In this issue of Blood, Sun and colleagues1  report that patients with chronic lymphocytic leukemia (CLL) treated with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib experience a partial reconstitution of normal B cells and humoral immunity.

In 1952, Ogden Carr Bruton described the X-linked agammaglobulinemia,2  or Bruton agammaglobulinemia, an inherited immunodeficiency condition caused by mutations in the gene encoding for BTK and characterized by the absence of mature B cells.3  BTK is critical for the maturation of pre–B cells to mature B cells and essential for the signaling pathway mediated by the B-cell receptor (BCR) that regulates B-cell survival, activation, differentiation, and interaction with the microenvironment.4 

The inhibition of BTK has recently emerged as a crucial strategy for treating B-cell malignancies such as CLL5-7  or mantle cell lymphoma.8  Ibrutinib, a US Food and Drug Administration–approved, orally administered irreversible inhibitor of BTK, has shown to be highly effective in controlling relapsed/refractory or previously untreated CLL. Of note, the antitumor activity of BTK inhibition not only depends on the disruption of BCR signaling but also on targeting Toll-like receptor signaling and B-cell adhesion and migration. In patients with CLL, treatment with ibrutinib obtains an overall response rate of 90%.5-7  This combination of effects is interesting because CLL is characterized by an immune dysregulation, leading to hypogammaglobulinemia and recurrent infections. Considering the crucial role of BTK on normal B-cell functioning, the effect of ibrutinib treatment on immunoglobulin levels and risk of infection in patients with CLL needs to be characterized. Conversely, a differential sensitivity of CLL vs normal B cells to BTK inhibition could potentially permit immune recovery with ibrutinib treatment.

To better define these 2 dichotomous outcomes, Sun et al1  characterized humoral immunity and normal B-cell subpopulations after treatment with ibrutinib in 86 patients with previously untreated or relapsed/refractory CLL who had received ibrutinib for at least 12 months. They found that there was a decrease in serum immunoglobulin (Ig)G levels starting at 6 months of treatment that became profound by 24 months (reduced to 23% of normal). Tumor-derived clonal serum IgM levels decreased in all cases (n = 11), whereas nonclonal serum IgM levels remained unchanged at 24 months after a transient improvement at 6 months. In contrast, serum IgA levels continuously increased during treatment in 82% of the patients. Of note, the great majority of patients with normal baseline levels of IgG or IgM experienced a decrease, whereas normal IgA levels at baseline remained unchanged. Importantly, these observations add to previous observations in which patients treated with ibrutinib experience a decrease in serum IgG and IgM, but not IgA.5-7  Whether these changes in serum immunoglobulin were due to changes in clonal and nonclonal B cells was addressed by analyzing the serum levels of free light chains (FLCs) and their relation with the κ or λ restriction of their CLL cells. Thus, free κ light chains in κ-clonal CLL are likely derived from tumoral cells. Patients treated with ibrutinib experienced a normalization of the κ/λ ratios, whereas the nonclonal FLCs remained stable or slightly higher, pointing to a recovery of normal B cells.

Because recovery of normal B cells is important in understanding the changes in immunoglobulin levels, the total number of normal B cells and a variety of B-cell subpopulations, from immature to memory B cells, were subsequently analyzed by flow cytometry. In total, 78% of treatment-naïve and 29% of relapsed/refractory CLL patients exhibited normal B cells that could be detected circulating after 12 months of therapy, although the normal B-cell count remained abnormally low in the majority of patients. Interestingly, however, the pattern of recovery of normal B-cell subpopulations, analyzed in a small series of 4 patients, differed from that of normal individuals, indicating that the reconstitution of normal B cells at this time point is still partial.

What do these immunologic changes mean for the risk of infection? Unsurprisingly, Sun and colleagues1  found that infections were more frequent during the first 6 months and in patients with relapsed/refractory CLL. Remarkably, however, those patients with a ≥50% increase in serum IgA levels had a lower rate of infection. This finding is of particular interest because one of the long-term adverse events in CLL patients treated with ibrutinib is the appearance of pneumonia.7 

Ibrutinib treatment in patients with CLL resulted in a partial reconstitution of the humoral immunity and the normal B-cell subpopulations, rendering a lower rate of infection. Important questions remain, including whether these effects could be a consequence of the higher activity that ibrutinib shows in controlling CLL, rather than a direct effect on the immune system. In addition, immunodeficiency in CLL is due not only to humoral defects but also to dysregulation of the normal T and natural killer cell compartment, aspects not analyzed in the study by Sun and colleagues.1  Thus, effects of ibrutinib on the whole immune system are not yet well understood and require an extensive investigation. Presumably, this incomplete immunologic reconstitution cannot be explained by the direct effect on the disruption of the BCR. Therefore, effects of BTK inhibition in other signaling pathways in which BTK might be participating, or even off-target effects that affect the immune reconstitution, warrant further investigation. Lastly, the exact mechanism by which serum IgA levels, but not IgG or IgM levels, are clearly increased after treatment with ibrutinib remains unknown; is there some BTK-specific effect on immunoglobulin switch or consequence of this so-called normal B-cell population that is emerging? In contrast, patients with CLL treated with chemoimmunotherapy experience a decrease of all serum immunoglobulin levels,9  whereas treatment with lenalidomide increased serum immunoglobulin levels across all classes.10 

Ibrutinib is the first approved drug that targets the BCR pathway and represents one of the most important changes in the history of CLL therapy. Because ibrutinib is given continuously, longer follow-up is needed to precisely determine the effects of this drug on the immunologic system.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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