Skip to main content

Advertisement

Log in

Philadelphia-Positive Acute Lymphoblastic Leukemia: Current Treatment Options

  • Leukemia (A Aguayo, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

The Philadelphia chromosome (Ph), t(9;22), is seen in about 20 % to 30 % of adults diagnosed with acute lymphoblastic leukemia (ALL). It has been associated with poorer prognosis compared with Ph-negative ALL. Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogenic protein from this translocation have been incorporated into treatment regimens used to treat patients with Ph-positive ALL. Imatinib has been the most widely used TKI with several published trials showing it produced better outcomes when combined with chemotherapy. Dasatinib, a more potent inhibitor than imatinib, has also been evaluated with promising results. However, relapses still occur at a high rate, and allogeneic stem cell transplant is considered, so far, a better curative option in first remission. Additional strategies have also included incorporation of TKIs in the post-transplant setting and the use of newer third generation TKIs. This review provides an update on emerging therapies for adults with Ph-positive ALL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Wetzler M, Dodge RK, Mrozek K, et al. Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood. 1999;93:3983–93.

    PubMed  CAS  Google Scholar 

  2. Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult acute lymphoblastic leukemia. Cancer. 2003;98:1337–54.

    Article  PubMed  Google Scholar 

  3. Burmeister T, Schwartz S, Bartram CR, Gokbuget N, Hoelzer D, Thiel E. Patients' age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group. Blood. 2008;112:918–9.

    Article  PubMed  CAS  Google Scholar 

  4. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290–3.

    Article  PubMed  CAS  Google Scholar 

  5. 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;5:196–9.

    PubMed  CAS  Google Scholar 

  6. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354:166–78.

    Article  PubMed  CAS  Google Scholar 

  7. Gleissner B, Gokbuget N, Bartram CR, 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;99:1536–43.

    Article  PubMed  CAS  Google Scholar 

  8. Vitale A, Guarini A, Chiaretti S, Foa R. The changing scene of adult acute lymphoblastic leukemia. Curr Opin Oncol. 2006;18:652–9.

    Article  PubMed  CAS  Google Scholar 

  9. Fielding AK, Rowe JM, Richards SM, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009;113:4489–96.

    Article  PubMed  CAS  Google Scholar 

  10. 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;100:1965–71.

    Article  PubMed  CAS  Google Scholar 

  11. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108:28–37.

    Article  PubMed  CAS  Google Scholar 

  12. 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;110:727–34.

    Article  PubMed  CAS  Google Scholar 

  13. Hu Y, Liu Y, Pelletier S, 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;36:453–61.

    Article  PubMed  CAS  Google Scholar 

  14. Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci U S A. 2006;103:16870–5.

    Article  PubMed  CAS  Google Scholar 

  15. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658–61.

    Article  PubMed  CAS  Google Scholar 

  16. 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;65:4500–5.

    Article  PubMed  Google Scholar 

  17. Hiwase DK, Saunders V, Hewett D, et al. Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res. 2008;14:3881–8.

    Article  PubMed  CAS  Google Scholar 

  18. Li S. Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma. 2008;49:19–26.

    Article  PubMed  CAS  Google Scholar 

  19. Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2010;116:3409–17.

    Article  PubMed  CAS  Google Scholar 

  20. SPRYCEL® (dasatinib) [package insert].

  21. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41.

    Article  PubMed  CAS  Google Scholar 

  22. Ottmann O, Dombret H, Martinelli G, 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 2 study. Blood. 2007;110:2309–15.

    Article  PubMed  CAS  Google Scholar 

  23. Porkka K, Martinelli G, Ottmann OG, et al. Dasatinib efficacy in patients with imatinib-resistant/-intolerant Philadelphia-chromosome-positive acute lymphoblastic leukemia: 24-month data from START-L. Haematologica. 2008;93 Suppl 1:1(EHA 2008 abstract).

  24. Lilly MB, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010;85:164–70.

    PubMed  CAS  Google Scholar 

  25. Ravandi F, Kantarjian HM, Cortes J, et al. Combination of the hypercvad regimen with Dasatinib is effective in patients with relapsed Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) and lymphoid blast phase chronic myeloid leukemia (CML-LB). Blood. 2009;114:806–7.

    Google Scholar 

  26. Liu-Dumlao T, O'Brien S, Cortes JE, et al. Combination of the hypercvad regimen with dasatinib in patients with relapsed Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) or lymphoid blast phase of chronic myeloid leukemia (CML-LB). ASH Annual Meeting Abstracts. Blood. 2011;118:2578.

    Google Scholar 

  27. • Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118:6521–8.

    Article  PubMed  CAS  Google Scholar 

  28. Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116:2070–7.

    Article  PubMed  CAS  Google Scholar 

  29. Lee HJ, Kantarjian HM, Thomas DA, et al. Long-term follow-up of combined hypercvad (hCVAD) regimen with dasatinib (Db) in the front line therapy of patients (pts) with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). ASH Annual Meeting Abstracts. Blood. 2011;118:1512.

    Google Scholar 

  30. Rousselot P, Cayuela JM, Hayette S, et al. Dasatinib (sprycel) and chemotherapy for first-line treatment in elderly patients with de novo Philadelphia positive ALL (EWALL-Ph-01): analysis of response and resistance. Haematologica. 2009;94 Suppl 2:195(EHA 2009 abstract).

  31. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–51.

    Article  PubMed  Google Scholar 

  32. TASIGNA® (nilotinib) [package insert].

  33. Kim D-Y, Joo YD, Lee J-H, et al. Nilotinib combined with multi-agent chemotherapy for adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: interim results of Korean Adult ALL Working Party Phase 2 Study. ASH Annual Meeting Abstracts. Blood. 2011;118:1517.

    Google Scholar 

  34. Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia. 2011;26:959–62.

    Google Scholar 

  35. Gambacorti-Passerini C, Khoury HJ, Pinczowski H, et al. Clinical activity of bosutinib by mutational status in patients with previously treated Philadelphia chromosome-positive leukemias. ASH Annual Meeting Abstracts. Blood. 2010;116:3434.

    Google Scholar 

  36. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Initial findings from the PACE trial: a pivotal phase 2 study of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. ASH Annual Meeting Abstracts. Blood. 2011;118:109.

    Google Scholar 

  37. Cortes JE, Talpaz M, Kantarjian HM, et al. A Phase 1 Study of DCC-2036, a novel oral inhibitor of BCR-ABL kinase, in patients with Philadelphia chromosome positive (Ph+) leukemias including patients with T315I mutation. ASH Annual Meeting Abstracts. Blood. 2011;118:601.

    Google Scholar 

  38. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111:1827–33.

    Article  PubMed  CAS  Google Scholar 

  39. Arnold R, Massenkeil G, Bornhauser M, et al. Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease. Leukemia. 2002;16:2423–8.

    Article  PubMed  CAS  Google Scholar 

  40. Martino R, Giralt S, Caballero M, et al. Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukemia: a feasibility study. Haematologica. 2003;88:555–60.

    PubMed  Google Scholar 

  41. Mohty M, Labopin M, Tabrizzi R, et al. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica. 2008;93:303–6.

    Article  PubMed  Google Scholar 

  42. Stein AS, Palmer JM, O'Donnell MR, et al. Reduced-intensity conditioning followed by peripheral blood stem cell transplantation for adult patients with high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2009;15:1407–14.

    Article  PubMed  Google Scholar 

  43. Shimoni A, Leiba M, Schleuning M, et al. Prior treatment with the tyrosine kinase inhibitors dasatinib and nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not increase SCT Toxicity in patients with chronic myelogenous leukemia and philadelphia positive acute lymphoblastic leukemia. Leukemia. 2009;23:190–4.

    Article  PubMed  CAS  Google Scholar 

  44. •• Schultz KR, Bowman WP, Aledo A, et al. Improved Early Event-Free Survival With Imatinib in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: a Children's Oncology Group Study. J Clin Oncol. 2009;27:5175–81.

    Article  PubMed  CAS  Google Scholar 

  45. 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;109:2791–3.

    PubMed  CAS  Google Scholar 

  46. Pfeifer H, Wassmann B, Bethge WA, et al. Updated long-term results of a randomized comparison of prophylactic and pre-emptive imatinib following allogeneic stem cell transplantation for Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). ASH Annual Meeting Abstracts. Blood. 2011;118:247.

    Google Scholar 

  47. Ravandi F, Thomas DA, O'Brien S, et al. Detection of minimal residual leukemia predicts the outcome of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia treated with tyrosine kinase inhibitors plus chemotherapy. ASH Annual Meeting Abstracts. Blood. 2011;118:1453.

    Google Scholar 

  48. Zhou Y, Jorgensen JL, Saliba RM, et al. Pre-transplant minimal residual disease detected by multiparameter flow cytometric analysis predicts for disease relapse in adult patients with acute lymphoblastic leukemia post allogeneic hematopoietic stem cell transplantation. ASH Annual Meeting Abstracts. Blood. 2011;118:3072.

    Google Scholar 

  49. Pfeifer H, Cazzaniga G, Spinelli O, et al. International standardization of minimal residual disease assessment for in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) expressing m-BCR-ABL transcripts: updated results of quality control procedures by the EWALL and ESG-MRD-ALL consortia. ASH Annual Meeting Abstracts. Blood. 2011;118:2535.

    Google Scholar 

  50. Ravandi F, Kebriaei P. Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2009;23:1043–63.

    Article  PubMed  Google Scholar 

  51. Bloomfield CD, Goldman AI, Alimena G, et al. Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia. Blood. 1986;67:415–20.

    PubMed  CAS  Google Scholar 

  52. Gotz G, Weh HJ, Walter TA, et al. Clinical and prognostic significance of the Philadelphia chromosome in adult patients with acute lymphoblastic leukemia. Ann Hematol. 1992;64:97–100.

    Article  PubMed  CAS  Google Scholar 

  53. 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;85:2025–37.

    PubMed  CAS  Google Scholar 

  54. Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A Collaborative Study of the Group Francais de Cytogenetique Hematologique. Blood. 1996;87:3135–42.

  55. Secker-Walker LM, Prentice HG, Durrant J, Richards S, Hall E, Harrison G. Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA. MRC Adult Leukaemia Working Party. Br J Haematol. 1997;96:601–10.

    Article  PubMed  CAS  Google Scholar 

  56. Faderl S, Kantarjian HM, Thomas DA, et al. Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma. 2000;36:263–73.

    Article  PubMed  CAS  Google Scholar 

  57. 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;100:2357–66.

    Article  PubMed  CAS  Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. Schrappe M, Arico M, Harbott J, et al. Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood. 1998;92:2730–41.

    PubMed  CAS  Google Scholar 

  60. 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;20:1526–32.

    Article  PubMed  CAS  Google Scholar 

  61. Delannoy A, Delabesse E, Lheritier V, et al. The long-term outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) in the imatinib era. Haematologica. 2009;Suppl 2:30(EHA 2009 abstract).

  62. 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;24:460–6.

    Article  PubMed  CAS  Google Scholar 

  63. 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;109:1408–13.

    Article  PubMed  Google Scholar 

  64. Ribera JM, Oriol A, Gonzalez M, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. 2010;95:87–95.

    Article  PubMed  CAS  Google Scholar 

  65. Bassan R, Rossi G, Pogliani EM, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol. 2010;28:3644–52.

    Article  PubMed  CAS  Google Scholar 

  66. 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;108:1469–77.

    Article  PubMed  CAS  Google Scholar 

  67. Pfeifer H, Goekbuget N, Volp C, et al. Long-term outcome of 335 adult patients receiving different schedules of imatinib and chemotherapy as front-line treatment for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). ASH Annual Meeting Abstracts. Blood. 2010;116:173.

    Google Scholar 

  68. Fielding AK, Buck G, Lazarus HM, et al. Imatinib significantly enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukaemia: final results of the UKALLXII/ECOG2993 trial. ASH Annual Meeting Abstracts. Blood. 2010;116:169.

    Google Scholar 

  69. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396–407.

    Article  PubMed  CAS  Google Scholar 

  70. Thomas DA, O'Brien SM, Faderl S, et al. Long-term outcome after hyper-CVAD and imatinib (IM) for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL). J Clin Oncol. 2010;28 Suppl 15:488s(ASCO 2010 abstract #6506).

  71. Foa R, Vitale A, Guarini A, et al. Line Treatment of Adult Ph+ Acute Lymphoblastic Leukemia (ALL) Patients. Final results of the GIMEMA LAL1205 Study. ASH Annual Meeting Abstracts. Blood. 2008;112:305.

    Google Scholar 

  72. Lee S, Kim D-W, Kim Y-J, et al. First-line dasatinib plus conventional chemotherapy in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL): interim analysis of the Korean Prospective Phase II Study. ASH Annual Meeting Abstracts. 2011;118:1516.

    Google Scholar 

Download references

Disclosure

T. Liu-Dumlao: none; H. Kantarjian: none; D. A. Thomas: none; S. O’Brien: none; F. Ravandi: honoraria from Bristol Myers.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Farhad Ravandi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu-Dumlao, T., Kantarjian, H., Thomas, D.A. et al. Philadelphia-Positive Acute Lymphoblastic Leukemia: Current Treatment Options. Curr Oncol Rep 14, 387–394 (2012). https://doi.org/10.1007/s11912-012-0247-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-012-0247-7

Keywords

Navigation