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

Abstract

• Ibrutinib allows for partial reconstitution of normal B cells and humoral immunity in patients with chronic lymphocytic leukemia.• Infection rate decreased with time on ibrutinib and was inversely correlated with improvements in serum IgA.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 k-clonal CLL cases, clonal (k) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (l) 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 5 .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL.

Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib

“…The risk of infection appears to be highest in the first 6 months and decreases thereafter, consistent with indications of improving immune function on ibrutinib. 6 Although Pneumocystis jirovecii pneumonia (PCP) has been rarely reported in previously untreated CLL, 7,8 treatment with a fludarabine-based regimen has long been thought to increase the risk of PCP 9 and prophylaxis is recommended for patients treated with chemoimmunotherapy. 3,4,10 Here we report, for the first time, 5 cases of PCP in 96 CLL patients treated with singleagent ibrutinib under 2 prospective studies.…”

The Bruton tyrosine kinase inhibitor ibrutinib abrogates triggering receptor on myeloid cells 1-mediated neutrophil activation

“…The secondary immune defect as the underlying cause of frequent infections is in part due to hypoimmunoglobulinemia or diminished T-and B-cell responses suppressing protective immunity. 1 In addition, such recurrent infections may also be treatment related, for example, by cytotoxic agents causing neutropenia, but also by other mechanisms, such as the late onset neutropenia associated with rituximab after achieving complete remission. 2 In this context, targeting the Bruton tyrosine kinase (BTK), a critical non-receptor tyrosin kinase in B-cell development and activation, is a novel treatment approach apparently avoiding the cytotoxic side effects of established regimens.…”

Atypical Infections in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Patients Treated with Ibrutinib

“…Absence of BTK activity, originally described in X linked agammaglobulinemia [18], is characterized by defects in B cell development and function as well as severe reduction in serum Ig levels. A recent retrospective analysis of Ig levels in treatment naïve (n=52) and relapsed/refractory (n=32) CLL patients treated with single agent ibrutinib was reported [19]. Compared with baseline values IgG levels decreased significantly 12 and 24 months after initiating ibrutinib, were unchanged at 6 months, IgM levels increased transiently at 6 and 12 months and IgA levels increased significantly at 6 months of treatment, and thereafter.…”