Pulmonary toxicity of mTOR inhibitors. Comparisons of two populations: Solid organ recipients and cancer patients - 19/06/22

Doi : 10.1016/j.therap.2022.05.008

Sébastien Gendarme ^a,⁎ , Jean Pastré ^a, Eliane M. Billaud ^b, Laure Gibault ^c, Romain Guillemain ^d, Stéphane Oudard ^e,^f, Jacques Medioni ^e,^f, Agnès Lillo-Lelouet ^g, Dominique Israël-Biet ^a,^f
^a Service de pneumologie, centre de compétence maladies pulmonaires rares, hôpital européen Georges-Pompidou, AP–HP, 75000 Paris, France
^b Service de pharmacologie, hôpital européen Georges-Pompidou, AP–HP, 75000 Paris, France
^c Service d’anatomopathologie et cytologie, hôpital européen Georges-Pompidou, AP–HP, 75000 Paris, France
^d Unité de transplantation cardiaque et pulmonaire, hôpital européen Georges-Pompidou, AP–HP, 75000 Paris, France
^e Service d’oncologie médicale, hôpital européen Georges-Pompidou, AP–HP, 75000 Paris, France
^f Université de Paris, 75000 Paris, France
^g Centre de pharmacovigilance, hôpital européen Georges-Pompidou, AP–HP, 75000 Paris, France

^⁎Corresponding author.

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Summary

Introduction

Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients.

Material and methods

We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed.

Results

Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3–35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values.

Conclusion

Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease.

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Keywords : TOR serine-threonine kinases, Adverse drug reactions, Interstitial lung disease, Everolimus, Sirolimus