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.

  • Review
  • Published:

Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukaemia

Abstract

ALL in which the Philadelphia (Ph) chromosome is detected is one of the few diseases in which there is almost unequivocal agreement that a matched sibling allogeneic haematopoietic stem cell transplant in first CR is the most appropriate therapy for patients within certain age limits. Extension of allogeneic stem cell transplant to patients without matched sibling donors or to older individuals is increasingly possible due to unrelated donors, umbilical cord blood and reduced-intensity conditioning regimens. Here, we carefully review evidence supporting current practice and examine recent evidence relating to the use of newer allogeneic transplant technologies in Ph-pos ALL. We explore the burgeoning literature on the role of tyrosine kinase inhibitors in this disease and summarize their impact on the transplant practice.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Gleissner B, Gokbuget N, Bartram CR, Janssen B, Rieder H, Janssen JW et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood 2002; 99: 1536–1543.

    Article  CAS  Google Scholar 

  2. Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007; 109: 3189–3197.

    Article  CAS  Google Scholar 

  3. Jones LK, Saha V . Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 2005; 130: 489–500.

    Article  Google Scholar 

  4. Hermans A, Heisterkamp N, von Linden M, van Baal S, Meijer D, van der Plas D et al. Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell 1987; 51: 33–40.

    Article  CAS  Google Scholar 

  5. Castor A, Nilsson L, Astrand-Grundstrom I, Buitenhuis M, Ramirez C, Anderson K et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 2005; 11: 630–637.

    Article  CAS  Google Scholar 

  6. Secker-Walker LM, Craig JM, Hawkins JM, Hoffbrand AV . Philadelphia positive acute lymphoblastic leukemia in adults: age distribution, BCR breakpoint and prognostic significance. Leukemia 1991; 5: 196–199.

    CAS  PubMed  Google Scholar 

  7. Faderl S, Kantarjian HM, Thomas DA, Cortes J, Giles F, Pierce S et al. Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma 2000; 36: 263–273.

    Article  CAS  Google Scholar 

  8. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995; 85: 2025–2037.

    CAS  PubMed  Google Scholar 

  9. Preti HA, O'Brien S, Giralt S, Beran M, Pierce S, Kantarjian HM . Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 1994; 97: 60–65.

    Article  CAS  Google Scholar 

  10. Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, Thomas X et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia—results of the prospective multicenter LALA-94 trial. Blood 2002; 100: 2357–2366.

    Article  CAS  Google Scholar 

  11. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007; 109: 944–950.

    Article  CAS  Google Scholar 

  12. Mughal T, Goldman JM . Optimal management of patients with newly diagnosed chronic phase chronic myeloid leukemia in 2007. Clin Lymphoma Myeloma 2007; 7 (Suppl 3): S95–S101.

    Article  CAS  Google Scholar 

  13. Forman SJ, O'Donnell MR, Nademanee AP, Snyder DS, Bierman PJ, Schmidt GM et al. Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1987; 70: 587–588.

    CAS  PubMed  Google Scholar 

  14. Chao NJ, Blume KG, Forman SJ, Snyder DS . Long-term follow-up of allogeneic bone marrow recipients for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1995; 85: 3353–3354.

    CAS  PubMed  Google Scholar 

  15. Barrett AJ, Horowitz MM, Ash RC, Atkinson K, Gale RP, Goldman JM et al. Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1992; 79: 3067–3070.

    CAS  PubMed  Google Scholar 

  16. Snyder DS, Nademanee AP, O'Donnell MR, Parker PM, Stein AS, Margolin K et al. Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission. Leukemia 1999; 13: 2053–2058.

    Article  CAS  Google Scholar 

  17. Goldstone AH, Prentice HG, Durrant J, Franklin IM, Harrison G, Richards SM et al. Allogeneic transplant (related or unrelated donor) is the preferred treatment for acute adult Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL). Results from the International ALL Trial (MRC UKALLXII/ECOG E2993). Blood 2001; 98: 856a (abstract).

    Article  Google Scholar 

  18. Rowe JM, Buck G, Fielding AK, Tallman MS, Burnett AK, Chopra R et al. In adults with standard-risk acute lymphoblastic leukaemia (ALL) the greatest benefit is achieved from an allogeneic transplant in first complete remission (CR) and an autologous transplant is less effective than conventional consolidation/maintenance chemotherapy: final results of the international ALL trial (MRC UKALLXII/ECOG2993). Blood 2006; 108: 2a (abstract).

    Article  Google Scholar 

  19. Gassas A, Sung L, Saunders EF, Doyle JJ . Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens. Bone Marrow Transplant 2006; 38: 739–743.

    Article  CAS  Google Scholar 

  20. Marks DI, Forman SJ, Blume KG, Perez WS, Weisdorf DJ, Keating A et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant 2006; 12: 438–453.

    Article  CAS  Google Scholar 

  21. Dahlke J, Kroger N, Zabelina T, Ayuk F, Fehse N, Wolschke C et al. Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation. Bone Marrow Transplant 2006; 37: 155–163.

    Article  CAS  Google Scholar 

  22. Gutierrez-Aguirre CH, Gomez-Almaguer D, Cantu-Rodriguez OG, Gonzalez-Llano O, Jaime-Perez JC, Herena-Perez S et al. Non-myeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: results of a multicenter study. Bone Marrow Transplant 2007; 40: 535–539.

    Article  CAS  Google Scholar 

  23. Kiehl MG, Kraut L, Schwerdtfeger R, Hertenstein B, Remberger M, Kroeger N et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission. J Clin Oncol 2004; 22: 2816–2825.

    Article  Google Scholar 

  24. Sierra J, Radich J, Hansen JA, Martin PJ, Petersdorf EW, Bjerke J et al. Marrow transplants from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1997; 90: 1410–1414.

    CAS  PubMed  Google Scholar 

  25. Arico M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 2000; 342: 998–1006.

    Article  CAS  Google Scholar 

  26. Cornelissen JJ, Carston M, Kollman C, King R, Dekker AW, Lowenberg B et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood 2001; 97: 1572–1577.

    Article  CAS  Google Scholar 

  27. Marks DI, Bird JM, Cornish JM, Goulden NJ, Jones CG, Knechtli CJ et al. Unrelated donor bone marrow transplantation for children and adolescents with Philadelphia-positive acute lymphoblastic leukemia. J Clin Oncol 1998; 16: 931–936.

    Article  CAS  Google Scholar 

  28. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 2007; 369: 1947–1954.

    Article  Google Scholar 

  29. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004; 351: 2265–2275.

    Article  CAS  Google Scholar 

  30. Marks DI, Aversa F, Lazarus HM . Alternative donor transplants for adult acute lymphoblastic leukaemia: a comparison of the three major options. Bone Marrow Transplant 2006; 38: 467–475.

    Article  CAS  Google Scholar 

  31. Kahl C, Storer BE, Sandmaier BM, Mielcarek M, Maris MB, Blume KG et al. Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2007; 110: 2744–2748.

    Article  CAS  Google Scholar 

  32. Arnold R, Massenkeil G, Bornhauser M, Ehninger G, Beelen DW, Fauser AA et al. Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease. Leukemia 2002; 16: 2423–2428.

    Article  CAS  Google Scholar 

  33. Martino R, Giralt S, Caballero MD, Mackinnon S, Corradini P, Fernandez-Aviles F et al. Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukemia: a feasibility study. Haematologica 2003; 88: 555–560.

    PubMed  Google Scholar 

  34. Tavernier E, Boiron JM, Huguet F, Bradstock K, Vey N, Kovacsovics T et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia 2007; 21: 1907–1914.

    Article  CAS  Google Scholar 

  35. Preudhomme C, Henic N, Cazin B, Lai JL, Bertheas MF, Vanrumbeke M et al. Good correlation between RT–PCR analysis and relapse in Philadelphia (Ph1)-positive acute lymphoblastic leukemia (ALL). Leukemia 1997; 11: 294–298.

    Article  CAS  Google Scholar 

  36. Radich J, Gehly G, Lee A, Avery R, Bryant E, Edmands S et al. Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation. Blood 1997; 89: 2602–2609.

    CAS  PubMed  Google Scholar 

  37. Shimoni A, Kroger N, Zander AR, Rowe JM, Hardan I, Avigdor A et al. Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias. Leukemia 2003; 17: 290–297.

    Article  CAS  Google Scholar 

  38. Wassmann B, Pfeifer H, Scheuring U, Klein SA, Gokbuget N, Binckebanck A et al. Therapy with imatinib mesylate (Glivec) preceding allogeneic stem cell transplantation (SCT) in relapsed or refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL). Leukemia 2002; 16: 2358–2365.

    Article  CAS  Google Scholar 

  39. Towatari M, Yanada M, Usui N, Takeuchi J, Sugiura I, Takeuchi M et al. Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood 2004; 104: 3507–3512.

    Article  CAS  Google Scholar 

  40. Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 2004; 103: 4396–4407.

    Article  CAS  Google Scholar 

  41. de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 2007; 109: 1408–1413.

    Article  CAS  Google Scholar 

  42. Wassmann B, Pfeifer H, Stadler M, Bornhauser M, Bug G, Scheuring UJ et al. Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2005; 106: 458–463.

    Article  CAS  Google Scholar 

  43. Ottmann OG, Wassmann B, Pfeifer H, Giagounidis A, Stelljes M, Duhrsen U et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer 2007; 109: 2068–2076.

    Article  CAS  Google Scholar 

  44. Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2007; 110: 727–734.

    Article  CAS  Google Scholar 

  45. Hu Y, Liu Y, Pelletier S, Buchdunger E, Warmuth M, Fabbro D et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 2004; 36: 453–461.

    Article  CAS  Google Scholar 

  46. Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a Phase II study. Blood 2007; 110: 2309–2315.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

AKF is supported by the Leukaemia Research Fund.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A K Fielding.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fielding, A., Goldstone, A. Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukaemia. Bone Marrow Transplant 41, 447–453 (2008). https://doi.org/10.1038/sj.bmt.1705904

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705904

Keywords

This article is cited by

Search

Quick links