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

Abstract

Ibrutinib is not known to confer risk for Pneumocystis jirovecii pneumonia (PCP). We observed 5 cases of PCP in 96 patients receiving single-agent ibrutinib, including 4 previously untreated. Clinical presentations included asymptomatic pulmonary infiltrates, chronic cough, and shortness of breath. The diagnosis was often delayed. Median time from starting ibrutinib to occurrence of PCP was 6 months (range, 2-24). The estimated incidence of PCP was 2.05 cases per 100 patient-years (95% confidence interval, 0.67-4.79). At the time of PCP, all patients had CD4 T-cell count >500/μL (median, 966/μL) and immunoglobulin G (IgG) >500 mg/dL (median, 727 mg/dL). All patients underwent bronchoalveolar lavage. P jirovecii was identified by polymerase chain reaction in all 5 cases; direct fluorescence antibody staining was positive in 1. All events were grade ≤2 and resolved with oral therapy. Secondary prophylaxis was not given to 3 patients; after 61 patient-months of follow up, no recurrence occurred. Lack of correlation with CD4 count and IgG level suggests that susceptibility to PCP may be linked to Bruton tyrosine kinase (BTK) inhibition. If confirmed, this association could result in significant changes in surveillance and/or prophylaxis, possibly extending to other BTK inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT01500733 and #NCT02514083.

Figure 1

Estimated cumulative incidence rate and radiologic presentation of P jirovecii in a CLL patient treated with ibrutinib. (A) The estimated cumulative incidence of PCP in CLL is 4.5% at 1 year on ibrutinib, and 5.6% at 2 years and thereafter. The cumulative incidence of PCP was estimated by considering deaths or early discontinuation of ibrutinib without PCP as competing risk events; otherwise, patients on ibrutinib treatment were censored at the last follow up if no PCP was observed. (B-E) Chest CT images of 2 patients are shown who were diagnosed with and treated for PCP while on ibrutinib. The first patient presented with multifocal ground-glass opacificies (B), which significantly improved after treatment of PCP (C). The second patient presented with unilateral nodular infiltrates (D), which resolved after treatment (E).