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Use of Lenalidomide in 5q-Myelodysplastic Syndrome Provides Novel Treatment Prospects in Management of Pulmonary SarcoidosisLenalidomide in Pulmonary Sarcoidosis FREE TO VIEW

Mahsa Jafari Giv, MBBS (Honours); Alam Yoosuff, MBBS (Honours), MPH; Ali Bazargan, MD
Author and Funding Information

From the Department of Haematology (Drs Jafari Giv and Bazargan), St. Vincent’s Hospital, Melbourne, VIC; and Finley Medical Centre (Dr Yoosuff), Finley, NSW, Australia.

CORRESPONDENCE TO: Mahsa Jafari Giv, MBBS (Honours), Department of Haematology, St. Vincent’s Hospital (Melbourne), 59 Victoria Parade, Fitzroy, Melbourne, VIC, Australia, 3065; e-mail: mahsa.JAFARIGIV@svha.org.au


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):e35-e37. doi:10.1378/chest.14-2529
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We present the case of a 71-year-old woman with a long-standing history of refractory pulmonary sarcoidosis, who, upon commencement of treatment with lenalidomide for her newly diagnosed 5q-myelodysplastic syndrome, showed a remarkable, immediate, unexpected response and recovery of her sarcoidosis-related symptoms, improvement of her vital capacity, and complete clearance of her bibasal alveolor infiltrates. To our knowledge, this is the first case to report on the significant and immediate efficacy of lenalidomide in the management of pulmonary sarcoidosis. It provides a potential role for the use of lenalidomide as a novel therapeutic agent in patients with refractory pulmonary sarcoidosis.

Figures in this Article

Sarcoidosis affects individuals from all racial and age groups; however, to date, no optimal therapies to effectively manage this condition have been discovered.1 The efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) with the isolated 5q-clone has been well established.2 There is also evidence to support the use of lenalidomide in the treatment of refractory cutaneous sarcoidosis.3 However, there have been no reports demonstrating the potential effects of lenalidomide as a therapeutic option in patients with pulmonary sarcoidosis.

A 71-year-old woman with a 12-year history of stage IV pulmonary sarcoidosis, with no extrapulmonary organ involvement, was evaluated for refractory and worsening dyspnea (Medical Research Council breathlessness scale 5/5) despite long-term therapy with methotrexate and inhaled and systemic corticosteroids. Immediately prior to commencement of lenalidomide, she was taking 15 mg of prednisolone and 400 μg of inhaled budesonide daily. Full blood examination revealed marked macrocytic anemia (hemoglobin level, 81 g/L; mean corpuscular volume, 114 fL). She was a never smoker and had a history of hypertension managed with perindopril.

Further investigation of her macrocytic anemia was unyielding; therefore, a bone marrow biopsy was performed, which revealed hypocellular marrow with trilineage dysplasia consistent with 5q-MDS, with no evidence of noncaseating granulomas. The patient was started on lenalidomide, 10 mg daily.

During investigations to establish the diagnosis of 5q-MDS, the patient became transfusion dependent and experienced severe dyspnea, fatigue, and a considerable decline in quality of life. A repeat chest CT scan with contrast revealed a number of irregular masses within the lung, with bibasal alveolar infiltrates that had developed within a 12-month period (Fig 1). Biopsy specimens were taken and histopathologically confirmed as sarcoidosis. Following this, the patient was continued on lenalidomide.

Figure Jump LinkFigure 1 –  Chest CT scan with contrast, prior to treatment with lenalidomide, demonstrating a number of irregular masses.Grahic Jump Location

After two cycles of treatment with lenalidomide, the patients’ dyspnea, fatigue, daily activity, and quality of life showed significant improvement, and her lung function testing demonstrated a remarkable increase in vital capacity, from 1.73 L to 1.93 L. Of particular significance, a repeat CT scan of the chest 4 months after commencement of lenalidomide therapy demonstrated complete clearance of bibasal alveolar infiltrates (Fig 2). During this period, given her excellent response, the dose of prednisolone was reduced from 15 mg daily to 5 mg on alternate days, and she continues to take lenalidomide.

Figure Jump LinkFigure 2 –  Chest CT scan with contrast 4 mo after therapy with lenalidomide, showing interval resolution of masses and clearance of bibasal alveolar infiltrates.Grahic Jump Location

Lenalidomide has shown efficacy in patients with transfusion-dependent 5q-MDS.2 It is proposed that it acts as an immunomodulatory agent, which selectively inhibits the del(5q) clone. Sarcoidosis is a multisystem granulomatous disorder of unknown cause, associated with a CD4+ T-helper cell immune-mediated response resulting in granulomatous formation.4 Furthermore, tumor necrosis factor (TNF) levels and TNF receptor concentrations are increased in this disease.5

Lenalidomide has been shown to be an immunomodulator, altering both cellular and humoral limbs of the immune system. It inhibits the production of TNF-α through increasing degradation of its messenger RNA and enhancing activity of α1-acid-glycoprotein, which also has intrinsic anti-TNF-α activity.6 Studies of lenalidomide and other thalidomide derivatives have confirmed that they are capable of enhancing the proliferative and functional capacity of the T lymphocytes by amplifying the costimulatory signaling pathways that ultimately activate the effector responses and suppress inflammation.7 In addition, lenalidomide has potent antiproliferative, cytotoxic, and antiangiogenic properties.8 This multimodal mechanism of action may be the key to the potential effectiveness of lenalidomide in sarcoidosis.

Lenalidomide is the first manufactured analog of thalidomide, with greater potency and fewer side effects.9 The efficacy of thalidomide in the management of sarcoidosis has been reported by a number of studies. Fazzi et al10 concluded that thalidomide was effective in the management of 19 patients with chronic steroid-refractory cutaneous and pulmonary sarcoidosis.10 Judson et al11 studied 10 patients with refractory pulmonary sarcoidosis treated with thalidomide, and found efficacy in three patients. However, they encountered poor tolerance of thalidomide because of its side effects.

Thalidomide has further been reported to be effective in the management of steroid-refractory cutaneous sarcoidosis.12,13 A recent evaluation of thalidomide in cutaneous sarcoidosis did not confirm the efficacious effects previously reported when thalidomide was administered at a lower dose with a shorter duration of therapy.14 The use of lenalidomide in sarcoidosis has been reported in a single patient with refractory cutaneous sarcoidosis who also demonstrated noticeable improvement of skin lesions without side effects.3

Despite the evidence in the literature supporting the therapeutic effects of lenalidomide on cutaneous sarcoidosis, as well as the effects of thalidomide on cutaneous and pulmonary sarcoidosis, the effects of lenalidomide use on pulmonary sarcoidosis have not been reported. This case demonstrates a potential role for the use of lenalidomide as a novel therapeutic agent in patients with refractory pulmonary sarcoidosis. New clinical studies are needed to further confirm this effect because this could lead to significant clinical benefits for patients with pulmonary sarcoidosis.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

MDS

myelodysplastic syndrome

TNF

tumor necrosis factor

Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357(21):2153-2165. [CrossRef] [PubMed]
 
Fenaux P, Giagounidis A, Selleslag D, et al; MDS-004 Lenalidomide del5q Study Group. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118(14):3765-3776. [CrossRef] [PubMed]
 
Dalm VA, van Hagen PM. Efficacy of lenalidomide in refractory lupus pernio. JAMA Dermatol. 2013;149(4):493-494. [CrossRef] [PubMed]
 
Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000;12(1):71-76. [CrossRef] [PubMed]
 
Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med. 2001;135(1):27-31. [CrossRef] [PubMed]
 
Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000;96(9):2943-2950. [PubMed]
 
McDaniel JM, Pinilla-Ibarz J, Epling-Burnette PK. Molecular action of lenalidomide in lymphocytes and hematologic malignancies. Adv Hematol. 2012;2012:513702. http://dx.doi.org/10.1155/2012/513702. Accessed November 14, 2014.
 
Pallotti MC, Nannini M, Agostinelli C, et al. Long-term durable response to lenalidomide in a patient with hepatic epithelioid hemangioendothelioma. World J Gastroenterol. 2014;20(22):7049-7054. [CrossRef] [PubMed]
 
Anderson KC. Lenalidomide and thalidomide: mechanisms of action—similarities and differences. Semin Hematol. 2005;42(4)(suppl 4):S3-S8. [CrossRef] [PubMed]
 
Fazzi P, Manni E, Cristofani R, et al. Thalidomide for improving cutaneous and pulmonary sarcoidosis in patients resistant or with contraindications to corticosteroids. Biomed Pharmacother. 2012;66(4):300-307. [CrossRef] [PubMed]
 
Judson MA, Silvestri J, Hartung C, Byars T, Cox CE. The effect of thalidomide on corticosteroid-dependent pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23(1):51-57. [PubMed]
 
Baughman RP, Judson MA, Teirstein AS, Moller DR, Lower EE. Thalidomide for chronic sarcoidosis. Chest. 2002;122(1):227-232. [CrossRef] [PubMed]
 
Nguyen YT, Dupuy A, Cordoliani F, et al. Treatment of cutaneous sarcoidosis with thalidomide. J Am Acad Dermatol. 2004;50(2):235-241. [CrossRef] [PubMed]
 
Droitcourt C, Rybojad M, Porcher R, et al. A randomized, investigator-masked, double-blind, placebo-controlled trial on thalidomide in severe cutaneous sarcoidosis. Chest. 2014;146(4):1046-1054. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Chest CT scan with contrast, prior to treatment with lenalidomide, demonstrating a number of irregular masses.Grahic Jump Location
Figure Jump LinkFigure 2 –  Chest CT scan with contrast 4 mo after therapy with lenalidomide, showing interval resolution of masses and clearance of bibasal alveolar infiltrates.Grahic Jump Location

Tables

References

Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357(21):2153-2165. [CrossRef] [PubMed]
 
Fenaux P, Giagounidis A, Selleslag D, et al; MDS-004 Lenalidomide del5q Study Group. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118(14):3765-3776. [CrossRef] [PubMed]
 
Dalm VA, van Hagen PM. Efficacy of lenalidomide in refractory lupus pernio. JAMA Dermatol. 2013;149(4):493-494. [CrossRef] [PubMed]
 
Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000;12(1):71-76. [CrossRef] [PubMed]
 
Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med. 2001;135(1):27-31. [CrossRef] [PubMed]
 
Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000;96(9):2943-2950. [PubMed]
 
McDaniel JM, Pinilla-Ibarz J, Epling-Burnette PK. Molecular action of lenalidomide in lymphocytes and hematologic malignancies. Adv Hematol. 2012;2012:513702. http://dx.doi.org/10.1155/2012/513702. Accessed November 14, 2014.
 
Pallotti MC, Nannini M, Agostinelli C, et al. Long-term durable response to lenalidomide in a patient with hepatic epithelioid hemangioendothelioma. World J Gastroenterol. 2014;20(22):7049-7054. [CrossRef] [PubMed]
 
Anderson KC. Lenalidomide and thalidomide: mechanisms of action—similarities and differences. Semin Hematol. 2005;42(4)(suppl 4):S3-S8. [CrossRef] [PubMed]
 
Fazzi P, Manni E, Cristofani R, et al. Thalidomide for improving cutaneous and pulmonary sarcoidosis in patients resistant or with contraindications to corticosteroids. Biomed Pharmacother. 2012;66(4):300-307. [CrossRef] [PubMed]
 
Judson MA, Silvestri J, Hartung C, Byars T, Cox CE. The effect of thalidomide on corticosteroid-dependent pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23(1):51-57. [PubMed]
 
Baughman RP, Judson MA, Teirstein AS, Moller DR, Lower EE. Thalidomide for chronic sarcoidosis. Chest. 2002;122(1):227-232. [CrossRef] [PubMed]
 
Nguyen YT, Dupuy A, Cordoliani F, et al. Treatment of cutaneous sarcoidosis with thalidomide. J Am Acad Dermatol. 2004;50(2):235-241. [CrossRef] [PubMed]
 
Droitcourt C, Rybojad M, Porcher R, et al. A randomized, investigator-masked, double-blind, placebo-controlled trial on thalidomide in severe cutaneous sarcoidosis. Chest. 2014;146(4):1046-1054. [CrossRef] [PubMed]
 
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