Mutations in ABL kinase domain are associated with inferior progression-free survival
Bibliographic record
Abstract
Imatinib mesylate is currently the drug of choice for all phases of chronic myeloid leukemia (CML). Despite the initial high rates of hematological and cytogenetic responses, many patients develop resistance. We prospectively studied 40 patients with CML with primary cytogenetic resistance to imatinib mesylate. A semi-nested reverse transcriptase-PCR approach was used for amplification of the ABL kinase domain, which was then subjected to direct sequencing for the detection of point mutations. Expression of BCR-ABL transcripts was quantified using the real-time Taqman assay, and BCR-ABL gene amplification was detected using fluorescence in situ hybridization. Twelve different point mutations were detected in 18/40 (45%) patients. Five patients had mutations in the P-loop region and 13 had mutations in other regions of the BCR-ABL kinase domain. Progression-free survival at 2 years was inferior for patients with mutations compared to those without mutations (72% vs. 95%, p < 0.0045). The BCR-ABL fusion gene was over-expressed in five patients (5/18); the mean BCR-ABL/ABL ratio was 75.38 vs. 28.72 for imatinib responders, p < 0.001. Amplification of the BCR-ABL fusion gene was detected in 4/40 (10%) patients. Point mutation was the major mechanism of primary cytogenetic resistance to imatinib mesylate in the present study. Patients with mutations had inferior progression-free survival compared to those without mutations. Regular monitoring for the presence of point mutations in the ABL kinase region may identify such patients early, with an opportunity to intervene.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".