Infection with Ibrutinib in patients with Chronic Lymphocytic Leukemia (CLL): How strong is the association?

To the Editor,

We read the recent review by Tillman et al. [1] with great interest and wanted to revisit the association of ibrutinib with increased risk of infection. Based on our clinical experience and the results of ibrutinib trials, we agree with the authors regarding the possibility of increased risk of infections with ibrutinib. [2,3] However, chronic lymphocytic leukemia (CLL) and other B-cell malignancies by themselves confer increased risk of infections owing to acquired defects of the innate and adaptive immunity secondary to the disease process, hypogammaglobulinemia, and T-cell and complement dysfunction, among others. [4,5] The authors have succinctly summarized the rate and types of infections in the ibrutinib arms of the trials. However, this review does not reveal if the rates of these infections were higher compared to the other treatment arms in those trials. Hence, we conducted a meta-analysis of published phase 3 randomized controlled trials (RCTs) to determine if the risk of infections with ibrutinib were truly greater compared to other treatments in patients with CLL.

We conducted a systematic search of EMBASE, PubMed, and meeting abstracts through January 20, 2018, with appropriate keywords to find all the phase III RCTs comparing ibrutinib with other agents or placebo in patients with CLL and also reporting rates of infection as adverse events. The search strategy, study selection, data extraction, and analysis were done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We pooled the point estimates from each study using the generic inverse-variance method of Der Simonian and Laird. [6] All data analyses were performed using the Stata SE 15.1 software from StataCorp LP.

Three phase III studies (RESONATE, RESONATE-2, and HELIOS) with a total of 1227 patients (617 in the ibrutinib arm and 610 in control arm) were included in the final analysis. [7–9] Ibrutinib was compared with ofatumumab in RESONATE, chlorambucil in RESONATE-2, and with placebo in the HELIOS study. In RESONATE-2, ibrutinib was administered as first-line therapy, whereas in other two trials it was used in previously treated patients. In the HELIOS study, patients in both arms (ibrutinib and placebo) also received concurrent bendamustine and rituximab. Characteristics of the trials included in the analysis are summarized in Table 1. The pooled risk ratio (RR) with ibrutinib for all grades of infection was 1.20 (95% CI: 0.81-1.76; p= 0.36) [Figure IA]. Across the three studies, the two most commonly reported types of infection were pneumonia and upper respiratory tract infection, with pooled RR of 1.15 (95% CI: 0.81-1.64; p=0.43) and 1.08 (95% CI: 0.81-1.43; p=0.62), respectively [Figure 1B and 1C]. We conducted a sensitivity analysis by excluding one study at a time to assess the stability of the results of the meta-analysis, and none of the results was significantly altered. The publication bias among the studies was assessed from the funnel plot and did not show significant asymmetry. Egger’s regression test was not performed due to the low number of studies. Our meta-analysis did not show any significant increase in the risk of infection associated with ibrutinib in patients with CLL.

Table 1.

Salient features of phase III studies included in the final analysis

Author	Study name	Year	Study type	Dose (mg)	Median duration of follow up	Line of therapy	Compared with	Total no. of patients
								Ibrutinib	Other
Byrd et al.	RESONATE	2014	Multicenter, open-label	420 qd	9.4 months	>1	Ofatumumab	195	191
Burger et al.	RESONATE-2	2015	International, open-label, randomized	420 qd	18.4 months	1	Chlorambucil	135	132
Khan et al.	HELIOS	2016	International, double-blind, placebo-controlled	420 qd	17 months	>1	Placebo	287	287

Figure 1:

Forest Plots showing the pooled risk ratio of total infection(A), pneumonia (B), and URTI (C) in CLL patients on Ibrutinib vs control[*URTI=Upper Respiratory Tract Infection; *CLL=Chronic Lymphocytic Leukemia]

The systematic review by Tillman et al. [1] reported the infection rates with ibrutinib across multiple clinical trials of different phases (I-III) in various B-cell malignancies. Our study included phase III RCTs in CLL and did not show any statistically significant increased risk of infection with ibrutinib when compared to controls. One of the limitations of our analysis is the fact that we have combined studies with ibrutinib used in the frontline and in relapse, and infection rates may vary between these two groups of patients. However, we agree with the authors that future well designed prospective studies with longer follow up are needed to truly evaluate the association between ibrutinib and risk of infections in patients with lymphoid malignancies.