Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Conditioning Regimens

Stable long-term pulmonary function after fludarabine, antithymocyte globulin and i.v. BU for reduced-intensity conditioning allogeneic SCT

Bone Marrow Transplantation volume 49, pages 622–627 (2014)Cite this article

Subjects

Abstract

Lung function decline is a well-recognized complication following allogeneic SCT (allo-SCT). Reduced-intensity conditioning (RIC) and in vivo T-cell depletion by administration of antithymocyte globulin (ATG) may have a protective role in the occurrence of late pulmonary complications. This retrospective study reported the evolution of lung function parameters within the first 2 years after allo-SCT in a population receiving the same RIC regimen that included fludarabine and i.v. BU in combination with low-dose ATG. The median follow-up was 35.2 months. With a median age of 59 years at the time of transplant, at 2 years, the cumulative incidences of non-relapse mortality was as low as 9.7%. The cumulative incidence of relapse was 33%. At 2 years, the cumulative incidences of extensive chronic GVHD (cGVHD) and of pulmonary cGVHD were 23.1% and 1.9%, respectively. The cumulative incidences of airflow obstruction and restrictive pattern were 3.8% and 9.6%, respectively. Moreover, forced expiratory volume (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio remained stable from baseline up to 2 years post transplantation (P=0.26, P=0.27 and P=0.07, respectively). These results correspond favorably with the results obtained with other RIC regimens not incorporating ATG, and suggest that ATG may have a protective pulmonary role after allo-SCT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Savani BN, Montero A, Srinivasan R, Singh A, Shenoy A, Mielke S et al. Chronic GVHD and pretransplantation abnormalities in pulmonary function are the main determinants predicting worsening pulmonary function in long-term survivors after stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 1261–1269.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Walter EC, Orozco-Levi M, Ramirez-Sarmiento A, Vigorito A, Campregher PV, Martin PJ et al. Lung function and long-term complications after allogeneic hematopoietic cell transplant. Biol Blood Marrow Transplant 2010; 16: 53–61.

    Article  PubMed  Google Scholar 

  3. Savani BN, Montero A, Wu C, Nlonda N, Read E, Dunbar C et al. Prediction and prevention of transplant-related mortality from pulmonary causes after total body irradiation and allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 223–230.

    Article  PubMed  Google Scholar 

  4. Yoshihara S, Tateishi U, Ando T, Kunitoh H, Suyama H, Onishi Y et al. Lower incidence of bronchiolitis obliterans in allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning compared with myeloablative conditioning. Bone Marrow Transplant 2005; 35: 1195–1200.

    Article  CAS  PubMed  Google Scholar 

  5. Soule BP, Simone NL, Savani BN, Ning H, Albert PS, Barrett AJ et al. Pulmonary function following total body irradiation (with or without lung shielding) and allogeneic peripheral blood stem cell transplant. Bone Marrow Transplant 2007; 40: 573–578.

    Article  CAS  PubMed  Google Scholar 

  6. Ditschkowski M, Elmaagacli AH, Trenschel R, Peceny R, Koldehoff M, Schulte C et al. T-cell depletion prevents from bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia after allogeneic hematopoietic stem cell transplantation with related donors. Haematologica 2007; 92: 558–561.

    Article  PubMed  Google Scholar 

  7. Duncker C, Dohr D, Harsdorf S, Duyster J, Stefanic M, Martini C et al. Non-infectious lung complications are closely associated with chronic graft-versus-host disease: a single center study of incidence, risk factors and outcome. Bone Marrow Transplant 2000; 25: 1263–1268.

    Article  CAS  PubMed  Google Scholar 

  8. Bacigalupo A, Chien J, Barisione G, Pavletic S . Late pulmonary complications after allogeneic hematopoietic stem cell transplantation: diagnosis, monitoring, prevention, and treatment. Semin Hematol 2012; 49: 15–24.

    Article  PubMed  Google Scholar 

  9. Martin PJ, Chien JW . What we know and mostly do not know about bronchiolitis obliterans syndrome. Bone Marrow Transplant 2012; 47: 1–4.

    Article  CAS  PubMed  Google Scholar 

  10. Uhlving HH, Buchvald F, Heilmann CJ, Nielsen KG, Gormsen M, Muller KG . Bronchiolitis obliterans after allo-SCT: clinical criteria and treatment options. Bone Marrow Transplant 2012; 47: 1020–1029.

    Article  CAS  PubMed  Google Scholar 

  11. Bacigalupo A . Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bone Marrow Transplant 2005; 35: 225–231.

    Article  CAS  PubMed  Google Scholar 

  12. Sorror ML, Giralt S, Sandmaier BM, De Lima M, Shahjahan M, Maloney DG et al. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 2007; 110: 4606–4613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mohty M, Jacot W, Faucher C, Bay JO, Zandotti C, Collet L et al. Infectious complications following allogeneic HLA-identical sibling transplantation with antithymocyte globulin-based reduced intensity preparative regimen. Leukemia 2003; 17: 2168–2177.

    Article  CAS  PubMed  Google Scholar 

  14. Brissot E, Chevallier P, Guillaume T, Delaunay J, Ayari S, Dubruille V et al. Prophylaxis with mycophenolate mofetil and CsA can decrease the incidence of severe acute GVHD after antithymocyte globulin-based reduced-intensity preparative regimen and allo-SCT from HLA-matched unrelated donors. Bone Marrow Transplant 2010; 45: 786–788.

    Article  CAS  PubMed  Google Scholar 

  15. Malard F, Szydlo RM, Brissot E, Chevallier P, Guillaume T, Delaunay J et al. Impact of cyclosporine-A concentration on the incidence of severe acute graft-versus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2010; 16: 28–34.

    Article  CAS  PubMed  Google Scholar 

  16. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  17. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991; 144: 1202–1218.

    Article  Google Scholar 

  18. Crapo RO, Morris AH, Gardner RM . Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981; 123: 659–664.

    CAS  PubMed  Google Scholar 

  19. American Thoracic Society. Recommendations for a standard technique. Single breath carbon monoxide diffusing capacity (transfer factor). Am Rev Respir Dis 1987; 136: 1299–1307.

    Article  Google Scholar 

  20. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  PubMed  Google Scholar 

  21. Frisk P, Arvidson J, Hedenstrom H . A longitudinal study of pulmonary function after stem cell transplantation, from childhood to young adulthood. Pediatr Blood Cancer 2012; 58: 775–779.

    Article  PubMed  Google Scholar 

  22. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: 1813–1821.

    Article  PubMed  Google Scholar 

  23. Sharma S, Nadrous HF, Peters SG, Tefferi A, Litzow MR, Aubry MC et al. Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings. Chest 2005; 128: 1385–1392.

    Article  PubMed  Google Scholar 

  24. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  25. Krejci M, Brychtova Y, Doubek M, Tomiska M, Navratil M, Racil Z et al. Long-term results of allogeneic hematopoietic stem cell transplantation after reduced-intensity conditioning with busulfan, fludarabine, and antithymocyte globulin. Neoplasma 2011; 58: 406–414.

    Article  CAS  PubMed  Google Scholar 

  26. Malard F, Cahu X, Clavert A, Brissot E, Chevallier P, Guillaume T et al. Fludarabine, antithymocyte globulin, and very low-dose busulfan for reduced-intensity conditioning before allogeneic stem cell transplantation in patients with lymphoid malignancies. Biol Blood Marrow Transplant 2011; 17: 1698–1703.

    Article  CAS  PubMed  Google Scholar 

  27. Milano F, Au MA, Boeckh MJ, Deeg HJ, Chien JW . Evaluating the impact of antithymocyte globulin on lung function at 1 year after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17: 703–709.

    Article  CAS  PubMed  Google Scholar 

  28. Lahzami S, Schoeffel RE, Pechey V, Reid C, Greenwood M, Salome CM et al. Small airways function declines after allogeneic haematopoietic stem cell transplantation. Eur Respir J 2011; 38: 1180–1188.

    Article  CAS  PubMed  Google Scholar 

  29. Gopal R, Ha CS, Tucker SL, Khouri IF, Giralt SA, Gajewski JL et al. Comparison of two total body irradiation fractionation regimens with respect to acute and late pulmonary toxicity. Cancer 2001; 92: 1949–1958.

    Article  CAS  PubMed  Google Scholar 

  30. Santo Tomas LH, Loberiza Jr FR, Klein JP, Layde PM, Lipchik RJ, Rizzo JD et al. Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia. Chest 2005; 128: 153–161.

    Article  PubMed  Google Scholar 

  31. Kelsey CR, Horwitz ME, Chino JP, Craciunescu O, Steffey B, Folz RJ et al. Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors. Int J Radiat Oncol Biol Phys 2011; 81: 812–818.

    Article  PubMed  Google Scholar 

  32. Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant 2006; 12: 560–565.

    Article  PubMed  Google Scholar 

  33. Afessa B, Litzow MR, Tefferi A . Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 28: 425–434.

    Article  CAS  PubMed  Google Scholar 

  34. Soiffer RJ, Lerademacher J, Ho V, Kan F, Artz A, Champlin RE et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood 2011; 117: 6963–6970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Peric Z, Cahu X, Chevallier P, Brissot E, Malard F, Guillaume T et al. Features of Epstein-Barr virus (EBV) reactivation after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Leukemia 2011; 25: 932–938.

    Article  CAS  PubMed  Google Scholar 

  36. Socie G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 2011; 117: 6375–6382.

    Article  CAS  PubMed  Google Scholar 

  37. Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood 2011; 117: 4651–4657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ginsberg JP, Aplenc R, McDonough J, Bethel J, Doyle J, Weiner DJ . Pre-transplant lung function is predictive of survival following pediatric bone marrow transplantation. Pediatr Blood Cancer 2010; 54: 454–460.

    Article  PubMed  Google Scholar 

  39. Patriarca F, Skert C, Sperotto A, Damiani D, Cerno M, Geromin A et al. Incidence, outcome, and risk factors of late-onset noninfectious pulmonary complications after unrelated donor stem cell transplantation. Bone Marrow Transplant 2004; 33: 751–758.

    Article  CAS  PubMed  Google Scholar 

  40. Chang PM, Chiou TJ, Yen CC, Hsiao LT, Liu JH, Chen PM . Diffusion capacity predicts long-term survival after allogeneic bone marrow transplantation for acute lymphoblastic leukemia. J Chin Med Assoc 2008; 71: 234–240.

    Article  PubMed  Google Scholar 

  41. Yanada M, Naoe T, Iida H, Sakamaki H, Sakura T, Kanamori H et al. Myeloablative allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: significant roles of total body irradiation and chronic graft-versus-host disease. Bone Marrow Transplant 2005; 36: 867–872.

    Article  CAS  PubMed  Google Scholar 

  42. Chiou TJ, Tung SL, Wang WS, Tzeng WF, Yen CC, Fan FS et al. Pulmonary function changes in long-term survivors of chronic myelogenous leukemia after allogeneic bone marrow transplantation: a Taiwan experience. Cancer Invest 2002; 20: 880–888.

    Article  PubMed  Google Scholar 

  43. Lund MB, Brinch L, Kongerud J, Boe J . Lung function 5 yrs after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide. Eur Respir J 2004; 23: 901–905.

    Article  CAS  PubMed  Google Scholar 

  44. Crawford SW, Pepe M, Lin D, Benedetti F, Deeg HJ . Abnormalities of pulmonary function tests after marrow transplantation predict nonrelapse mortality. Am J Respir Crit Care Med 1995; 152: 690–695.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the nursing staff for providing excellent care for our patients and the following physicians, N. Blin, A. Clavert, V. Dubruille, T. Gastinne, B. Mahe, F. Mechinaud and F. Rialland, for their dedicated patient care. FM was supported by educational grants from the ‘Association for Training, Education and Research in Hematology, Immunology and Transplantation’ (ATERHIT). We also thank the ‘Région Pays de Loire’, the ‘Association pour la Recherche sur le Cancer’, the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’, the ‘Association Laurette Fuguain’, the IRGHET and the ‘Ligue Contre le Cancer’ (Comités Grand-Ouest) for their generous and continuous support for our clinical and basic research work. Our group is supported by several grants from the French National Cancer Institute (PHRC, INCa to MM).

Author contributions

SD collected, assembled and analyzed PFT data and wrote the manuscript. FM helped in collecting, assembling and analyzing data, and performed statistical analyses and wrote the manuscript. AC performed and analyzed PFT data and helped in collecting, assembling and analyzing PFT data. PC, TG, JD, PM and SLG recruited patients and commented on the manuscript. PG helped in collecting PFT data and commented on the manuscript. BD helped in analyzing PFT data and performed statistical analysis. PL analyzed data and wrote the manuscript. MM recruited patients, supervised research, analyzed data and wrote the manuscript. All authors approved submission of the manuscript for publication purposes.

Author information

Author notes

  1. S Dirou and F Malard: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre Hospitalier et Universitaire (CHU) de Nantes, l’institut du thorax, Service de Pneumologie, Nantes, France

    S Dirou, A Chambellan, P Germaud, B Delasalle, P Lemarchand & M Mohty

  2. Faculté de Médecine, Université de Nantes, Nantes, France

    S Dirou, F Malard, A Chambellan, P Moreau, B Delasalle, P Lemarchand & M Mohty

  3. CHU de Nantes, Service d'Hématologie Clinique, Université de Nantes, Nantes, France

    F Malard, P Chevallier, T Guillaume, J Delaunay, P Moreau & M Mohty

  4. CRNCA, UMR 892 INSERM - 6299 CNRS, Nantes, France

    F Malard, P Moreau & M Mohty

  5. Centre d'Investigation Clinique en Cancérologie (CI2C), CHU de Nantes, Nantes, France

    P Moreau & M Mohty

  6. INSERM, UMR1087, l’institut du thorax, Nantes, France

    B Delasalle & P Lemarchand

  7. CNRS, UMR 6291, Nantes, France

    B Delasalle & P Lemarchand

Authors
  1. S Dirou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Malard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Chambellan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Chevallier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Germaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Guillaume
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Delaunay
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Moreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. B Delasalle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P Lemarchand
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Mohty.

Ethics declarations

Competing interests

MM and PM received lecture honoraria and research support from Sanofi whose product is discussed in this manuscript. The remaining authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dirou, S., Malard, F., Chambellan, A. et al. Stable long-term pulmonary function after fludarabine, antithymocyte globulin and i.v. BU for reduced-intensity conditioning allogeneic SCT. Bone Marrow Transplant 49, 622–627 (2014). https://doi.org/10.1038/bmt.2014.15

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2014.15

Keywords

This article is cited by

Search

Advanced search

Quick links