Subcutaneous vs. Intravenous Immunoglobulins in Patients with CLL

Study Objectives

The main aim of this study was to compare the occurrence of bacterial and fungal (proven or probable) infections before and after immunoglobulin replacement therapy. 

Other objectives included comparing SCIG and IVIG from several aspects:

• Concentration of IgG, IgA, and IgM in serum
• Cumulative incidence of infections
• Annual incidence of infections during IGRT, regardless of severity
• Adverse events during IGRT
• Discontinuation of therapy
• Switch between SCIG and IVIG
• Bleeding in patients also treated with ibrutinib

Methodology and Course of Study, Patient Population

The study included patients older than 18 years with CLL at any treatment stage, who had received IGRT for at least 3 months and were not on concomitant immunosuppressive medication except for CLL therapy. The choice between SCIG and IVIG was at the discretion of the attending physician, and serum Ig concentrations were evaluated within 3 months before starting therapy (baseline) and then at 3, 6, and 12 months during IGRT. IVIG was administered every 3 or 4 weeks. 

Data from a total of 116 patients with a median age of 69 years were analyzed, 54% of whom were men. The median time from CLL diagnosis to the start of IGRT was 10 years, and 91% of patients had already undergone at least one line of CLL treatment, with 78% receiving an anti-CD20 monoclonal antibody, 25% using ibrutinib, and 3.4% receiving venetoclax. In terms of prognostic factors, 16% of patients had a TP53 mutation or deletion, and 48% had unmutated IGVH. 

The IVIG group included 49 patients, and the SCIG group included 88 patients, including 28 who switched from IVIG. Both groups were comparable in clinical and biological factors, except for age (SCIG recipients were older). Two formulations of SCIG were administered: a 16% formulation and a 20% formulation. The median monthly dose of immunoglobulins was 15.0 g/L for IVIG and 18.8 g/L for SCIG (p < 0.0001). 

Results

Serum IgG concentrations increased in both groups, but were higher at 6 and 12 months in patients receiving SCIG (median ∼6 g/L), with no differences between the two SCIG formulations. IgA and IgM concentrations remained stable. 

A total of 254 infections were recorded, 94% of which were bacterial and 6% fungal. Respiratory infections, including pneumonia, were the most common. The number of infections decreased in the SCIG group during treatment (from 2.59 to 1.42 events/patient-year), but increased in the IVIG group (from 2.31 to 3.14 events/patient-year). The first infection occurred significantly later in individuals who achieved IgG concentrations above 6 g/L after 6 months of therapy. 

A total of 71% of patients discontinued IVIG therapy due to switching to SCIG for recurrent infections (83%), death (13%), or infusion reactions (4%). Those who switched to SCIG subsequently achieved higher IgG concentrations (after at least 6 months of administration) than those who remained on IVIG. In the SCIG group, 36% of patients discontinued therapy due to death (81%) and recurrent local reactions (19%). None of the participants switched from subcutaneous to intravenous form.

Regarding safety, IGRT was generally well tolerated, with infusion-related adverse events occurring more frequently in patients on IVIG therapy. The frequency of hematomas was not increased in patients on ibrutinib in combination with IGRT. 

Conclusion

Patients receiving subcutaneous immunoglobulins achieved higher serum IgG concentrations, fewer adverse events, and a lower incidence of infections compared to those receiving intravenous immunoglobulins in this retrospective observational study, especially when serum IgG reached ≥ 6 g/L. 

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Source: Visentin A., Molinari M. C., 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 (1): 274−283, doi: 10.3390/curroncol30010022.