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Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature.

Lopez P, Kohler S, Dimri S - J Transplant (2014)

Bottom Line: The event was more frequent in patients with a late switch to mTORi.In most cases, ILD was reversed after prompt mTORi discontinuation.ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.

View Article: PubMed Central - PubMed

Affiliation: Novartis Pharma AG, Postfach, 4002 Basel, Switzerland.

ABSTRACT
Interstitial lung disease (ILD) has been reported with the use of mammalian target of rapamycin inhibitors (mTORi). The clinical and safety databases of three Phase III trials of everolimus in de novo kidney (A2309), heart (A2310), and liver (H2304) transplant recipients (TxR) were searched using a standardized MedDRA query (SMQ) search for ILD followed by a case-by-case medical evaluation. A literature search was conducted in MEDLINE and EMBASE. Out of the 1,473 de novo TxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR) representing an incidence of 0.4%. Everolimus was discontinued in three of the four heart TxR, resulting in ILD improvement or resolution. Outcome was fatal in the kidney TxR (in whom everolimus therapy was continued) and in the liver TxR despite everolimus discontinuation. The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.

No MeSH data available.


Related in: MedlinePlus

Clinical and safety database search flow diagram (studies A2309, A2310, and H2304).
© Copyright Policy - open-access
Related In: Results  -  Collection


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fig1: Clinical and safety database search flow diagram (studies A2309, A2310, and H2304).

Mentions: Applying the SMQ search strategy to the entire study safety population (including control patients), a total of 30 events were retrieved from the clinical and safety databases (Figure 1). Following detailed medical review, drug-induced ILD was excluded in 23 events on the basis of the predefined exclusion criteria. Evidence of lung or systemic infection was found in 19 of these events. The other four cases were excluded because in one patient ILD was due to rheumatoid arthritis with lung involvement, one event was erroneously coded as ILD during database processing but was in fact a case of renal interstitial fibrosis, one case had insufficient information to permit accurate diagnosis, and one patient had stopped study medication 168 days prior to diagnosis of ILD. The remaining seven cases were determined to be drug-induced ILD. Six were confirmed as everolimus-induced ILD (four in heart transplant patients and one each in kidney and liver transplant patients) and one case was identified in a patient in the tacrolimus control arm of the liver transplant study.


Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature.

Lopez P, Kohler S, Dimri S - J Transplant (2014)

Clinical and safety database search flow diagram (studies A2309, A2310, and H2304).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4281397&req=5

fig1: Clinical and safety database search flow diagram (studies A2309, A2310, and H2304).
Mentions: Applying the SMQ search strategy to the entire study safety population (including control patients), a total of 30 events were retrieved from the clinical and safety databases (Figure 1). Following detailed medical review, drug-induced ILD was excluded in 23 events on the basis of the predefined exclusion criteria. Evidence of lung or systemic infection was found in 19 of these events. The other four cases were excluded because in one patient ILD was due to rheumatoid arthritis with lung involvement, one event was erroneously coded as ILD during database processing but was in fact a case of renal interstitial fibrosis, one case had insufficient information to permit accurate diagnosis, and one patient had stopped study medication 168 days prior to diagnosis of ILD. The remaining seven cases were determined to be drug-induced ILD. Six were confirmed as everolimus-induced ILD (four in heart transplant patients and one each in kidney and liver transplant patients) and one case was identified in a patient in the tacrolimus control arm of the liver transplant study.

Bottom Line: The event was more frequent in patients with a late switch to mTORi.In most cases, ILD was reversed after prompt mTORi discontinuation.ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.

View Article: PubMed Central - PubMed

Affiliation: Novartis Pharma AG, Postfach, 4002 Basel, Switzerland.

ABSTRACT
Interstitial lung disease (ILD) has been reported with the use of mammalian target of rapamycin inhibitors (mTORi). The clinical and safety databases of three Phase III trials of everolimus in de novo kidney (A2309), heart (A2310), and liver (H2304) transplant recipients (TxR) were searched using a standardized MedDRA query (SMQ) search for ILD followed by a case-by-case medical evaluation. A literature search was conducted in MEDLINE and EMBASE. Out of the 1,473 de novo TxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR) representing an incidence of 0.4%. Everolimus was discontinued in three of the four heart TxR, resulting in ILD improvement or resolution. Outcome was fatal in the kidney TxR (in whom everolimus therapy was continued) and in the liver TxR despite everolimus discontinuation. The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation.

No MeSH data available.


Related in: MedlinePlus