ABSTRACT
BACKGROUND: In this study we aimed to evaluate appropriate time points for mutation analysis of chronic myeloid leukemia. PATIENTS AND METHODS: In total, 961 blood samples obtained from 605 chronic-phase chronic myeloid leukemia patients treated with imatinib were subjected to Sanger sequencing to detect BCR-ABL1 mutations. Mutation frequencies at landmark time points (3, 6, and 12 months) were assessed with 16 landmark responses defined by European LeukemiaNet and 2 additional responses, including a complete hematologic response (CHR) at 3 months and a complete cytogenetic response (CCyR) at 12 months. RESULTS: After 12 months of imatinib treatment of 605 patients, 28 (4.6%) patients harbored 33 mutations, including 23 (69.7%) highly resistant T315I and P-loop mutations. Sequencing data from 650 samples were compared with cytogenetic responses. The mutation frequencies in optimal, warning, and failure groups were 0.5% (2/430), 1.8% (2/110), and 19.1% (21/110), respectively. The molecular response was assessed using 956 samples, and the mutation frequencies were 0.7% (3/425), 3.4% (12/358), and 7.6% (14/173) for the optimal, warning, and failure groups, respectively. For the 2 additional responses, the mutation frequencies in patients with CHR at 3 months and with CCyR at 12 months were 0% (0/160) and 1.7% (4/242), respectively. Overall, mutations were frequently detected at 3-month cytogenetic failure (25.0%), 12-month cytogenetic failure (23.2%), and 6-month cytogenetic failure (10.5%) using response-mutation association analysis. CONCLUSION: Irrespective of mutation frequency, failure of achievement of a cytogenetic response should be conducted with appropriate mutation analysis.
Subject(s)
Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mutation , Protein Interaction Domains and Motifs , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Child , Cytogenetic Analysis , Female , Fusion Proteins, bcr-abl/chemistry , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Male , Middle Aged , Young AdultABSTRACT
The present study aimed to assess the clinical impact of BCR-ABL1 transcript levels determined at an earlier time point than the 3-month early molecular response (EMR) in chronic-phase chronic myeloid leukemia (CML-CP) patients. BCR-ABL1 transcript levels of CML-CP patients (n = 258; median age, 43 [range, 18-81] years) treated with various tyrosine kinase inhibitors (TKIs) were determined at 4 weeks (28 ± 3 days) and at every 3 months of treatment initiation. At 4 weeks, receiver operating characteristic curves revealed that cutoff values of BCR-ABL1 transcripts for achieving major molecular responses (MMRs) by 12 and 60 months were 40.89% and 39.16%, respectively (95% CI, 0.658-0.772 and 95% CI, 0.643-0.758; P < 0.0001). With 40% of BCR-ABL1 transcripts at 4 weeks (very early MR; VEMR), patients with VEMR achieved higher 3-month EMR and 4-week VEMR significantly associated with higher cumulative incidences of 5-year MMR (89.1% vs 72.3%; P < 0.001) and 5-year deep molecular response (DMR) (56.5% vs 29.4%; P = 0.001). Furthermore, event-free survival (EFS)-a (93.0% vs 84.8%; P = 0.068) and EFS-b (71.1% vs 57.9%; P = 0.061) by 5 years were also marginally significant. VEMR and 3-month EMR were achieved in 89 patients, with significantly superior outcomes. In multivariate analyses, lower leukocyte count (P = 0.008) and frontline second-generation TKI therapy size (P < 0.001) were significantly associated with VEMR achievement, but not baseline BCR-ABL1 level and CML duration. In conclusion, the 4-week BCR-ABL1 transcript levels including VEMR could be important to predict long-term outcomes and may provide additional information about innate intrinsic sensitivity to CML among individuals.
Subject(s)
Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/administration & dosage , Adult , Aged , Aged, 80 and over , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukocyte Count , Male , Middle Aged , Prognosis , Protein Kinase Inhibitors/pharmacology , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
BACKGROUND/AIMS: The aim of this study was to identify the role of BCR-ABL1 transcript level as a predictor for post-transplant relapse and outcome in patients who underwent allogeneic stem cell transplantation (SCT) for chronic phase (CP) chronic myeloid leukemia (CML). METHODS: Of 101 patients receiving allograft in CML CP, 85 had available quantitative reverse transcriptase polymerase chain reaction data at post-transplant 3 months. These patients were divided into two groups according to molecular response (MR4.5), defined as a BCR-ABL1 transcript level ≤ 0.0032% on the international scale, at 3 months based on receiver operating characteristic curve analysis of relapse. RESULTS: The 4-year overall survival and event-free survival (EFS) were 80.6% and 57.3%, respectively, and the cumulative incidence of relapse at 4 years was 29.6% after a median follow-up of 126.4 months. We performed multivariate analyses including potential variables to evaluate the early predictive role of MR4.5 at 3 months and found that MR4.5 at 3 months was associated with a higher EFS (p = 0.028) and showed a trend for a lower relapse rate (p = 0.089). CONCLUSIONS: our results imply that frequent molecular monitoring and immune suppressive therapy modulation are required for patients without reduction of BCR-ABL1 transcripts to this level after SCT.
Subject(s)
Biomarkers, Tumor/genetics , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/surgery , Stem Cell Transplantation , Adolescent , Adult , Area Under Curve , Disease-Free Survival , Drug Therapy, Combination , Female , Graft vs Host Disease/etiology , Humans , Immunosuppressive Agents/therapeutic use , Kaplan-Meier Estimate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Male , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Proportional Hazards Models , ROC Curve , Recurrence , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors , Stem Cell Transplantation/adverse effects , Stem Cell Transplantation/mortality , Time Factors , Transplantation, Homologous , Treatment Outcome , Young AdultABSTRACT
To explore the factors for achieving early molecular responses (EMR; BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months) by imatinib (IM), baseline characteristics including individual BCR-ABL1 transcript level, dose intensity, and IM trough level on day 29 were analyzed in 286 chronic phase chronic myeloid leukemia patients. Distinct predictive factors for achieving EMR at 3 months and 6 months were noted. Blast count at diagnosis and IM trough level on day 29 were significantly associated with an achievement of 3-month EMR. Early decline of BCR-ABL1 transcript, low Sokal risk, and mean daily dose (≥350mg/day) by 6 months were associated with an achievement of 6-month EMR. Understanding the predictive factors for EMR may provide additional information to guide clinical decisions on the changing therapies at each landmark.
