Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy.

We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.

[1]  Simona Soverini,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. , 2006, Blood.

[2]  D. Ross,et al.  Cancer treatment with kinase inhibitors: what have we learnt from imatinib? , 2004, British Journal of Cancer.

[3]  Francisco Cervantes,et al.  Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. , 2003, The New England journal of medicine.

[4]  R. Herrmann,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. , 2004, Blood.

[5]  P. Marlton,et al.  Myeloid leukemia : methods and protocols , 2006 .

[6]  M. Baccarani,et al.  Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. , 2002, Blood.

[7]  J. Goldman.  How I treat chronic myeloid leukemia in the imatinib era. , 2007, Blood.

[8]  H. Kantarjian,et al.  Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. , 2002, Blood.

[9]  B. Druker,et al.  Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy , 2002, Leukemia.

[10]  A. Hochhaus,et al.  Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance , 2004, Leukemia.

[11]  H. Kantarjian,et al.  Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. , 2003, Blood.

[12]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[13]  B. Druker,et al.  Bcr-Abl inhibition as a modality of CML therapeutics. , 2001, Biochimica et biophysica acta.

[14]  R. Larson,et al.  Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. , 2002, Blood.

[15]  C. Barthe,et al.  Roots of clinical resistance to STI-571 cancer therapy. , 2001, Science.

[16]  W. M. Smit,et al.  Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia. , 2008, Blood.

[17]  K. Kolibaba,et al.  Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. , 2000, Blood.

[18]  Nicholas Moore,et al.  Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. , 2007, Blood.

[19]  T. Hughes,et al.  Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL , 2006, Leukemia.

[20]  H. Kantarjian,et al.  Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. , 2003, Blood.

[21]  P. Manley,et al.  Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. , 2007, Blood.

[22]  Gabriela Chiosis,et al.  BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. , 2002, Blood.

[23]  B. Druker.  Imatinib and chronic myeloid leukemia: validating the promise of molecularly targeted therapy. , 2002, European journal of cancer.

[24]  J. Kuriyan,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. , 2002, Cancer cell.

[25]  C. L. Perkins,et al.  CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. , 2000, Blood.

[26]  Francisco Cervantes,et al.  Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. , 2006, The New England journal of medicine.

[27]  C. Sawyers,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. , 2001, The New England journal of medicine.

[28]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[29]  T. Hughes,et al.  Detection of BCR-ABL mutations and resistance to imatinib mesylate. , 2006, Methods in molecular medicine.

[30]  B. Druker,et al.  Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. , 2000, The Journal of clinical investigation.

[31]  M. Baccarani,et al.  Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. , 2002, The New England journal of medicine.

[32]  H. Kantarjian,et al.  Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  Susan Branford,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. , 2003, Blood.

[34]  M. Deininger,et al.  Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. , 2007, Blood.

[35]  Susan Branford,et al.  Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. , 2003, The New England journal of medicine.

[36]  J. Radich,et al.  Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. , 2007, Blood.

[37]  A. B. Lyons,et al.  In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML. , 2005, Blood.

[38]  M. Pirmohamed,et al.  Expression of the Uptake Drug Transporter hOCT1 is an Important Clinical Determinant of the Response to Imatinib in Chronic Myeloid Leukemia , 2008, Clinical pharmacology and therapeutics.

[39]  Branford,et al.  Monitoring chronic myeloid leukaemia therapy by real‐time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics , 1999, British journal of haematology.

[40]  Susan O'Brien,et al.  Chronic myelogenous leukemia: A review and update of therapeutic strategies , 2003, Cancer.

[41]  P. Paschka,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 α , 2002, Leukemia.

[42]  L. To,et al.  Measurement of in vivo BCR-ABL kinase inhibition to monitor imatinib-induced target blockade and predict response in chronic myeloid leukemia. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  H. Kantarjian,et al.  Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-α , 2004 .

[44]  Susan Branford,et al.  Molecular monitoring of chronic myeloid leukemia. , 2003, Seminars in hematology.

[45]  A. Hochhaus,et al.  Clinical resistance to imatinib: mechanisms and implications. , 2004, Hematology/oncology clinics of North America.

[46]  H. Kantarjian,et al.  Result of high-dose imatinib mesylate in patients with Philadelphia chromosome – positive chronic myeloid leukemia after failure of interferon - , 2003 .

[47]  H. Kantarjian,et al.  High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. , 2004, Blood.

[48]  R. Herrmann,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. , 2002, Blood.

[49]  B. Druker,et al.  Roots of Clinical Resistance to STI-571 Cancer Therapy , 2001, Science.