A standard treatment for the hypogammaglobulinemia in patients with chronic lymphocytic leukemia (CLL) is immunoglobulin replacement therapy (IgRT), which is administered at a dose of 0.4 g/kg monthly when IgG levels dip below 6 g/L in patients with CLL who have a history of infections. Research published in EBioMedicine, however, suggests that increasing the target dose level could lead to better control of CLL.1

The retrospective study included 116 patients from the Sunnybrook CLL clinic who had a gap of at least 5 years between initial CLL diagnosis and the receipt of a first treatment. Investigators obtained information about immunoglobulin levels and other humoral components through patient records and pathology reports.

Across the cases, the researchers determined that those patients who had a benign clinical course of disease maintained IgG values above 8 g/L, whereas those who experienced disease progression had levels near 6 g/L. And, they found that serum β2M levels increased in patients with IgG levels that did not reach at least 9 g/L, but declined in those patients who had reached levels of at least 9 g/L. “Taken together, these observations suggested target IgG levels above those that prevent infections might have antileukemia activity as indicated by lowered TNFα and β2M levels,” the authors wrote.1

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Next, the study authors concluded that Hizentra® (immune globulin subcutaneous [human] 20% liquid) better controlled CD83 expression at a dose of 15 g/L, suggesting this dose could inhibit B-cell receptor (BCR) activation (BCR signaling drives CLL progression). In contrast, across the 25 patient samples examined, Hizentra did not influence BCR activation at dose levels of 4 g/L.

BCR activation prompts the production of TNFα; high concentrations of Hizentra were also found to inhibit spontaneous TNFα production. And, when Hizentra was combined with another inhibitor of TNFα (ibrutinib) in 2 patient samples it was determined that Hizentra enhanced ibrutinib’s inhibitory effect. Inhibition of both BCR activation and TNFα production, therefore, can increase CLL cell death in vitro, the investigators determined.

Thus, IgRT administered at doses at the upper limit of normal could play a role in the control of CLL itself, not just in the control of infections associated with the condition: “endogenous IgG levels that remain above 8 g/L are associated with an indolent clinical course and maintenance of IgG levels in the high-normal range (9­-12 g/L) with IgRT in the absence of paraprotein is associated with biochemical evidence of disease control.”1 Keeping plasma IgG levels near 15 g/L with high-dose IGRT — which could be achieved with an altered dose schedule of administration every 3 weeks, rather than the standard 4-week cycle — could keep patient trough levels higher, the authors reasoned.

They cautioned that results from their in vitro assay may not accurately reflect what could happen with high-dose IgRT in vivo, and also offered that the “failure to reach IgG levels above 9 g/L replacement in some patients may simply reflect rapid catabolism of IgG and represent an epiphenomena of more aggressive disease that is independent of the IgG level.”

Disclosure: Funding for this study was provided by CSL Behring.


  1. Spaner DE, Venema R, Huang J, et al. Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia [published online August 30, 2018]. EbioMedicine. doi: 10.1016/j.ebiom.2018.08.045