Abstract A135: Evaluation of CPX-351 (cytarabine:daunorubicin) liposome injection efficacy in acute lymphoblastic leukemia (ALL) xenograft models
Bibliographic record
Abstract
Abstract CPX-351 is a liposome formulation of cytarabine (Cyt) and daunorubicin (Daun) in which the ratio of the two drugs (5:1, mol:mol) maximizes synergy. The marked increase in efficacy observed for CPX-351 vs the free drug cocktail is associated with passive targeting of the synergistic drug ratio to bone marrow where drug-loaded liposomes are preferentially taken up by leukemia cells. Clinical testing of CPX-351 to date has focused on acute myelogenous leukemia (AML), however significant antileukemic activity may also be achievable against ALL. Investigations were undertaken by the Pediatric Preclinical Testing Program (PPTP) of the NCI to provide evidence for CPX-351 treatment-related antileukemic activity against representative pediatric ALL xenograft models. The maximum tolerated dose (MTD) of CPX-351 was established by i.v. dose escalation in non-engrafted NOD/SCID mice with a q2dx3 schedule. Leukemia engraftment was established by i.v. inoculation of either ALL-4 (B-precursor) or ALL-8 (T-lineage) cells into NOD/SCID mice. Drug or vehicle buffer (control) treatment was initiated when the %huCD45+ cells in the peripheral blood was greater than 1% for each cohort. An experimental end-point for each mouse was attained when either the %huCD45+ was greater-than or equal to 25% (an event) or if the mouse reached day 42 without an event. Two measures of antitumor activity were used: 1) an objective response measure (ORM) modeled after the clinical setting; and 2) a time to event measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. Non-engrafted NOD/SCID mice exhibited increased sensitivity to CPX-351 with a corresponding MTD that was roughly 50% of that observed in immune competent mice. Treatment with CPX-351, at a Cyt:Daun dose of 5 units/kg (5 mg/kg Cyt + 2.2 mg/kg Daun), was very effective and yielded objective responses in all evaluable leukemia-bearing mice in both leukemia models. In the ALL-4 model, treatment with CPX-351 induced a median event-free survival (EFS) of 31.0 days (6.8 days for control), which corresponded to a leukemia growth delay (LGD) of 24.2 days (p<0.0001 by logrank test) and resulted in a median ORM score of CR (4CR/3PR). Similar results were obtained in the ALL-8 leukemia model with a median EFS of 32.8 days (10.8 days for controls) and a LGD of 22.0 days (p<0.0001 by logrank test) which resulted in a median ORM score of PR (4PR/3CR). Comparison of drug concentrations observed in the plasma of mice and AML patients after CPX-351 treatment revealed comparable drug exposure in these two settings. CPX-351 exhibits potent antileukemic activity against both a B-cell and T-cell ALL xenograft model at doses that provide clinically relevant plasma drug exposure. Thus, CPX-351 may warrant consideration as a treatment candidate for ALL. (Supported by NCI NO1CM42216) Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A135.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.001 |
| 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".