Presence of Prior-to-Treatment BCR-ABL Mutations In CD34+CD38- Stem Cells of Newly Diagnosed Chronic Phase CML Patients and Their Correlation with Imatinib Resistance: Implications of Cancer Pharmacogenomics and Pre-Therapeutic Genetic Testing In Personalized Treatment of BCR-ABL+ Leukemia
Bibliographic record
Abstract
Abstract Abstract 2278 Introduction: BCR-ABL oncogene makes leukemic cells unstable, leading to mutations in BCR-ABL itself as well as other genes1. Studies have shown that prior-to-treatment BCR-ABL mutations do exist in CD34+CD38- (primitive) CML cells2, a population with stem cell like properties responsible for disease persistence, Imatinib (IM) resistance and relapses3. There are also reports regarding association of such pre-existing BCR-ABL mutations (PEM) and Imatinib resistance4. Therefore, the objective of this study was to find BCR-ABL PEM in CD34+38- cells from newly diagnosed CML patients and their correlation with IM resistance. Methods: CD34+CD38- cells from 100 newly diagnosed, untreated, chronic-phase Ph+ CML patients were analyzed for PEM using multiplex allele specific (AS) PCR5 and sequencing AS-PCR products. All of the patients resistant to IM (400mg/day), irrespective of their PEM status, were analyzed by multiplex AS-PCR and DNA sequencing5 for post-therapeutic BCR-ABL mutations, to see if PEM persist in IM resistant patients. T-test was applied to see any significant difference with respect to IM resistance between IM resistant patients with PEM (Group1) and without PEM (Group2). Results & Discussion: Thirty two out of 100 patients showed at least one PEM (Table 1, Figure 1). During a follow-up of 12–18 months, all patients with PEM manifested IM resistance (32/32,100%). On the other hand, 24/68 patients without PEM manifested IM resistance (35.3%). This shows a significant difference between two groups of patients with respect to IM resistance (100% vs. 35.3%, p=<0.01). On mutational analysis of IM resistant patients, those with PEM persisted with same mutations present before treatment (32/32=100%) while only 21/24 patients manifesting acquired IM resistance (87.5%) harbored BCR-ABL mutations (Table 1). In IM resistant patients, we detected mutations F311V, M351T, Y253F and T315I. All IM resistant patients except with T315I and Y253F showed completed hematological and cytogenetic responses to Imatinib dose escalation (600-800mg/day) or Nilotinib. Our results are in accordance with previous reports3-5. On the basis of this study, it is concluded that BCR-ABL PEM are present in primitive, innately resistant CD34+38- stem cells from a considerable number of CML patients before start of the therapy. This cell population proliferates under selective pressure of the drug to become major cell population, leading to resistant to tyrosine kinase inhibitors like Imatinib and Nilotinib. Therefore, we recommend testing of BCR-ABL mutations in CML stem cell population before start of TKI treatment using sensitive, validated techniques like ASO-PCR and DHPLC, and utilization of this mutation data in clinical management, hence in patient-tailored treatment. References: Disclosures: No relevant conflicts of interest to declare.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.000 | 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".