Miliary tuberculosis after initiation of ibrutinib in chronic lymphocytic leukemia

Wang, Song‐Yau; Ebert, Thomas; Jaekel, Nadja; Schubert, Stefan; Niederwieser, Dietger; Al-Ali, Haifa Kathrin

doi:10.1007/s00277-015-2385-0

Cited by 19 publications

(16 citation statements)

References 8 publications

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“…28 , 29 Treatments with rapamycin or its derivatives show immunosuppressant activity and are extensive used in organ transplant cases, and case studies in organ transplant patients have mentioned a higher risk of Mtb infection and reactivation of LTBI as possible side-effects with administration of everolimus (a derivative of rapamycin), 30 , 31 the mechanism between everolimus administration and reactivation of LTBI is not clearly understood, however, the negative consequences of everolimus can be overcome by co-administration with CYP3A4 enzyme inducers. 32 The situation is similar with ibrutinib administration in CLL patients, one case report showed military tuberculosis after initiation of ibrutinib in one CLL patient who had received complex treatments including an allogeneic stem cell transplantation, 33 and Ana Colado reported that ibrutinib used at doses founded in the plasma treated CLL patients (0.03-0.3 μM) impaired immune mechanisms that contributed to control of Mtb infection in M1 macrophages. 34 We also found no significant effects of ibrutinib on intracellular Mtb growth at low concentrations (1 and 3 μM), the inhibibiton effect of ibrutinib on intracellular Mtb growth was observed at a relative higher concentration (10 μM) compared to the one reported in the plasma of treated patients, and we found ibrutinib could decrease Mtb loads in mediastinal lymph node and spleen, but not in the lung where was the site for majority of Mtb resident.…”

Section: Discussionmentioning

confidence: 95%

Ibrutinib suppresses intracellular mycobacterium tuberculosis growth by inducing macrophage autophagy

Wen

Liu

et al. 2020

Journal of Infection

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Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. The host-directed therapy is a promising strategy for TB treatment that synergize with anti-TB treatment drugs. In this study, we found that the anti-chronic lymphocytic leukemia drug, ibrutinib, inhibited the growth of intracellular Mtb in human macrophages. Mechanisms studies showed that ibrutinib treatment significantly decreased p62 and increased LC3b proteins in Mtb infected macrophages. In addition, ibrutinib increased LC3b colocalization with intracellular Mtb and auto-lysosome fusion. Furthermore, inhibition of autophagy by using siRNA targeting ATG7 abolished the effect of ibrutinib-mediated suppression of intracellular Mtb. Next, we found that ibrutinib induced autophagy was through inhibition of BTK/Akt/mTOR pathway. Finally, we confirmed that ibrutinib treatment significantly reduced Mtb load in mediastinal node and spleen of Mtb infected mice. In conclusion, our data suggest that ibrutinib is a potential host-directed therapy candidate against TB.

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Section: Discussionmentioning

confidence: 95%

Ibrutinib suppresses intracellular mycobacterium tuberculosis growth by inducing macrophage autophagy

Wen

Liu

et al. 2020

Journal of Infection

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“…Opportunistic infections in patients on ibrutinib treatment including cases with aspergillosis and atypical PCP have also been reported, . In addition, Song‐Yau Wang described a patient who developed milliary tuberculosis shortly after initiation of ibrutinib . In this respect, we also describe a patient with fatal severe necrotizing pneumonia due to invasive aspergillosis and mucormycosis, complicated by intra‐alveolar hemorrhage.…”

Section: Discussionmentioning

confidence: 63%

“…13 In addition, Song-Yau Wang described a patient who developed milliary tuberculosis shortly after initiation of ibrutinib. 14 In this respect, we also describe a patient with fatal severe necrotizing pneumonia due to invasive aspergillosis and mucormycosis, complicated by intra-alveolar hemorrhage. Our first patient improved after empirical treatment for PCP, despite that the diagnosis was not proved.…”

Section: Casementioning

confidence: 91%

Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma

Kreiniz

Bejar

Polliack³

et al. 2017

Hematological Oncology

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In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly "biological drugs." One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib. The first case was a 70-year-old woman with relapsed CLL who developed bilateral pneumonia with hypoxia 1 week after starting ibrutinib. She did not respond to broad-spectrum antibiotics and was treated empirically with trimethoprim-sulphamethoxazole and improved. In the second case, we describe a 76-year-old woman with relapsed CLL who developed recurrent pneumonia after 3 years of treatment with ibrutinib. Presuming that ibrutinib was the cause of pneumonitis with secondary infection, it was stopped with subsequent improvement. The third patient a 67 year-old man died because of severe bilateral necrotizing pneumonia due to invasive aspergillosis and mucormycosis with pulmonary hemorrhage. The fourth patient with relapsed mantle cell lymphoma died because of severe bilateral pneumonia, caused by pseudomonas and candida, despite receiving appropriate antibiotics. From this experience, we hypothesize that the etiology of severe pneumonia associated with ibrutinib treatment is probably multifactorial, involving factors like preexisting immune-suppression, drug induced pneumonitis and infections. We suggest that patients with CLL or other lymphoproliferative disorders with suspected pneumonia during monotherapy with ibrutinib should be very carefully evaluated and need to undergo complete diagnostic workup to establish an exact diagnosis. Understanding which patients with CLL or lymphoma treated with kinase inhibitors are at a higher risk for developing pulmonary complications could be one of the important future challenges, when selecting the best available therapy for these patients.

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“…Our case adds to the growing number of case reports documenting outcomes of atypical infection in ibrutinib‐treated CLL and lymphoma patients. We believe that our unique case further stimulates interest in the hypothesis that ibrutinib therapy over time may lead to immune reconstitution and activation, which may result in reduced infection‐related morbidity and mortality …”

mentioning

confidence: 83%

“…We believe that our unique case further stimulates interest in the hypothesis that ibrutinib therapy over time may lead to immune reconstitution and activation, which may result in reduced infectionrelated morbidity and mortality. 7,8…”

mentioning

confidence: 99%

Ibrutinib and antimicrobial therapy in a heavily pretreated patient with chronic lymphocytic leukaemia and disseminated cutaneous non‐tuberculous mycobacterial infection: successful surgery‐free approach

Maddy

O’Brien

Campbell

2018

Internal Medicine Journal

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Miliary tuberculosis after initiation of ibrutinib in chronic lymphocytic leukemia

Cited by 19 publications

References 8 publications

Ibrutinib suppresses intracellular mycobacterium tuberculosis growth by inducing macrophage autophagy

Ibrutinib suppresses intracellular mycobacterium tuberculosis growth by inducing macrophage autophagy

Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma

Ibrutinib and antimicrobial therapy in a heavily pretreated patient with chronic lymphocytic leukaemia and disseminated cutaneous non‐tuberculous mycobacterial infection: successful surgery‐free approach

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