Real-world evidence from Japan in patients with hematological malignancies and secondary hypogammaglobulinemia treated with 20% subcutaneous immunoglobulin, Ig20Gly: A retrospective cohort study.

1. Introduction

Inherited diseases that cause partial or total impairment of components of the immune system are called primary immunodeficiency (PID), and diseases caused by impairment of immunity due to non-inherited disease are called secondary immunodeficiency (SID). [ 1 ] The most common subtype of SID is secondary antibody deficiency, which is characterized by declines in the level and function of serum immunoglobulins called secondary hypogammaglobulinemia (SHG). [ 2 ] Patients with hematological malignancies develop SID due to the characteristics of the disease itself, B cell targeted therapies including chimeric antigen receptor-T cell (CAR-T) therapy and bispecific T cell engager therapy, which are being increasingly used in recent years, and hematopoietic cell transplantation and exhibit SHG. [ 3 – 8 ] SID and SHG have been reported to be related to an increase in the risk of severe infection and poor outcome, [ 9 , 10 ] and it is important to evaluate immunoglobulin replacement therapy (IgRT) at an appropriate timing. The data concerning IgRT have been derived primarily from PID patients and have been extrapolated to SID patients, [ 11 , 12 ] and there are only reports of clinical trials and studies of small groups regarding SID patients. [ 13 – 16 ]

Glycine-stabilized 20% subcutaneous immunoglobulin (Ig20Gly; Cuvitru®, Takeda Pharmaceutical K.K., Osaka, Japan) was developed for the prevention of infection in PID and SID patients. [ 17 , 18 ] It was approved in Europe and the United States in 2016 and is currently approved and marketed in more than 30 countries. Ig20Gly, which was launched in Japan on January 24, 2024, has an effect or efficacy against agammaglobulinemia or hypogammaglobulinemia and is under health insurance coverage.

Immunoglobulin is a limited resource and an expensive drug, and the standards or recommendations for its administration vary among countries. [ 19 ] Evidence about IgRT is primarily the result of clinical trials performed before 2000 or their meta-analyses, [ 20 ] and recent real-world data in the era of developed B cell targeted therapies are scarce. The objective of this study is to evaluate the safety and efficacy of Ig20Gly in Japanese patients with hematological malignancies accompanied by SID.

2. Material and methods

The patients who were administered Ig20Gly at least once in and after January 2024 at Tottori Prefectural Central Hospital were enrolled in this retrospective study (data cutoff was on January 23, 2025, 1 year after the marketing of Ig20Gly). The judgments about the initiation of IgRT, dose of Ig20Gly, and dosing intervals were left to the discretion of the physician in charge. The subjects included those who were using l-proline-stabilized 20% subcutaneous immunoglobulin (IgPro20; Hizentra®, CSL Behring K.K., Tokyo, Japan) and those who switched from the above drug. Information about the patient characteristics, hematological parameters including IgG, presence or absence of histories of infection before and after IgRT, and all adverse events during and after Ig20Gly administration was collected from clinical records. The incidence of infection was calculated as the number of cases/patient-years separately during the 1 year before the beginning of IgRT (period A), during the period of IgPro20 administration (period B), and during the period of Ig20Gly administration (period C).

Infection was defined as bacterial, fungal, or viral infection that required the administration of antibacterial, antifungal, or antiviral drugs regardless of whether the causative bacteria or virus was identified, infection that required hospitalization, or an equivalent condition. Patients who lacked data of serum IgG measurement before and after IgRT, HIV patients, and patients who had received solid organ transplantation were excluded.

For statistical analysis, we described the background and event occurrence of the group targeted for the analysis. Body size and IgG levels varied widely among individuals and were presented as averages. Regarding the incidence of infection, we did not use specialized analysis, such as Poisson regression analysis, because patients who have developed an infection once tend to be prone to recurrence. Instead, we simply described the incidence of infections.

This is a retrospective study conducted at Tottori Prefectural Central Hospital, Tottori, Japan. It was carried out in compliance with the Declaration of Helsinki and was approved by the Ethical Committee of Tottori Prefectural Central Hospital (Approval No. 2024-64).

3. Results

The background of the 27 patients is shown in Table 1 . Their median age was 68 years (range: 47–80), and more than 70% were male. The underlying hematological disease was lymphomas in 13, myeloma or related diseases in 13, and 1 patient undergoing long-term steroid therapy for chronic graft-versus-host disease after allogeneic transplantation for acute lymphoblastic leukemia. All patients had a history of the use of an antibody drug and steroid, the median number of treatment regimens was 4, and treatment for hematological disease was continued in 12. Ten were after autologous transplantation, 2 were after allogeneic transplantation, and 4 were after CAR-T therapy. The treatment was switched from IgPro20 in 18, and Ig20Gly was newly introduced in 9. Reasons for switching from IgPro20 to Ig20Gly included insufficient increase in IgG levels, and suboptimal tolerability due to adverse events. No patients were switched from intravenous immunoglobulin to IgPro20 or Ig20Gly, or received home self-injection. In period A, 25 patients had received antibody therapy, CAR-T or transplantation therapy, 1 patient had received the above treatment within 6 months, and 1 patient had received the above treatment more than 1 year ago. In period B, 12 patients had received antibody therapy, CAR-T or transplantation therapy, 2 patients had received the above treatment within 6 months, 2 patients had received the above treatment more than 6 months but <1 year, and 2 patients had received the above treatment more than 1 year ago. In period C, 12 patients had received antibody therapy, CAR-T or transplantation therapy, 4 patients had received the above treatment within 6 months, 1 patient had received the above treatment more than 6 months but <1 year, and 10 patients had received the above treatment more than 1 year ago. Period A was after the COVID-19 epidemic except for 2 patients (periods B and C were all after the COVID-19 epidemic).

The dose of subcutaneous immunoglobulin (SCIG) administration was left to the discretion of the physician in charge, and the mean dose per administration was 74.4 ± 10.1 mg/kg for IgPro20 and 121.9 ± 59.1 mg/kg for Ig20Gly, being higher for Ig20Gly (Table 2 ). While the mean IgG level was 3.6 ± 1.5 g/L in period A, the IgG trough level in all patients was 3.7 ± 1.3 g/L and 4.7 ± 1.5 g/L in period B and period C, respectively, being higher in Period C in proportion to the dose (Table 2 ). Regarding IgM and IgA levels, 7 patients could not be evaluated, and most patients did not change during periods A, B, and C. However, 2 patients had increased IgA levels in period C and 1 patient had increased IgM levels in period C. Regarding prophylactic antibiotics, antifungals, and antivirals, in period A, 9 patients received antibiotics, 9 patients received antivirals, and 2 patients received antifungals; in period B, 10 patients received antibiotics and 10 patients received antivirals; and in period C, 9 patients received antibiotics and 7 patients received antivirals (No antifungal drugs were administered during periods B and C).

The incidence of infection was compared among periods A to C (Table 3 ). While it was 3.67/patient-years in period A, it was lower in the SCIG groups, being 1.81/patient-years in period B and 1.32/patient-years in period C. After SCIG, mainly bacterial and viral infections were reduced.

In period C, Ig20Gly was administered a total of 228 times. Adverse events associated with Ig20Gly administration occurred in 18 (66.7%) of all patients (Table 4 ). No systemic adverse event was observed in any patient, all being local adverse events. In the 18 patients, 69 local adverse events were observed, that is, 35 cases of erythema at the injection site (44.4%) in 12 patients, 16 cases of swelling at the injection site (25.9%) in 7 patients, 15 cases of pruritus at the injection site (22.2%) in 6 patients, and 3 cases of pain at the injection site (11.1%) in 3 patients, in descending order of frequency. All local adverse events that occurred were grade 1.

4. Discussion

This study presents the first real-world data from SID patients treated with Ig20Gly in Japan. The results that Ig20Gly reduced the incidence of infection in patients with SID, and few systemic and only mild local adverse events were observed, suggesting a high level of safety.

SHG is frequently observed in patients with B cell malignancies such as chronic lymphocytic leukemia, non-Hodgkin lymphoma, and myeloma. [ 21 ] These conditions are related to multifactorial immunodeficiency caused by the underlying disease, its treatments, or both, and infection is known to be the primary cause of death in these conditions. [ 22 ] Strategies to reduce infection, which include vaccination, preventive antibacterial therapy, and IgRT, are important for the quality of life, continuation of treatment, and mortality rate. [ 23 ] According to a recent meta-analysis, [ 24 ] preventive antibacterial therapy significantly reduced the incidence of infection in myeloma patients, but it is associated with concern over the development of resistance and pandemics. Regarding IgRT, large-scale randomized clinical trials in SID patients and evidence about infection and mortality are limited, and many of them were reported in the 1990s. [ 25 , 26 ] While its usefulness has recently been reported by small-scale prospective/retrospective studies and meta-analyses, [ 13 – 16 , 20 ] immunoglobulin is a limited and expensive resource, so it is necessary to define the indications for its use. While the use of IgRT is permitted only if responses to vaccination are poor, and antibacterial therapies are ineffective, in some countries such as the United Kingdom, it can be used when hypogammaglobulinemia is observed regardless of the frequency or severity of infection in others. [ 12 , 27 , 28 ] Because of the differences in its indications and the system for insurance coverage, universal guidelines for its use are difficult to formulate. However, B cell targeted therapies for patients with hematological disorders are rapidly evolving, and guidance about IgRT is an urgent issue for clinicians who struggle with infections daily.

The data about the use of IgRT in SID patients mentioned above are based on reports of the use of existing SCIG including primarily IVIG and IgRo20, and there have been few reports of the use of Ig20Gly in SID patients. In Japan, it is not common to consider indications of IgRT by evaluating responses to vaccine, and SCIG can be used for SHG under insurance coverage regardless of responses to antibacterial drugs. However, the frequency of use of SGIG varies by region, and reports on SCIG from Asian and Middle Eastern countries are limited. [ 19 , 29 ] Concerning the supply of drugs, IgPro20 was the only available SCIG until recently, and, in addition, it was administered once a week until a new regimen (once every 2 weeks) was approved in June 2023, causing inconvenience to patients. [ 30 ] Although the sale of Ig20Gly was started in Japan on January 24, 2024, all clinical trials in Western countries and Japan cited in the application for approval were performed in PID patients. We evaluated the safety and efficacy of Ig20Gly in patients with hematological malignancies accompanied by SID in Japan 1 year after its marketing.

Our data were obtained retrospectively, and the judgment about the indications of IgRT was left to the discretion of the physician in charge. However, the IgG level before the beginning of IgRT was <4.0 g/L (Table 2 ), and there were repeated episodes of infection during the 1 year before its beginning with an incidence of 3.67/patient-years, so the patients treated with Ig20Gly are considered to have met the indications for IgRT presented by the European Medicines Agency. [ 19 , 21 , 23 , 27 ] The mean IgG trough value during IgPro20 administration was 3.7 g/L. Although this was not significantly different to the value at the start of IgRT (mean 3.6 g/L), the incidence of infections decreased. The reasons for this include the time since chemotherapy and the effects of prophylactic antibacterial, antifungal, and antiviral drugs, as mentioned above. In period B, the proportion of patients receiving prophylactic antibacterial and antiviral drugs was higher than in period A, which may have led to a decrease in bacterial and viral infections, as shown in Table 3 . With regard to period C, the proportion of prophylactic antibacterial and antiviral drugs administered was similar to that in period A. However, the higher IgG trough values and the time interval since chemotherapy may have contributed to the difference in infection rates. Regarding the difference in dosage between IgPro20 and Ig20Gly, if the target is to administer 5 to 6 g at a time, it is possible that this difference arose because, due to the effort involved in administration, 1 vial of IgPro20 with the maximum specification (4 g/20 mL) was used, which is slightly less, while 1 vial of Ig20Gly with the maximum specification (8 g/40 mL) was used, which is slightly more, in order to make more efficient use of medical resources.

The results of representative clinical trials of Ig20Gly regarding the incidence of infection and the frequency of adverse events are shown below. In a phase II/III trial in 77 PID patients performed in North America, the incidence of all infections was 2.41/patient-years, and the incidences of all nonserious adverse events and local adverse events were 37.8% and 24.3%, respectively. [ 31 ] In a phase II/III trial in 49 PID patients in Europe, the incidence of all infections was 2.04/patient-years, and the incidences of all non-serious adverse events and local adverse events were 41.7% and 35.4%, respectively. [ 32 ] In a recently reported phase III trial in 17 PID patients in Japan, the incidences of all adverse events and local adverse events were 70.6% and 58.8%, respectively. [ 33 ] Concerning IgPro20, the data of a phase III trial in 25 PID patients in Japan and real-world data obtained from a total of 85 patients with PID or SID have been reported. [ 13 ] In the former, the incidence of all infections was 2.98/patient-years, and the incidences of all adverse events and local adverse events were 84.0% and 80.0%, respectively. In the latter, the incidence of all infections per patient during 6 months was 0.39, and the incidences of all adverse events and local adverse events were 45.9% and 20.0%, respectively. Naturally, it is not appropriate to compare studies that vary in method, patient population, or treatment, but the understanding of the patient background in the original papers helps readers with interpretation of the presented data. What is important in this study is that the incidence of infection deceased after IgRT compared with that during the 1 year before the beginning of IgRT in the same population.

This study includes the following limitations: firstly, it was retrospective in nature. Secondly, the affects of chemotherapy were not the same in each period. Thirdly, although the use of prophylactic antibacterial, antifungal, and antiviral drugs was as mentioned above, no information was available on vaccinations. Fourthly, the setting of the dosage of SCIG, the dosing interval, and the target IgG trough level was entrusted to the discretion of the attending physician. Fifthly, the observation period of the Ig20Gly group was insufficiently prolonged, and long-term observation is necessary for the future. Sixth, it remains difficult to determine if there is a statistically significant discrepancy because a specialized analysis of infection rates has not been conducted. Seventh, there were no unified standards for the evaluation of local adverse events, and the judgments about adverse events were left to the medical staff in charge, which left room for underrating. However, the indications for IgRT were generally appropriately selected, and the actual conditions of patients at actual intervals between visits were recorded. In addition, some patients in period B and patients in period C included patients who did not experience any of the 4 seasons, so the influence of seasonal infections cannot necessarily be excluded, but there were no patients who did not experience the winter season.

In conclusion, Ig20Gly administered in real clinical situations reduced infections in SID patients compared with the level before the beginning of IgRT with few systemic adverse events and only mild local adverse events. It is important to avoid unfortunate interruptions of treatment for underlying disease due to repeated or severe infections, and the prevention of infection focusing on the population that needs IgRT is necessary.

Acknowledgments

We thank Medical English Service ( www.med-english.com ) for editing this manuscript.

Author contributions

Writing – original draft: Yoshinori Hashimoto.

Writing – review & editing: Saaya Hosoda, Hiromi Omura, Takayuki Tanaka.

Abbreviations: CAR-T chimeric antigen receptor-T cell IgPro20 l-proline-stabilized 20% subcutaneous immunoglobulin IgRT immunoglobulin replacement therapy Ig20Gly glycine-stabilized 20% subcutaneous immunoglobulin PID primary immunodeficiency SCIG subcutaneous immunoglobulin SHG secondary hypogammaglobulinemia SID secondary immunodeficiency

The study data were analyzed anonymously and the patient privacy was protected. The patients were assured that participation was voluntary and that they may opt out of information disclosure. Written informed consent requirements were waived for this study by the Ethics Committee of Tottori Prefectural Central Hospital.

This study was performed according to the principles of the Declaration of Helsinki, and was approved by the Ethics Committee of Tottori Prefectural Central Hospital (Approval No. 2024-64).

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Hashimoto Y, Hosoda S, Omura H, Tanaka T. Real-world evidence from Japan in patients with hematological malignancies and secondary hypogammaglobulinemia treated with 20% subcutaneous immunoglobulin, Ig20Gly: A retrospective cohort study. Medicine 2025;104:42(e45145).

Contributor Information

Saaya Hosoda, Email: saaya.hosoda@tp-ch.jp.

Hiromi Omura, Email: omura-h@tp-ch.jp.

Takayuki Tanaka, Email: tanaka-tak@tp-ch.jp.

References

[1] Patel SY, Carbone J, Jolles S. The expanding field of secondary antibody deficiency: causes, diagnosis, and management. Front Immunol. 2019;10:33.

[2] Shah N, Mustafa SS, Vinh DC. Management of secondary immunodeficiency in hematological malignancies in the era of modern oncology. Crit Rev Oncol Hematol. 2023;181:103896.

[3] Thiruvengadam SK, Sheng Y, Huang CY, et al. Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T-cell therapy. Blood Adv. 2022;6:2045–54.

[4] Cappell KM, Sherry RM, Yang JC, et al. Long-term follow-up of anti-CD19 chimeric antigen receptor T-Cell therapy. J Clin Oncol. 2020;38:3805–15.

[5] Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29:2259–67.

[6] Thieblemont C, Karimi YH, Ghesquieres H, et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia. 2024;38:2653–62.

[7] Suga M, Fuji S, Tada Y, et al. A single-institution pre-post comparison of subcutaneous immunoglobulin replacement therapy in allogeneic haematopoietic cell transplantation recipients. Br J Haematol. 2024;204:260–7.

[8] Arai Y, Yamashita K, Mizugishi K, et al. Risk factors for hypogammaglobulinemia after allo-SCT. Bone Marrow Transplant. 2014;49:859–61.

[9] Link H, Kerkmann M, Holtmann L; Working Groups Supportive Care (AGSMO). Medical Oncology (AIO) of the German Cancer Society (DKG). Immunoglobulin substitution in patients with secondary antibody deficiency in chronic lymphocytic leukemia and multiple myeloma: a representative analysis of guideline adherence and infections. Support Care Cancer. 2022;30:5187–200.

[10] Ye C, Chen W, Gao Q, et al. Secondary immunodeficiency and hypogammaglobulinemia with IgG Levels of <5 g/L in patients with multiple myeloma: a retrospective study between 2012 and 2020 at a university hospital in China. Med Sci Monit. 2021;27:e930241.

[11] Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol. 2010;137:21–30.

[12] Jolles S, Chapel H, Litzman J. When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach. Clin Exp Immunol. 2017;188:333–41.

[13] Imai K, Ishii T, Nonoyama S, et al. Real-world results with IgPro20 for hypo- or agammaglobulinemia in Japan. Pediatr Int. 2022;64:e15362.

[14] Vacca A, Melaccio A, Sportelli A, Solimando AG, Dammacco F, Ria R. Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial. Clin Immunol. 2018;191:110–5.

[15] Hirata A, Miyashita K, Tanaka T, et al. Serum immunoglobulin G as a discriminator of infection in follicular lymphoma patients undergoing chemotherapy with bendamustine in combination with rituximab. Hematology. 2022;27:384–95.

[16] Visentin A, Molinari MC, Pravato S, et al. A retrospective study on the efficacy of subcutaneous immunoglobulin as compared to intravenous formulation in patients with chronic lymphocytic leukemia and secondary antibody deficiency. Curr Oncol. 2022;30:274–83.

[17] Suez D, Kriván G, Jolles S, et al. Safety and tolerability of subcutaneous immunoglobulin 20% in primary immunodeficiency diseases from two continents. Immunotherapy. 2019;11:1057–65.

[18] Keith PK, Cowan J, Kanani A, et al. Transitioning subcutaneous immunoglobulin 20% therapies in patients with primary and secondary immunodeficiencies: canadian real-world study. Allergy Asthma Clin Immunol. 2022;18:70.

[19] Ar MC, El Fakih R, Gabbassova S, et al. Management of humoral secondary immunodeficiency in hematological malignancies and following hematopoietic stem cell transplantation: regional perspectives. Leuk Res. 2023;133:107365.

[20] Chai KL, Wong J, Weinkove R, et al. Interventions to reduce infections in patients with hematological malignancies: a systematic review and meta-analysis. Blood Adv. 2023;7:20–31.

[21] Sim B, Ng JY, Teh BW, Talaulikar D. Immunoglobulin replacement in hematological malignancies: a focus on evidence, alternatives, dosing strategy, and cessation rule. Leuk Lymphoma. 2023;64:18–29.

[22] Jolles S, Giralt S, Kerre T, et al. Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: a systematic literature review. Front Oncol. 2023;13:1098326.

[23] Otani IM, Lehman HK, Jongco AM, et al. Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: a Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees. J Allergy Clin Immunol. 2022;149:1525–60.

[24] Mohyuddin GR, Aziz M, McClune B, Abdallah AO, Qazilbash M. Antibiotic prophylaxis for patients with newly diagnosed multiple myeloma: systematic review and meta-analysis. Eur J Haematol. 2020;104:420–6.

[25] Boughton BJ, Jackson N, Lim S, Smith N. Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia. Clin Lab Haematol. 1995;17:75–80.

[26] Molica S, Musto P, Chiurazzi F, et al. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica. 1996;81:121–6.

[27] Jolles S, Michallet M, Agostini C, et al. Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus. Eur J Haematol. 2021;106:439–49.

[28] Wong J, Wood EM, Crispin P, Weinkove R, McQuilten ZK; Australasian Leukaemia and Lymphoma Group (ALLG) Supportive Care Group. Managing hypogammaglobulinaemia secondary to haematological malignancies in Australia and New Zealand: a clinician survey. Intern Med J. 2019;49:358–63.

[29] Jolles S, Sleasman JW. Subcutaneous immunoglobulin replacement therapy with Hizentra, the first 20% SCIG preparation: a practical approach. Adv Ther. 2011;28:521–33.

[30] Jolles S, Rojavin MA, Lawo JP, et al. Long-term efficacy and safety of Hizentra® in patients with primary immunodeficiency in Japan, Europe, and the United States: a review of 7 phase 3 trials. J Clin Immunol. 2018;38:864–75.

[31] Suez D, Stein M, Gupta S, et al. Efficacy, safety, and pharmacokinetics of a novel human immune globulin subcutaneous, 20 % in patients with primary immunodeficiency diseases in North America. J Clin Immunol. 2016;36:700–12.

[32] Borte M, Kriván G, Derfalvi B, et al. Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a phase 2/3 study in Europe in patients with primary immunodeficiencies. Clin Exp Immunol. 2017;187:146–59.

[33] Kanegane H, Endo A, Okada S, et al. Pharmacokinetics, safety, and efficacy of 20% subcutaneous immunoglobulin (Ig20Gly) administered weekly or every 2 weeks in Japanese patients with primary immunodeficiency diseases: a phase 3, open-label study. Immunother Adv. 2024;4:ltae001.