Incidence and Type of Opportunistic Infections during Ibrutinib Treatment at a Single Academic Center

Abstract

BACKGROUND: Ibrutinib is an irreversible inhibitor of Burton's tyrosine kinase (BTK) in the B-cell receptor (BCR) signaling cascade and is a practice changing treatment for chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits Interleukin-2 Inducible Kinase (ITK) in T-cells and has demonstrated immunomodulatory effects. Recently, cases of opportunistic infections (OI) have been reported during ibrutinib treatment including pneumocystis jirovecii pneumonia (PJP), cryptococcus, and fusarium. To date there are no reports on OI in large unselected cohorts of patients taking ibrutinib. We conducted a single-institution retrospective study to determine the incidence and type of OI during ibrutinib treatment as well as outcomes and characteristics associated with risk. METHODS: We reviewed medical records of all patients treated with ibrutinib at the Ohio State University between June 1st 2010 and March 31st 2016. Patients who received ibrutinib for graft versus host disease were excluded. All charts were initially reviewed by one of the investigators and patients with OI were independently reviewed by a second investigator. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All OI occurring after the first dose of ibrutinib were recorded. Onset of OI was considered as the time of first presentation for a complaint related to OI. Time to OI was calculated from the date of starting ibrutinib until the onset of OI or censored at the last assessment date, discontinuation of ibrutinib, or death prior to OI as competing risks. The cumulative incidence of OI was estimated and the Fine and Gray regression models were used to examine the association between patient characteristics and risk of OI. Covariates with significance level of p<0.20 from univariable analyses were further evaluated in a multivariable analysis using a stepwise selection procedure, retaining those with p<0.05 in the final model. RESULTS: The cohort included 566 patients. Median age was 65 (range 23-89) and 70.1% (397/566) were men. The majority of patients had CLL (73.7%, 417/566). Other diagnoses included mantle cell lymphoma (9.9%, 56/566), indolent B-cell malignancies (8.1%, 46/566; 11 Waldenström's Macroglobulinemia, 13 Hairy Cell Leukemia, 15 Follicular Lymphoma, 6 Marginal Zone Lymphoma, and 1 Prolymphocytic Leukemia), and aggressive lymphoma (8.3%, 47/566; 35 diffuse large B-cell or transformed lymphoma and 12 Richter's syndrome). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/566) of patients were treatment naïve. Ibrutinib was prescribed on clinical trial for 80.9% (458/566) of patients with the rest receiving it as standard of care. A second agent was given with ibrutinib in 30.9% (175/566) of cases and was most often a monoclonal antibody (81.7%, 143/175). Use of antiviral prophylaxis was common (78.6%, 445/566) with fewer patients receiving PJP (44.9%, 254/566) or fungal (11.5%, 65/566) prophylaxis. The most utilized prophylactic antifungal agent was fluconazole (70.8%, 46/65). Total ibrutinib exposure for the cohort was 1,225 person-years with a median exposure of 1.98 (range 0.008-6.40) years. Median duration of follow-up was 2.69 (range 0.03-6.40) years. Twenty-three of 566 (4.1%) patients developed an OI at a median of 0.39 (range 0.03-4.33) years after starting ibrutinib. The cumulative incidence of OI was 2.3% (95% CI: 1.3-3.8%) at 0.5 years and increased to 4.7% (95% CI: 3.0-7.0-%) at 5 years. Types of OI and outcomes are detailed in Table 1. Median survival of the entire cohort was not reached. Among 23 OI patients, the median survival after infection was 1.39 years. Univariable analysis revealed ≥3 prior treatments (HR 2.61), diabetes (HR 3.03), pulmonary disease (HR 2.81), chronic kidney disease (HR 2.56), and liver disease (HR 6.42) were associated with an increased risk for OI (p<0.05). In a multivariable analysis ≥3 prior treatments (HR 2.87, 95% CI: 1.12-7.35; p=0.028), diabetes (HR 3.63, 95% CI: 1.50-8.77; p=0.004), and liver disease (HR 7.53, 95% CI: 2.14-26.49; p=0.002) retained independent association with OI development. CONCLUSIONS: The cumulative incidence of OI during ibrutinib treatment was low (4.7% at 5 years) and the most common type was invasive fungal (61%) with no PJP cases. Three or greater prior treatments, diabetes, and liver disease were independently associated with risk for OI. Disclosures Byrd: Janssen: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II ‘proof-of-concept’ iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network

“…We observed therapeutic responses in patients with wt CD79, wt MYD 88 and in patients with MYD88 mutations but wt CD79B. The risk of aspergillosis during treatment with ibrutinib has been estimated as 2% in a cohort of 566 patients with non-CNS B-cell malignancies 21 and 4% and 11% in early-phase studies for R/R PCNSL patients treated with ibrutinib single agent 14,15 . An inhibition of both BTK and ITK, involved in innate and adaptive immunity, were suggested mechanisms underlying the risk of fungal infection, which could be enhanced by the frequent exposure to corticosteroids in PCNSL patients, especially patients experiencing relapse 22 23 .…”

Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib

“…This is consistent with data from Ohio State University. 21 Opportunistic infections were identified in 23/566 ibrutinibexposed patients (4.1%), IFI representing nearly half the cases.…”

Combinations or sequences of targeted agents in CLL: is the whole greater than the sum of its parts (Aristotle, 360 BC)?

“…Several reports suggest an increased risk of opportunistic infections with TA monotherapies. [66][67][68][69] BTK is a critical part of the innate immune response against Aspergillus, and BTK activation increases levels of reactive oxygen species and nitric oxide, and proteases, which are all important in eliminating the fungal infections. 70,71 Notably, patients who receive ibrutinib are at a higher risk of developing invasive Aspergillus infection.…”