High risk of infection in ‘real‐world’ patients receiving ibrutinib, idelalisib or venetoclax for mature B‐cell leukaemia/lymphoma

Abstract Objective The infection risk in patients receiving ibrutinib, idelalisib or venetoclax for chronic lymphocytic leukaemia (CLL) or B‐cell lymphoma treated outside of clinical trials is incompletely defined. We sought to identify the severe infection rate and associated risk factors in a ‘real‐world’ cohort. Methods We conducted a retrospective cohort study of adult patients with CLL or lymphoma treated with ibrutinib, idelalisib or venetoclax. Results Of 67 patients identified (ibrutinib n = 53, idelalisib n = 8 and venetoclax n = 6), 32 (48%) experienced severe infection. Severe infection occurred at a rate of 65 infections per 100 person‐years, with a median of 17.8 months of therapy. Median time to first infection (IQR) was 5.4 months (1.4–15.9). Poor baseline Eastern Cooperative Oncology Group (ECOG) performance status and high Charlson Comorbidity Index (CCI) score associated with increased risk of severe infection [hazard ratios (95% CI) 1.57 (1.07–2.31, p = .018) and 1.3 (1.05–1.62, p = .016) respectively]. Conclusion The severe infection rate for patients receiving ibrutinib, idelalisib or venetoclax for lymphoma and CLL exceeded those reported in clinical trials. Patients with poor ECOG or high CCI should be closely monitored for early signs of infection and prevention strategies actively pursued. Further prospective research is required to define optimal antimicrobial prophylaxis recommendations.

What is the central finding of your work?
Poor performance status and a higher comorbidity burden associates with an increased risk of infection in these patients.

What is the specific clinical relevance of your work?
Patients receiving these therapies should be monitored with a high index of suspicion for infection and appropriate infection prevention strategies employed. These targeted agents have established themselves as effective nonchemotherapy therapeutics that are generally well tolerated. There is, however, an increasing appreciation of an associated infection risk. [1][2][3] The risk of infection should be considered in the context of immune dysfunction resulting from the underlying haematological malignancy, which is a hallmark of CLL. 4 Factors associated with immune dysfunction in CLL include reduced T-cell and natural killer cell function, defective antibody dependent cellular cytotoxicity and neutrophil function and reduced complement activity. 2,4 Hypogammaglobulinemia is variably associated with an increased risk of infection. 4 The exposure adjusted rate of major infection in treatment naïve CLL patients has been reported to be 8.5 per 100 person-years. 5 Patient-specific risk factors for infection include age, comorbidities, functional status, number and type of prior lines of therapy, disease stage and refractoriness to treatment, and type of therapy. 2 In clinical trials using ibrutinib alone or in combination with a monoclonal antibody, the rate of severe infection ranged from 12.8% to 45%. [6][7][8][9][10] Median follow-up ranged from 27 to 65 months, with varying patient demographics. A systematic review of 22 prospective clinical trials using ibrutinib for a range of haematological malignancies, reported an overall severe infection rate of 28%. 11 'Real world' data for ibrutinib are limited to a few retrospective cohort studies, with heterogeneous reporting of infectious outcomes. Severe infection rates ranged from 2% to 25% with median follow-up from 12 to 19.7 months in patients being treated for CLL or lymphoma. 5,[12][13][14][15] One study reported the incidence rate of severe infection to be 37.5 per 100 person-years. 5 The increased risks of Pneumocystis jiroveci pneumonia (PJP) and cytomegalovirus (CMV) infections are well established with idelalisib, with safety communications mandating PJP antimicrobial prophylaxis and CMV laboratory and clinical monitoring. Clinical trials have reported severe infection rates of 24%-39% (median follow-up 14 months). 4,16,17 A 'real-world' study identified that 48.3% of patients with CLL experienced severe infection at a rate of 80.1 events per 100 person-years. 18 In contrast, in clinical trials using venetoclax for previously untreated and relapsed/refractory (RR) CLL, severe infections occurred in 17.5%-22% of patients (median follow-up 16-28.1 months). [19][20][21] One 'real-world' study on compassionate access venetoclax reported a severe infection rate of 25.4%. 22 In summary, reported infection rates in the 'real-world' setting for these novel therapies remains limited, despite increasing use in clinical practice. We sought to define rates of severe infection in the context of ibrutinib, idelalisib or venetoclax treatment for lymphoma and chronic lymphocytic leukaemia, and to identify associated risk factors.

| Study design
Single centre, retrospective cohort study across five sites of a tertiarylevel hospital network serving a patient population catchment of 1.

| Definitions
The World Health Organisation classification (2016) was used to define CLL/SLL, MCL, WM, FL and MZL. 25 The Lugano classification was used to stage SLL, MCL, FL and MZL and the Binet classification was used to stage CLL. 26,27

| Statistical analysis
Descriptive statistics were calculated using Microsoft Excel Office 16 ® and GraphPad Prism 9 ® . Continuous variables are presented as median with the first and third quartile, or minimum and maximum.
Categorical variables are presented as numbers and proportions and were compared using Pearson's chi-square tests or Fisher's exact tests. Incidence rates and 95% confidence intervals (95% CI) were calculated separately for episode of first severe infection and for all severe infections, per 100 person-years. Person-years were calculated from the date of treatment commencement to the date of first severe infection, or the date of last follow-up during treatment, respectively.
The Kaplan-Meier method was used to plot overall survival as a function of time and comparisons between curves were made using the log-rank test. Univariate analysis for time to first infection was performed using Cox proportional hazards regression with results reported as hazard ratios (HR) and 95% CI. A two-sided p value of .05 was chosen to indicate statistical significance. All statistical analyses were performed using SAS software version 9Á4 (SAS Institute, Cary, NC, USA).

| Infection related outcomes and risk factors
Thirty-two (48%) of the 67 patients experienced at least one severe infective episode ( Table 2 (Table 3).  Table 1).
The following disease response assessments were documented prior to   T A B L E 3 Incidence rate of severe infection.  Table 2).  Table 3). Of the 79 cases of severe infection, 63 (80%) were community acquired, eight (10%)

Invasive fungal infections (IFI
were acquired in residential care facilities and eight (10%) had onset in the hospital setting. Of the community and residential care acquired infections, the median time between symptom onset and hospital admission was two days (IQR 1-6).

| DISCUSSION
This study demonstrated a high rate of severe infection in a 'real-world' cohort of patients with long-term follow-up. The severe infection rate was higher than that reported in clinical trials and prior post-marketing studies, with one in 10 patients dying from infectionrelated causes. Over two-thirds of those with severe infection experienced recurrent events. Our report details the proportion of patients affected by severe infection and provides additional data on the exposure-adjusted incident rate. The incidence rate for all infective episodes was 1.5 and 1.8 times higher than those reported in prior 'real world' studies for ibrutinib and idelalisib respectively. 5 has been associated with a reduced risk of infection. 5,8,12 Our study was likely underpowered to detect a significant impact of these risk factors, did not assess IgA levels and had insufficient data to analyse the impact of hypogammaglobulinemia. Most infections occurred within the first 18 months, which aligns with other studies reporting the majority of infections occurring early in treatment, within the first 6-12 months 8,12 or waning over time. 6 This may be explained from partial reconstitution of humoral immunity 8,15 or increasing depth of disease response over time. 9 Given the high rates of severe infection  30 They have increased specificity for the BTK receptor and fewer off target effects, including inhibition of interleukin-2-inducible T-cell kinase, which has a key role in T-cell maturation and function. 4,11,30 The risk of severe infection in this population requires ongoing review in the contemporary treatment setting.

| CONCLUSION
Our data demonstrates that the 'real-world' population receiving

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.