CASE REPORT – THORACIC
Interactive CardioVascular and Thoracic Surgery 21 (2015) 260–262 doi:10.1093/icvts/ivv122 Advance Access publication 13 May 2015
Cite this article as: Zhang J, Chen F, Ueki T, Date H. Imatinib for sclerodermatous graft-versus-host disease in lung transplantation. Interact CardioVasc Thorac Surg 2015;21:260–2.
Imatinib for sclerodermatous graft-versus-host disease in lung transplantation Jitian Zhanga, Fengshi Chena, Toshimitsu Uekib and Hiroshi Datea,* a b
Departments of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan
* Corresponding author. Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Tel: +81-75-7514975; fax: +81-75-7514974; e-mail: [email protected] (H. Date). Received 12 February 2015; received in revised form 8 April 2015; accepted 21 April 2015
Abstract Imatinib has been proposed as a treatment for sclerodermatous chronic graft-versus-host disease (GVHD) due to its antifibrotic activity. Because imatinib has a potentially adverse effect on wound healing, the safety of its perioperative use in lung transplantation is unknown. Herein, we present a patient who underwent bilateral living-donor lobar lung transplantation for pulmonary complications after bone marrow transplantation, who had also received treatment with imatinib for sclerodermatous GVHD. Imatinib was discontinued 3 weeks before lung transplantation, but was resumed 1 week postoperatively for an exacerbation of sclerodermatous GVHD. Seven months after the postoperative the patient continues to do well without complications. Keywords: Lung transplantation • Imatinib • Sclerodermatous graft-versus-host disease
INTRODUCTION Despite medical advances in haematopoietic stem-cell transplantation (HSCT), chronic, progressive and irreversible pulmonary complications after HSCT, such as bronchiolitis obliterans and pulmonary fibrosis, remain the leading causes of death. No effective medical therapy has been established and currently lung transplantation is the only therapeutic option [1]. Sclerodermatous GVHD presents therapeutic challenges, especially for patients with severe skin lesions limiting thoracic movement. Imatinib mesylate, a tyrosine kinase inhibitor, has shown efficacy in the treatment of chronic GVHD, with overall response rates of 50–80% for fibrotic skin symptoms reported in two open-label studies [2]. However, imatinib mesylate theoretically has an adverse effect on wound healing. In lung transplantation, complications related to bronchial anastomoses may be fatal. Herein, we report successful livingdonor lobar lung transplantation (LDLLT) in a patient who received treatment with imatinib mesylate for sclerodermatous GVHD in the perioperative period.
CASE REPORT A 19-year old female patient underwent bone marrow transplantation for the treatment of acute myelogenous leukaemia. Sixteen months later, she developed sclerodermatous chronic GVHD, which was refractory to the usual immunosuppressant therapy. Her movements became severely limited because of the sclerodermatous skin changes, and she was eventually treated with imatinib mesylate
100 mg/day. Subsequently, her skin condition improved; however, she developed pulmonary fibrosis related to her chronic GVHD. Despite treatment with prednisolone and tacrolimus, her pulmonary disease gradually worsened. At the age of 24, a pneumonic process exacerbated her chronic pulmonary GVHD, and she required mechanical ventilation. Her cutaneous disease remained stable when imatinib mesylate was temporarily discontinued during steroid pulse therapy and high-dose prednisone therapy following pulse therapy. Since she was on mechanical ventilation for >3 months without any possibility of weaning from the ventilator, she was referred to our hospital and LDLLT was carried out because of the patient’s extremely poor prognosis. Chest radiography showed severe pulmonary damage due to pulmonary complications after bone marrow transplantation (Fig. 1). Preoperatively, her tidal volume was 2.5 ml/kg, even while being ventilated with bilevel positive airway pressure of 20 and 5 cmH2O, with a respiratory rate of 40 breaths/min. The patient’s father donated a right lower lobe, and her mother donated a left lower lobe. Three weeks before LDLLT, imatinib mesylate was discontinued. LDLLT was successfully carried out with extracorporeal membrane oxygenation. The early postoperative course was uneventful with the exception of an episode of acute rejection on postoperative day 6 requiring treatment with steroid pulse therapy. On postoperative day 7, she complained of a sensation of progressive skin tightness. There were no problems regarding wound healing on the skin and at the bronchial anastomotic sites. Her symptoms were limited to the skin, and we consequently resumed treatment with imatinib mesylate 100 mg/day for an apparent exacerbation of her sclerodermatous GVHD. Within several days of restarting therapy, her cutaneous
© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
261
Figure 1: Preoperative chest radiograph showing bilateral interstitial opacities, pleural thickening and pleural effusions indicating interstitial pneumonitis.
Figure 2: Postoperative chest radiograph showing improved pulmonary permeability.
symptoms began to gradually improve. The patient was weaned off the ventilator 3 weeks after the LDLLT. Postoperative bronchoscopy showed no complications involving the bronchial anastomoses. She was discharged home 3 months after the LDLLT. Chest radiography showed an excellent lung condition (Fig. 2). Seven months after the LDLLT, the patient requires no oxygen supplementation, and her activities of daily living continue to improve.
preoperatively planned to resume administration of imatinib mesylate at least 4 weeks after the LDLLT. Despite the early resumption of therapy, no adverse effect on healing was observed. Since imatinib mesylate is a promising treatment of sclerodermatous chronic GVHD, we will likely encounter more patients being treated with imatinib mesylate, who are to undergo lung transplantation. Our experience documents the safe and efficacious use of imatinib mesylate for the treatment of sclerodermatous GVHD 1 week after lung transplantation. However, the bronchial anastomosis is carried out at the lobar bronchus of the graft in LDLLT, leading to a relatively better retrograde blood supply at the anastomotic site compared with the common brain-dead donor lung transplantation where the main bronchus is anastomosed. Therefore, in brain-dead donor lung transplantation, imatinib mesylate must be used more cautiously because of an inferior blood supply at the bronchial anastomosis. In this patient, we had to resume imatinib mesylate earlier than we planned, but we must be more careful and even aware of the possibility of lethal complications in resuming imatinib mesylate in patients that have undergone brain-dead donor lung transplantation.
DISCUSSION With advances in the field of HSCT, the number of patients living with potentially fatal pulmonary complications after HSCT has also increased. LDLLT represents an alternative approach to deceaseddonor lung transplantation for such patients in countries where a severe donor shortage exists, particularly in Japan [1, 3]. In general, mechanical ventilation is considered as a relative contraindication for lung transplantation. However, in the current case, the general condition of the patient gradually recovered because of the medical treatment during the 3 months when she was on mechanical ventilation. She could even ambulate by herself owing to the intensive physiotherapy before lung transplantation. Imatinib mesylate exerts a selective inhibition of the pathways involved in collagen production in dermal fibroblasts [2]. Imatinib has recently been proposed as an adjunctive treatment in chronic GVHD because of its antifibrotic activity [4]. However, because the antifibrotic effect may adversely affect wound healing, there has been a concern that it might hinder the healing of bronchial anastomoses in lung transplantation patients. The first study of the postoperative use of sirolimus, which also has inhibitory effects on fibroblast proliferation, in lung transplantation reported a high incidence of bronchial anastomotic dehiscence, which in some cases proved fatal [5]. Experimental studies on everolimus, which is a derivative of sirolimus, revealed a decrease in traction resistance of bronchial anastomoses that persisted for at least 4 weeks postoperatively. Although there are no reports on cessation of imatinib mesylate during the perioperative period, we had
CONCLUSION The perioperative administration of imatinib mesylate improved sclerodermatous chronic GVHD without any apparent deleterious effect on wound healing, and imatinib mesylate may be used cautiously in patients who have recently undergone LDLLT. Conflict of interest: none declared.
REFERENCES [1] Chen F, Yamane M, Inoue M, Shiraishi T, Oto T, Minami M et al. Less maintenance immunosuppression in lung transplantation following hematopoietic stem cell transplantation from the same living donor. Am J Transplant 2011; 11:1509–16.
CASE REPORT
J. Zhang et al. / Interactive CardioVascular and Thoracic Surgery
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J. Zhang et al. / Interactive CardioVascular and Thoracic Surgery
[2] Olivieri A, Locatelli F, Zecca M, Sanna A, Cimminiello M, Raimondi R et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood 2009;114:709–18. [3] Sato M, Okada Y, Oto T, Minami M, Shiraishi T, Nagayasu T et al. Registry of the Japanese Society of Lung and Heart-Lung Transplantation: official Japanese lung transplantation report, 2014. Gen Thorac Cardiovasc Surg 2014:62:594–601.
[4] Wolff D, Schleunning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M et al. Consensus conference on clinical practice in chronic GVHD: secondline treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2011:17:1–17. [5] de Pablo A, Santos F, Sole A, Borro JM, Cifrian JM, Laporta R et al. Recommendations on the use of everolimus in lung transplantation. Transplant Rev (Orlando) 2013;27:9–16.
Interactive CardioVascular and Thoracic Surgery 21 (2015) 260–262 doi:10.1093/icvts/ivv122 Advance Access publication 13 May 2015
Cite this article as: Zhang J, Chen F, Ueki T, Date H. Imatinib for sclerodermatous graft-versus-host disease in lung transplantation. Interact CardioVasc Thorac Surg 2015;21:260–2.
Imatinib for sclerodermatous graft-versus-host disease in lung transplantation Jitian Zhanga, Fengshi Chena, Toshimitsu Uekib and Hiroshi Datea,* a b
Departments of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan
* Corresponding author. Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Tel: +81-75-7514975; fax: +81-75-7514974; e-mail: [email protected] (H. Date). Received 12 February 2015; received in revised form 8 April 2015; accepted 21 April 2015
Abstract Imatinib has been proposed as a treatment for sclerodermatous chronic graft-versus-host disease (GVHD) due to its antifibrotic activity. Because imatinib has a potentially adverse effect on wound healing, the safety of its perioperative use in lung transplantation is unknown. Herein, we present a patient who underwent bilateral living-donor lobar lung transplantation for pulmonary complications after bone marrow transplantation, who had also received treatment with imatinib for sclerodermatous GVHD. Imatinib was discontinued 3 weeks before lung transplantation, but was resumed 1 week postoperatively for an exacerbation of sclerodermatous GVHD. Seven months after the postoperative the patient continues to do well without complications. Keywords: Lung transplantation • Imatinib • Sclerodermatous graft-versus-host disease
INTRODUCTION Despite medical advances in haematopoietic stem-cell transplantation (HSCT), chronic, progressive and irreversible pulmonary complications after HSCT, such as bronchiolitis obliterans and pulmonary fibrosis, remain the leading causes of death. No effective medical therapy has been established and currently lung transplantation is the only therapeutic option [1]. Sclerodermatous GVHD presents therapeutic challenges, especially for patients with severe skin lesions limiting thoracic movement. Imatinib mesylate, a tyrosine kinase inhibitor, has shown efficacy in the treatment of chronic GVHD, with overall response rates of 50–80% for fibrotic skin symptoms reported in two open-label studies [2]. However, imatinib mesylate theoretically has an adverse effect on wound healing. In lung transplantation, complications related to bronchial anastomoses may be fatal. Herein, we report successful livingdonor lobar lung transplantation (LDLLT) in a patient who received treatment with imatinib mesylate for sclerodermatous GVHD in the perioperative period.
CASE REPORT A 19-year old female patient underwent bone marrow transplantation for the treatment of acute myelogenous leukaemia. Sixteen months later, she developed sclerodermatous chronic GVHD, which was refractory to the usual immunosuppressant therapy. Her movements became severely limited because of the sclerodermatous skin changes, and she was eventually treated with imatinib mesylate
100 mg/day. Subsequently, her skin condition improved; however, she developed pulmonary fibrosis related to her chronic GVHD. Despite treatment with prednisolone and tacrolimus, her pulmonary disease gradually worsened. At the age of 24, a pneumonic process exacerbated her chronic pulmonary GVHD, and she required mechanical ventilation. Her cutaneous disease remained stable when imatinib mesylate was temporarily discontinued during steroid pulse therapy and high-dose prednisone therapy following pulse therapy. Since she was on mechanical ventilation for >3 months without any possibility of weaning from the ventilator, she was referred to our hospital and LDLLT was carried out because of the patient’s extremely poor prognosis. Chest radiography showed severe pulmonary damage due to pulmonary complications after bone marrow transplantation (Fig. 1). Preoperatively, her tidal volume was 2.5 ml/kg, even while being ventilated with bilevel positive airway pressure of 20 and 5 cmH2O, with a respiratory rate of 40 breaths/min. The patient’s father donated a right lower lobe, and her mother donated a left lower lobe. Three weeks before LDLLT, imatinib mesylate was discontinued. LDLLT was successfully carried out with extracorporeal membrane oxygenation. The early postoperative course was uneventful with the exception of an episode of acute rejection on postoperative day 6 requiring treatment with steroid pulse therapy. On postoperative day 7, she complained of a sensation of progressive skin tightness. There were no problems regarding wound healing on the skin and at the bronchial anastomotic sites. Her symptoms were limited to the skin, and we consequently resumed treatment with imatinib mesylate 100 mg/day for an apparent exacerbation of her sclerodermatous GVHD. Within several days of restarting therapy, her cutaneous
© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
261
Figure 1: Preoperative chest radiograph showing bilateral interstitial opacities, pleural thickening and pleural effusions indicating interstitial pneumonitis.
Figure 2: Postoperative chest radiograph showing improved pulmonary permeability.
symptoms began to gradually improve. The patient was weaned off the ventilator 3 weeks after the LDLLT. Postoperative bronchoscopy showed no complications involving the bronchial anastomoses. She was discharged home 3 months after the LDLLT. Chest radiography showed an excellent lung condition (Fig. 2). Seven months after the LDLLT, the patient requires no oxygen supplementation, and her activities of daily living continue to improve.
preoperatively planned to resume administration of imatinib mesylate at least 4 weeks after the LDLLT. Despite the early resumption of therapy, no adverse effect on healing was observed. Since imatinib mesylate is a promising treatment of sclerodermatous chronic GVHD, we will likely encounter more patients being treated with imatinib mesylate, who are to undergo lung transplantation. Our experience documents the safe and efficacious use of imatinib mesylate for the treatment of sclerodermatous GVHD 1 week after lung transplantation. However, the bronchial anastomosis is carried out at the lobar bronchus of the graft in LDLLT, leading to a relatively better retrograde blood supply at the anastomotic site compared with the common brain-dead donor lung transplantation where the main bronchus is anastomosed. Therefore, in brain-dead donor lung transplantation, imatinib mesylate must be used more cautiously because of an inferior blood supply at the bronchial anastomosis. In this patient, we had to resume imatinib mesylate earlier than we planned, but we must be more careful and even aware of the possibility of lethal complications in resuming imatinib mesylate in patients that have undergone brain-dead donor lung transplantation.
DISCUSSION With advances in the field of HSCT, the number of patients living with potentially fatal pulmonary complications after HSCT has also increased. LDLLT represents an alternative approach to deceaseddonor lung transplantation for such patients in countries where a severe donor shortage exists, particularly in Japan [1, 3]. In general, mechanical ventilation is considered as a relative contraindication for lung transplantation. However, in the current case, the general condition of the patient gradually recovered because of the medical treatment during the 3 months when she was on mechanical ventilation. She could even ambulate by herself owing to the intensive physiotherapy before lung transplantation. Imatinib mesylate exerts a selective inhibition of the pathways involved in collagen production in dermal fibroblasts [2]. Imatinib has recently been proposed as an adjunctive treatment in chronic GVHD because of its antifibrotic activity [4]. However, because the antifibrotic effect may adversely affect wound healing, there has been a concern that it might hinder the healing of bronchial anastomoses in lung transplantation patients. The first study of the postoperative use of sirolimus, which also has inhibitory effects on fibroblast proliferation, in lung transplantation reported a high incidence of bronchial anastomotic dehiscence, which in some cases proved fatal [5]. Experimental studies on everolimus, which is a derivative of sirolimus, revealed a decrease in traction resistance of bronchial anastomoses that persisted for at least 4 weeks postoperatively. Although there are no reports on cessation of imatinib mesylate during the perioperative period, we had
CONCLUSION The perioperative administration of imatinib mesylate improved sclerodermatous chronic GVHD without any apparent deleterious effect on wound healing, and imatinib mesylate may be used cautiously in patients who have recently undergone LDLLT. Conflict of interest: none declared.
REFERENCES [1] Chen F, Yamane M, Inoue M, Shiraishi T, Oto T, Minami M et al. Less maintenance immunosuppression in lung transplantation following hematopoietic stem cell transplantation from the same living donor. Am J Transplant 2011; 11:1509–16.
CASE REPORT
J. Zhang et al. / Interactive CardioVascular and Thoracic Surgery
262
J. Zhang et al. / Interactive CardioVascular and Thoracic Surgery
[2] Olivieri A, Locatelli F, Zecca M, Sanna A, Cimminiello M, Raimondi R et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood 2009;114:709–18. [3] Sato M, Okada Y, Oto T, Minami M, Shiraishi T, Nagayasu T et al. Registry of the Japanese Society of Lung and Heart-Lung Transplantation: official Japanese lung transplantation report, 2014. Gen Thorac Cardiovasc Surg 2014:62:594–601.
[4] Wolff D, Schleunning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M et al. Consensus conference on clinical practice in chronic GVHD: secondline treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2011:17:1–17. [5] de Pablo A, Santos F, Sole A, Borro JM, Cifrian JM, Laporta R et al. Recommendations on the use of everolimus in lung transplantation. Transplant Rev (Orlando) 2013;27:9–16.
