Monitoring Chronic Myelogenous Leukemia in the Age of Tyrosine Kinase Inhibitors

Authors:
Jerald P. Radich From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Search for other papers by Jerald P. Radich in
Current site
Google Scholar
PubMed
Close
 MD
and
Vivian Oehler From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Search for other papers by Vivian Oehler in
Current site
Google Scholar
PubMed
Close
 MD
Full access

Tyrosine kinase inhibitors (TKIs) are now standard up-front therapy for chronic myeloid leukemia (CML). Patients with newly diagnosed chronic-phase CML treated with the TKI imatinib mesylate typically experience a complete cytogenetic remission. Outcomes for patients with advanced-phase disease are distinctly worse. Unfortunately, a small proportion of chronic-phase patients experience relapse during this therapy, and most with advanced-phase disease develop resistance to imatinib mesylate after months of therapy. Hematopoietic cell transplantation remains the only curative approach for CML and can salvage patients with advanced-phase disease. Therefore, physicians must carefully monitor patients with chronic-phase CML treated with TKIs so that they can undergo hematopoietic cell transplant (or treatment with another TKI or experimental therapy) before frank progression occurs. Fortunately, monitoring CML using cytogenetic and molecular methods (i.e., quantitative polymerase chain reaction) effectively defines end points that correlate highly with outcome.

Correspondence: Jerald P. Radich, MD, Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Avenue North, Seattle, WA 98109. E-mail: jradich@fhcrc.org
  • Collapse
  • Expand
  • 1.

    Hansen JA, Gooley TA, Martin PJ et al.. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 1998;338:962968.

  • 2.

    O'Brien SG, Guilhot F, Larson RA et al.. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med 2003;348:9941004.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Mauro MJ, Deininger MW. Chronic myeloid leukemia in 2006: a perspective. Haematologica 2006;91:152158.

  • 4.

    Druker BJ, Guilhot F, O'Brien SG et al.. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:24082417.

  • 5.

    Druker BJ, O'Brien SG, Cortes J, Radich J. Chronic myelogenous leukemia. In: Broudy VC, Abkowitz JL, Vose JM, eds. American Society of Hematology Education Program Book. Washington, DC: American Society of Hematology, 2002:111135.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Talpaz M, Silver RT, Druker BJ et al.. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002;99:19281937.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Sawyers CL, Hochhaus A, Feldman E et al.. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002;99:35303539.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    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;233:212214.

  • 9.

    Faderl S, Talpaz M, Estrov Z et al.. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164172.

  • 10.

    Wang JY. Regulation of cell death by the Abl tyrosine kinase. Oncogene 2000;19:56435650.

  • 11.

    Melo JV, Deininger MW. Biology of chronic myelogenous leukemia— signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004;18:545568.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Radich JP, Gehly G, Gooley T et al.. Polymerase chain reaction detection of BCR/ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 1995;85:26322638.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Radich JP, Gooley T, Bryant E et al.. The significance of bcr-abl molecular detection in chronic myeloid leukemia patients ``late,'' 18 months or more after transplantation. Blood 2001;98:17011707.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    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;108:2837.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Mensink E, van de Locht A, Schattenberg A et al.. Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukemia patients using real-time quantitative RT-PCR. Br J Haematol 1998;102:768774.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Kaeda J, O'Shea D, Szydlo RM et al.. Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplant for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 2006;107:41714176.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Hughes TP, Kaeda J, Branford S et al.. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myelogenous leukemia. N Engl J Med 2003;349:14231432.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Goldman J, Hughes T, Radich J et al.. Continuing reduction in level of residual disease after 4 years in patients with CML in chronic phase responding to first-line imatinib in the IRIS study [abstract]. Blood 2005;106:51a. Abstract 163.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Cortes J, Talpaz M, O'Brien S et al.. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 2005;11:34253432.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Marin D, Kaeda J, Szydlo R et al.. Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: patterns of residual leukaemia and prognostic factors for cytogenetic relapse. Leukemia 2005;19:507512.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Merx K, Muller MC, Kreil S et al.. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. Leukemia 2002;16:15791583.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Wang L, Pearson K, Ferguson JE, Clark RE. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol 2003;120:990999.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Branford S, Rudzki Z, Harper A et al.. Imatinib produces significantly superior molecular responses compared with interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia 2003;17:24012409.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    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;2:117125.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Soverini S, Colarossi S, Gnani A et al.. Frequency, distribution and prognostic value of ABL kinase domain (KD) mutations in different subsets of Philadelphia-positive (Ph+) patients (Pts) resistant to imatinib (IM) by the Gimema Working Party on CML [abstract]. Blood 2005;106:131a. Abstract 435.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Soverini S, Martinelli G, Rosti G et al.. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol 2005;23:41004109.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Branford S, Rudzki Z, Walsh S et al.. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003;102:276283.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Nicolini FE, Corm S, Le QH et al.. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 2006;20:10611066.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Talpaz M, Shah NP, Kantarjian H et al.. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:25312541.

  • 30.

    Kantarajian H, Giles F, Wunderle L et al.. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:25422551.

  • 31.

    Giles FJ, Cortes J, Jones D et al.. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphoblastic leukemia with the T315I BCR-ABL mutation. Blood 2007;109:500502.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Hochhaus A, Kreil S, Corbin A et al.. Roots of clinical resistance to STI-571 cancer therapy [abstract]. Science 2001;293:2163.

  • 33.

    Branford S, Rudzki Z, Walsh S et al.. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 2002;99:34723475.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Branford S, Rudzki Z, Parkinson I et al.. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood 2004;104:29262932.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Andersen MK, Pedersen-Bjergaard J, Kjeldsen L et al.. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia 2002;16:13901393.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Bumm T, Muller C, Al-Ali HK et al.. Emergence of clonal cytogenetic abnormalities in Ph-cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003;101:19411949.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    O'Dwyer ME, Gatter KM, Loriaux M et al.. Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. Leukemia 2003;17:481487.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Chee YL, Vickers MA, Stevenson D et al.. Fatal myelodysplastic syndrome developing during therapy with imatinib mesylate and characterised by the emergence of complex Philadelphia negative clones. Leukemia 2003;17:634635.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    O'Brien S, Berman E, Bhalla K et al.. NCCN Chronic myelogenous leukemia clinical practice guidelines in oncology. JNCCN 2007;5:xxxxxx.

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1215 700 85
PDF Downloads 147 46 4
EPUB Downloads 0 0 0