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Imatinib as Rescue Therapy in a Patient With Pulmonary Hypertension Associated With Gaucher DiseaseImatinib for Pulmonary Hypertension in Gaucher FREE TO VIEW

Nadine Al-Naamani, MD; Kari E. Roberts, MD; Nicholas S. Hill, MD, FCCP; Ioana R. Preston, MD, FCCP
Author and Funding Information

From the Department of Medicine, Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Boston, MA.

CORRESPONDENCE TO: Ioana R. Preston, MD, FCCP, Department of Medicine, Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, 800 Washington St, Mailbox 257, Boston, MA 02111; e-mail: ipreston@tuftsmedicalcenter.org.


This article was presented in poster form at the 2014 American Thoracic Society Annual Meeting, May 20, 2014, San Diego, CA.

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


Chest. 2014;146(3):e81-e83. doi:10.1378/chest.13-2795
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Published online

Pulmonary hypertension (PH) is a known complication of Gaucher disease (GD) and splenectomy. Although it resembles World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH), PH due to GD or splenectomy is part of WHO group 5. There are no clinical trials testing therapies in PH due to GD or splenectomy. Several reports suggest that PAH-specific therapies are beneficial in patients with PH due to GD, although data are insufficient to formulate a treatment algorithm for these patients. The tyrosine kinase inhibitor imatinib has been investigated in the treatment of severe PAH, but not in PH WHO group 5. We report a patient with GD and splenectomy who developed PH that progressed while on conventional PAH-specific therapy and improved once imatinib was added to her treatment regimen. This is the first report, to our knowledge, describing significant subjective and objective improvements in response to imatinib in a patient with WHO group 5 PH.

Figures in this Article

Gaucher disease (GD), the most common lysosomal storage disease, affects about 20,000 individuals in the United States.1 Pulmonary hypertension (PH) is a known complication of GD2-4 as well as splenectomy5 and is classified as PH World Health Organization group 5.6 Pathologic changes of PH in GD and splenectomy include pulmonary vascular remodeling and plexogenic vasculopathy, similar to group 1 pulmonary arterial hypertension (PAH).7-10 Few data are available on the treatment of PH due to GD or splenectomy.11-15 Imatinib was investigated as a potential treatment of severe PAH.16,17 Here, we report the use of imatinib in a patient with severe refractory PH due to GD and splenectomy.

A woman, aged 29 years, with GD type 1 treated with enzyme replacement and remote splenectomy was admitted with severe, progressive dyspnea on exertion, New York Heart Association (NYHA) functional class (FC) IV. An echocardiogram revealed normal left ventricular function, a severely dilated right ventricle with moderately reduced function, normal left atrium, a moderately dilated right atrium, and elevated pulmonary artery pressures (> 60 mm Hg). A chest CT scan and a ventilation/perfusion lung scan ruled out pulmonary emboli. Pulmonary function tests showed an isolated moderate reduction in diffusion capacity of carbon monoxide (56% predicted). Liver ultrasound showed fatty infiltration without evidence of portal hypertension. Serologic evaluation was unremarkable. Right-sided heart catheterization (RHC) diagnosed severe PH (Table 1).

Table Graphic Jump Location
TABLE 1  ] Time Course of Clinical Status, Exercise Capacity, and Hemodynamic Results

Mean values are given in parentheses. FC = functional class; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; RHC = right-sided heart catheterization; WU = Wood unit.

The patient was started on IV treprostinil, and the dose was titrated over 3 months to 20 ng/kg/min with improvement in symptoms to NYHA FC III, with mild symptoms of prostacyclin excess (headache and loose stools). The addition of tadalafil produced severe laryngeal edema. After 4 months of monotherapy, ambrisentan 5 mg/d was added with further improvement in her symptoms to NYHA FC II. Six months later, her dyspnea on exertion worsened again to NYHA FC III. Attempts at raising the treprostinil dose led to intolerable symptoms of prostacyclin excess, whereas ambrisentan at 10 mg/d caused severe nasal congestion. An echocardiogram showed persistence of severe right ventricular dilatation; RHC showed persistent severe hemodynamic impairment (Table 1). Given the lack of other approved PAH therapies and that she was not receiving anticoagulation therapy, imatinib was added at 200 mg/d for 4 weeks then titrated to 400 mg/d. She tolerated it well except for mild periorbital and facial edema initially, which resolved with diuresis. Her symptoms gradually improved and, after 6 months on imatinib, she was NYHA FC I, with improvement sustained for > 1 year. RHC after 14 months on imatinib showed marked hemodynamic improvement (Fig 1, Table 1).

Figure Jump LinkFigure 1  Time course of hemodynamics before and after initiation of imatinib. CI = cardiac index; mPAP = mean pulmonary artery pressure; PVR = pulmonary vascular resistance; WU = Wood unit.Grahic Jump Location

Although GD and asplenia are known risk factors for PH,5,11 data are limited on the treatment of this entity due to lack of randomized controlled trials. Case reports suggest PAH therapies such as prostacyclins,12,15 endothelin receptor antagonists, and phosphodiesterase-5 inhibitors11,14 improve symptoms in GD-associated PH. In postsplenectomy PH, treatment with pulmonary vasodilators is a reasonable choice if thromboembolism has been excluded.13 We report, to our knowledge, the first case of imatinib use in a patient with severe PH, GD, and splenectomy, who failed to maintain improvement on dual PAH therapy. Given the presence of two risk factors for PH, we cannot ascertain whether imatinib was ameliorating PH due to GD, splenectomy, or both.

Platelet-derived growth factor is a vascular smooth muscle cell mitogen that activates signal transduction pathways associated with smooth muscle hyperplasia and has been implicated in the pathogenesis of PH.18 Imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor, α and β kinases, Abl, DDR, and c-KIT, was investigated as treatment of PAH group 1.16,17 When added to conventional PAH-specific therapy in patients with severe PAH, imatinib improved 6-min walk distance (the primary end point), cardiac output, and pulmonary vascular resistance without impact on functional class, time to clinical worsening, or mortality.16 Adverse side effects included nausea, vomiting, diarrhea, facial and peripheral edema, and anemia. The drug was not approved by the regulatory agencies due to a high dropout rate in addition to an increased incidence of subdural hematomas in patients treated with imatinib and concomitant anticoagulation.16

In this patient with severe progressive PH despite optimal vasodilator therapy and with no indication for anticoagulation, we elected to start imatinib and obtained long-term beneficial results. In the setting of rare diseases where sufficiently large clinical trials are not feasible, anecdotal experiences such as this case describing the effects of off-label rescue therapies like imatinib in patients with PH recalcitrant to traditional therapies are important tools for the clinician. Sharing experiences of treatment successes in this group of patients is important in formulating expert opinion and future recommendations.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Hill has received research grant support from Actelion Pharmaceuticals US, Inc; Bayer AG; Gilead; Ikaria, Inc; Novartis Corporation; and United Therapeutics Corporation and also serves as a consultant to Gilead. Dr Preston has received research grant support from Actelion; Aires Pharmaceuticals, Inc/Mast Therapeutics, Inc; Gilead; Novartis Corporation; and United Therapeutics Corporation and also serves as a consultant to Actelion Pharmaceuticals US, Inc; Bayer AG; Gilead; and United Therapeutics Corporation. Drs Al-Naamani and Roberts have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: This work was performed at Tufts Medical Center. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

FC

functional class

GD

Gaucher disease

NYHA

New York Heart Association

PAH

pulmonary arterial hypertension

PH

pulmonary hypertension

RHC

right-sided heart catheterization

Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249-254. [CrossRef] [PubMed]
 
Pastores GM, Miller A. Pulmonary hypertension in Gaucher’s disease. Lancet. 1998;352(9127):580. [CrossRef] [PubMed]
 
Mistry PK, Sirrs S, Chan A, et al. Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy. Mol Genet Metab. 2002;77(1-2):91-98. [CrossRef] [PubMed]
 
Elstein D, Klutstein MW, Lahad A, Abrahamov A, Hadas-Halpern I, Zimran A. Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet. 1998;351(9115):1544-1546. [CrossRef] [PubMed]
 
Hoeper MM, Niedermeyer J, Hoffmeyer F, Flemming P, Fabel H. Pulmonary hypertension after splenectomy? Ann Intern Med. 1999;130(6):506-509. [CrossRef] [PubMed]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. [CrossRef] [PubMed]
 
Ross DJ, Spira S, Buchbinder NA. Gaucher cells in pulmonary-capillary blood in association with pulmonary hypertension. N Engl J Med. 1997;336(5):379-381. [CrossRef] [PubMed]
 
den Bakker MA, Grünberg K, Boonstra A, van Hal PT, Hollak CE. Pulmonary arterial hypertension with plexogenic arteriopathy in enzyme-substituted Gaucher disease. Histopathology. 2012;61(2):324-326. [CrossRef] [PubMed]
 
Dawson A, Elias DJ, Rubenson D, et al. Pulmonary hypertension developing after alglucerase therapy in two patients with type 1 Gaucher disease complicated by the hepatopulmonary syndrome. Ann Intern Med. 1996;125(11):901-904. [CrossRef] [PubMed]
 
Christman BW. Lipid mediator dysregulation in primary pulmonary hypertension. Chest. 1998;114(3_suppl):205S-207S. [CrossRef] [PubMed]
 
Lo SM, Liu J, Chen F, et al. Pulmonary vascular disease in Gaucher disease: clinical spectrum, determinants of phenotype and long-term outcomes of therapy. J Inherit Metab Dis. 2011;34(3):643-650. [CrossRef] [PubMed]
 
Leuchte HH, Baumgartner RA, Behr J. Treatment of severe pulmonary hypertension with inhaled iloprost. Ann Intern Med. 2003;139(4):306. [CrossRef] [PubMed]
 
Lahm T, Chakinala MM. World Health Organization group 5 pulmonary hypertension. Clin Chest Med. 2013;34(4):753-778. [CrossRef] [PubMed]
 
Fernandes CJ, Jardim C, Carvalho LA, Farias AQ, Filho MT, Souza R. Clinical response to sildenafil in pulmonary hypertension associated with Gaucher disease. J Inherit Metab Dis. 2005;28(4):603-605. [CrossRef] [PubMed]
 
Bakst AE, Gaine SP, Rubin LJ. Continuous intravenous epoprostenol therapy for pulmonary hypertension in Gaucher’s disease. Chest. 1999;116(4):1127-1129. [CrossRef] [PubMed]
 
Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128-1138. [CrossRef] [PubMed]
 
Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182(9):1171-1177. [CrossRef] [PubMed]
 
Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79(4):1283-1316. [PubMed]
 

Figures

Figure Jump LinkFigure 1  Time course of hemodynamics before and after initiation of imatinib. CI = cardiac index; mPAP = mean pulmonary artery pressure; PVR = pulmonary vascular resistance; WU = Wood unit.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Time Course of Clinical Status, Exercise Capacity, and Hemodynamic Results

Mean values are given in parentheses. FC = functional class; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; RHC = right-sided heart catheterization; WU = Wood unit.

References

Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249-254. [CrossRef] [PubMed]
 
Pastores GM, Miller A. Pulmonary hypertension in Gaucher’s disease. Lancet. 1998;352(9127):580. [CrossRef] [PubMed]
 
Mistry PK, Sirrs S, Chan A, et al. Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy. Mol Genet Metab. 2002;77(1-2):91-98. [CrossRef] [PubMed]
 
Elstein D, Klutstein MW, Lahad A, Abrahamov A, Hadas-Halpern I, Zimran A. Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet. 1998;351(9115):1544-1546. [CrossRef] [PubMed]
 
Hoeper MM, Niedermeyer J, Hoffmeyer F, Flemming P, Fabel H. Pulmonary hypertension after splenectomy? Ann Intern Med. 1999;130(6):506-509. [CrossRef] [PubMed]
 
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. [CrossRef] [PubMed]
 
Ross DJ, Spira S, Buchbinder NA. Gaucher cells in pulmonary-capillary blood in association with pulmonary hypertension. N Engl J Med. 1997;336(5):379-381. [CrossRef] [PubMed]
 
den Bakker MA, Grünberg K, Boonstra A, van Hal PT, Hollak CE. Pulmonary arterial hypertension with plexogenic arteriopathy in enzyme-substituted Gaucher disease. Histopathology. 2012;61(2):324-326. [CrossRef] [PubMed]
 
Dawson A, Elias DJ, Rubenson D, et al. Pulmonary hypertension developing after alglucerase therapy in two patients with type 1 Gaucher disease complicated by the hepatopulmonary syndrome. Ann Intern Med. 1996;125(11):901-904. [CrossRef] [PubMed]
 
Christman BW. Lipid mediator dysregulation in primary pulmonary hypertension. Chest. 1998;114(3_suppl):205S-207S. [CrossRef] [PubMed]
 
Lo SM, Liu J, Chen F, et al. Pulmonary vascular disease in Gaucher disease: clinical spectrum, determinants of phenotype and long-term outcomes of therapy. J Inherit Metab Dis. 2011;34(3):643-650. [CrossRef] [PubMed]
 
Leuchte HH, Baumgartner RA, Behr J. Treatment of severe pulmonary hypertension with inhaled iloprost. Ann Intern Med. 2003;139(4):306. [CrossRef] [PubMed]
 
Lahm T, Chakinala MM. World Health Organization group 5 pulmonary hypertension. Clin Chest Med. 2013;34(4):753-778. [CrossRef] [PubMed]
 
Fernandes CJ, Jardim C, Carvalho LA, Farias AQ, Filho MT, Souza R. Clinical response to sildenafil in pulmonary hypertension associated with Gaucher disease. J Inherit Metab Dis. 2005;28(4):603-605. [CrossRef] [PubMed]
 
Bakst AE, Gaine SP, Rubin LJ. Continuous intravenous epoprostenol therapy for pulmonary hypertension in Gaucher’s disease. Chest. 1999;116(4):1127-1129. [CrossRef] [PubMed]
 
Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128-1138. [CrossRef] [PubMed]
 
Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182(9):1171-1177. [CrossRef] [PubMed]
 
Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79(4):1283-1316. [PubMed]
 
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