Correspondence

Sirolimus for Lymphangioleiomyomatosis Lesions

N Engl J Med 2008; 358:1963-1964May 1, 2008

Article

To the Editor:

Bissler et al. and Davies et al. (Jan. 10 issue)1,2 report the beneficial effects of sirolimus on renal angiolipoma in patients with lymphangioleiomyomatosis (LAM). In contrast to the findings of Bissler et al., Davies et al. observed no benefit in lung function from sirolimus in their patients with LAM. We now describe a 41-year-old woman with LAM who underwent right-lung transplantation and subsequently had radiologic improvement in the native lung after undergoing sirolimus therapy, which was used in combination with cyclosporine and prednisolone for post-transplantation immunosuppression.

Histologic examination of the explanted lung confirmed the diagnosis of LAM. The patient's postoperative course was uneventful (Figure 1AFigure 1High-Resolution Computed Tomographic (CT) Scan of the Patient's Thorax.). Two years after transplantation, she reported the subacute onset of shortness of breath and a productive cough with milky-colored sputum (150 ml per day). Her peripheral-blood white-cell count was normal. High-resolution computed tomography (CT) showed diffuse ground-glass opacities and consolidation of the right lower lobe of the right transplanted lung as well as bilateral pleural effusions (Figure 1B). Bronchoalveolar-lavage culture was sterile with a differential cell count showing predominantly macrophages. A transbronchial lung biopsy was not performed owing to marked respiratory failure. Recurrence of LAM was considered the most likely diagnosis.

Treatment with 2 mg of sirolimus per day was started, and a mean trough level of 2.6 ng per milliliter was achieved. The patient had a steady improvement in exercise capacity, with a marked reduction in the volume of sputum. Her forced expiratory volume in 1 second (FEV₁) returned to the baseline value. Nine months after the initiation of sirolimus therapy, high-resolution CT showed progressive radiologic improvement in the lesions thought to be LAM in the native lung (Figure 1C). The patient remains well 2 years later and is receiving 3 mg of sirolimus per day.

The change in the findings on imaging is interesting, though complete resolution of cystic disease was not observed. However, this is not surprising, given the advanced nature of the primary disease. We suggest that sirolimus remains an attractive option in the treatment of LAM and speculate that it may be more effective when used at a low dose in combination with calcineurin inhibitors.

Jim J. Egan, M.D.
Kaspar Friedrich Remund, M.D.
Mater Misericordiae University Hospital, Dublin 7, Ireland

Paul Corris, M.D.
Freeman Hospital High Heaton, Newcastle upon Tyne DE7 7DN, United Kingdom

Dr. Egan reports receiving lecture fees from Boehringer Ingelheim and GlaxoSmithKline. No other potential conflict of interest relevant to this letter was reported.

2 References

1. 1

   Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358:140-151
   Full Text | Web of Science | Medline

2. 2

   Davies DM, Johnson SR, Tattersfield AE, et al. Sirolimus in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med 2008;358:200-203
   Full Text | Web of Science | Medline

Author/Editor Response

Egan et al. report improvement in post–lung-transplantation respiratory failure after the addition of sirolimus to the immunosuppressive regimen in a patient with LAM. The patient's presentation with chyloptysis, bilateral effusions, and septal thickening is consistent with lymphatic obstruction, which could be due to the infiltration of LAM cells or post-transplantation lymphoproliferative disorder. Because a biopsy was not performed to document the recurrence of LAM and new lung cysts did not develop, it is not known whether the beneficial effects of sirolimus in this patient reflected the same mechanism that resulted in the improved pulmonary function observed in some, but not all, patients in our series. Preliminary data from the interim analysis of the trial reported by Davies et al. showed no effect of sirolimus on declining lung function in the four patients with LAM for whom data were available.1 However, only two of their patients had a convincing drop in FEV₁ or forced vital capacity, whereas the condition of the other two patients either remained stable or improved. A randomized, controlled trial, such as the Multicenter International LAM Efficacy of Sirolimus Trial (NCT00414648), is required to define the role of sirolimus in the treatment of LAM.

Egan et al. also posit that their results may reflect synergy between sirolimus and a calcineurin inhibitor. Competition for metabolism through cytochrome P-450 (CYP3A4) or a combination of effects on cell-signaling pathways2,3 theoretically could play a role in the beneficial effects of sirolimus in this patient. Optimal treatment of tuberous sclerosis complex and LAM will probably require combination therapies.

John J. Bissler, M.D.
Lisa R. Young, M.D.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039
john.bissler@cchmc.org

Francis X. McCormack, M.D.
University of Cincinnati College of Medicine, Cincinnati, OH 45267

3 References

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   Paul E, Thiele E. Efficacy of sirolimus in treating tuberous sclerosis and lymphangioleiomyomatosis. N Engl J Med 2008;358:190-192
   Full Text | Web of Science | Medline

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   Yang YP, Liang ZQ, Gu ZL, Qin ZH. Molecular mechanism and regulation of autophagy. Acta Pharmacol Sin 2005;26:1421-1434
   CrossRef | Web of Science | Medline

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   Browne GJ, Proud CG. A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 2004;24:2986-2997
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Citing Articles (5)

Citing Articles

1. 1

   Michael Haidinger, Johannes Werzowa, Thomas Weichhart, Marcus D. Säemann. (2011) Targeting the dysregulated mammalian target of rapamycin pathway in organ transplantation: killing 2 birds with 1 stone. Transplantation Reviews 25:4, 145-153
   CrossRef

2. 2

   Emilio Ansótegui Barrera, Nuria Mancheño Franch, Francisco Vera-Sempere, José Padilla Alarcón. (2011) Linfangioleiomiomatosis. Archivos de Bronconeumología 47:2, 85-93
   CrossRef

3. 3

   Ramón Peces, Emilio Cuesta-López, Carlos Peces, Rafael Selgas. (2011) Giant Bilateral Renal Angiomyolipomas and Lymphangioleiomyomatosis Presenting after Two Successive Pregnancies Successfully Treated with Surgery and Rapamycin. TheScientificWorldJOURNAL 11, 2115-2123
   CrossRef

4. 4

   Emilio Ansótegui Barrera, Nuria Mancheño Franch, Francisco Vera-Sempere, José Padilla Alarcón. (2011) Lymphangioleiomyomatosis. Archivos de Bronconeumología (English Edition) 47:2, 85-93
   CrossRef

5. 5

   Kuniaki Seyama, Toshio Kumasaka, Masatoshi Kurihara, Keiko Mitani, Teruhiko Sato. (2010) Lymphangioleiomyomatosis: A Disease Involving the Lymphatic System. Lymphatic Research and Biology 8:1, 21-31
   CrossRef