Should mammalian target of rapamycin inhibitors be stopped in women with lymphangioleiomyomatosis awaiting lung transplantation?

Abstract

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease characterized by proliferation of smooth muscle like cells (LAM cells) that have mutations in the tuberous sclerosis gene (TSC2), leading to the activation of the mammalian target of rapamycin (mTOR). Rapamycin, an inhibitor of the mTOR pathway, has been shown in a landmark clinical trial to halt the decline in lung function, as long as it is used continuously. Women with severe pulmonary LAM still progress to require lung transplantation. The use of inhibitors of the mTOR pathway immediately after transplant has been linked to bronchial anastomotic dehiscence, a potentially fatal complication of lung transplantation. Currently, it is recommended that women with LAM stop taking rapamycin once listed for lung transplant, which could potentially lead to faster lung function decline while awaiting organ transplantation. Here we review the existing evidence and discuss potential recommendations for the management of the inhibitors of the mTOR pathway while awaiting lung transplantation.

Keywords::

• bronchial dehiscence
• everolimus
• lung transplant
• lymphangioleiomyomatosis
• mTOR inhibitors
• sirolimus
• TSC

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that can occur primarily in women, either in sporadic form or in association with germline mutations in the tuberous sclerosis (TSC)1 or TSC2 gene. LAM is characterized by the proliferation of a smooth muscle like cells that carry bi-allelic inactivating mutations in TSC2 [1], leading to lung destruction and cyst formation. Further, sporadic LAM or LAM/TSC can be associated with renal tumors (angiomyolipomas) and axial lymphatic involvement. Extrapulmonary tumors have been found to have identical mutations in TSC2, leading to the hypothesis that LAM cells can metastasize, a theory substantiated by the identification of circulating LAM cells [1]. Current thought on disease pathogenesis proposes its reclassification as a low-grade malignancy [2].

Tuberin, the protein product of TSC2, a key component of the TSC protein complex, is an important negative regulator of the mammalian target of rapamycin (mTOR) complex 1. As expected, inactivating mutations in TSC2 lead to the activation of mTOR in LAM [3].

mTOR inhibitors in LAM & TSC

Inhibitors of the mTOR pathway are commonly used for immunosuppression in solid organ transplant, and are in increased use in malignancy. Sirolimus (Rapamune^®) and everolimus (Afinitor^®) are two different inhibitors of the mTOR pathway that have been investigated in LAM and TSC. One important difference between the two drugs is their respective half-lives; sirolimus has a half-life of 60 h versus 18–35 h for everolimus [4]. Since in LAM and TSC the mTOR pathway is activated, both these inhibitors have been investigated in vitro and in preclinical models, showing significant benefit in TSC-associated tumors and neurological manifestations. The preclinical studies led to subsequent clinical trials that have demonstrated benefit of mTOR inhibition in various clinical presentations associated with TSC and in LAM.

In LAM, a seminal randomized, double-blind placebo-controlled clinical trial, the Multicenter International LAM Efficacy of Sirolimus (MILES) trial, demonstrated that sirolimus can stabilize the rate of decline in forced expiratory volume in 1 s (FEV1) in women with moderately severe disease [5]. However, consistent with the cytostatic activity of mTOR inhibitors and with previous clinical trials in TSC-related tumors, there is a need for continued use of sirolimus since lung function decline resumes after therapy is stopped.

Lung transplantation in LAM

Lung transplantation remains an option for women with LAM who have severe abnormalities in lung function and exercise capacity [6]. Prior to the successful trial of sirolimus in LAM, about one-third of women with LAM progressed to require lung transplantation [6]. Lung transplantation leads to significant improvement in lung function (FEV1, diffusing capacity of carbon monoxide and pulmonary arterial oxygen tension) and most indicators of quality of life [7]. The 5-year survival after lung transplant in LAM is 65% [7]. Consistent with the ability of LAM cells to metastasize, LAM can rarely recur after lung transplantation [8]. However, these recurrences are incidentally found and to date, have not been shown to be of clinical relevance or to affect post-transplant survival.

The lung allocation score, waiting time and their impact on women with LAM

In the USA, as a result of the high incidence of death on the waiting list in the lung transplant candidate population under an allocation system based upon waiting time, the Lung Allocation Scoring system based upon disease severity was instituted in 2005 to determine lung allocation priority [9]. The goals of the new allocation system were to minimize deaths on the waiting list while optimizing the likelihood of survival in the first post-transplant year. As part of the allocation algorithm, disease categories were defined to reflect similar rates of disease progression and survival benefits in response to transplant within groups.

Initial group categorizations were based upon the four most common indications for lung transplantation: chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis and pulmonary hypertension. Rare lung diseases were grouped together with these more common diagnoses based upon pathophysiology and the available survival data. LAM, a predominantly obstructive disease, was categorized with chronic obstructive pulmonary disease and other obstructive diseases. Patients with idiopathic pulmonary fibrosis, because of their short median survival from the time of diagnosis as well as the demonstrated survival benefit after lung transplantation, receive priority for allocation on the basis of their underlying lung disease under the Lung Allocation Scoring system. As a result, most patients with obstructive lung disease experience relatively longer wait times for transplantation. Hence, optimization of LAM management is imperative, even for women actively awaiting lung transplantation.

Risks of mTOR inhibitors in lung transplantation

At the time of lung procurement, the bronchial blood supply is interrupted. The anastomotic site is then reliant on retrograde flow from the pulmonary arterial circulation. The revascularization of the transplanted lung bronchial circulation may take 2–4 weeks and leaves the anastomotic site susceptible to ischemia, with the greatest risk occurring during the early time period after lung transplantation. Inhibitors of the mTOR pathway are potent immunomodulators because of their ability to block IL-2–mediated activation of T and B cells [2]. In addition, they are known inhibitors of cell proliferation, including fibroblasts and blood endothelial cells. Exposure to these drugs, either as part of LAM management or as immunosuppressants in transplant recipients, may result in delayed wound healing and bronchial revascularization, which could contribute to delayed bronchial anastomotic healing. Two separate studies [10,11] have shown that mTOR inhibition in the immediate post-transplant period can result in bronchial dehiscence, a serious and often fatal complication after lung transplant. In the first study that examined 15 patients who were receiving sirolimus as part of a standard post-transplant immunosuppression protocol, 4 (26%) patients developed bronchial anastomotic dehiscence, a much higher rate than the expected 2–3%. This led to the death of one patient. In this study, sirolimus levels were between 10 and 15 ng/ml. In the second study in which three of four patients developed bronchial anastomotic dehiscence, sirolimus levels were kept between 4 and 10 ng/ml. The time to bronchial dehiscence was between 2 weeks and 6 months after lung transplantation. This has lead to a black box warning regarding the use of sirolimus in the setting of lung transplantation: ‘Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen. The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended’ [12].

Currently, most lung transplant programs request that women with LAM stop mTOR inhibition while awaiting lung transplantation, consistent with the recommendations of the European Respiratory Society [13].

Should mTOR inhibitors be stopped in women with LAM listed for lung transplant?

In the MILES study, the rate of decline in FEV1 in the placebo group was −12 ± 2 ml per month versus 1 ± 2 in the sirolimus group. A query of the United Network for Organ Sharing database in the USA showed that the median wait-time for lung transplant for women with LAM was 664 days (range: 129–749). If discontinuation of sirolimus is required for lung transplant listing, women with LAM on the lung transplant list could potentially lose more than 200 ml in FEV1 while awaiting lung transplantation, potentially compromising survival to transplant, rendering them too sick to be transplanted, and significantly impacting their quality of life on the waiting list.

To address this critical question, it is important to note that the two studies showing significant risk of bronchial dehiscence were conducted with the use of sirolimus commencing immediately post-transplant and continued as part of the postoperative immunosuppressive regimen. In addition, and at least in one of the studies, serum trough levels of rapamycin were kept between 10 and 15 ng/ml, which is significantly higher than the current accepted management of rapamycin in LAM [14]. To date, there is no evidence that mTOR inhibitors taken up until the time of transplant would result in similar risks of bronchial anastomotic dehiscence. In this respect, we have recently reported the results of the use of everolimus in idiopathic pulmonary fibrosis [15]. Twenty-one patients from this trial went on to receive lung transplants; 5 of 11 patients who were randomized to everolimus took everolimus up to and including the morning of transplant. No patient developed bronchial dehiscence. Whether these results apply to sirolimus is unclear, but these data provide the first evidence that the continuation of mTOR inhibitors, specifically everolimus at low therapeutic levels (3–8 ng/ml), while awaiting lung transplantation is likely safe for women with LAM.

The use of mTOR inhibitors post-transplant

There is a paucity of data regarding the use of mTOR inhibitors in lung transplant recipients for LAM- or TSC-related complications. Even though LAM can recur in the allograft, this is rarely a clinical issue and does not warrant change of immunosuppression to mTOR inhibitors. Although the earliest published report [16] of resumption of mTOR inhibition specifically for a LAM-related complication post-transplant (chylous effusion) occurred at 5 months post-lung transplantation, without any bronchial anastomosis-related complications, we have used everolimus safely within 3 months of transplant for the same indication. Indeed, in our recent study of 84 patients who received delayed-onset everolimus at 4–12 weeks, no patient developed anastomotic complications [17]. Another recent report where mTOR inhibitors were commenced at 9 months post-transplant was associated with a favorable outcome [18].

Conclusion

It is generally agreed that mTOR inhibitors should not be used in the immediate post-lung transplant period, and that commencement should be delayed until the bronchial anastomosis has healed. As for their use in women with LAM who are awaiting lung transplantation, a frank discussion between the lung transplant team and patients is warranted. As our data are limited to the pre-transplant use of everolimus, and sirolimus has a half-life almost double that of everolimus and could potentially be present in the blood stream for a longer period after transplant, consideration could also be given to intra-class alteration of therapy for candidates on the waiting list. However, on the balance of the evidence to date, and weighing the potential risks and benefits, we suggest that mTOR inhibitors, particularly everolimus, are likely safe to be used up until lung transplantation. The risk–benefit ratio favors keeping mTOR inhibitor trough levels in the low therapeutic range. For women with LAM and TSC who may benefit from mTOR inhibition post-lung transplant for other manifestations of their disease, mTOR inhibitors use could be initiated after evidence of bronchial anastomotic healing is observed by an experienced lung transplant bronchoscopist. The coordinated management of medical therapy for lung transplant candidates and recipients with LAM and TSC, involving LAM providers as well as transplant physicians, can allow for optimization of lung health and quality of life, both while awaiting and after lung transplantation.

Financial & competing interests disclosure

Research in the El-Chemaly laboratory is supported by funds from the NIH/NHLBI and the Department of Defense Congressionally Directed Medical Research Program. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.