines for immunization","url":"https://www.cdc.gov/vaccines/hcp/imz-best-practices/altered-immunocompetence.html"},{"label":"Hypogammaglobulinemia is a class effect of bispecific T-cell engagers: a Bayesian disproportionality analysis of a national database (Leuk Res 2026)","url":"https://doi.org/10.1016/j.leukres.2026.108327"}],"tags":["rejuvenation","survivorship","transplant","evidence:moderate","immune","antibody"],"related":["rejuv-tx-immune-reconstitution-timeline","rejuv-tx-infection-by-phase","rejuv-tx-revaccination","rejuv-tx-prolonged-cytopenias","lymphoma-tx-immunoglobulin-replacement"],"cancers":[],"sections":["rejuvenation","supportive-care"],"technologies":["car-t"],"targets":[],"drugs":["human-normal-immunoglobulin","rituximab"],"companies":[],"institutions":[],"pathways":[],"terms":["hypogammaglobulinaemia","late-effects"],"trials":[],"people":[],"bottlenecks":["b-survivorship","b-toxicity-qol"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"principle":"Antibody-mediated immunity depends on a continuously replenished pool of plasma cells. Removing the B lineage removes replenishment; removing BCMA-expressing cells removes the long-lived pool itself, which is why BCMA-directed therapy produces deeper and more durable hypogammaglobulinaemia than CD19-directed therapy. Replacement with pooled immunoglobulin substitutes for the missing product without restoring the missing cells, so it must continue while the deficit does.","strengths":["A large, mechanistically coherent reduction in serious infection during immunoglobulin exposure: incidence rate ratio 0.10 in the myeloma bispecific cohort","The deficit is measured by a cheap, standard blood test","Subcutaneous administration can be given at home","The problem is predictable from the target, so it can be anticipated before treatment starts"],"limitations":["The strongest evidence is a 37-patient retrospective study, not a randomised trial","Pharmacovigilance signals describe reporting, not incidence","Immunoglobulin supply is limited and depends on plasma donation","Replacement interferes with vaccination, so the two schedules must be planned together","Not everyone with a low IgG needs replacement, and thresholds for starting vary between centres"]},"route":"/technologies/rejuv-tx-b-cell-aplasia-and-immunoglobulin/","neighbours":{"technology":[{"id":"rejuv-tx-what-to-ask-for","kind":"technology","name":"After a transplant or cell therapy: what to ask for","route":"/technologies/rejuv-tx-what-to-ask-for/"},{"id":"rejuv-tx-prolonged-cytopenias","kind":"technology","name":"Blood counts that do not come back after CAR-T: ICAHT","route":"/technologies/rejuv-tx-prolonged-cytopenias/"},{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"id":"rejuv-tx-infection-by-phase","kind":"technology","name":"Infection risk after transplant and cell therapy, phase by phase, and the prophylaxis that follows it","route":"/technologies/rejuv-tx-infection-by-phase/"},{"id":"rejuv-tx-immune-reconstitution-timeline","kind":"technology","name":"Rebuilding an immune system: the timeline, lineage by lineage","route":"/technologies/rejuv-tx-immune-reconstitution-timeline/"},{"id":"rejuv-tx-revaccination","kind":"technology","name":"Revaccination after transplant: the schedules, and where the UK and the US differ","route":"/technologies/rejuv-tx-revaccination/"}],"term":[{"id":"hypogammaglobulinaemia","kind":"term","name":"Hypogammaglobulinaemia and infection risk after B-cell therapies","route":"/terms/hypogammaglobulinaemia/"},{"id":"lymphoma-tx-immunoglobulin-replacement","kind":"term","name":"Immunoglobulin replacement after CAR-T, bispecifics and long anti-CD20 treatment","route":"/terms/lymphoma-tx-immunoglobulin-replacement/"},{"id":"late-effects","kind":"term","name":"Late effects and survivorship toxicity","route":"/terms/late-effects/"}],"section":[{"id":"rejuvenation","kind":"section","name":"Recovery & Rejuvenation","route":"/fronts/rejuvenation/"},{"id":"supportive-care","kind":"section","name":"Supportive Care & Survivorship","route":"/fronts/supportive-care/"}],"drug":[{"id":"human-normal-immunoglobulin","kind":"drug","name":"Human normal immunoglobulin (IVIg)","route":"/drugs/human-normal-immunoglobulin/"},{"id":"rituximab","kind":"drug","name":"Rituximab","route":"/drugs/rituximab/"}],"bottleneck":[{"id":"rejuv-agenda-thymus-does-not-regrow","kind":"bottleneck","name":"Nothing in routine use rebuilds an adult's thymus","route":"/bottlenecks/rejuv-agenda-thymus-does-not-regrow/"},{"id":"b-survivorship","kind":"bottleneck","name":"Survivorship and late effects are neglected","route":"/bottlenecks/b-survivorship/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"idea":[{"id":"idea-rejuv-thymic-regeneration-in-adults","kind":"idea","name":"Find out whether an adult thymus can be made to work again, with an endpoint a clinician would act on","route":"/ideas/idea-rejuv-thymic-regeneration-in-adults/"}]}}