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Acute Leukaemia

Transplant-related toxicity and mortality: an AIEOP prospective study in 636 pediatric patients transplanted for acute leukemia

Bone Marrow Transplantation volume 29, pages 93–100 (2002)Cite this article

Abstract

Hematopoietic stem cell transplantation can cure high-risk acute leukemia (AL), but the occurrence of non-leukemic death is still high. The AIEOP conducted a prospective study in order to assess incidence and relationships of early toxicity and transplant-related mortality (TRM) in a pediatric population. Between 1990 and 1997 toxicities reported in eight organs (central nervous system, heart, lungs, liver, gut, kidneys, bladder, mucosa) were classified into three grades (mild, moderate, severe) and prospectively registered for 636 consecutive children who underwent autologous (216) or allogeneic (420) transplantation, either from an HLA compatible related (294), or alternative (126) donor in 13 AIEOP transplant centers. Overall, 47% of the patients are alive in CR (3-year EFS: 45.2%, s.e.: 2.1), 19% died in CR at a median of 60 days (90-day TRM: 14.3%, s.e.: 1.4), 34% relapsed. Toxicity of any organ, but mucosa and gut, was positively correlated with early death; moderate and severe toxicity to heart, lungs, liver and kidneys significantly increased early TRM, with estimated relative risks of 9.1, 5.5, 2.7 and 2.8, respectively, as compared to absent or mild toxicity. Patients with grade III–IV aGVHD experienced more than double (56% vs 19%) TRM than patients with grade 0–II aGVHD. A higher cumulative toxicity score, estimating the impact of toxicity on TRM, was significantly associated with transplantation from an alternative donor. Quantitative assessment allowed us to describe the extent to which ‘grade’ of toxicity and ‘type’ of involved organs were related to mortality and pre-transplant characteristics and yielded a prognostic score potentially useful to compare different conditioning regimens and predict probability of early death.

Bone Marrow Transplantation (2002) 29, 93–100. doi:10.1038/sj.bmt.1703337

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References

  1. Thomas ED, Blume KG, Forman SJ . Hematopoietic Cell Transplantation, 2nd edn Blackwell Science: Malden, MA 1999

    Google Scholar 

  2. Uderzo C, Rondelli R, Dini G et al. High-dose vincristine, fractionated total-body irradiation and cyclophosphamide as conditioning regimen in allogeneic and autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission: a 7-year Italian multicentre study Br J Haematol 1995 89: 790 797

    Article  CAS  PubMed  Google Scholar 

  3. Messina C, Cesaro S, Rondelli R on behalf of the AIEOP/FONOP-TMO Group et al. Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in Italy Bone Marrow Transplant 1998 21: 1015 1021

    Article  CAS  PubMed  Google Scholar 

  4. Barrett AJ, Horowitz MM, Ollack BH et al. Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in second remission New Engl J Med 1994 331: 1253 1258

    Article  CAS  PubMed  Google Scholar 

  5. Weisdorf DJ, Billet AL, Hannan P et al. Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia Blood 1997 90: 2962 2968

    CAS  PubMed  Google Scholar 

  6. Balduzzi A, Gooley T, Anasetti C et al. Unrelated donor marrow transplantation in children Blood 1995 86: 3247 3256

    CAS  PubMed  Google Scholar 

  7. Casper J, Camitta B, Truitt R et al. Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia Blood 1995 85: 2354 2360

    CAS  PubMed  Google Scholar 

  8. Zecca M, Pession A, Messina C et al. Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings J Clin Oncol 1999 17: 1838 1846

    Article  CAS  PubMed  Google Scholar 

  9. Nesbit ME, Buckley JD, Feig SA et al. Chemotherapy for induction of remission of childhood acute myeloid leukemia followed by marrow transplantation or multiagent chemotherapy: a report from the Childrens Cancer Study Group J Clin Oncol 1994 12: 127 135

    Article  PubMed  Google Scholar 

  10. Bonetti F, Zecca M, Pession A et al. Total-body irradiation and melphalan is a safe and effective conditioning regimen for autologous bone marrow trasplantation in children with acute myeloid leukemia in first remission. The Italian Association for Pediatric Hematology and Oncology-Bone Marrow Transplantation Group J Clin Oncol 1999 17: 3729 3735

    Article  CAS  PubMed  Google Scholar 

  11. Aversa F, Tabilio A, Velardi A et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype New Engl J Med 1998 339: 1186 1193

    Article  CAS  PubMed  Google Scholar 

  12. Bearman SI, Appelbaum FR, Buckner CD et al. Regimen-related toxicity in patients undergoing bone marrow transplantation J Clin Oncol 1988 6: 1562 1568

    Article  CAS  PubMed  Google Scholar 

  13. Perry AR, Rivlin MM, Goldstone AH . Bone marrow transplant patients with life-threatening organ failure: when should treatment stop? J Clin Oncol 1999 17: 289 303

    Article  Google Scholar 

  14. Iguchi A, Kobayashi R, Yoshida M et al. Neurological complications after stem cell transplantation in childhood Bone Marrow Transplant 1999 24: 647 652

    Article  CAS  PubMed  Google Scholar 

  15. Graus F, Saiz A, Sierra J . Neurologic complications of autologous and allogeneic bone marrow transplantation in patients with leukemia: a comparative study Neurology 1996 46: 1004 1009

    Article  CAS  PubMed  Google Scholar 

  16. Braverman AC, Antin JH, Plappert MT et al. Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens J Clin Oncol 1991 9: 1215 1223

    Article  CAS  PubMed  Google Scholar 

  17. Jain B, Floreani AA, Anderson JR et al. Cardiopulmonary function and autologous bone marrow transplantation: results and predictive value for respiratory failure and mortality Bone Marrow Transplant 1996 17: 561 568

    CAS  PubMed  Google Scholar 

  18. Soubani AO, Miller KB, Hassoun PM . Pulmonary complications of bone marrow transplantation Chest 1996 109: 1066 1077

    Article  CAS  PubMed  Google Scholar 

  19. Weiner RS, Bortin MM, Gale RP et al. Interstitial pneumonitis after bone marrow transplantation. Assessment of risk factors Ann Intern Med 1986 104: 168 175

    Article  CAS  PubMed  Google Scholar 

  20. Shulman HM, Hinterberger W . Hepatic veno-occlusive disease – liver toxicity syndrome after bone marrow transplantation Bone Marrow Transplant 1992 10: 197 214

    CAS  PubMed  Google Scholar 

  21. Kami M, Mori S, Tanikawa S et al. Risk factors for hepatic veno-occlusive disease after bone marrow transplantation: retrospective analysis of 137 cases at a single institution Bone Marrow Transplant 1997 20: 397 402

    Article  CAS  PubMed  Google Scholar 

  22. Cox GJ, Matsui SM, Lo RS et al. Etiology and outcome of diarrhea after marrow transplantation: a prospective study Gastroent 1994 107: 1398 1407

    Article  CAS  Google Scholar 

  23. Hill GR, Crawford JM, Cooke KR et al. Total body irradiation and acute graft-versus-host-disease: the role of gastrointestinal damage and inflammatory cytokines Blood 1997 90: 3204 3213

    CAS  PubMed  Google Scholar 

  24. Yee GC, Kennedy MS, Deeg HJ et al. Cyclosporine-associated renal dysfunction in marrow transplant recipients Transplant Proc 1985 17 (Suppl. 1): 196 201

    Google Scholar 

  25. Cartoni C, Arcese W, Avvisati G et al. Role of ultrasonography in the diagnosis and follow-up of hemorrhagic cystitis after bone marrow transpantation Bone Marrow Transplant 1993 12: 463 467

    CAS  PubMed  Google Scholar 

  26. Rapoport AP, Miller Watelet FL, Linder T et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants J Clin Oncol 1999 17: 2446 2453

    Article  CAS  PubMed  Google Scholar 

  27. Hierholzer JC . Adenoviruses in the immunocompromised host Clin Microbiol Rev 1992 5: 262 274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bedi A, Miller CB, Hanson JL et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation J Clin Oncol 1995 13: 1103 1109

    Article  CAS  PubMed  Google Scholar 

  29. Wingard JR . Advances in the management of infectious complications after bone marrow transplantation Bone Marrow Transplant 1990 6: 371 383

    CAS  PubMed  Google Scholar 

  30. Przepiorka D, Weisdorf D, Martin P et al. Consensus conference on acute GVHD grading Bone Marrow Transplant 1995 15: 825 828

    CAS  PubMed  Google Scholar 

  31. Marubini E, Valsecchi MG . Analysing Survival Data from Clinical Trials and Observational Studies J Wiley & Sons: Chichester 1995 pp 331 362

    Google Scholar 

  32. Kaplan EL, Meier P . Nonparametric estimation for incomplete oservations J Am Stat Assoc 1958 53: 457 481

    Article  Google Scholar 

  33. Hosmer DW, Lemeshow S . Applied Logistic Regression J Wiley & Sons: New York 1981

    Google Scholar 

  34. Dini G, Cancedda R, Locatelli F et al. Unrelated donor bone marrow transplantation: an update of the experience of the Italian Bone Marrow Transplant Group (GITMO) Haematol 2001 86: 451 456

    CAS  Google Scholar 

  35. Sokal JE, Cox EB, Baccarani M . Prognostic discrimination in ‘good risk’ chronic granulocytic leukemia Blood 1984 63: 789 799

    CAS  PubMed  Google Scholar 

  36. Riehm H, Feickert HJ, Schrappe M et al. Therapy results in five ALL-BFM studies since 1970. Implications of risk factors for prognosis Haematol Blood Transfus 1987 30: 139

    CAS  PubMed  Google Scholar 

  37. Hasford J, Pfirrmann M, Hehlmann R et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa J Natl Cancer Inst 1998 90: 850 858

    Article  CAS  PubMed  Google Scholar 

  38. Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative toconventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases Blood 1998 91: 756 763

    CAS  PubMed  Google Scholar 

  39. Sandmaier BM, McSweeney P, Yu C, Storb R . Nonmyeloablative transplants: preclinical and clinical results Semin Oncol 2000 27 (Suppl. 5): 78 81

    Google Scholar 

Download references

Acknowledgements

The authors wish to thank Miss Sara Vaghi for secretarial assistance, Miss Joanna Upton for linguistic consultancy and the ‘Comitato Maria Letizia Verga per lo studio e la cura della leucemia del bambino’ for its continuous support. Moreover the authors are grateful to the medical and nursing staff of each participating center as follows: Dipartimento di Scienze Pediatriche Università di Pavia, Unità di Oncoematologia e Trapianto di Midollo Osseo, Policlinico S Matteo: F Locatelli, G. Giorgiani, P Comolli; Istituto G Gaslini, Unità Trapianto Midollo Osseo: G Dini, E Lanino, L Manfredini, S Dallorso; Clinica Pediatrica, Università degli Studi di Milano–Bicocca, Centro Trapianto Midollo Osseo: G Masera, C Uderzo, A Balduzzi, D Longoni, C Arrigo, B Nicolini, E Biagi; Dipartimento di Scienze Pediatriche e dell'Adolescenza, Università degli Studi di Torino: E Madon, F Fagioli, A Busca; Cattedra di Ematologia, Università degli Studi di Roma: W Arcese, AP Iori, G Meloni; Clinica di Oncoematologia Pediatrica, Università di Padova: L Zanesco, C Messina, S Cesaro, M Pillon, S Varotto; Clinica Pediatrica Università degli Studi di Bologna, Policlinico S Orsola-Malpighi: G Paolucci, A Pession, A Prete, R Rondelli; Clinica Pediatrica Centro Trapianti, Istituto per l'Infanzia Burlo Garofolo, Trieste: L Tamaro, M Andolina, M Rabusin; Clinica Pediatrica Università di Brescia, Spedali Civili di Brescia: AG Ugazio, F Porta, U Verzeri; Clinica Pediatrica, Università di Pisa: P Macchia, C Favre, M Narni; Unità Organica di Pediatria, Reparto di Onco-Ematologia-TMO, Ospedale R Silvestrini, Perugia: A Amici, P Zucchetti, S Ceppi; Dipartimento di Ematologia Pediatrica, Ospedale Pausilipon, Napoli: V Poggi, M Ripaldi, C De Fusco, G Zanotta; Clinica Pediatrica, Università di Cagliari, Centro Trapianto Midollo Osseo: A Cao, F Argiolu, A Piroddi, A Sanna.

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Authors and Affiliations

  1. Clinica Pediatrica, Università degli Studi di Milano-Bicocca, Centro Trapianto Midollo Osseo, Monza, Italy

    A Balduzzi, D Silvestri, A Rovelli & C Uderzo

  2. Dipartimento di Scienze Pediatriche, Università di Pavia, Unità di Oncoematologia e Trapianto di Midollo Osseo, Policlinico S Matteo, Pavia, Italy

    F Locatelli & G Giorgiani

  3. Istituto G Gaslini, Unità Trapianto Midollo Osseo, Genova, Italy

    L Manfredini & E Lanino

  4. Dipartimento di Scienze Pediatriche e dell'Adolescenza, Università degli Studi di Torino, Torino, Italy

    A Busca & F Fagioli

  5. Cattedra di Ematologia, Università degli Studi di Roma, Roma, Italy

    AP Iori

  6. Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy

    C Messina

  7. Clinica Pediatrica, Policlinico S Orsola-Malpighi, Università degli Studi di Bologna, Bologna, Italy

    A Prete & R Rondelli

  8. Clinica Pediatrica Centro Trapianti, Istituto per l'Infanzia Burlo Garofolo, Trieste, Italy

    M Andolina

  9. Clinica Pediatrica, Università di Brescia, Spedali Civili di Brescia, Brescia, Italy

    F Porta

  10. Clinica Pediatrica, Università di Pisa, Pisa, Italy

    C Favre

  11. Unità Organica di Pediatrica, Reparto di Onco-Ematologia – TMO, Ospedale R Silvestrini, Perugia, Italy

    S Ceppi

  12. Dipartimento di Ematologia Pediatrica, Ospedale Pausilipon, Napoli, Italy

    C De Fusco

  13. Dipartimento di Medicina Clinica e Biotecnologia Sanitaria, Università degli Studie di Milano-Bicocca, Milano, Italy

    MG Valsecchi

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Balduzzi, A., Valsecchi, M., Silvestri, D. et al. Transplant-related toxicity and mortality: an AIEOP prospective study in 636 pediatric patients transplanted for acute leukemia. Bone Marrow Transplant 29, 93–100 (2002). https://doi.org/10.1038/sj.bmt.1703337

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