The Predictive Value of Intracellular Imatinib Levels in Chronic Myeloid Leukemia
Bibliographic record
Abstract
Abstract Background: Plasma levels of imatinib have been shown to be predictive of disease response in chronic phase chronic myeloid leukemia (CML). However, the ultimate site of action of imatinib is intracellular. While intracellular imatinib has been reported to be correlated with plasma imatinib, the use of intracellular imatinib for the prediction of clinical outcomes is unclear. The concentration of intracellular imatinib depends on many factors including the level of alpha-1-acid glycoprotein, which binds to imatinib and prevents intracellular uptake, and the OCT-1 transporter, which mediates the influx of imatinib across the plasma membrane of leukemic cells. We conducted the present study of newly diagnosed CML patients with the primary objective of determining if intracellular levels of imatinib two weeks after treatment initiation predicted major molecular response. The secondary objectives were to elucidate the relationships between the levels of OCT-1 and plasma imatinib with intracellular imatinib. Methods: We prospectively studied newly diagnosed chronic phase CML patients in Canada who were treated with standard dose imatinib (400 mg). We measured both intracellular and extracellular (plasma) levels of imatinib by tandem mass spectrometry at two weeks, four weeks, and twelve months after enrollment. Additionally, we measured transcript levels of OCT-1 and BCR-Abl by q-rt-PCR before treatment, at six months, and at twelve months to determine therapeutic response. Results: Eighty-one patients were screened. A total of 76 patients entered the study, and 55 completed the study per protocol. Patient information is shown in Table 1. There was a significant correlation between intracellular imatinib levels at two weeks and a 2-log reduction of BCR-Abl transcript at six months (r=0.390; 95% CI = 0.136 - 0.595; p = 0.004) (Figure 1), but not at twelve months (r=0.183; 95% CI = -0.094 - 0.434; p = 0.194). Notably, intracellular imatinib levels and plasma levels of imatinib were highly correlated at two weeks (r=0.698; 95% CI = 0.559-0.799; p <0.001) and four weeks (0.699; 95% CI = 0.555 - 0.802; p < 0.001) but not between four weeks and twelve months (r= 0.230; 95% CI = -0.040 - 0.469; p = 0.094). There was no correlation between intracellular imatinib levels at two weeks and the pre-treatment OCT-1 transcript level (r=0.072; 95% CI = -0.166 to 0.301; p =0.556). Conclusions: Intracellular imatinib levels at two weeks was moderately predictive of a disease response at six months as indicated by a 2-log reduction in BCR-Abl transcript. OCT-1 transcript levels did not have utility for predicting intracellular imatinib levels. Measurement of intracellular Imatinib levels may prove to have utility in identifying patients who would benefit from adjustments to therapy. Disclosures Hillis: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Busque:Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy; BMS: Consultancy. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".