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.

Bone marrow transplant in Ph+ ALL patients

Summary:

Although the outcome for Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) with conventional chemotherapy is poor, the outcome after a sibling-matched allogeneic bone marrow transplantation (BMT) seems to be significantly better. The surprising success of allogeneic BMT may be because of disease response to high-dose chemotherapy combined with a graft-versus-leukemia effect. However, less than 30% of patients have a matched related donor available, and some of them will be too old/not fit for conventional BMT. While young patients who do not have a matched related donor should be considered for matched unrelated donor (MUD) transplant, older patients may be treated with autologous stem cell transplantation (ASCT) or rarely considered for a low-intensity MUD transplant. The efficacy of autologous BMT compared with chemotherapy is still debatable, although the new tyrosine kinase inhibitor Imatinib may be used for pretransplant purging/post-transplant therapy, aiming to improve autologous and allogeneic BMT results. The advantage of low-intensity sib/MUD allograft compared with chemotherapy is not proven either and is currently under investigation. However, if shown to be curative, low-intensity allograft may significantly improve the outcome of older Ph+ ALL patients, who are not eligible for conventional allograft.

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

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

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

    CAS  PubMed  Google Scholar 

  2. Uckun FM, Nachman JB, Sather HN et al. Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies: a report from the Children's Cancer Group. Cancer 1998; 1: 83:2030–2039.

    Google Scholar 

  3. Heisterkamp N, Stephenson JR, Groffen J et al. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukemia. Nature 1983; 306: 239–242.

    CAS  PubMed  Article  Google Scholar 

  4. Ben-Neriah Y, Daley GQ, Mes-Masson AM et al. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science 1986; 233: 212–214.

    CAS  PubMed  Article  Google Scholar 

  5. Konopka JB, Watanabe SM, Witte ON . An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell 1984; 37: 1035–1042.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  7. Larson RA, Dodge RK, Burns CP 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 

  8. Preti HA, O'Brien S, Giralt S et al. Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 1994; 97: 60–65.

    CAS  Article  PubMed  Google Scholar 

  9. Goldstone AH, Prentice HG, Durrant IJ et al. Allogeneic transplant (related or unrelated donor) is the preferred treatment for adult Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL). Results From The International ALL Trial (MRC UKALLXII/ECOG E2993). 2001: Blood 98: 856a (abstract).

    Google Scholar 

  10. Snyder DS, Nademanee AP, O'Donnell MR 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.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Barrett AJ, Horowitz MM, Ash RC et al. Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1992; 79: 3067–3070.

    CAS  PubMed  Google Scholar 

  14. Stockschlader M, Hegewisch-Becker S, Kruger W et al. Bone marrow transplantation for Philadelphia-chromosome-positive acute lymphoblastic leukemia. Bone Marrow Transplant 1995; 16: 663–667.

    CAS  PubMed  Google Scholar 

  15. 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 

  16. Cornelissen JJ, Carston M, Kollman C 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.

    CAS  Article  PubMed  Google Scholar 

  17. Sierra J, Radich J, Hansen JA 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 

  18. Snyder DS, Negrin RS, Blume KG et al. Allogeneic boine marrow transplantation for BCR–ABL positive acute lymphoblastic leukemia (abstract). Ann Hematol 1999; 78 (Suppl. 2): 59.

    Google Scholar 

  19. Dombret H, Gabert J, Boiron JM 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.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  21. Schaap N, Schattenberg A, Bar B et al. Induction of graft-versus-leukemia to prevent relapse after partially lympho-cyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions. Leukemia 2001; 15: 1339–1346.

    CAS  PubMed  Article  Google Scholar 

  22. Uzunel M, Mattsson J, Jaksch M et al. The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia. Blood 2001; 98: 1982–1984.

    CAS  Article  PubMed  Google Scholar 

  23. Atta J, Fauth F, Keyser M et al. Purging in BCR–ABL-positive acute lymphoblastic leukemia using immunomagnetic beads: comparison of residual leukemia and purging efficiency in bone marrow vs peripheral blood stem cells by semiquantitative polymerase chain reaction. Bone Marrow Transplant 2000; 25: 97–104.

    CAS  Article  PubMed  Google Scholar 

  24. Dunlop LC, Powles R, Singhal S et al. Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Bone Marrow Transplant 1996; 17: 365–369.

    CAS  PubMed  Google Scholar 

  25. Brenner MK, Rill DR, Moen RC et al. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet 1993; 341: 85–86.

    CAS  PubMed  Article  Google Scholar 

  26. Martin H, Atta J, Bruecher J et al. In patients with BCR–ABL-positive ALL in CR peripheral blood contains less residual disease than bone marrow: implications for autologous BMT. Ann Hematol 1994; 68: 85–87.

    CAS  Article  PubMed  Google Scholar 

  27. Radich J, Gehly G, Lee A 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 

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

    CAS  PubMed  Article  Google Scholar 

  29. Morishima Y, Miyamura K, Kojima S et al. Autologous BMT in high risk patients with CALLA-positive ALL: possible efficacy of ex vivo marrow leukemia cell purging with monoclonal antibodies and complement. Bone Marrow Transplant 1993; 11: 255–259.

    CAS  PubMed  Google Scholar 

  30. Coustan-Smith E, Sancho J, Hancock ML et al. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 2002; 100: 2399–2402.

    CAS  PubMed  Article  Google Scholar 

  31. Martino R, Sergio G, Caballero MD et al. Allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in acute lymphoblastic leukemia. 2002; submitted.

  32. Cave H, van der Werff ten Bosch J, Suciu S et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer – Childhood Leukemia Cooperative Group. N Engl J Med 1998; 339: 591–598.

    CAS  PubMed  Article  Google Scholar 

  33. Van Dongen JJ, Seriu T, Panzer-Grumayer ER et al. Prognostic value of minimal residual disease in acute lymphoblastic leukemia in childhood. Lancet 1998; 352:1731–1738.

    CAS  Article  PubMed  Google Scholar 

  34. Mortuza FY, Papaioannou M, Moreira IM et al. Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol 2002; 20:1094–1104.

    PubMed  Article  Google Scholar 

  35. Brisco J, Hughes E, Neoh SH et al. Relationship between minimal residual disease and outcome in adult acute lymphoblastic leukemia. Blood. 1996 ; 87: 5251–5256.

    CAS  PubMed  Google Scholar 

  36. Foroni L, Coyle LA, Papaioannou M et al. Molecular detection of minimal residual disease in adult and childhood acute lymphoblastic leukemia reveals differences in treatment response. Leukemia 1997; 11: 1732–1741.

    CAS  PubMed  Article  Google Scholar 

  37. Hermans A, Heisterkamp N, von Linden M et al. Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia.Cell 1987; 51: 33–40.

    CAS  PubMed  Article  Google Scholar 

  38. Clark SS, McLaughlin J, Timmons M et al. Expression of a distinctive BCR–ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL). Science 1988; 239: 775–777.

    CAS  PubMed  Article  Google Scholar 

  39. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.

    CAS  Article  PubMed  Google Scholar 

  40. Lugo TG, Pendergast AM, Muller AJ et al. Tyrosine kinase activity and transformation potency of bcr–abl oncogene products. Science 1990; 247: 1079–1082.

    CAS  PubMed  Article  Google Scholar 

  41. Kantarjian H, Sawyers C, Hochhaus A et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652.

    CAS  PubMed  Article  Google Scholar 

  42. Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–1042.

    CAS  PubMed  Article  Google Scholar 

  43. Talpaz M, Sawyers CL, Kantarjain H et al. Activity of an ABL specific tyrosine kinase inhibitor in patients with BCR–ABL positive acute leukemia including chronic myelogenous leukemia in blast crisis. Proc Am Soc Clinl Oncol 2000; 19: 4a.

    Google Scholar 

  44. Ottmann OG, Sawyers C, Drucker B et al. The international STI571 Study group. A Phase 12 study to determine the safety and anti-leukemic effects of STI571 in adult patients with Philadelphia chromosome positive acute leukemia. Blood 2000; 96: 828a.

    Google Scholar 

  45. Uckun FM, Messinger Y, Chen CL et al. Treatment of therapy-refractory B-lineage acute lymphoblastic leukemia with an apoptosis-inducing CD19-directed tyrosine kinase inhibitor. Clin Cancer Res 1999; 5: 3906–3913.

    CAS  PubMed  Google Scholar 

  46. Mendel DB, Schreck RE, West DC et al. The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function. Clin Cancer Res 2000; 6: 4848–4858.

    CAS  PubMed  Google Scholar 

  47. Kardinal C, Konkol B, Lin H et al. Chronic myelogenous leukemia blast cell proliferation is inhibited by peptides that disrupt Grb2–SoS complexes. Blood 2001 15; 98: 1773–1781.

    CAS  PubMed  Article  Google Scholar 

  48. Faderl S, Kantarjian HM, Talpaz M . Chronic myelogenous leukemia: update on biology and treatment: signal transduction-based strategies for the treatment of CML. Oncology 1999; 13: 169–184.

    PubMed  Google Scholar 

  49. Wall NR, Mohammad RM, Reddy KB et al. Bryostatin 1 induces ubiquitination and proteasome degradation of Bcl-2 in the human acute lymphoblastic leukemia cell line. Rehab Int J Mol Med 2000; 5: 165–171.

    CAS  Google Scholar 

  50. Wall NR, Mohammad RM, Al-Katib AM . Bax: Bcl-2 ratio modulation by bryostatin 1 and novel antitubulin agents is important for susceptibility to drug induced apoptosis in the human early pre-B acute lymphoblastic leukemia cell line. Rehab Leuk Res 1999; 23:881–888.

    CAS  Article  Google Scholar 

  51. Elliott PJ, Ross JS . The proteasome: a new target for novel drug therapies. Am J Clin Pathol 2001; 116: 637–646.

    CAS  PubMed  Article  Google Scholar 

  52. An WG, Hwang SG, Trepel JB et al. Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia 2000 I; 14: 1276–1283.

    CAS  PubMed  Article  Google Scholar 

  53. Richardson GP, Barlogi B, Berenson J et al. Phase II study of the proteasome inhibitor PS-341 in multiple myeloma (MM) patients (pts) with relapsed/refractory disease. Proc Am Soc clin Oncol 2002; 21: 11a.

    Google Scholar 

  54. Blaise D, Attal M, Reiffers J et al. Randomized study of recombinant interleukin-2 after autologous bone marrow transplantation for acute leukemia in first complete remission. Eur Cytokine Netw 2000; 11: 91–98.

    CAS  PubMed  Google Scholar 

  55. Blaise D, Attal M, Pico JL et al. The use of a sequential high dose recombinant interleukin 2 regimen after autologous bone marrow transplantation does not improve the disease free survival of patients with acute leukemia transplanted in first complete remission. Leuk Lymphoma 1997; 25: 469–478.

    CAS  PubMed  Article  Google Scholar 

  56. Visani G, Martinelli G, Piccaluga P et al. Alpha-interferon improves survival and remission duration in P-190BCR-ABL positive adult acute lymphoblastic leukemia. Leukemia 2000; 14: 22–27.

    CAS  PubMed  Article  Google Scholar 

  57. Jandula BM, Nomdedeu J, Marin P et al. Rituximab can be useful as treatment for minimal residual disease in bcr–abl-positive acute lymphoblastic leukemia. Bone Marrow Transplant 2001; 27: 225–227.

    CAS  PubMed  Article  Google Scholar 

  58. Jendreyko N, Bernt K, Gaedicke G et al. Antitumour activity of calicheamicin Q doxorubicin and anti-CD19 immunoconjugates in a human pre-B ALL. Cell Line 2001 Blood; 98: 105a.

    Google Scholar 

  59. Dyer MJ, Hale G, Hayhoe FG et al. Effects of CAMPATH-1 antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype. Blood 1989; 73:1431–1439.

    CAS  PubMed  Google Scholar 

  60. Mehta J, Powles R, Treleaven J et al. Autologous transplantation with CD52 monoclonal antibody-purged marrow for acute lymphoblastic leukemia: long-term follow-up. Leuk Lymphoma 1997; 25: 479–486.

    CAS  PubMed  Article  Google Scholar 

  61. Nakase K, Kita K, Miwa H et al. Expression pattern of hybrid phenotype in adult acute lymphoblastic leukemia. Cancer Detect Prev 2001; 25: 394–405.

    CAS  PubMed  Google Scholar 

  62. Aversa F, Tabilio A, Velardi A et al. Full haplotype mismatched transplant in high risk acute leukemia patients. Blood 2001; 98: 669a.

    Google Scholar 

  63. Ruggeri L, Capanni M, Casucci M et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 1999; 94: 333–339.

    CAS  PubMed  Google Scholar 

  64. Weiden PL, Sullivan KM, Flournoy N et al. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981; 304: 1529–1533.

    CAS  PubMed  Article  Google Scholar 

  65. Yazaki M, Andoh M, Ito T et al. Successful prevention of hematological relapse for a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic bone marrow transplantation by donor leukocyte infusion. Bone Marrow Transplant 1997; 19: 393–394.

    CAS  Article  PubMed  Google Scholar 

  66. Collins Jr RH, Shpilberg O, Drobyski WR et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–434.

    PubMed  Article  Google Scholar 

  67. Slavin S, Naparstek E, Nagler A et al. Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation. Blood 1996; 87: 2195–2204.

    CAS  PubMed  Google Scholar 

  68. Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 1995; 86: 2041–2050.

    CAS  PubMed  Google Scholar 

  69. Rowe JM, Richards SM, Burnett AK et al. Favorable results of allogeneic bone marrow transplantation (BMT) for adults with Philadelphia (Ph)-chromosome-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR): results from the international ALL trial (MRC UKALL XII/ECOG E2993). Blood 2001; 98: 481a.

    Google Scholar 

  70. Jensen M, Tan G, Forman S et al. CD20 is a molecular target for scFvFc:zeta receptor redirected T cells: implications for cellular immunotherapy of CD20+ malignancy. Biol Blood Marrow Transplant 1998; 4: 75–83.

    CAS  PubMed  Article  Google Scholar 

  71. Snyder DS . Allogeneic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Biol Blood Marrow Transplant 2000; 6: 597–603.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr Rodrigo Martino for giving us his permission to quote his unpublished results.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Avivi, I., Goldstone, A. Bone marrow transplant in Ph+ ALL patients. Bone Marrow Transplant 31, 623–632 (2003). https://doi.org/10.1038/sj.bmt.1703899

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1703899

Keywords

  • autologous
  • allogeneic bone marrow transplantation
  • Ph+ ALL

Further reading

Search

Quick links