Comprehensive therapeutic outcomes of frontline imatinib mesylate in newly diagnosed chronic phase chronic myeloid leukemia patients in Korea: feasibility assessment of current ELN recommendation.
ABSTRACT Optimal responses during imatinib therapy are commonly defined following the European LeukemiaNet (ELN) recommendations. Achievements of these optimal responses have not, however, been comprehensively tested as response-related prognostic factors using single center data sets. We evaluated the parameters using long-term (median 63 months) outcomes from 363 chronic phase chronic myeloid leukemia patients treated with imatinib as frontline therapy at our center. Intention-to-treat analysis showed comparable rates of complete cytogenetic response (86 %), major molecular response (MMR, 54 %), and complete molecular response (MR(4.5), 8 %). Estimated overall survival, progression-free survival, and event-free survival at 7 years were 94, 88 and 84 %, respectively. Achievement of recommended optimal response at 6 months (major cytogenetic response) and 12 months (complete cytogenetic response) yielded significantly better overall, progression-free, and event-free survival. However, achievement of recommended optimal response at 18 months (MMR) provided marginal benefit only in event-free survival. Most ELN criteria were predictive of long-term outcomes, with the exception of the clinical significance of achieving MMR at 18 months. Treatment adherence in the early treatment period was one of the important independent predictors of favorable long-term outcome. Durable cytogenetic and molecular responses were maintained in a majority of patients treated with optimal dose intensity.
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ABSTRACT: Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown preclinical and phase 1 activity and safety in chronic myeloid leukemia. This phase 2 study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase 1 trial. The primary endpoint was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative, 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related nonhematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4, 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (NCT01602952; ClinicalTrials.gov).Haematologica 04/2014; · 5.94 Impact Factor
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ABSTRACT: The introduction of tyrosine kinase inhibitors has dramatically improved outcomes for many patients with chronic myeloid leukemia (CML), but some cases are resistant to this treatment. To compare the prognostic performance of Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) scores, patient outcomes and treatment responses were investigated following the European LeukemiaNet (ELN) 2013 recommendations. Seventy-three patients with newly diagnosed chronic-phase CML (CML-CP) treated with any tyrosine kinase inhibitor as initial therapy were analyzed. All scoring systems significantly predicted treatment response at 3 and 6 months; however, only the EUTOS score significantly predicted treatment response at 12 months, following the ELN 2013 recommendations. The 5-year event-free survival rates were 93 and 35 % in the low- and high-risk groups according to the EUTOS score (P < 0.0001). Moreover, the 5-year overall survival rates were 98 and 51 % in the low- and high-risk groups by EUTOS score (P < 0.0001). We suggest that the EUTOS score may provide a better stratification of CML-CP patients for predicting treatment response.International Journal of Hematology 08/2014; · 1.68 Impact Factor
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ABSTRACT: Imatinib was the first signal transduction inhibitor (STI), used in a clinical setting. It prevents a BCR-ABL protein from exerting its role in the oncogenic pathway in chronic myeloid leukemia (CML). Imatinib directly inhibits the constitutive tyrosine kinase activity. Imatinib binds to BCR-ABL kinase domain by preventing the transfer of a phosphate group to tyrosine on the protein substrate and the subsequent activation of phosphorylated protein. As the result, the transmission of proliferative signals to the nucleus is blocked and leukemic cell apoptosis is induced. The FDA has approved imatinib as first-line treatment for newly diagnosed CML in December 2002 following an International Randomized Study (IRIS), initiated in June 2000, comparing imatinib at a single daily dose 400 mg to IFN alpha plus cytarabine in newly diagnosed patients with CML in CP. Results from this study show the outstanding effectiveness of imatinib and its superiority with respect to the rates of complete hematological response (CHR), major and complete cytogenetic response (MCyR, CCyR). Patients randomized to imatinib arm at 8 - year data cut off continue to have a durable hematologic and cytogenetic responses, low progression rates to AP or BC, and remarkable survival outcomes. An overall survival (OS) rate is 85% for patients receiving imatinib (93% when only CML-related deaths and those prior to stem cell transplantation are considered). The results have been confirmed in the last years by several groups. According these cumulative results the rates of CCyR achieved after one year of therapy with imatinib at standard dose ranged from 49% to 77%, and the proportion of patients who achieved major molecular response (MMR) after one year ranged between 18% and 58%. Discontinuation of imatinib has been also tried in patients in MMR, a molecular relapse occurs in about one third of patients, generally within 6 months from imatinib cessation.Mediterranean Journal of Hematology and Infectious Diseases 01/2014; 6(1):e2014007.