The Muddied Waters of Ibrutinib Therapy

Pravda, Miri Schamroth; Pravda, Nili Schamroth; Lishner, Michael

doi:10.1159/000496555

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…Herein, we report that 85.70% of CLL and 36.36% of NHL patients were given ibrutinib, frequently given in combination with rituximab and/or corticosteroids. Most patients receiving ibrutinib at the time of infection had received chemotherapy prior to initiating ibrutinib [ 33 , 42 , 45 , 56 , 71 , 75 ]. Only two patients were treatment naïve prior to ibrutinib therapy, and one patient began ibrutinib co-currently with chemotherapy [ 33 , 42 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

A Systematic Review to Assess the Relationship between Disseminated Cerebral Aspergillosis, Leukemias and Lymphomas, and Their Respective Therapeutics

Sullivan

Baggett

O’Connell

et al. 2022

JoF

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Disseminated disease following invasive pulmonary aspergillosis (IPA) remains a significant contributor to mortality amongst patients with hematologic malignancies (HMs). At the highest risk of mortality are those with disseminated disease to the central nervous system, known as cerebral aspergillosis (CA). However, little is known about the risk factors contributing to disease amongst HM patients. A systematic review using PRISMA guidelines was undertaken to define HM patient subgroups, preventative measures, therapeutic interventions, and outcomes of patients with disseminated CA following IPA. The review resulted in the identification of 761 records, of which 596 articles were screened, with the final inclusion of 47 studies and 76 total patients. From included articles, the proportion of CA was assessed amongst HM patient subgroups. Further, pre-and post-infection characteristics, fungal species, and mortality were evaluated for the total population included and HM patient subgroups. Patients with acute myeloid leukemia and acute lymphoid lymphoma, patients receiving corticosteroids as a part of their HM therapeutic regimen, and anti-fungal prophylaxis constitute the top identified patient populations at risk for disseminated CA. Overall, information presented here indicates that measures for the prevention of IPA should be taken in higher-risk HM patient subgroups. Specifically, the type of anti-fungal therapy used should be carefully considered for those patients with IPA and increased risk for cerebral dissemination. Additional reports detailing patient characteristics are needed to define further the risk of developing disseminated CA from IPA in patients with HMs.

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Section: Discussionmentioning

confidence: 99%

A Systematic Review to Assess the Relationship between Disseminated Cerebral Aspergillosis, Leukemias and Lymphomas, and Their Respective Therapeutics

Sullivan

Baggett

O’Connell

et al. 2022

JoF

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“…Two further cases of IA and cryptococcal meningoencephalitis (CM) occurring early in the course of ibrutinib treatment in CLL and Waldenstrom Macroglobulinemia (WM) patients were described, in absence of classical risk factors for IFIs, such as neutropenia, lymphopenia, steroid treatment and HIV infection [33]. Beside these and other reports of sporadic cases of IA, mucormycosis and cryptococcosis [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] (Tables 1, 2), the incidence of opportunistic infections was evaluated in a large cohort of patients from a single Institution, finding 3% incidence of IFIs in patients affected by CLL or other lymphoproliferative disorders, treated with ibrutinib as single agents or combined with chemotherapy or steroids, with a median follow-up of 2.7 years (range 0.03-6.4) [52]. Similarly, Ruchlemer et al reported 28 patients with relapsed/refractory CLL or non-Hodgkin lymphoma with IFIs (89% proven, 11% probable).…”

Section: Clinical Incidence Of Fungal Infections In Ibrutinib-treated Patientsmentioning

confidence: 93%

Immunomodulatory effect of ibrutinib: Reducing the barrier against fungal infections

et al. 2020

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The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is increasingly used in the treatment of chronic lymphocytic leukemia (CLL). Moreover, very promising results have been reported in other B-cell malignancies, including primary central nervous system lymphoma (PCNSL). Although well-tolerated in the majority of patients, ibrutinib demonstrates in some cases troublesome toxicities, including invasive fungal infections (IFIs). In the present review, we summarize clinical manifestations of IFIs in patients treated with ibrutinib, generally characterized by an early onset, mild clinical manifestations, asymptomatic/low symptomatic pulmonary localization and high incidence of central nervous system (CNS) involvement. IFI risk appears particularly increased in patients receiving ibrutinib associated with other immune modulator agents, especially with steroids or immune-chemotherapy. Moreover, the immunomodulatory effect of ibrutinib is described, pointing the attention on the involvement of specific molecules targeted by ibrutinib in innate and adaptive response to fungal infection. Overall, the findings indicate the ibrutinib may rapidly impair innate immune cell functions, while concomitantly restoring an effective protective potential of adaptive immune compartment. A correct awareness, especially when other predisposing factors are present, is warranted about the potential risk of IFIs in ibrutinibtreated patients.

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“…Overall, the commonest reported fungi were Candida, followed by P. jirovecii and Cryptococcus. In the RCTs and LTE studies, no cases of endemic mycotic infections (histoplasmosis, coccidioidomycosis and blastomycosis) were observed, but Candida albicans (n = 3) C. glabrata (n = 1) C. parapsilosis (n = 1) C. [11,77,78], pulmonary (n = 1) [79], myocardial (n = 1) [80], cryptococcosis disseminated (n = 2) [81,82], CNS (n = 4) [20,83,84], pneumonia (n = 1) [83], empyema (n = 2) [19,85], Candida pneumonia (n = 2) [86,87], mucormycosis invasive (n = 1) [86], abdominal (n = 1) [84], sinus (n = 1) [88] skin (n = 2) [89,90], PJP (n = 5) [25] Acalabrutinib (Calquence) PJP Pneumocystis jirovecii pneumonia; PCM paracoccidioidomycosis *Single centre retrospective analysis. #Meta-analysis of everolimus and temsirolimus randomised controlled trials presumably few patients were enrolled from regions where these organisms are endemic [45].…”

Section: Janus Kinase/signal Transducers and Activators Of Transcriptmentioning

confidence: 96%

“…Ibrutinib is a BTK inhibitor that results in decreased B cell survival (Table 1). Although the prominent effect is on B cells, other haemopoietic cells are affected, including T cells, natural killer cells and macrophages [11]. BTK has emerged as a key player in innate immunity.…”

Section: Bruton Tyrosine Kinase Inhibitormentioning

confidence: 99%

Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections

Bechman

Galloway

Winthrop

2019

Curr Fungal Infect Rep

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Purpose of Review This review discusses fungal infections associated with licenced small-molecule protein kinase inhibitors. For each major drug class, the mechanism of action and targeted pathways and the impact on host defence against fungi are described. Recent Findings Protein kinase inhibitors are successfully used in the treatment of malignancies and immune-mediated diseases, targeting signalling pathways for a broad spectrum of cytokines and growth-stimuli. These agents predispose to fungal infections by the suppression of integral components of the adaptive and innate immune response. Summary The greatest risk of fungal infections is seen with bruton tyrosine kinase inhibitors, e.g. ibrutinib. Infections are also reported with agents that target mTOR, Janus kinase and break point cluster (Bcr) gene-Abelson (Abl) tyrosine kinase (BCR-ABL). The type of fungal infection fits mechanistically with the specific pathway targeted. Infections are often disseminated and present soon after the initiation of therapy. The pharmacokinetic profile, possibility of off-target kinase inhibition, and underlying disease pathology contribute to infection risk. Keywords Small-molecule protein kinases inhibitors. BTK inhibitor. mTOR inhibitor. JAK inhibitor. BCR-ABL inhibitor. Fungal infections

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The Muddied Waters of Ibrutinib Therapy

Cited by 5 publications

References 24 publications

A Systematic Review to Assess the Relationship between Disseminated Cerebral Aspergillosis, Leukemias and Lymphomas, and Their Respective Therapeutics

A Systematic Review to Assess the Relationship between Disseminated Cerebral Aspergillosis, Leukemias and Lymphomas, and Their Respective Therapeutics

Immunomodulatory effect of ibrutinib: Reducing the barrier against fungal infections

Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections

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