Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.

Trial registration: ClinicalTrials.gov NCT01500733 NCT15007330 NCT01500733.

Figures

Figure 1

Serum IgG, IgA, and IgM levels on ibrutinib compared with pretreatment baseline. Scatter plot of change in (A) IgG (n = 35 at 6 and 12 months; n = 21 at 24 months), (B) IgA (n = 43 at 6 and 12 months; n = 28 at 24 months), and (C) IgM (n = 34 at 6 and 12 months; n = 23 at 24 months), in treatment-naive (○) and relapsed or refractory (♦) patients. Only paired data are shown. Horizontal lines denote median values. Titers of polyreactive (D) IgG, (E) IgA, and (F) IgM (mean ± SEM) prior to treatment (PRE), and at 6 and 12 months (n = 21). Statistical significance is indicated by *P < .05, **P < .01, ***P < .001, or ****P < .0001.

Figure 2

Serum FLCs prior to treatment and on ibrutinib. Box and whisker plots (10th-90th percentile) of (A) serum κ:λ ratio, (B) κ FLC, and (C) λ FLC in κ-clonal CLL (n = 39). Box-and-whisker plots (10th-90th percentile) of (D) serum κ:λ ratio, (E) κ FLC, and (F) λ FLC in λ-clonal CLL (n = 28). Only paired data are shown. Y-axis is in log2 scale. Dotted lines illustrate the normal range. Statistical significance is indicated by *P < .05, **P < .01, ***P < .001, ****P < .0001, or ns (P ≥ .05) compared with pretreatment baseline.

Figure 3

Detection of normal B cells and BAFF levels in the peripheral blood. (A) Percentage of normal B cells of total B cells at baseline (PRE) and 12 months (n = 45). (B) Percentage of normal B cells of total B cells at baseline (Pre) and 24 months (n = 16). (C) Absolute normal B-cell count and (D) ALC in treatment-naive (○) and relapsed/refractory (♦) patients at 12 (n = 67) and 24 months (n = 38) on log10 scale. Horizontal lines denote median values. Dotted lines illustrate the normal range. (E) Box-and-whisker plot (10th-90th percentile) of serum BAFF in ibrutinib-treated patients at baseline, 6, and 12 months (n = 21) and healthy controls (n = 6). Statistical significance is indicated by **P < .01, ***P < .001, ****P < .0001, or ns (P ≥ .05). ALC, absolute lymphocyte count.

Figure 4

Cumulative mean number of infections. (A) Cumulative mean number of infections in TN, R/R, and all patients. (B) Cumulative mean number of infections in patients with ≥ (dotted line) or <1.5 FC (solid line) in IgA at 12 months compared with pretreatment baseline. FC, fold change; R/R, relapsed/refactory; TN, treatment-naive.