Editor’s note: Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections due to impaired humoral and cellular immunity. Bruton’s tyrosine kinase inhibitors (BTKi) are crucial in CLL treatment. Recent studies have shown an increased incidence of invasive fungal diseases (IFDs) (0.5% to 12.1%) in patients receiving BTKi treatment, particularly central nervous system infections. From April 14th to 17th, 2024, the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT2024) was held in Glasgow, UK. At the meeting, a retrospective study from KU Leuven in Belgium showed that the incidence of IFDs in CLL patients receiving BTKi treatment was 4.6%, and IFDs mainly occurred in the presence of concurrent risk factors. The researchers stated that the study data did not support routine use of antifungal prophylaxis in CLL patients receiving BTKi treatment. “Oncology Frontier – Hematology Frontier” invited Professor Yang Liang from Sun Yat-sen University Affiliated Cancer Hospital to provide insightful commentary on this study.
Research Method:
This retrospective study analyzed the medical records of CLL patients treated with BTKi at KU Leuven Hospital from January 2013 to July 2023.
Research Results:
A total of 175 patients were identified (median age at diagnosis was 64 years), with 16/175 (9.1%, NA = 8) and 11/175 (6.3%, NA = 8) presenting high-risk Rai or Binet scores, respectively. In the cohort, 45 patients (44.6%, NA = 56) had unmutated IgVH status, and 43 patients (24.6%, NA = 21) had deletion/mutation of 17p/TP53. The mean follow-up time for the entire cohort was 117 months, with 32% of patients deceased. Six patients (3.4%) underwent hematopoietic stem cell transplantation (HSCT). One-third of patients (61/175, 34.8%) had hypogammaglobulinemia and required IVIG therapy. Sixteen percent of patients (26/175, 14.8%) had diabetes, and 11.4% (20/175) had other pulmonary diseases. BTKi therapy in CLL patients started on average 82 months (range 0-252 months) after diagnosis and after receiving an average of one prior line of therapy (range 0-5 times). Half of the patients (49.7%) initiated BTKi as first-line therapy. Nearly half of the patients (49.4%) continued BTKi therapy until the last follow-up. Among the 175 patients receiving BTKi treatment, 6 patients (3.4%) had recovered from IFDs before starting BTKi treatment, and 4 patients (2.3%) received trimethoprim/sulfamethoxazole (TPM/SMX) prophylaxis during BTKi treatment. Eight patients (4.6%) receiving or previously receiving BTKi treatment were diagnosed with IFDs, including one patient diagnosed with Pneumocystis pneumonia (PCP) followed by invasive aspergillosis (IA) 14 months later. These patients did not undergo HSCT or receive antifungal prophylaxis. Pulmonary involvement was the only site of infection, with Aspergillus being the predominant pathogen (77.8%), followed by Candida and Pneumocystis. Seven out of nine (77.8%) fungal infections occurred on average 751 days (range 46-2053 days) after starting BTKi (2 cases occurred after discontinuation of BTKi, with an average of 426 days, both during active treatment with Venetoclax). Common concurrent risk factors included neutropenia (22.2%), corticosteroid use (66.7%), chemotherapy-immunotherapy in the last 12 months (33.3%), severe illness (66.7%), and severe viral pneumonia (33.3%). Notably, one patient was diagnosed with possible IFDs solely due to CLL and treatment with Ibrutinib without other risk factors.
Table 1. Characteristics of Patients Diagnosed with IFDs
Research Conclusion:
This single-center retrospective study showed an incidence of 4.6% for IFDs in CLL patients receiving BTKi treatment. Interestingly, only pulmonary infections were observed, with no cases of central nervous system infections found. IFDs mainly occurred in the presence of concurrent risk factors. The study data did not support routine use of antifungal prophylaxis in CLL patients receiving BTKi treatment.
Professor Yang Liang’s Comments:
CLL, as a B-cell malignancy, causes defects in the body’s immune system, especially humoral immunity, increasing susceptibility to various infectious pathogens. With the application of BTKi, there is an increased risk of infection, especially in the early stages of treatment when the immune function of the body has not yet recovered. IFDs, as a common infectious disease in patients with hematological immunodeficiency in hematology, may increase in incidence after CLL patients receive BTKi treatment. However, whether routine antifungal prophylaxis is needed for this patient population requires rigorous confirmation through randomized controlled trials (RCTs). If complications occur, it likely indicates further impairment of the patient’s immune metabolic state, and the use of BTKi may further increase the incidence of IFDs in the short term. As IFDs are serious infections with a certain mortality rate, it is essential to pay attention to fungal infection prevention in the treatment of CLL and other lymphatic system tumors, to enhance treatment success rates, improve long-term survival rates and quality of life for CLL patients, and reduce the incidence of complications and mortality.
Original Article Link: [https://ebmt2024.abstractserver.com/program/#/details/presentations/1171](https://ebmt2024.abstractserver.com/program/#/details/presentations/1171)
