Current Hematologic Malignancy Reports

, Volume 2, Issue 3, pp 183–189 | Cite as

New approaches to the management of Philadelphia chromosome-positive acute lymphocytic leukemia

  • Deborah A. Thomas
  • Susan O’Brien
  • Jorge Cortes
  • Hagop Kantarjian


The discovery of targeted ABL tyrosine kinase inhibitors has allowed significant advances in the treatment of de novo Philadelphia chromosome (Ph)-positive ALL. Whereas the outcome with standard chemotherapy was previously dismal, the use of imatinib in front-line therapy has improved relapse-free survival and overall survival, even in the absence of allogeneic stem cell transplantation in first complete remission (particularly for those with comorbidities or lack of a suitable donor). However, the emergence of resistance to imatinib presents a new therapeutic challenge. Novel tyrosine kinase inhibitors with enhanced inhibitory potency against ABL and other kinases may further improve on the results observed with imatinib. Optimal use of these novel agents in the treatment schema of Ph-positive ALL will be paramount in ensuring continued success in the eradication of this disease.


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References and Recommended Reading

  1. 1.
    Faderl S, Kantarjian HM, Talpaz M, Estrov Z: Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 1998, 91:3995–4019.PubMedGoogle Scholar
  2. 2.
    Larson RA: Management of acute lymphoblastic leukemia in older patients. Semin Hematol 2006, 43:126–133.PubMedCrossRefGoogle Scholar
  3. 3.
    Rowley JD: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]. Nature 1973, 243:290–293.PubMedCrossRefGoogle Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    Heisterkamp N, Jenster G, ten Hoeve J, et al.: Acute leukaemia in bcr/abl transgenic mice. Nature 1990, 344:251–253.PubMedCrossRefGoogle Scholar
  6. 6.
    Lugo TG, Pendergast AM, Muller AJ, Witte ON: Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990, 247:1079–1082.PubMedCrossRefGoogle Scholar
  7. 7.
    Voncken JW, Kaartinen V, Pattengale PK, et al.: BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice. Blood 1995, 86:4603–4611.PubMedGoogle Scholar
  8. 8.
    Tauchi T, Okabe S, Miyazawa K, Ohyashiki K: The tetramerization domain-independent Ras activation by BCR-ABL oncoprotein in hematopoietic cells. Int J Oncol 1998, 12:1269–1276.PubMedGoogle Scholar
  9. 9.
    Skorski T, Kanakaraj P, Nieborowska-Skorska M, et al.: Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood 1995, 86:726–736.PubMedGoogle Scholar
  10. 10.
    Chai SK, Nichols GL, Rothman P: Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. J Immunol 1997, 159:4720–4728.PubMedGoogle Scholar
  11. 11.
    Ilaria RL Jr, Van Etten RA: P210 and P190 BCR/ABL induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 1996, 271:31704–31710.PubMedCrossRefGoogle Scholar
  12. 12.
    Faderl S, Kantarjian HM, Thomas DA, et al.: Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma 2000, 36:263–273.PubMedCrossRefGoogle Scholar
  13. 13.
    Radich JP: Philadelphia chromosome-positive acute lymphocytic leukemia. Hematol Oncol Clin North Am 2001, 15:21–36.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    Pane F, Cimino G, Izzo B, et al.: Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia. Leukemia 2005, 19:628–635.PubMedGoogle Scholar
  16. 16.
    Barrett AJ, Horowitz MM, Ash RC, et al.: Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1992, 79:3067–3070.PubMedGoogle Scholar
  17. 17.
    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.PubMedGoogle Scholar
  18. 18.
    Avivi I, Goldstone AH: Bone marrow transplant in Ph+ ALL patients. Bone Marrow Transplant 2003, 31:623–632.PubMedCrossRefGoogle Scholar
  19. 19.
    Schindler T, Bornmann W, Pellicena P, et al.: Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 2000, 289:1938–1942.PubMedCrossRefGoogle Scholar
  20. 20.
    Heinrich MC, Blanke CD, Druker BJ, Corless CL: Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 2002, 20:1692–1703.PubMedCrossRefGoogle Scholar
  21. 21.
    Apperley JF, Gardembas M, Melo JV, et al.: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002, 347:481–487.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002, 100:1965–1971.PubMedCrossRefGoogle Scholar
  24. 24.
    Pfeifer H, Wassmann B, Hofmann WK, et al.: Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate. Clin Cancer Res 2003, 9:4674–4681.PubMedGoogle Scholar
  25. 25.
    Leis JF, Stepan DE, Curtin PT, et al.: Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma 2004, 45:695–698.PubMedCrossRefGoogle Scholar
  26. 26.
    Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 2004, 103:4396–4407.PubMedCrossRefGoogle Scholar
  27. 27.
    Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 2006, 24:460–466.PubMedCrossRefGoogle Scholar
  28. 28.
    Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2006, 108:1469–1477.PubMedCrossRefGoogle Scholar
  29. 29.
    Lee S, Kim YJ, Min CK, et al.: The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2005, 105:3449–3457.PubMedCrossRefGoogle Scholar
  30. 30.
    Thomas DA, Kantarjian HM, Cortes J, et al.: Outcome with the hyper-CVAD and imatinib mesylate regimen as frontline therapy for adult Philadelphia (Ph) positive acute lymphocytic leukemia (ALL) [abstract]. Blood 2006, 108:87a–88a (Abstract 284).Google Scholar
  31. 31.
    de Labarthe A, Rousselot P, Huguet-Rigal F, 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.PubMedCrossRefGoogle Scholar
  32. 32.
    Goldstone AH, Prentice HG, Durrant J, et al.: Allogeneic transplant (related or unrelated donor) is the preferred treatment for adult Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Results from the international ALL trial (MRC UKALLXII/ECOG E2993) [abstract]. Blood 2001, 98:856a (Abstract 3556).CrossRefGoogle Scholar
  33. 33.
    Jabbour E, Cortes J, Kantarjian HM, et al.: Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 2006, 108:1421–1423.PubMedCrossRefGoogle Scholar
  34. 34.
    Wassmann B, Pfeifer H, Stadler M, et al.: Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2005, 106:458–463.PubMedCrossRefGoogle Scholar
  35. 35.
    Anderlini P, Sheth S, Hicks K, et al.: Re: Imatinib mesylate administration in the first 100 days after stem cell transplantation [letter]. Biol Blood Marrow Transplant 2004, 10:883–884.PubMedCrossRefGoogle Scholar
  36. 36.
    Carpenter PA, Snyder DS, Flowers ME, et al.: Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood 2007, 109:2791–2793.PubMedGoogle Scholar
  37. 37.
    Delannoy A, Delabesse E, Lheritier V, et al.: Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia 2006, 20:1526–1532.PubMedCrossRefGoogle Scholar
  38. 38.
    Vignetti M, Fazi P, Cimino G, et al.: Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood 2007, 109:3676–3678.PubMedCrossRefGoogle Scholar
  39. 39.
    Ottmann OG, Wassmann B, Pfeifer H, 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.PubMedCrossRefGoogle Scholar
  40. 40.
    Pfeifer H, Wassmann B, Pavlova 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, In press.Google Scholar
  41. 41.
    Hofmann WK, Komor M, Wassmann B, et al.: Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. Blood 2003, 102:659–661.PubMedCrossRefGoogle Scholar
  42. 42.
    Jones D, Luthra R, Kantarjian H, et al.: Kinase domain point mutations in Ph+ acute lymphoblastic leukemia (ALL) and lymphoid blast crisis of chronic myeloid leukemia (CML) and their emergence following therapy with Bcr-Abl kinase inhibitors [abstract]. Blood 2006, 108:519a (Abstract 1831).Google Scholar
  43. 43.
    Azam M, Latek RR, Daley GQ: Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003, 112:831–843.PubMedCrossRefGoogle Scholar
  44. 44.
    Gorre ME, Mohammed M, Ellwood K, et al.: Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001, 293:876–880.PubMedCrossRefGoogle Scholar
  45. 45.
    Hochhaus A, Kreil S, Corbin AS, et al.: Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002, 16:2190–2196.PubMedCrossRefGoogle Scholar
  46. 46.
    Shah NP, Nicoll JM, Nagar B, et al.: Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002, 2:117–125.PubMedCrossRefGoogle Scholar
  47. 47.
    Thomas J, Wang L, Clark RE, Pirmohamed M: Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004, 104:3739–3745.PubMedCrossRefGoogle Scholar
  48. 48.
    Donato NJ, Wu JY, Stapley J, et al.: BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003, 101:690–698.PubMedCrossRefGoogle Scholar
  49. 49.
    Shah NP, Tran C, Lee FY, et al.: Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004, 305:399–401.PubMedCrossRefGoogle Scholar
  50. 50.
    Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006, 354:2531–2541.PubMedCrossRefGoogle Scholar
  51. 51.
    Coutre S, Martinelli G, Dombret H, et al.: Dasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): the CA180015 “START-L” study [abstract]. J Clin Oncol 2006, 24:344s (Abstract 6528).Google Scholar
  52. 52.
    O’Hare T, Walters DK, Stoffregen EP, et al.: In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005, 65:4500–4505.PubMedCrossRefGoogle Scholar
  53. 53.
    Weisberg E, Manley PW, Breitenstein W, et al.: Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005, 7:129–141.PubMedCrossRefGoogle Scholar
  54. 54.
    Kantarjian H, Giles F, Wunderle L, et al.: Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006, 354:2542–2551.PubMedCrossRefGoogle Scholar
  55. 55.
    Cortes J, Kantarjian HM, Baccarani M, et al.: A phase 1/2 study of SKI-606, a dual inhibitor of Src and Abl kinases, in adult patients with Philadelphia chromosome positive (Ph) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory or intolerant of imatinib [abstract]. Blood 2006, 108:Abstract 168.Google Scholar
  56. 56.
    Kimura S, Naito H, Segawa H, et al.: NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 2005, 106:3948–3954.PubMedCrossRefGoogle Scholar
  57. 57.
    Giles FJ, Cortes J, Jones D, et al.: MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007, 109:500–502.PubMedCrossRefGoogle Scholar
  58. 58.
    O’Hare T, Pollock R, Stoffregen EP, et al.: Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood 2004, 104:2532–2539.PubMedCrossRefGoogle Scholar
  59. 59.
    O’Hare T, Walters DK, Stoffregen EP, et al.: Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. Clin Cancer Res 2005, 11:6987–6993.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  • Deborah A. Thomas
    • 1
  • Susan O’Brien
  • Jorge Cortes
  • Hagop Kantarjian
  1. 1.Department of Leukemia, Unit 428The University of Texas MD Anderson Cancer CenterHoustonUSA

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