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Frontiers in Hematology ·

Volume 5 - 2026 | https://doi.org/10.3389/frhem.2026.1904290

Immunoglobulin replacement therapy in hematologic malignancy–associated secondary immunodeficiency: roles of SCIG and IVIG

  • Erika Seaquist1
  • Anna Majapuro-Hirvonen2
  • Rashelle Van Wagoner2*corresponding author
  • Brent Rutland2
  1. 1Center for Cancer and Blood Disorders, Intermountain Primary Children’s Hospital, Salt Lake City, UT, United States
  2. 2Medical and Clinical Affairs, KORU Medical Systems, Mahwah, NJ, United States
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Abstract

Secondary immunodeficiency (SID) is an increasingly recognized complication among patients with hematologic malignancies and targeted cellular therapies, including CAR-T therapy, contributing to recurrent infections, increased healthcare utilization, and reduced HRQoL. Recent literature, guideline recommendations, real-world evidence (RWE), and selected clinical studies were reviewed to evaluate current approaches to intravenous and subcutaneous immunoglobulin replacement therapy (IgRT; IVIG and SCIG, respectively) in hematologic malignancy-associated SID. Both IVIG and SCIG provide effective humoral immune support, while current evidence indicates that SCIG provides more consistent steady-state IgG concentrations with reduced peak-to-trough fluctuations and fewer systemic adverse events. Emerging evidence also supports pharmacokinetically informed approaches that integrate IgG concentrations, infection burden, clinical response, and individual patient characteristics to guide long-term IgRT management. IgRT remains an important component of supportive treatment for patients with hematologic malignancy-associated SID who have documented hypogammaglobulinemia and recurrent, severe, or persistent infections. Current evidence supports both IVIG and SCIG as effective treatment options, with SCIG offering advantages for many patients requiring long-term therapy through more consistent IgG exposure, fewer systemic adverse events, and the convenience of home-based administration. Future IgRT strategies should emphasize evidence-informed patient selection, therapeutic monitoring, immune reconstitution, and responsible stewardship of plasma-derived immunoglobulin resources. Additional prospective studies are needed to define optimal monitoring strategies, treatment duration, and criteria for initiation and discontinuation to further improve long-term outcomes.

Keywords

1 Introduction

Secondary immunodeficiency (SID) is increasingly recognized as a major complication of hematologic malignancies (HM) and modern oncologic therapies, including anti-CD20 therapies, hematopoietic stem cell transplantation (HSCT), and CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy (1–11). The mechanisms underlying SID vary according to the underlying HM and its treatment. B-cell-depleting therapies, HSCT, and CAR-T-cell therapy frequently result in prolonged hypogammaglobulinemia, impaired humoral immunity, and delayed immune reconstitution, contributing to recurrent infections, increased healthcare utilization, and reduced health-related quality-of-life (HRQoL) (1, 2, 4, 6, 10, 12–14).

The spectrum of immune dysfunction varies according to the underlying malignancy and treatment, with B-cell depletion primarily affecting humoral immunity, whereas HSCT and CAR-T therapy may result in broader immune defects that influence infection susceptibility and supportive care requirements (1–14).

As the use of cellular therapies and B-cell-depleting therapies continues to expand, the prevalence of therapy-associated SID and long-term immunoglobulin replacement therapy (IgRT) requirements are expected to increase substantially (2–7, 10, 15). IgRT has emerged as an increasingly important component of supportive immuno-hematologic care, with growing emphasis on infection prevention, optimized treatment selection, and support of humoral immunity.

Both intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) are effective strategies for infection prevention and immune support in patients with antibody deficiency associated with HM and post-transplant immune dysfunction (1, 13, 14, 16, 17). However, substantial heterogeneity exists across oncology-associated SID populations with respect to baseline immune status, treatment-related immunosuppression, comorbidities, and infection susceptibility (1, 12–14). Diagnostic frameworks developed for primary antibody deficiency (PAD) also demonstrate substantial heterogeneity in quantitative and functional immune abnormalities, highlighting limitations in directly extrapolating PAD criteria to acquired SID (18–21). These differences highlight the importance of patient-specific dosing and pharmacokinetically informed approaches that consider IgG exposure, trough concentrations, dosing interval, and clinical response in long-term supportive oncology care (1, 13, 14, 16).

Emerging evidence suggests that SCIG provides comparable clinical effectiveness to IVIG while offering advantages in pharmacokinetic stability, home-based administration, patient autonomy, and reduced systemic adverse events (16, 17, 22–29).

Increasing emphasis has also been placed on tailored IgRT strategies, including IgG trough optimization, pharmacokinetically informed dosing approaches, and integration of patient-reported outcomes (PROs) and healthcare resource utilization into long-term treatment planning (13, 14, 17, 30–36).

This Mini Review summarizes recent developments in IgRT for SID associated with HMs, focusing on comparative roles of IVIG and SCIG, pharmacokinetic-informed treatment strategies, outcomes, and emerging approaches to optimized IgRT (1, 13, 14, 17, 37). Particular attention is given to infection prevention, immune reconstitution, therapeutic monitoring, and practical considerations that may inform future treatment strategies.

2 Patient-centered IgRT in hematologic malignancy-associated SID

The growing use of IgRT in oncology-associated SID has intensified the need for practical, evidence-based strategies that support long-term treatment outcomes and sustainable healthcare resource utilization (1, 13, 14). Both IVIG and SCIG are effective in reducing infection burden and improving HRQoL outcomes in patients with HMs, post-transplant immune dysfunction, and treatment-related hypogammaglobulinemia (1, 13, 14, 16, 17, 38, 39). However, heterogeneity in patient phenotypes, underlying immune dysfunction, comorbidities, treatment-related immunosuppression, and pharmacokinetic responses contributes to variability in clinical outcomes, highlighting the importance of individualized IgRT strategies (1, 13, 14, 16).

2.1 Infection prevention, pharmacokinetic stability, and IgG trough management

Real-world evidence (RWE) and clinical studies consistently demonstrate substantial reductions in infections, hospitalizations, and healthcare utilization following initiation of IgRT in oncology-associated SID populations (16, 17, 22, 23, 38, 39). In the Ontario Immunoglobulin Treatment Case Registry, IgRT was associated with an 82.6% reduction in annual infections, an 84.6% reduction in emergency department visits, and an 83.3% reduction in hospitalizations (17). In a Japanese cohort with HM-associated SHG, 20% SCIG reduced infection rates from 3.67 to 1.32 infections per patient-year (22). Post-marketing data with IgPro20 similarly demonstrated reductions in infections and serious bacterial infections (23). Randomized controlled trials and consensus guidelines support both IVIG and SCIG as effective strategies for infection prevention in patients with SID associated with chronic lymphocytic leukemia (CLL), lymphoma, and post-transplant immune dysfunction (13, 14, 38, 39). Maintenance of adequate serum IgG trough levels remains a central pharmacokinetic goal of long-term IgRT management (13, 16, 24–26, 37). Compared with IVIG, SCIG provides more consistent steady-state IgG concentrations and reduces the cyclical peaks and troughs associated with intermittent intravenous administration (24–26, 33). In a retrospective comparison of 131 patients with secondary antibody deficiency (SAD) and 102 with PAD, SCIG produced comparable reductions in infection burden in SAD despite lower doses and lower steady-state IgG trough concentrations, suggesting that IgRT requirements may differ between PAD and SAD (16).

2.2 Safety, quality-of-life outcomes, and home-based immunoglobulin therapy

Adverse event profiles differ substantially between IVIG and SCIG and remain important considerations in long-term IgRT management for oncology-associated SID. IVIG is associated with a higher incidence of systemic adverse reactions, including headache, fever, nausea, thromboembolic events, aseptic meningitis, hemolysis, and, less commonly, renal dysfunction or anaphylaxis. Systemic reactions occur in approximately 20–50% of patients and 5–15% of infusions, with most reactions being mild to moderate in severity (40–43).

In contrast, SCIG is associated with fewer systemic adverse events but a higher frequency of localized injection-site reactions, including erythema, swelling, and rash, which are typically mild and self-limited (22, 23). Emerging evidence suggests that facilitated SCIG (fSCIG) may further improve tolerability and reduce hospital burden while maintaining clinical effectiveness (27–29).

Beyond infection prevention, PROs, treatment satisfaction, and HRQoL measures are increasingly recognized as important components of long-term IgRT management. Real-world studies demonstrate that SCIG is associated with improved treatment convenience, greater patient autonomy, and enhanced HRQoL outcomes, particularly through home-based self-administration and reduced dependence on infusion centers (17, 30–32, 44). These improvements include higher treatment satisfaction, greater independence with home therapy, reduced treatment burden, and improved HRQoL across multiple PRO domains (30, 31). Patients transitioning from IVIG to SCIG frequently reported improved treatment satisfaction and reduced treatment burden (17).

2.3 Healthcare resource utilization and treatment sustainability

Healthcare resource utilization and treatment sustainability are increasingly important considerations in the long-term management of oncology-associated SID. Although both IVIG and SCIG are associated with substantial treatment costs, SCIG may reduce overall healthcare expenditure through home-based administration, decreased infusion-center utilization, and reduced hospitalization rates. Home-based SCIG reduces hospital visits while maintaining clinical effectiveness and has consistently demonstrated favorable patient satisfaction and resource utilization in real-world studies (22, 30, 31, 34–36). Cost-effectiveness analyses suggest that home-based SCIG may provide improved quality-adjusted life outcomes and lower annual healthcare costs compared with hospital-based IVIG administration, supporting more efficient and patient-centered IgRT strategies for long-term oncology care (34–36). In a 10-year cost-utility analysis, home-based SCIG was associated with greater quality-adjusted life years (3.51 vs 3.07 quality-adjusted life years) and lower cumulative healthcare costs than hospital-based IVIG, supporting SCIG as the dominant treatment strategy from a healthcare system perspective (34).

3 Long-term immune reconstitution, real-world evidence, and healthcare sustainability

3.1 Long-term outcomes and emerging oncology populations

Long-term observational studies and registry-based analyses suggest that IgRT provides sustained reductions in infection burden and healthcare utilization in patients with oncology-associated SID (17, 27–29).

Persistent hypogammaglobulinemia following HSCT, anti-CD20 therapy, and CD19-directed CAR-T therapy remains a major clinical challenge, particularly in patients with delayed immune reconstitution and recurrent infections. These populations represent an emerging model of acquired immune dysfunction in which delayed B-cell recovery and impaired humoral reconstitution increasingly require individualized immunologic treatment strategies (2–11).

Despite expanding use of IgRT in HMs, important evidence gaps remain in pediatric populations, solid tumors, elderly patients, and patients receiving emerging cellular and targeted therapies (1, 13, 14). As the use of CAR-T therapies and B-cell-depleting therapies continues to increase, the population of patients with prolonged antibody deficiency and complex immune reconstitution needs is expected to expand (2, 4–11).

3.2 Real-world evidence and individualized treatment strategies

RWE and registry-based analyses continue to advance understanding of immune recovery patterns, treatment utilization, and long-term immunotherapy strategies across SID populations (16, 17, 28, 29). Compared with randomized controlled trials, observational studies may better reflect treatment variability, administration preferences, healthcare resource utilization, and long-term outcomes across diverse clinical settings.

3.3 Resource stewardship and healthcare sustainability

Responsible stewardship of plasma-derived immunoglobulin products is becoming increasingly important as global demand continues to rise (13, 34–36). Cost-effectiveness analyses suggest that SCIG may reduce cumulative healthcare expenditures and improve quality-adjusted life outcomes in patients requiring long-term therapy (34–36). These findings support evidence-informed patient selection and sustainable utilization of immunoglobulin resources while maintaining effective infection prevention in oncology-associated SID (1, 13, 14, 28, 29).

4 Guideline recommendations and practical implementation strategies

4.1 Guideline-based IgRT and individualized dosing

Guidance from the American Academy of Allergy, Asthma, and Immunology (AAAAI) and other international societies, including the British Committee for Standards in Hematology (BCSH), the National Comprehensive Cancer Network (NCCN), and the European Society for Immunodeficiencies (ESID), supports the use of IVIG or SCIG in patients with secondary hypogammaglobulinemia (SHG) due to hematologic or oncologic disease who have documented hypogammaglobulinemia and recurrent or severe infections (1, 13, 14). The AAAAI recommends an individualized IVIG dosing range of 0.4–0.8 g/kg every 28 days when clinically indicated for SID due to HM or oncologic therapy (1). SCIG dosing should be guided by infection control and clinical response; comparative real-world data suggest that patients with SAD may achieve similar infection reduction at lower doses and IgG trough concentrations than patients with PAD (16).

Guideline and consensus recommendations commonly consider IgRT in patients with CLL or MM who have marked hypogammaglobulinemia (often IgG <400–500 mg/dL) together with recurrent or severe infections, particularly when infections persist despite appropriate antimicrobial management (1, 13, 14). Functional antibody responses may further inform IgRT initiation in selected patients. In CLL, inadequate responses to diphtheria, tetanus, or pneumococcal vaccination may support IgRT in patients with SHG and recurrent bacterial infections; European guidance also recognizes specific antibody failure as an indication for IgRT in appropriate patients (1). In HSCT recipients, routine prophylactic IVIG administration is generally not recommended; however, IVIG or SCIG may be considered in patients with persistent hypogammaglobulinemia (IgG <400 mg/dL) and recurrent or severe infections (1, 13). In the setting of CAR-T therapy, individualized IgRT strategies are increasingly recommended for patients with persistent hypogammaglobulinemia and recurrent or severe infections, with baseline immune assessment recommended prior to therapy initiation (1).

In Europe, the use of IgRT in SID is supported by expert consensus statements and treatment recommendations, including the European Expert Consensus for SAD in Hematological Malignancies. In 2019, the European Medicines Agency approved an expanded indication for IgRT in patients with SID. However, regional variability remains regarding initiation criteria, dosing strategies, monitoring, and discontinuation of IgRT. The European consensus statements were developed to support harmonization of clinical practice and to provide guidance for patient-centered management (14, 45).

The European recommendations support consideration of IgRT in patients with HMs who have hypogammaglobulinemia associated with recurrent, severe, or persistent infections, particularly when antimicrobial prophylaxis alone is insufficient. The guidance further emphasizes treatment strategies based on infection burden, IgG levels, comorbidities, patient preference, venous access, and treatment setting. Registry studies additionally demonstrate sustained infection reduction together with durable treatment persistence during long-term SCIG therapy in routine clinical practice (16, 17, 22, 28, 39).

SCIG is recognized as an effective alternative to IVIG, particularly for long-term maintenance therapy, home-based administration, improved treatment flexibility, and reduced healthcare resource utilization. These recommendations align with broader European treatment practices supporting individualized approaches to IgRT administration in oncology-associated SID (14, 45).

4.2 Practical implementation of IgRT: patient selection, monitoring, and reassessment

There is no universally accepted IgG trough target for HM-associated SID. Decisions regarding initiation and continuation of IgRT should therefore integrate serum IgG concentrations with the patient’s infection history, underlying hematologic disease, degree of immune dysfunction, ongoing immunosuppressive therapy, and evidence of immune reconstitution rather than relying on IgG levels alone. Monitoring should aim to maintain IgG concentrations sufficient to reduce the risk of recurrent or severe infections, recognizing that treatment goals should be guided by overall clinical response rather than achievement of a single numeric threshold (1, 13, 14).

Patients with HMs who have documented SHG accompanied by recurrent, severe, or persistent infections despite optimized antimicrobial prophylaxis and other appropriate supportive care should be considered for IgRT. Consistent with current guideline recommendations, IgRT should complement, rather than replace, antimicrobial prophylaxis and other supportive measures when clinically indicated (1, 13, 14).

The choice between SCIG and IVIG is influenced by patient characteristics, administration logistics, monitoring requirements, venous access, treatment goals, and patient preference. IVIG is typically administered in hospitals or infusion centers and requires venous access and monitoring for systemic adverse reactions, with infusions given every 3 to 4 weeks (1, 46, 47). SCIG is administered more frequently, often weekly, biweekly, or monthly using fSCIG and is designed for home-based self-administration or nurse-supported outpatient care, providing more consistent IgG exposure and a reduced risk of systemic adverse events (4, 24–26, 31, 32, 40, 46, 47). Patients requiring long-term IgRT, those with poor venous access, recurrent systemic reactions to IVIG, or those who prefer home-based therapy may be particularly appropriate candidates for SCIG (13, 16, 28, 29, 48). Facilitated SCIG may further expand administration flexibility by enabling larger infusion volumes and less frequent infusions while maintaining favorable safety and tolerability profiles (27–29).

Because immunoglobulin products are derived from human plasma and global demand continues to increase, IgRT should be reserved for patients with documented immune dysfunction and clinically significant infections who are most likely to benefit. Appropriate patient selection, periodic reassessment, and timely discontinuation when clinically appropriate support both optimal patient outcomes and responsible stewardship of immunoglobulin resources. Optimal monitoring intervals and treatment duration have not been universally established for HM-associated SID. The frequency of reassessment should be individualized according to the underlying hematologic disease, infection burden, ongoing immunosuppressive therapy, and evidence of immune recovery, with more frequent monitoring during periods of active treatment or changing clinical status.

The primary objective of IgRT is prevention of recurrent and severe infections, rather than achievement of a universal serum IgG target (13). Successful long-term IgRT implementation also requires ongoing monitoring of infection frequency, serum IgG concentrations, adverse events, and PROs. Monitoring of immunoglobulin concentrations before and following B-cell-depleting therapy may also help identify patients at increased risk for persistent hypogammaglobulinemia and infectious complications (1, 13, 14, 49).

Patients should be reassessed periodically to determine whether IgRT should be continued, modified, or discontinued based on infection burden, serum IgG concentrations, treatment tolerability, changes in immunosuppressive therapy, and evidence of immune recovery (1, 13, 14). Following B-cell-depleting therapy, assessment of immune recovery may include serum immunoglobulin levels and B-cell reconstitution; however, validated biomarker thresholds for IgRT discontinuation have not been established (1, 13, 14, 50). Temporary interruption or discontinuation may be considered in selected patients who remain free of infections and demonstrate evidence of immune recovery, with reinitiation if recurrent infections develop (1, 13, 14, 51).

Practical considerations for IgRT initiation, route selection, monitoring, modification, and discontinuation in HM-associated SID are summarized in Table 1.

Table 1. Practical framework for IgRT initiation, route selection, monitoring, modification, and discontinuation in HM-associated SID.

DecisionPractical considerationsKey references
Initiate IgRTDocumented SHG with recurrent, severe, or persistent infections; consider infection history, IgG concentration, underlying HM/therapy, vaccine-specific antibody responses where appropriate, and response to antimicrobial/supportive measures(1, 13, 14)
Select IVIGNeed for supervised administration; inability or preference not to self-administer; clinical circumstances favoring intermittent intravenous treatment(1, 13, 14, 46, 47)
Select SCIGLong-term therapy; poor venous access; systemic reactions to IVIG; preference for home administration; need for more stable IgG exposure(13, 16, 28, 29, 48)
MonitorInfection frequency/severity, serum IgG, adverse events, treatment tolerability, ongoing immunosuppression, and immune reconstitution; consider B-cell monitoring following B-cell-directed therapy(1, 13, 14, 49, 50)
Assess immune recoverySerum immunoglobulin levels and, following B-cell-directed therapy, peripheral B-cell recovery assessed by flow cytometry when clinically appropriate; validated biomarker thresholds for IgRT discontinuation have not been established(13, 14, 49, 50)
Modify IgRTPersistent infections, inadequate clinical response, adverse events, changing immune status, or treatment burden(1, 13, 14)
Consider discontinuationSustained infection control plus evidence of immune recovery; reassess after withdrawal and restart if clinically significant infections recur(1, 13, 14, 51)
StewardshipUse IgRT alongside appropriate antimicrobial/supportive measures and periodically reassess continued need(13, 14, 34–36)

HM, hematologic malignancy; IgG, immunoglobulin G; IgRT, immunoglobulin replacement therapy; IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulin; SHG, secondary hypogammaglobulinemia; SID, secondary immunodeficiency.

4.3 Current clinical development and emerging evidence

Several ongoing and planned clinical trials are expected to contribute additional evidence on SCIG utilization in SID populations over the coming years. These studies include observational registries, post-marketing evaluations, and prospective investigations evaluating SCIG use in patients with hematologic malignancies, post-transplant immune dysfunction, and SID following CAR-T therapy (52). Although study designs and timelines vary, these investigations may provide important insights into evolving clinical practice and optimized IgRT.

Table 2 summarizes selected clinical studies investigating SCIG use in secondary immunodeficiency and mixed PID/SID populations identified through clinical trial registries (53–60).

Table 2. Selected clinical studies investigating SCIG use in secondary immunodeficiency and mixed PID/SID populations identified through clinical trial registries.

Trial titleRegistry IDPopulationStatusSponsorLocation
Observational Study of Subcutaneous Immunoglobulin (Cutaquig®) in Patients With Primary and Secondary ImmunodeficiencyNCT04354129Mixed PID/SIDActive, not recruitingUniversity of Alberta; Octapharma (collaborator)Canada
Real-world Usage of HyQvia in Multiple Myeloma Adults With Secondary ImmunodeficiencyNCT05879757HM-associated SID: multiple myelomaRecruitingTakedaU.S., EU, South America
Immunoglobulin for Hypogammaglobulinemia Due to Chimeric Antigen Receptor T Cell Therapy (ICART)NCT06989541CAR-T-associated SHG/SIDRecruitingUniversity of AlbertaCanada
Study of immune deficiency patients treated with SCIG (IgPro20, Hizentra®) on weekly and biweekly schedules2015-004977-34Mixed PID/SIDCompleted, publishedCSL BehringEU/EEA
Facilitated SCIG use in pediatric patients with primary or secondary immunodeficiency diseasesDRKS00015436Mixedpediatric PID/SIDCompleted, publishedTakeda/ShireGermany
Effect of SCIG Gammanorm on IgG subclasses and immunity in patients with SIDNCT03369301SIDCompleted, not yet publishedOctapharmaFrance
Humoral Immunodeficiency in CLL and Therapy With Subcutaneous IgNCT03730129HM-associated SID: CLLCompleted, publishedRochester General HospitalU.S
Safety, Tolerability, Patient Satisfaction and Cost of Cutaquig® TreatmentNCT03677557Mixed PID/SIDUnknown statusOttawa HospitalResearch InstituteCanada

CAR-T, chimeric antigen receptor T-cell; CLL, chronic lymphocytic leukemia; EEA, European Economic Area; EU, European Union; HM, hematologic malignancy; IgG, immunoglobulin G; PID, primary immunodeficiency; SCIG, subcutaneous immunoglobulin; SHG, secondary hypogammaglobulinemia; SID, secondary immunodeficiency.

Mixed PID/SID studies were retained when they included participants with secondary immunodeficiency and provided clinically relevant evidence regarding SCIG administration, safety, tolerability, pharmacokinetics, or patient-reported outcomes. PIDD-only studies were excluded.

Although IgRT is widely used in clinical practice for SID, regulatory approvals and labeled indications vary across products and geographic regions. In the United States, use of IVIG and SCIG for HM-associated SID may occur outside product-specific labeled indications and is frequently guided by expert consensus recommendations, clinical judgment, and payer requirements rather than standardized regulatory approval pathways. In contrast, selected European indications and ongoing clinical development programs have expanded evaluation of SCIG in SID populations and may provide additional evidence to support future implementation strategies, access considerations, and clinical decision-making. Current and ongoing studies are clinically important for evaluating safety, effectiveness, pharmacokinetic outcomes, patient-reported measures, and implementation of SCIG across diverse SID populations (30, 31, 53–60). Although individual studies are unlikely to alter international guidelines independently, the growing body of prospective studies and RWE is expected to contribute incrementally to evolving clinical practice by strengthening the evidence base for SCIG implementation across diverse oncology-associated SID populations.

5 Discussion

Current evidence supports both IVIG and SCIG as effective IgRT strategies for infection prevention in SID associated with HM (16, 17, 22, 23). For selected patients requiring long-term therapy, SCIG may offer practical advantages through more stable IgG exposure, fewer systemic adverse events, home-based administration, greater treatment autonomy, and improved PROs (24–26, 30, 31). SCIG may also reduce healthcare utilization and lower long-term healthcare costs while maintaining comparable infection prevention to IVIG (34–36).

Although available evidence consistently demonstrates reductions in infections, hospitalizations, and healthcare utilization with IgRT, evidence demonstrating improvements in overall survival remains limited because most available studies were not designed or powered to evaluate mortality outcomes. Moreover, IgRT primarily addresses humoral antibody deficiency and does not correct the broader cellular immune dysfunction that may occur after HSCT or CAR-T therapy (13, 14, 17, 30, 35).

The increasing complexity of oncology-associated SID, particularly following CAR-T therapy, HSCT, and B-cell-depleting therapies, reinforces the importance of individualized and pharmacokinetically informed treatment strategies (1, 2, 13, 14). Differences in regional practice patterns, regulatory approvals, access pathways, and healthcare delivery frameworks may also influence implementation and route selection for IgRT, underscoring the importance of ongoing clinical studies, RWE, and harmonized guidance to inform future clinical practice and implementation strategies in oncology-associated SID (13, 14, 45, 52, 54, 55, 59). Emerging evidence supports patient-centered treatment approaches that integrate infection history, pharmacokinetic variability, treatment tolerability, and healthcare resource considerations into long-term supportive care. fSCIG has also demonstrated favorable safety, tolerability, and effectiveness in SID populations (27–29, 31).

RWE and registry-based analyses continue to expand understanding of treatment utilization patterns, long-term outcomes, and patient-centered care models across diverse HM populations. However, important evidence gaps remain in pediatric populations, elderly patients, and patients receiving emerging cellular and targeted therapies. Additional prospective studies are needed to better define optimal dosing strategies, patient-specific IgG trough targets, treatment duration, and biomarkers predictive of treatment response.

5.1 Current challenges and research gaps

Despite increasing recognition of SID in HMs, several challenges remain in advancing IgRT. Existing evidence is limited by heterogeneous patient populations, variability in treatment thresholds, inconsistent monitoring strategies, and the predominance of observational studies, limiting direct comparisons across studies. Comparative prospective data evaluating SCIG and IVIG remain limited in HM populations, particularly among patients receiving cellular therapies and stem cell transplantation. Additional investigation is needed to define clinically meaningful biomarkers, refine IgG monitoring strategies, and establish individualized treatment pathways.

5.2 Future research and clinical priorities

Ongoing clinical studies are evaluating facilitated SCIG formulations, novel administration strategies, PROs, and CAR-T-associated SHG, which may further refine IgRT strategies for oncology-associated SID (28–31, 53–60).

As evidence from the studies emerges, future clinical development is expected to emphasize biomarker-guided treatment selection, patient-specific IgG trough targets, pharmacokinetically informed dosing approaches, and integration of real-world evidence into long-term oncology care models (1, 13, 14, 28, 29).

Research priorities include validated biomarkers of immune recovery, IgRT responsiveness, and infection susceptibility to better define initiation, monitoring, and discontinuation strategies.

6 Conclusion

IgRT remains an important component of supportive care for patients with HM-associated SID. Emerging evidence supports patient-centered selection of IVIG or SCIG based on infection burden, immune recovery, patient preference, and healthcare resource considerations (1, 13, 14). As global demand for immunoglobulin products continues to increase, evidence-informed patient selection, therapeutic monitoring, and responsible stewardship will be essential to optimize long-term outcomes (13, 34–36). Continued prospective studies together with real-world evidence will further refine monitoring strategies, treatment duration, and implementation of IgRT in oncology-associated SID (28–31, 53–60).

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/frhem.2026.1904290/full#supplementary-material

Supplementary material Supplementary material at the source

Footnotes

Edited by: Hong Zheng, Xinqiao Hospital, China

Reviewed by: Mark Ballow, University of South Florida, United States

Yoshinori Hashimoto, Tottori Prefectural Central Hospital, Japan

Statements

Conflict of interest

Authors AM-H, RV, and BR are employed by KORU Medical Systems.

The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Author contributions

ES: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. AM-H: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. RV: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. BR: Conceptualization, Methodology, Writing – original draft, Writing – review & editing.

References

  1. 1 Otani IM, Lehman HK, Jongco AM, Tsao LR, Azar AE, Tarrant TK. 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. doi: doi:10.1016/j.jaci.2022.01.025
  2. 2 Fu W, Chen J, Hu X. Immune reconstitution following allogeneic hematopoietic cell transplantation and CAR-T therapy: dynamics, determinants, and directions. Best Pract Res Clin Haematol. (2025) 38: 101634. doi: doi:10.1016/j.beha.2025.101634
  3. 3 Makos OL, D’Angelo CR. The shifting roles and toxicities of cellular therapies in B-cell malignancies. Transpl Infect Dis. (2023) 25: e14145. doi: doi:10.1111/tid.14145
  4. 4 Wudhikarn K, Perales MA. Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy. Bone Marrow Transplant. (2022) 57: 1477–88. doi: doi:10.1038/s41409-022-01756-w
  5. 5 Hernani R, Benzaquén A, Solano C. Toxicities following CAR-T therapy for hematological malignancies. Cancer Treat Rev. (2022) 111: 102479. doi: doi:10.1016/j.ctrv.2022.102479
  6. 6 Arya S, Shahid Z. Overview of infectious complications among CAR T-cell therapy recipients. Front Oncol. (2024) 14: 1398078. doi: doi:10.3389/fonc.2024.1398078
  7. 7 Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. (2023) 389: 148–57. doi: doi:10.1056/NEJMoa2301665
  8. 8 Meir J, Abid MA, Abid MB. State of the CAR-T: risk of infections with chimeric antigen receptor T-cell therapy and determinants of SARS-CoV-2 vaccine responses. Transplant Cell Ther. (2021) 27: 973–87. doi: doi:10.1016/j.jtct.2021.09.016
  9. 9 Gudiol C, Lewis RE, Strati P, Kontoyiannis DP. Chimeric antigen receptor T-cell therapy for the treatment of lymphoid malignancies: is there an excess risk for infection ? Lancet Haematol. (2021) 8: e216–28. doi: doi:10.1016/S2352-3026(20)30376-8
  10. 10 Riedel A, Phely L, Hug S, Faustmann P, Schröder J, Besemer B. Immunological consequences of CAR T-cell therapy: analysis of infectious complications and immune reconstitution. Blood Adv. (2025) 9: 3149–58. doi: doi:10.1182/bloodadvances.2024015346
  11. 11 Dicharry D, Malek AE. Unlocking the role of Treg cells, immune response, and infectious risk following CAR T-cell therapy in patients with cancer. Int J Mol Sci. (2025) 26: 1602. doi: doi:10.3390/ijms26041602
  12. 12 Cheng GS, Crothers K, Aliberti S, Bergeron A, Boeckh M, Chien JW. Immunocompromised host pneumonia: definitions and diagnostic criteria: an official American Thoracic Society workshop report. Ann Am Thorac Soc. (2023) 20: 341–53. doi: doi:10.1513/AnnalsATS.202212-1019ST
  13. 13 Goede JS, Baumann CK, Cathomas R, Khanna N, Lambert JF, Lehmann T. Rational use of immunoglobulins (IVIGs and SCIGs) in secondary antibody deficiencies. Swiss Med Wkly. (2024) 154: 3559. doi: doi:10.57187/s.3559
  14. 14 Jolles S, Michallet M, Agostini C, Albert MH, Edgar D, Ria R. Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus. Eur J Haematol. (2021) 106: 439–49. doi: doi:10.1111/ejh.13580
  15. 15 Wagle NS, Nogueira L, Devasia TP, Mariotto AB, Yabroff KR, Islami F. Cancer treatment and survivorship statistics, 2025. CA Cancer J Clin. (2025) 75: 305–39. doi: doi:10.3322/caac.70011
  16. 16 Cinetto F, Neri R, Vianello F, Visentin A, Barilà G, Gianese S. Subcutaneous immunoglobulins replacement therapy in secondary antibody deficiencies: real life evidence as compared to primary antibody deficiencies. PLoS One. (2021) 16: e0247717. doi: doi:10.1371/journal.pone.0247717
  17. 17 Abadeh A, Shehadeh S, Betschel S, Waserman S, Cameron DW, Cowan J. Clinical outcomes of immunoglobulin treatment for patients with secondary antibody deficiency: data from the Ontario immunoglobulin treatment case registry. PLoS One. (2023) 18: e0294408. doi: doi:10.1371/journal.pone.0294408
  18. 18 Ameratunga R, Longhurst H, Steele R, Woon ST. Comparison of diagnostic criteria for common variable immunodeficiency disorders (CVID) in the New Zealand CVID cohort study. Clin Rev Allergy Immunol. (2021) 61: 236–44. doi: doi:10.1007/s12016-021-08860-7
  19. 19 Janssen LMA, Reijnen ICGM, Milito C, Edgar D, Chapel H, de Vries E. Protocol for the unclassified primary antibody deficiency (unPAD) study: characterization and classification of patients using the ESID online registry. PLoS One. (2022) 17: e0266083. doi: doi:10.1371/journal.pone.0266083
  20. 20 Ameratunga R, Brewerton M, Slade C, Jordan A, Gillis D, Steele R. Comparison of diagnostic criteria for common variable immunodeficiency disorder. Front Immunol. (2014) 5: 415. doi: doi:10.3389/fimmu.2014.00415
  21. 21 Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. (2015) 136: 1186 – 1205.e1–78. doi: doi:10.1016/j.jaci.2015.04.049
  22. 22 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. Med (Baltimore). (2025) 104: e45145. doi: doi:10.1097/md.0000000000045145
  23. 23 Imai K, Ishii T, Nonoyama S, Yasumi T, Kanegane H, Fukushima T. Real-world results with IgPro20 for hypo- or agammaglobulinemia in Japan. Pediatr Int. (2022) 64: e15362. doi: doi:10.1111/ped.15362
  24. 24 Windegger TM, Lambooy CA, Hollis L, Morwood K, Weston HE, Lin Fung Y. Subcutaneous immunoglobulin therapy for hypogammaglobulinemia secondary to malignancy or related drug therapy. Transfus Med Rev. (2017) 31: 45 – 50. doi: doi:10.1016/j.tmrv.2016.06.006
  25. 25 Spadaro G, Pecoraro A, De Renzo A, Della Pepa R, Genovese A. Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia. Clin Immunol. (2016) 166–167: 103–4. doi: doi:10.1016/j.clim.2016.04.001
  26. 26 Lingman-Framme J, Fasth A. Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review. Drugs. (2013) 73: 1307–19. doi: doi:10.1007/s40265-013-0094-3
  27. 27 Dimou M, Iliakis T, Maltezas D, Bitsani A, Kalyva S, Koudouna A. Efficacy-safety of facilitated subcutaneous immunoglobulin in immunodeficiency due to hematological malignancies: a single-center retrospective analysis. Anticancer Res. (2018) 38: 4187–91. doi: doi:10.21873/anticanres.12712
  28. 28 Dimou M, Vacca A, Sánchez-Ramón S, Karakulska-Prystupiuk E, Lionikaite V, Siffel C. Real-world effectiveness, safety, and tolerability of facilitated subcutaneous immunoglobulin 10% in secondary immunodeficiency disease: a systematic literature review. J Clin Med. (2025) 14: 1203. doi: doi:10.3390/jcm14041203
  29. 29 Dimou M, Speletas M, Milito C, Pyzik A, Huscher D, Kamieniak M. Insights into facilitated subcutaneous immunoglobulin use in patients with secondary immunodeficiency diseases: a FIGARO subgroup analysis. Cancers (Basel). (2023) 15: 4524. doi: doi:10.3390/cancers15184524
  30. 30 Cowan J, Na I-K, Gladiator A, Kamieniak M, Mustafa SS. Patient-reported outcomes with subcutaneous immunoglobulin in secondary immunodeficiency. Front Immunol. (2025) 16: 1528414. doi: doi:10.3389/fimmu.2025.1528414
  31. 31 Martínez Mercader S, Garcia-Bustos V, Moral P, Martínez Buenaventura C, Escudero Vergara E, Montaner Bosch MC. Patient-centered outcomes with subcutaneous immunoglobulin use for infection control in primary and secondary immunodeficiencies: data of a GEIE Spanish registry. Front Immunol. (2025) 16: 1532367. doi: doi:10.3389/fimmu.2025.1532367
  32. 32 Avedova A, Deripapa E, Rodina Y, Mukhina A, Latysheva E, Yukhacheva D. Prospective multicenter study of treatment efficacy, safety, and quality of life in a large cohort of patients with inborn errors of immunity receiving subcutaneous immunoglobulin by the rapid push method. Front Immunol. (2025) 16: 1598491. doi: doi:10.3389/fimmu.2025.1598491
  33. 33 Abbott JK, Chan SK, MacBeth M, Crooks JL, Hancock C, Knight V. Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cycles. PLoS One. (2022) 17: e0265852. doi: doi:10.1371/journal.pone.0265852
  34. 34 Windegger TM, Nghiem S, Nguyen K, Fung Y, Scuffham PA. Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency. Vox Sang. (2019) 114: 237–46. doi: doi:10.1111/vox.12760
  35. 35 Carrillo de Albornoz S, Chai KL, Higgins AM, Petrie D, Wood EM, McQuilten ZK. A systematic review of the cost and cost-effectiveness of immunoglobulin treatment in patients with hematological malignancies. Int J Technol Assess Health Care. (2024) 40: e32. doi: doi:10.1017/S026646232400028X
  36. 36 Del Campo Guerola L, Garcia Sacristán AA, Portolés A, Jasso M, Guerra-Galán T, de la Fuente-Muñoz E. Economic impact of immunoglobulin replacement therapy in secondary immunodeficiency to hematological cancer: a single center observational study. Front Immunol. (2024) 15: 1413231. doi: doi:10.3389/fimmu.2024.1413231
  37. 37 Bauhofer A, Schimo S, Klausmann M. Benefits of immunoglobulin substitution in primary and secondary immunodeficiencies: interim analysis of a prospective, long-term non-interventional study. Int J Clin Pharmacol Ther. (2021) 59: 417–27. doi: doi:10.5414/CP203952
  38. 38 Reiser M, Borte M, Huscher D, Baumann U, Pittrow D, Sommer C. Management of patients with malignancies and secondary immunodeficiencies treated with immunoglobulins in clinical practice: long-term data of the SIGNS study. Eur J Haematol. (2017) 99: 169–77. doi: doi:10.1111/ejh.12900
  39. 39 Monleón Bonet C, Waser N, Cheng K, Tzivelekis S, Edgar JDM, Sánchez-Ramón S. A systematic literature review of the effects of immunoglobulin replacement therapy on the burden of secondary immunodeficiency diseases associated with hematological malignancies and stem cell transplants. Expert Rev Clin Immunol. (2020) 16: 911–21. doi: doi:10.1080/1744666X.2020.1807328
  40. 40 Aggarwal R, Charles-Schoeman C, Schessl J, Bata-Csörgő Z, Dimachkie MM, Griger Z. Trial of intravenous immune globulin in dermatomyositis. N Engl J Med. (2022) 387: 1264–78. doi: doi:10.1056/NEJMoa2117912
  41. 41 Kato H, Hayashi M, Ohashi W, Yamaguchi T, Tanaka S, Kozono A. A retrospective observational study of adverse reactions associated with intravenous immunoglobulin infusion. Front Immunol. (2021) 12: 740517. doi: doi:10.3389/fimmu.2021.740517
  42. 42 Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus Med Rev. (2013) 27: 171–8. doi: doi:10.1016/j.tmrv.2013.05.004
  43. 43 Cherin P, Marie I, Michallet M, Pelus E, Dantal J, Crave JC. Management of adverse events in the treatment of patients with immunoglobulin therapy: a review of evidence. Autoimmun Rev. (2016) 15: 71 – 81. doi: doi:10.1016/j.autrev.2015.09.002
  44. 44 Ghia D, Thota P, Ritchie T, Rana H, Minhas R, Moolji J. Feasibility and resource utilization of nurse-administered subcutaneous immunoglobulin therapy in antibody deficiency: a cross-sectional study. PLoS One. (2025) 20: e0316797. doi: doi:10.1371/journal.pone.0316797
  45. 45 Patel SY, Carbone J, Jolles S. The expanding field of secondary antibody deficiency: causes, diagnosis, and management. Front Immunol. (2019) 10: 33. doi: doi:10.3389/fimmu.2019.00033
  46. 46 Ness S. Intravenous and subcutaneous immunoglobulin treatment options. Am J Manag Care. (2019) 25: S99 – S104.
  47. 47 Bonilla FA. Intravenous and subcutaneous immunoglobulin G replacement therapy. Allergy Asthma Proc. (2016) 37: 426–31. doi: doi:10.2500/aap.2016.37.3987
  48. 48 Menon D, Sarpong E, Bril V. Practical aspects of transitioning from intravenous to subcutaneous immunoglobulin therapy in neuromuscular disorders. Can J Neurol Sci. (2022) 49: 161–7. doi: doi:10.1017/cjn.2021.56
  49. 49 Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. (2018) 1: e184169. doi: doi:10.1001/jamanetworkopen.2018.4169
  50. 50 Otani I, Labrosse R, DiGiacomo DV, Barmettler S. Quality and safety intervention: improving care of patients undergoing B cell-targeted therapies. J Allergy Clin Immunol Pract. (2026). doi: doi:10.1016/j.jaip.2026.06.023
  51. 51 Barmettler S, Price C. Continuing IgG replacement therapy for hypogammaglobulinemia after rituximab—for how long ? J Allergy Clin Immunol. (2015) 136: 1407–9. doi: doi:10.1016/j.jaci.2015.06.035
  52. 52 Day WG, Heald J, Grigsby S, Beale P, Pittman L, DeStefano CB. Management of secondary immunodeficiency following T-cell-engaging immunotherapeutic agents in B-cell non-Hodgkin lymphoma: implications for early-line treatment strategies. Lymphatics. (2024) 2: 244–59. doi: doi:10.3390/lymphatics2040019
  53. 53 ClinicalTrials.gov. Observational Study of Subcutaneous Immunoglobulin (Cutaquig) in Patients With Primary and Secondary Immunodeficiency. Bethesda (MD): National Library of Medicine (US) (2026). Available online at: https://clinicaltrials.gov/study/NCT04354129 (Accessed October 2, 2026).
  54. 54 ClinicalTrials.gov. Real-World Usage of Hyqvia in Multiple Myeloma Adults With Secondary Immunodeficiency. Bethesda (MD): National Library of Medicine (US) (2026). Available online at: https://clinicaltrials.gov/study/NCT05879757 (Accessed October 2, 2026).
  55. 55 ClinicalTrials.gov. Immunoglobulin for Hypogammaglobulinemia Due to Chimeric Antigen Receptor T Cell Therapy (ICART). Bethesda (MD): National Library of Medicine (US) (2025). Available online at: https://clinicaltrials.gov/study/NCT06989541 (Accessed October 2, 2026).
  56. 56 EU Clinical Trials Register. Study of Immune Deficiency Patients Treated With Subcutaneous Immunoglobulin (Igpro20, Hizentra®) on Weekly and Biweekly Schedules. Amsterdam (NL): European Medicines Agency (2016). Available online at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-004977-34/3rd (Accessed October 2, 2026).
  57. 57 German Clinical Trials Register (DRKS). Retrospective Data Analysis of Children Treated With Hyqvia for PID or SID. Freiburg (DE): German Institute for Medical Documentation and Information (2023). Available online at: https://www.drks.de/search/de/trial/DRKS00015436 (Accessed October 2, 2026).
  58. 58 ClinicalTrials.gov. The Effect of Subcutaneous Immunoglobulin Gammanorm on the Distribution of Igg Subclasses and on Immunity of Patients With Secondary Immunodeficiency. Bethesda (MD): National Library of Medicine (US) (2022). Available online at: https://clinicaltrials.gov/study/NCT03369301 (Accessed October 2, 2026).
  59. 59 ClinicalTrials.gov. Humoral Immunodeficiency in CLL and Therapy With Subcutaneous Ig. Bethesda (MD): National Library of Medicine (US) (2020). Available online at: https://clinicaltrials.gov/study/NCT03730129 (Accessed October 2, 2026).
  60. 60 ClinicalTrials.gov. Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment. Bethesda (MD): National Library of Medicine (US) (2020). Available online at: https://clinicaltrials.gov/study/NCT03677557 (Accessed October 2, 2026).

Citation

Seaquist, E., et al. (2026). Immunoglobulin replacement therapy in hematologic malignancy–associated secondary immunodeficiency: roles of SCIG and IVIG. Frontiers in Hematology, Volume 5. https://doi.org/
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5 - 2026

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Copyright © 2026 Seaquist, Majapuro-Hirvonen, Van Wagoner and Rutland.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Rashelle Van Wagoner

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