Publication Only: Chronic lymphocytic leukemia and related disorders - Clinical
Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK), a signaling molecule which is involved in the maturation of B-cells. BTK is essential in the signaling pathways mediated by the B-cell receptor (BCR) that modulates the pathogenesis of several B-malignancies, taking part in survival, activation and differentiation. This mechanism of action has also been advocated to cause increased susceptibility to infection; specifically, fungal infection has been acknowledged as a treatment-emergent adverse event. According to European Medicines Agency (EMA) ibrutinib is authorised in the EU for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), as a single agent is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL), in adult patients with CLL who have received at least one prior therapy, and for the treatment of adult patients with Waldenström's macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo immunotherapy.
Our aim is to evaluate the role of ibrutinib in the use of resources related to infection.
Records from patients under ibrutinib therapy have been revised to identify those admitted to hospital due to suspect of infection, and data from 2014 to 2018. Forty-three patients have been identified as being treated with ibrutinib in our center, 33 for chronic lymphocytic leukemia (CLL), 6 for mantle cell lymphoma (MCL) and 4 for Waldeström's macroglobulinemia (MW). Only 8 were treated with ibrutinib in first line, while 35 had been previously treated. Previous therapies mainly consisted in chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab or bendamustine and rituximab.
Forty episodes of admittance due to fever were identified in 24 patients, 8 of which had a single episode while 16 had two episodes. Thus 56% of patients under ibrutinib therapy have been admitted under suspect of infection. Median duration of ibrutinib therapy until first episode is 181 days. Absence of symptoms other than fever is very common in first episode (70%), while in second one a suspicion of respiratory tract infection is the commonest clinical judgement, (in 39,5% of episodes). Those who needed to be admitted to the hospital because of a second episode had positive microbiological test in 94% of patients, meanwhile just in 44.6% in first episodes. Microbiological test yielded gram-negative bacteria in 42% of patients, gram-positive bacteria in 21%, and respiratory viruses in 8%. Candida was obtained in cultures in 25% of patients and notably 2 cases of Aspergillus fumigatus infection were identified, one of them causing a fatal cerebral aspergillosis. Other two patients had atypical mycobacteria isolated in cultures, M. lentiflavum and M.gordonae. Most febrile episodes resolved but in four patients infection was the leading cause of death.
Infections are a common cause of admittance in patients under treatment with ibrutinib; repeated episodes are also very common. Atypical pathogens are frequent and cause important morbidity, mortality and resource use. Wide usage of ibrutinib thus requires special awareness, or even prophylaxis, due to this changing pattern of infections.