Immunoglobulin replacement therapy and infection risk in chronic lymphocytic leukemia: A systematic review and meta-analysis

Table 1 Characteristics of the included studies

Ref.	Study design	Setting	Intervention vs comparator	Number of participants IgRT/non-IgRT	IgRT administration and indications	Outcome	Incidence of infections
Boughton et al[15]	Prospective, double-blind RCT	Multicenter, United Kingdom, 12-month duration	IVIg vs albumin placebo	IVIg: 24/18 (placebo)	18 g IVIg every 3 weeks in patients with serum IgG levels < 5.5 g/L and a history of two or more recent infections	Number of patients experiencing infections and severe infections whilst treated with IVIg or albumin placebo	IVIg group: 7 failures1/24 albumin placebo: 11 failures/18
Carrillo de Albornoz et al[11]	Retrospective cohort	Australia, January 2008 to December 2022, 12-month duration	IVIg vs no IVIg	IVIg: 524/524	IVIg	Proportion of patients exhibiting serious infections	IVIg group: 0.672 events/patient/year. No IVIg group (cessation period): 0.456 events/patient/year
Jurlander et al[16]	Uncontrolled before-after observational study	Single center, Denmark	IVIg vs no IVIg	IVIg: 15/15	IVIg 10 g every 3 weeks in patients with serum IgG level below lower reference limit, a history of recurrent infections and a performance status enabling outpatient setting	Number of infection-related events (antibiotic prescriptions, hospital admissions due to infections, febrile episodes, severe infections) in the 12-month period that preceded IgRT compared to the number of infection-related events during the period of IgRT	IVIg group: 3/15. No IVIg group: 6/15
Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia[17]	Prospective double-blind RCT	International, multicenter, Germany, Luxembourg, United States, United Kingdom, Italy, 12 months duration	IVIg vs 0.9% sodium chloride solution placebo	IVIg: 28/29 (placebo) (completed 12 months of study)	IVIg 0.4 g/kg body weight every 3 weeks in patients with IgG < 50% LLN for the hospital laboratory or a history of one or more serious infections requiring systemic antibacterial therapy	Number of patients experiencing infections whilst treated with IVIg or sodium chloride placebo	IVIg group: 10/28. Sodium chloride placebo: 13/29
Günther and Dreger[18]	Prospective cohort	Single center, Germany, April 1997 to November 2010	IVIg vs no IVIg	IVIg: 5/5	IVIg 0.35 g/kg body weight every 3-4 weeks in patients with secondary immune deficiency with recurrent serious bacterial infections	Incidence of bacterial infections before and after starting IVIg	IVIg group: 8 events/patient/year. No IVIg group: 9 events/patient/year
Molica et al[7]	Cross sectional	Multicenter, Italy, 24-month duration	IVIg vs no IVIg		300 mg/kg IVIg every 4 weeks for at least 6 months in patients with IgG levels < 600 mg/dL and/or a history of at least one serious infectious episode in the 6-month period preceding entry into the study	Number and type of infections occurring. During the 24-month treatment period
Siffel et al[19]	Retrospective cohort	Single center, United States, October 2015 to March 2020, 12-month duration	IgRT vs no IgRT	IgRT: 118/118	serum IgG levels < 5.0 g/L, hypogammaglobulinemia diagnosis codes, and ≥ 1 major infection	Number of infections, severe infections, inti-infective use, hospitalizations, length of hospital stay for IgRT-treated and no-IgRT matched cohorts of patients with SID at 12-month follow-up	IgRT group: 7.93 events/patient/year. No IgRT group: 3.56 events/patient/year
Soumerai et al[10]	Retrospective cohort	Multicenter, United States, January 2010 and February 15, 2023, 12-month duration	IgRT vs no IgRT	IgRT: 137/137	Immune globulin infusion (human) 10%	Rate of infections, severe infections and associated antimicrobial use were compared 3 months, 6 months, and 12 months before vs after the index date	IgRT group: 71/137. No IgRT group: 87/137
Tadmor et al[20]	Retrospective cohort	Single center, Israel	IVIg vs no IVIg	IVIg: 326/4206	IVIg monthly Infection prevention in patients with IgG < 500 mg/L and recurrent infections (2 infections in 6 months or 3 in a year)	Pneumonia episodes over one year, hospitalizations for pneumonia	IVIg group: 13/326. No IVIg group: 463/4206
Visentin et al[21]	Retrospective cross sectional	Multicenter, Italy	IVIg vs no IVIg SCIg vs no SCIg	IVIg: 49/49; SCIg: 88/88	SCIG or IVIG every 3 weeks or 4 weeks to patients with hypogammaglobulinemia and recurrent infections according to AIFA indications	Rate of bacterial or mycotic infections of any grade before and after treatment with SCIg or IVIg. Incidence of grade ≥ 3 infections	IVIg group: 3.14 events/patient/year. No IVIg group: 2.31 events/patient/year. SCIg group: 2.59 events/patient/year. No SCIg group: 1.43 events/patient/year. The incidence of grade ≥ 3 infections remained stable with IVIg (0.80 events/patient the year before and during IVIg), while it decreased from 1.43 to 0.64 with SCIg

¹If individuals experienced three more infections during the course of the study, they were classified as treatment failures.

RCT: Randomized controlled trial; IVIg: Intravenous immunoglobulin; IgRT: Immunoglobulin replacement therapy; SCIg: Subcutaneous immunoglobulin; IgG: Immunoglobulin G; LLN: Lower limit of normal; SID: Secondary immunodeficiency; AIFA: Agenzia Italiana del Farmaco.