B-Cell Aplasia, Hypogammaglobulinemia Can Result in Serious, Life-Threatening Infections
A 42-year-old woman presented to the CAR T-cell therapy program for evaluation with a history of relapsed immunoglobin (IgG) lambda multiple myeloma (MM), primary (essential) hypertension (HTN), high cholesterol, and recurrent infections after cancer diagnosis including uncomplicated urinary tract infection, community-acquired pneumonia, shingles, SARS-CoV-2 infection, and herpes zoster over the past 3 years. For MM history, she received induction chemotherapy followed by autologous stem cell transplant (ASCT) and maintenance lenalidomide; at first relapse she received bortezomib, lenalidomide, and dexamethasone, and at second relapse she received daratumumab, carfilzomib, and dexamethasone. Shortly after second-line treatments, the patient experienced molecular progression of disease, as well as by bone marrow.
In preparation for ciltacabtagene autoleucel administration, the patient underwent echocardiogram, electrocardiogram, and pulmonary function testing, all of which were unremarkable. With respect to infectious disease, her workup revealed no active infections and immunity to herpes zoster virus, cytomegalovirus, hepatitis B, and COVID-19. Her pre-infusion IgG quantitative level was 526 mg/dL. She was on the prophylactic shingles medication valacyclovir, and she had not required granulocyte colony-stimulating factor (G-CSF) since her ASCT and was on a monthly regimen of immunoglobulins because of her high risk for infections with co-existing hypogammaglobulinemia. She went on to obtain medical clearance from her bone marrow transplantation attending physician, followed by lymphodepleting chemotherapy and her CAR T-cell infusion.
Her course was complicated by grade 1 cytokine release syndrome, treated with one dose of tocilizumab. She also had neutropenia requiring levofloxacin prophylaxis and pancytopenia without transfusion requirements, and she was discharged to home.
On her first outpatient follow-up visit (Day 18), the patient reported feeling fatigued but otherwise stable. Laboratory workup revealed that her absolute neutrophil count (ANC) was 600/μL, and her IgG quantitative level had dropped to 235 mg/dL. Given her history of hypogammaglobulinemia and increased risk for infections, the patient was started on weekly intravenous immunoglobulin (IVIG) replacement therapy to maintain her IgG levels and prevent further infections.
However, on her second outpatient follow-up visit, the patient reported experiencing multiple episodes of fever and chills. Laboratory workup revealed that she had developed a bloodstream infection with gram-positive cocci, likely originating from a central line catheter. She was admitted to the hospital and started on IV antibiotics, and her central line was removed. Her absolute neutrophil count continued to remain low, and she required multiple transfusions of blood products during her hospitalization.
Given her persistent neutropenia and increased risk for infections, the patient was started on G-CSF to stimulate the production of white blood cells. She was also started on prophylactic antibiotics and antifungal therapy to prevent further infections; her cytomegalovirus DNA by real-time PCR was rechecked weekly and not detected, indicating no serologic evidence of reactivation.
After a prolonged hospital stay, the patient's neutrophil count gradually improved, and she was eventually discharged home with a plan for continued G-CSF, IVIG replacement therapy, and prophylactic antibiotics and antifungals. Her CAR T-cell therapy was deemed to have achieved a very good partial response by Day 60, and she was scheduled for close follow-up with her oncology team.
This case study highlights the potential complications of CAR T-cell therapy in patients with pre-existing hypogammaglobulinemia and increased risk for infection. Patients with MM are especially prone to infection, with one study noting a 7-fold risk of infection for these patients compared with matched controls. Infection was found to be the cause of death for 22% of patients in the study by 1 year of follow-up.1 Early recognition and management of neutropenia, prophylactic measures, and prompt treatment of infections are critical to achieving a successful outcome in these patients.
In the process of destroying malignant B cells, CD19-directed CAR T cells can also inadvertently target healthy B cells. This is known as having an “on-target/off-tumor” effect and, although leading to high rates of remission, may lead to B-cell aplasia and recurrent infections in turn. B-cell aplasia can last for extremely long durations, most likely because it is representative of an ongoing process in which active CAR T cells continue to kill B cells as they mature.2 Although it is somewhat counterintuitive because of the higher risk for infection, this is why the duration of B-cell aplasia is a good indicator of the efficacy of therapy: short durations are associated with disease relapse.3 This reasoning is supported by data showing CAR T-cell expansion even in the settings of low leukemic disease burden or minimal residual disease, which suggests that both leukemic and B cells are important for the CAR T-cell expansion process.2
B-cell aplasia can lead to agammaglobulinemia and hypogammaglobulinemia, potentially resulting in sinopulmonary, bacterial, and other life-threatening infections.4 In fact, hypogammaglobulinemia occurred in 67% of patients beyond 90 days after CAR T-cell therapy in one study cohort of patients with B-cell acute lymphoblastic leukemia.5 Immunoglobulin replacement, which increases the level of serum immunoglobulin G (IgG), decreases the risk for sinopulmonary infections.3 Post–CAR T-cell administration immunoglobulin replacement is the standard of care for pediatric patients.6 Although there is a lack of data on the most effective frequency and mode of administration for immunoglobulin replacement in adults with B-cell aplasia, serum IgG levels of 720 to 1430 mg/dL have been shown to be protective against infections.3 For adults with hypogammaglobulinemia plus a history of recurrent or chronic infections, IV immunoglobulin replacement should be performed following CAR T-cell therapy.7 Those patients who develop B-cell aplasia and hypogammaglobulinemia and/or frequent infections may require long-term monthly SC or IV immunoglobulin replacement.
Regarding ciltacabtagene autoleucel specifically, the product insert notes that hypogammaglobulinemia was reported in 12% of patients, and IgG levels fell below 500 mg/dL post-infusion in 92% of patients. The product insert recommends IgG level monitoring and administration of IVIG for those patients with levels < 400 mg/dL.8 Long-term rates of hypogammaglobulinemia (up to 15 years) for patients who receive ciltacabtagene autoleucel are currently being studied (NCT05201781).
A 2021 study investigating rates of hypogammaglobulinemia for patients who received tisagenlecleucel or axicabtagene ciloleucel for treatment of diffuse large B-cell lymphoma, follicular lymphoma, or CNS lymphoma found that 72 of 89 patients had hypogammaglobulinemia post-infusion, with 13% of these cases (9 patients) being severe. The median time to nadir IgG levels was 2 months (interquartile range: 1-6 months).9
- Blimark C, Homberg E, Mellgvist U-H, et al. Multiple myeloma and infections: A population-based study on 9253 multiple myeloma patients. Haematologica. 2015;11:107-113.
- Chen GM, Melenhorst JJ, Tan K. B cell targeting in CAR T cell therapy: Side effect or driver of CAR T cell function? Sci Transl Med. 2022;14:eabn3353.
- Kozani PS, Kozani PS, Rahbarizadeh F. Optimizing the clinical impact of CAR-T cell therapy in B-cell acute lymphoblastic leukemia: Looking back while moving forward. Frontiers Immunol. 2021;12:765097.
- Williams O. Management of short-, medium-, and long-term complications in patients receiving CAR T-cell therapy. MultipleMyelomaHub. https://multiplemyelomahub.com/medical-information/management-of-short-medium-and-long-term-complications-in-patients-receiving-car-t-cell-therapy. Accessed May 1, 2023.
- Cordeiro A, Bezerra ED, Hirayama AV, et al. Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells. Biol Blood Marrow Transplant. 2020;26:26-33.
- Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-48.
- Topp M, Feuchtinger T. Management of hypogammaglobulinaemia and B-cell aplasia. In: Krӧger N, Gribben JG, Chabannon C, et al., eds. The EBMT/EHA CAR-T Cell Handbook. The European Society for Blood and Marrow Transplantation; 2022:147-49. Accessed April 18, 2023. https://doi.org/10.1007/978-3-030-94353-0_28
- Carvykti product insert. https://www.sec.gov/Archives/edgar/data/1801198/000115752322000274/a52587126ex99_1.htm. Accessed May 1, 2023.
- Barmettler S, Yang N, Farmer J, et al. Significant hypogammaglobulinemia in patients receiving CAR T-cell therapy. J Allergy Clin Immunol. 2021;147:Suppl AB1.