pci-32765 and Aspergillosis

Invasive mould infections (IMIs) are very rare in patients with lymphoid malignancies. However, IMIs, mostly due to Aspergillus species, have been increasingly reported in such patients receiving ibrutinib (IBR). There is paucity of information regarding non-Aspergillus invasive mould infections (NAIMIs) in this setting, OBJECTIVES: To review our recent experience and the published literature on the topic.. We present a case of invasive sinusitis caused by Fusarium in a patient with refractory chronic lymphocytic leukaemia (CLL) who was treated with IBR and review the 12 published cases of NAIMIs during IBR.. Nearly all cases of NAIMIs in the setting of IBR use were encountered in patients with CLL. Mixed fungal infections, brain involvement and late-onset infections were common.. Although rare, NAIMIs should be considered in patients who receive IBR.

Topics: Adenine; Aged; Anticarcinogenic Agents; Antifungal Agents; Aspergillosis; Aspergillus; Female; Fungi; Fusariosis; Fusarium; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mucorales; Mycoses; Piperidines

Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.

Topics: Adenine; Aspergillosis; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Time Factors

Topics: Adenine; Aspergillosis; Humans; Invasive Fungal Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines

Topics: Adenine; Aspergillosis; Humans; Invasive Fungal Infections; Piperidines; Spleen

Topics: Adenine; Adrenal Cortex Hormones; Aged; Aspergillosis; Aspergillus fumigatus; Brain Diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Tomography, X-Ray Computed

Topics: Adenine; Aged; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Aspergillus; Combined Modality Therapy; Discitis; Humans; Immunosuppressive Agents; Laminectomy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors; Rituximab; Voriconazole

Topics: Adenine; Antifungal Agents; Aspergillosis; Humans; Nitriles; Piperidines; Pyridines; Triazoles

In patients at high risk of opportunistic infections who present with isolated. neurological symptoms, it is lifesaving to consider Central Nervous System Aspergillosis (CNS-A). Ibrutinib use in chronic lymphocytic leukemia (CLL) has previously been associated with CNS-A. We provide a case report of a patient that presented with primary CNS-A on Ibrutinib therapy without any prior pulmonary or local paranasal signs of infection.. 74-year-old Caucasian male with CLL and no prior chemotherapy on ibrutinib for 6 months presented with three months of unsteady gait, occipital headache, and confusion. He has a history of pulmonary sarcoidosis on chronic prednisone 5 mg daily and chronic obstructive pulmonary disease (COPD). He was found to have a "brain abscess" on imaging. Emergent craniotomy confirmed Aspergillus and patient was treated with Voriconazole for 6 months. At six-month follow up, repeat magnetic resonance imaging (MRI) confirmed complete resolution of CNS lesion.. Our case reinforces the importance of being vigilant for isolated CNS-A in CLL patients on ibrutinib who present with neurological symptoms and signs, without prior or co-infection of sino-pulmonary tissue.

Topics: Adenine; Aged; Aspergillosis; Aspergillus; Central Nervous System Infections; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lung; Magnetic Resonance Imaging; Male; Piperidines; Pyrazoles; Pyrimidines; Voriconazole

Infections represent a cause of morbidity and mortality in patients affected by chronic lymphocytic leukemia (CLL). Introduction of new drugs in CLL clinical practice has showed impressive efficacy, in particular those targeting BTK. Among the consistent clinical data, an increasing number of reports describing the occurrence of unexpected opportunistic fungal infections has been reported during treatment with ibrutinib in the first 6 months of treatment. The reason underlying manifestations of invasive fungal infections in patients treated with ibrutinib is still under investigation. Our study aimed to understand the impact of BTK inhibition on immune response to fungal infection mediated by macrophages and CD14+ monocytic population obtained from CLL patients. Exposure to ibrutinib and acalabrutinib reduced signaling pathways activated by. •BTK inhibition affects a productive immune response of CLL-associated macrophages (NLC) during

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Aspergillosis; Aspergillus fumigatus; Humans; Immunity, Innate; Immunomodulation; Leukemia, Lymphocytic, Chronic, B-Cell; Macrophages; Phagocytosis; Piperidines; Signal Transduction; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

The Bruton tyrosine kinase inhibitor ibrutinib has become a leading therapy against chronic lymphoid leukemia. Recently, ibrutinib has been associated with the occurrence of invasive fungal infections, in particular invasive aspergillosis. The mechanisms underlying the increased susceptibility to fungal infections associated with exposure to ibrutinib are currently unknown. Innate immunity, in particular polymer-phonuclear neutrophils, represents the cornerstone of anti-

Topics: Adenine; Aspergillosis; Aspergillus fumigatus; Humans; Neutrophils; Piperidines; Spores, Fungal

Topics: Abscess; Adenine; Antifungal Agents; Aspergillosis; Humans; Leukemia, B-Cell; Lymphoma, B-Cell; Organ Specificity; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome

Topics: Adenine; Adult; Aspergillosis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mucormycosis; Neoplasm Recurrence, Local; Nervous System; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Antifungal Agents; Aspergillosis; Cerebrum; Humans; Male; Piperidines; Pyrazoles; Pyrimidines; Voriconazole

Topics: Adenine; Aspergillosis; Carcinoma, Hepatocellular; Humans; Invasive Fungal Infections; Liver Neoplasms; Piperidines; Pyrazoles; Pyrimidines; Signal Transduction; Sorafenib

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aspergillosis; Aspergillus fumigatus; Cells, Cultured; Humans; Macrophages; NF-kappa B; NFATC Transcription Factors; Phagocytosis; Piperidines; Pyrazoles; Pyrimidines

Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Animals; Aspergillosis; Brain Neoplasms; CD79 Antigens; Drug Therapy, Combination; Enzyme Inhibitors; Female; Gene Knockout Techniques; Humans; Lymphoma; Male; Mice; Mice, Knockout; Middle Aged; Myeloid Differentiation Factor 88; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Cryptococcosis; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Magnetic Resonance Imaging; Meningoencephalitis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia