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:

Transplant Toxicities

Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis

Bone Marrow Transplantation volume 50, pages 706–714 (2015)Cite this article

Subjects

Abstract

We performed a systematic review and meta-analysis of randomized controlled trials comparing autologous hematopoietic cell transplantation (HCT) with other treatment modalities to analyze the risk for various secondary malignancies (SMs). Relative risks (RR) with 95% confidence intervals were estimated and pooled. Our search yielded 36 trials. The median follow-up was 55 (range 12–144) months. Overall, the RR for developing SMs was 1.23 ((0.97–1.55), I2=4%, 9870 patients). Subgroup analysis of trials assessing TBI-containing preparative regimens and of patients with baseline lymphoproliferative diseases, showed there was a higher risk for SMs in patients given autografts (RR=1.61 (1.05–2.48), I2=14%, 2218 patients and RR=1.62 (1.12–2.33), I2=22%, 3343 patients, respectively). Among all patients, there was a higher rate of myelodysplastic syndrome MDS/AML in patients given HCT compared with other treatments (RR=1.71 (1.18–2.48), I2=0%, 8778 patients). The risk of secondary solid malignancies was comparable in the short term between patients given HCT and patients given other treatments (RR=0.95 (0.67–1.32), I2=0%, 5925 patients). We conclude that overall the risk of secondary MDS/AML is higher in patients given autologous HCT compared with other treatments. In the subgroup of patients given a TBI-based regimen and in those with a baseline lymphoproliferative disease, there was a higher risk of overall SMs.

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
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Forrest DL, Nevill TJ, Naiman SC, Le A, Brockington DA, Barnett MJ et al. Second malignancy following high-dose therapy and autologous stem cell transplantation: incidence and risk factor analysis. Bone Marrow Transplant 2003; 32: 915–923.

    Article  CAS  Google Scholar 

  2. Brown JR, Yeckes H, Friedberg JW, Neuberg D, Kim H, Nadler LM et al. Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 2005; 23: 2208–2214.

    Article  CAS  Google Scholar 

  3. Darrington DL, Vose JM, Anderson JR, Bierman PJ, Bishop MR, Chan WC et al. Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 1994; 12: 2527–2534.

    Article  CAS  Google Scholar 

  4. Friedberg JW, Neuberg D, Stone RM, Alyea E, Jallow H, LaCasce A et al. Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 1999; 17: 3128–3135.

    Article  CAS  Google Scholar 

  5. Metayer C, Curtis RE, Vose J, Sobocinski KA, Horowitz MM, Bhatia S et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study. Blood 2003; 101: 2015–2023.

    Article  CAS  Google Scholar 

  6. Ortega JJ, Olive T, de Heredia CD, Llort A . Secondary malignancies and quality of life after stem cell transplantation. Bone Marrow Transplant 2005; 35: S83–S87.

    Article  Google Scholar 

  7. Gyan E, Foussard C, Bertrand P, Michenet P, Le Gouill S, Berthou C et al. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 2009; 113: 995–1001.

    Article  CAS  Google Scholar 

  8. Appelbaum FR, Forman SJ, Blume KG . Thomas Hematopoietic Cell Transplantation, 4th edn, Wiley-Blackwell, Hoboken, NJ, 2009.

    Book  Google Scholar 

  9. Higgins JPT, Green S (eds). Cochrane handbook for systematic reviews of interventions: version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011. www.cochrane-handbook.org 2013.

  10. Dai L, O'Sullivan A, Kennedy R, Abbas M, Shuai Y, Passero VA et al. A randomized clinical trial of lenalidomide and dexamethazone with and without autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: interim study results. ASH Conference; 12 December 2011; San Diego, CA, USA. Abstract No. 4142.

  11. Jaccard A, Moreau P, Leblond V . Autologous Stem cell transplantation versus oral melphalan and high dose dexamethasone in patients with AL (primary) amyloidosis: long term follow-up of the french multicenter randomized trial. Blood 2005; 106: 421a.

    Google Scholar 

  12. Palumbo P, Cavallo F, Hardan I, Lupo B, Redoglia V, Levin M et al. Melphalan\prednisone\lenalidomide versus high-dose melphalane and autologous transplantation (MEL 200) in newly diagnosed MM patients <65 years: results of randomized phase III study. ASH Conference; 11 December 2011; San Diego, CA, USA. Abstract No. 3069.

  13. Brion A, Mahe B, Kolb B, Audhuy B, Colombat P, Maisonneuve H et al. Autologous transplantation in CLL patients with B and C Binet stages: final results of the prospective randomized GOELAMS LLC 98 trial. Bone Marrow Transplant 2012; 47: 542–548.

    Article  CAS  Google Scholar 

  14. Michallet M, Dreger P, Sutton L, Brand R, Richards S, van Os M et al. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood 2011; 117: 1516–1521.

    Article  CAS  Google Scholar 

  15. Sutton L, Chevret S, Tournilhac O, Divine M, Leblond V, Corront B et al. Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood 2011; 117: 6109–6119.

    Article  CAS  Google Scholar 

  16. Arakelyan N, Berthou C, Desablens B, de Guibert S, Delwail V, Moles MP et al. Early versus late intensification for patients with high-risk Hodgkin lymphoma-3 cycles of intensive chemotherapy plus low-dose lymph node radiation therapy versus 4 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation: five-year results of a randomized trial on behalf of the GOELAMS Group. Cancer 2008; 113: 3323–3330.

    Article  CAS  Google Scholar 

  17. Ladetto M, De Marco F, Benedetti F, Vitolo U, Patti C, Rambaldi A et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008; 111: 4004–4013.

    Article  CAS  Google Scholar 

  18. Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 2006; 108: 2540–2544.

    Article  CAS  Google Scholar 

  19. Deconinck E, Foussard C, Milpied N, Bertrand P, Michenet P, Cornillet-LeFebvre P et al. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 2005; 105: 3817–3823.

    Article  CAS  Google Scholar 

  20. Lenz G, Dreyling M, Schiegnitz E, Haferlach T, Hasford J, Unterhalt M et al. Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 2004; 22: 4926–4933.

    Article  Google Scholar 

  21. Martelli M, Gherlinzoni F, De Renzo A, Zinzani PL, De Vivo A, Cantonetti M et al. Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 2003; 21: 1255–1262.

    Article  Google Scholar 

  22. Olivieri A, Santini G, Patti C, Chisesi T, De Souza C, Rubagotti A et al. Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: long-term results by the NHLCSG. Ann Oncol 2005; 16: 1941–1948.

    Article  CAS  Google Scholar 

  23. Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 2002; 359: 2065–2071.

    Article  CAS  Google Scholar 

  24. Vitolo U, Liberati AM, Cabras MG, Federico M, Angelucci E, Baldini L et al. High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an "Intergruppo Italiano Linfomi" randomized trial. Haematologica 2005; 90: 793–801.

    CAS  PubMed  Google Scholar 

  25. Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S et al. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol 2006; 24: 370–378.

    Article  Google Scholar 

  26. Blade J, Rosinol L, Sureda A, Ribera JM, Diaz-Mediavilla J, Garcia-Larana J et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005; 106: 3755–3759.

    Article  CAS  Google Scholar 

  27. Coombes RC, Howell A, Emson M, Peckitt C, Gallagher C, Bengala C et al. High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol 2005; 16: 726–734.

    Article  CAS  Google Scholar 

  28. Crump M, Gluck S, Tu D, Stewart D, Levine M, Kirkbride P et al. Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. J Clin Oncol 2008; 26: 37–43.

    Article  CAS  Google Scholar 

  29. Gianni AM, Bregni M, Siena S, Brambilla C, Di Nicola M, Lombardi F et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290–1297.

    Article  CAS  Google Scholar 

  30. Haioun C, Lepage E, Gisselbrecht C, Salles G, Coiffier B, Brice P et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol—a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 2000; 18: 3025–3030.

    Article  CAS  Google Scholar 

  31. Hanrahan EO, Broglio K, Frye D, Buzdar AU, Theriault RL, Valero V et al. Randomized trial of high-dose chemotherapy and autologous hematopoietic stem cell support for high-risk primary breast carcinoma: follow-up at 12 years. Cancer 2006; 106: 2327–2336.

    Article  CAS  Google Scholar 

  32. Kaiser U, Uebelacker I, Abel U, Birkmann J, Trumper L, Schmalenberg H et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 2002; 20: 4413–4419.

    Article  CAS  Google Scholar 

  33. Moore HC, Green SJ, Gralow JR, Bearman SI, Lew D, Barlow WE et al. Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. J Clin Oncol 2007; 25: 1677–1682.

    Article  CAS  Google Scholar 

  34. Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C et al. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet 2005; 366: 1935–1944.

    Article  CAS  Google Scholar 

  35. Vredenburgh JJ, Madan B, Coniglio D, Ross M, Broadwater G, Niedzwiecki D et al. A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy. Bone Marrow Transplant 2006; 37: 1009–1015.

    Article  CAS  Google Scholar 

  36. Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 2005; 6: 649–658.

    Article  CAS  Google Scholar 

  37. Peters WP, Rosner GL, Vredenburgh JJ, Shpall EJ, Crump M, Richardson PG et al. Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol 2005; 23: 2191–2200.

    Article  Google Scholar 

  38. Zander AR, Kroger N, Schmoor C, Kruger W, Mobus V, Frickhofen N et al. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol 2004; 22: 2273–2283.

    Article  CAS  Google Scholar 

  39. Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmstrom P et al. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet 2000; 356: 1384–1391.

    Article  CAS  Google Scholar 

  40. Crown JP, Leyvraz S, Verrill M . Effect of tandem highdose chemotherapy (HDC) on long-term complete remissions (LTCR) in metastatic breast cancer (MBC), compared to conventional dose (CDC) in patients (pts) who were not selected on the basis of response to prior C: Mature results of IBDIS-I. J Clin Oncol 2004; 22: 14s (abstract 631).

    Article  Google Scholar 

  41. Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003; 349: 7–16.

    Article  CAS  Google Scholar 

  42. Tallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 2003; 349: 17–26.

    Article  CAS  Google Scholar 

  43. Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000; 92: 225–233.

    Article  CAS  Google Scholar 

  44. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 2009; 27: 1007–1013.

    Article  CAS  Google Scholar 

  45. Milligan DW, Ruiz De Elvira MC, Kolb HJ, Goldstone AH, Meloni G, Rohatiner AZ et al. Secondary leukaemia and myelodysplasia after autografting for lymphoma: results from the EBMT. EBMT Lymphoma and Late Effects Working Parties. European Group for Blood and Marrow Transplantation. Br J Haematol 1999; 106: 1020–1026.

    Article  CAS  Google Scholar 

  46. Eichenauer DA, Thielen I, Haverkamp H, Franklin J, Behringer K, Halbsguth T et al. Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood 2014; 123: 1658–1664.

    Article  CAS  Google Scholar 

  47. Döhner H, Estey EH, Amadori S, Appelbaum FR . Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.

    Article  Google Scholar 

  48. Travis LB, Hill DA, Dores GM, Gospodarowicz M, van Leeuwen FE, Holowaty E et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 2003; 290: 465–475.

    Article  Google Scholar 

  49. van Leeuwen FE, Klokman WJ, Stovall M, Dahler EC, van't Veer MB, Noordijk EM et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 2003; 95: 971–980.

    Article  Google Scholar 

Download references

Author information

Author notes

  1. I Vaxman and R Ram: These authors contributed equally to this work.

Authors and Affiliations

  1. Medicine A, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel

    I Vaxman & M Lahav

  2. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    I Vaxman, R Ram, A Gafter-Gvili, L Vidal, M Yeshurun, M Lahav & O Shpilberg

  3. BMT Unit, Sourasky Medical Center, Tel Aviv, Israel

    R Ram

  4. Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Tel Aviv, Israel

    A Gafter-Gvili, L Vidal & M Yeshurun

  5. Institute of Hematology, Assuta Medical Center, Tel Aviv, Israel

    O Shpilberg

Authors
  1. I Vaxman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Ram
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Gafter-Gvili
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Yeshurun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Lahav
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. O Shpilberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Ram.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vaxman, I., Ram, R., Gafter-Gvili, A. et al. Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis. Bone Marrow Transplant 50, 706–714 (2015). https://doi.org/10.1038/bmt.2014.325

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2014.325

This article is cited by

Search

Advanced search

Quick links