title: A novel therapeutic approach to the treatment of scleroderma-associated pulmonary complications: safety and efficacy of combination therapy with imatinib and cyclophosphamide.
abstract: OBJECTIVE
  Scleroderma-related interstitial lung disease (SSc-ILD) has limited therapeutic options due to unclear pathogenesis. Recently, PDGF receptor (PDGFR) amplification has been postulated to cause fibrosis. We hypothesized that a combination of immunosuppressive agents, e.g. cyclophosphamide (CYC) and imatinib (PDGFR inhibitor), might be useful for treating SSc-related ILD. Our objective was to evaluate the safety and efficacy of this combination therapy in scleroderma-related pulmonary disease.
  
  
  METHODS
  Five patients with advanced SSc-ILD underwent comprehensive cardiopulmonary evaluation, followed by administration of oral imatinib (200 mg/day) and intravenous CYC (500 mg every 3 weeks). Safety was assessed by close monitoring of complete blood count, liver and cardiac functions. Efficacy was evaluated by measuring pulmonary functions at 6 and 12 months.
  
  
  RESULTS
  Of the five patients in the study, four had severe and one had mild restrictive lung disease. All patients tolerated the combination treatment without myelosuppression, deterioration of liver functions or cardiac status. Only one patient had mild fluid overload requiring diuretics. Two patients completed 1 yr of treatment. Only the patient with mild restrictive lung disease showed improvement in pulmonary function.
  
  
  CONCLUSIONS
  The combination of intravenous CYC and oral imatinib was well-tolerated without major side effects. Clinical improvement was seen in only the patient with mild restrictive disease. To our knowledge, this is the first study examining the safety, tolerability and efficacy of imatinib in combination with CYC in scleroderma-related pulmonary disease. Large prospective trials are needed to further determine optimal timing, dose and duration of this regimen.
authors.affiliation: Division of Hematology/Oncology, Newark Beth Israel Medical Center, Newark, NJ 07112, USA. isabnani@sbhcs.com
authors.forename: I
authors.initials: I
authors.lastname: Sabnani
authors.forename: M J
authors.initials: MJ
authors.lastname: Zucker
authors.forename: E D
authors.initials: ED
authors.lastname: Rosenstein
authors.forename: D A
authors.initials: DA
authors.lastname: Baran
authors.forename: L H
authors.initials: LH
authors.lastname: Arroyo
authors.forename: P
authors.initials: P
authors.lastname: Tsang
authors.forename: M
authors.initials: M
authors.lastname: Zubair
authors.forename: V
authors.initials: V
authors.lastname: Rivera
mesh_terms: D000328:Adult; D001549:Benzamides; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D017563:Lung Diseases, Interstitial / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000150:complications*; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D007166:Immunosuppressive Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003520:Cyclophosphamide; D011505:Protein-Tyrosine Kinases