Randomized study of imatinib for chronic myeloid leukemia: comparing standard dose escalation with aggressive escalation.

In 2007, we conducted a prospective randomized study to compare an aggressive dose escalation (group B, n = 123) with the standard dose escalation proposed by European LeukemiaNet (group A, n = 122). In group B, if patients did not achieve a complete cytogenetic response (CCyR) at 3 months or did not achieve a major molecular response (MR3) at 6 months, imatinib was increased to 600 mg. At 6 months CCyR was achieved in 69.4% and 78.7% of patients in groups A and B, respectively. The rate of MR3 at 12 months and 24 months were similar in group A (52.1% and 70.0%) and group B (58.7% and 68.3%). The cumulative incidence of withdrawal by failure without accelerated/blast phase was higher in group A than in group B (9.2% vs 2.5% at 24 months). At 3 and 6 months, the protocol called for the imatinib dose to increase to 600 mg in 90 patients (74.4%) in group B. Among the 42 patients who received increased dose according to the protocol, 25 (60.0%) achieved MR3 at 12 months, whereas only 14 (35.0%) of 40 patients who did not receive an increased dose achieved MR3 (P < .05). The number of patients who withdrew from this study was similar (group A, 20%; group B, 21%). The early aggressive dose escalation failed to produce a better molecular response at 12 months. However, for patients who tolerate imatinib well, but show inadequate response at an early time point, aggressive dose escalation may contribute to achieving a better outcome. This study was registered at http://www.umin.ac.jp/ctr/ as #R000000965.

[1]  Francisco Cervantes,et al.  Long‐Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia , 2017, The New England journal of medicine.

[2]  M. Baccarani,et al.  Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  I. Flinn,et al.  Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial , 2016, Leukemia.

[4]  Y. Kanda,et al.  Investigation of the freely available easy-to-use software ‘EZR' for medical statistics , 2012, Bone Marrow Transplantation.

[5]  T. Naoe,et al.  Long‐term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML202 study , 2012, Cancer science.

[6]  Martin C. Müller,et al.  Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). , 2010, Blood.

[7]  F. Mahon.  Remission in CML: is DNA useful? , 2010, Blood.

[8]  Manuel Ayala,et al.  Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. , 2010, The New England journal of medicine.

[9]  Ricardo Pasquini,et al.  Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. , 2010, The New England journal of medicine.

[10]  Susan Branford,et al.  Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  H. Kantarjian,et al.  Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. , 2009, Blood.

[12]  T. Kyo,et al.  [Correlation of quantification of major bcr-abl mRNA between TMA (transcription mediated amplification) method and real-time quantitative PCR]. , 2009, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[13]  Giovanni Martinelli,et al.  Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. , 2009, Blood.

[14]  J. Radich,et al.  Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia , 2009, Leukemia.

[15]  M. Tomonaga,et al.  Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group , 2009, International journal of hematology.

[16]  H. Kantarjian,et al.  Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. , 2009 .

[17]  A. Schwarer,et al.  Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of Response. , 2008 .

[18]  Deborah L White,et al.  Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. , 2008, Blood.

[19]  Jaspal Kaeda,et al.  Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Tillmann Krahnke,et al.  Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. , 2008, Blood.

[21]  F. Michor.  Chronic Myeloid Leukemia Blast Crisis Arises from Progenitors , 2007, Stem cells.

[22]  H. Kantarjian,et al.  Outcome of patients with Philadelphia chromosome‐positive chronic myelogenous leukemia post‐imatinib mesylate failure , 2007, Cancer.

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

[24]  Francisco Cervantes,et al.  Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. , 2006, Blood.

[25]  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 .

[26]  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.

[27]  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.

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

[29]  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.

[30]  C. Sawyers.  Chronic myeloid leukemia. , 1999, The New England journal of medicine.

[31]  M. Bar‐eli,et al.  The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia. , 1991, The Journal of clinical investigation.