Abstract 287: CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes
Bibliographic record
Abstract
Abstract Background: CPX-351, a synergistic ratio of cytarabine (Cyt) and daunorubicin (Daun) co-encapsulated in a nano-scale carrier, has demonstrated improved complete remission and overall survival rates compared to conventional Cyt + anthracycline treatments in two randomized clinical trials and is currently being evaluated in a Phase 3 trial vs 7+3 Cyt:Daun. To determine whether these effects are attributable to liposome-mediated altered drug PK or specific AML blast genotypes/phenotypes, we investigated the ex vivo cytotoxic potency of CPX-351 against fresh AML blast samples. Cytotoxicity results were correlated with patient characteristics as well as CPX-351 cellular uptake and molecular phenotype status including FLT3-ITD, NPM1 and CEBPα. Methods: Peripheral blood was obtained at diagnosis from patients with AML. White blood cells were isolated on Ficoll gradients. Cells were incubated over graded concentrations of CPX-351 for 72 hr at which time cell viability was assessed by MTS assay. Cell viability values were normalized to patient-matched untreated cells. Patient-specific IC50 values were calculated and correlated with clinically-relevant disease features. Uptake of intact CPX-351 liposomes by AML cells was determined by monitoring cells for daunorubicin fluorescence by flow cytometry. Results: CPX-351 cytotoxicity was evaluated in 53 AML patient specimens. CPX-351 IC50 values ranged from 0.03:0.006 uM to 10:2 uM (Cyt:Daun), and all values were significantly lower than the 72 hour plasma drug concentration of 60:12 uM Cyt:Daun observed in patients receiving CPX-351. Sensitivity to CPX-351 was similar regardless of cytogentic risk, NPM1 and CEBPα status as well as whether the patients went on to achieve a CR or PD upon receiving standard 7+3 Cyt:Daun after blast samples were taken. Surprisingly, AML blasts exhibiting the FLT3-ITD phenotype exhibited some of the lowest IC50 values and as a group were 5-fold more sensitive to CPX-351 than those with wild type FLT3. Flow cytometric analysis revealed a correlation between uptake of CPX-351 into AML blasts and its cytotoxic potency. Taken together, the data are consistent with clinical observations where CPX-351 retains significant anti-leukemic activity in AML patients exhibiting high-risk characteristics that are typically associated with poor outcomes when treated with conventional regimens. Conclusions: The profile of ex vivo AML blast sensitivity to CPX-351 mirrors the efficacy profile observed clinically and may provide a means to identify specific AML patient genotypes/phenotypes that could benefit most from CPX-351 treatment. The increased sensitivity of FLT3-ITD+ blasts to CPX-351 is an example of how such analyses may identify additional AML patient populations warranting further clinical investigation. Citation Format: Max Gordon, Paul Tardi, Lawrence D. Mayer, Jeffrey Tyner. CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 287.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| 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) | 0.003 | 0.001 |
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".