Lack of Inhibition of AKT Predicts Clinical Resistance to Therapy with Imatinib + Reinduction Chemotherapy in Relapsed/Refractory c-Kit+ Acute Myeloid Leukemia.
Bibliographic record
Abstract
Abstract Abstract 2073 Poster Board II-50 Patients age 18-65 with acute myeloid leukemia (AML) who had persistent leukemia after 3+7 induction with cytarabine and daunorubicin, or relapsed within 24 months of achieving CR, and whose blasts were c-kit (CD117) positive, were enrolled in a phase I/II clinical trial with imatinib on Days 1-10 combined with mitoxantrone 10 mg/m2/day IV Days 4-8, etoposide 100 mg/m2/day IV Days 4-8 and cytarabine 1.5 g/m2 IV q12h × 4 doses on Days 9-10. Imatinib was escalated through 3 dose levels (200, 300, 400 mg daily) in successive 6 patient cohorts. The combination was well-tolerated up to 400 mg/day imatinib, and an additional 15 patients were enrolled at this dose level. Of the 21 patients treated at the 400 mg imatinib dose, 13 (62 %) achieved CR, 7 (33 %) were non-responders, and one died during reinduction. The CR rate was 82% (9/11) among patients with standard risk AML karyotpye, compared to 33% (3/9) for patients with adverse risk karyotype. The CR rate for primary 3+7 non-responders was 6/14 (43%) vs. 7/7 (100%) for relapsed patients. For 14 patients on the Phase II portion of the study, AML blasts from peripheral blood were assayed for pAKT and pERK by flow cytometry, after stimulation with stem cell factor, on Days 1 and 4, pre- and 1 and 2 hours post-imatinib dosing on each day. A heterogeneous response pattern was seen, with some samples exhibiting marked inhibition of pAKT and/or pERK after imatinib therapy, while others demonstrated little change in levels. Of 8 patients achieving CR with re-induction, 6 demonstrated marked (>50%) pAKT inhibition with imatinib therapy, 1 showed no inhibition, while 1 showed intermediate levels of inhibition. In contrast, all 6 non-responders to re-induction demonstrated a lack of pAKT inhibition with imatinib therapy (p<0.01). Of 5 patients with adverse risk karyotype, 4 demonstrated lack of pAKT inhibition with imatinib therapy and none of these responded to re-induction; the remaining patient whose blasts demonstrated pAKT sensitivity to imatinib did achieve CR with re-induction. In contrast pERK inhibition did not correlate with response to therapy. These results indicate that lack of pAKT inhibition in vivo correlates with resistance to re-induction therapy using this regimen. Further studies using agents that are able to inhibit AKT more effectively are warranted to try to overcome drug resistance in this setting. The treatment regimen appears active in relapsed patients, but this requires confirmation in a larger series. Disclosures: Off Label Use: Imatinib for c-kit positive AML.
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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) | 0.002 | 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".