Evaluation of CPX-351 (cytarabine:daunorubicin) Liposome Injection Anti-Leukemic Activity Against Primary Patient Leukemia Cells
Bibliographic record
Abstract
Abstract Abstract 2886 Background: 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 versus the free drug cocktail is associated with targeting of the synergistic drug ratio to bone marrow where drug-loaded liposomes are preferentially taken up by leukemia cells, resulting in leukemia selective cytotoxicity. Clinical testing of CPX-351 to date has focused on acute myeloid leukemia (AML), however significant anti-leukemic activity may also be achievable against other leukemia diagnoses. Investigations were undertaken to examine the relative cytotoxic potency of CPX-351 against a panel of fresh samples obtained from patients with chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and AML as well as select other rare myeloid and lymphoid malignancies. Cytotoxicity results were correlated with patient characteristics including response to chemotherapy, patient age, white blood cell count, blast percentage, disease status, malignant cell immunophenotype, cytogenetics, and known molecular lesions as well as diagnosis-specific criteria such as FAB status, risk stratification, and Rai stage. Additionally, CPX-351 uptake was measured in selected leukemia cell samples. Methods: Peripheral blood or bone marrow was obtained from patients with a variety of leukemia diagnoses. White blood cells were isolated on Ficoll gradients followed by red cell lysis. Cells were incubated in 96-well plates over graded concentrations of CPX-351 (ranging from 10/2 nM to 10,000/2,000 nM) for 3 days at which time cell viability was assessed by subjecting cells to a tetrazolium-based cell viability assay (MTS). All cell viability values were normalized to untreated cells from the same patient. Based on the cell viability curve for each subject, a patient-specific IC50 was calculated and correlated with clinically-relevant features of each patient's disease. Finally, uptake of CPX-351 into leukemia cells was evaluated in select samples by assessment of daunorubicin cellular fluorescence. Result: As of July 31, 2010, CPX-351 cytotoxicity was evaluated in 35 patient specimens, comprising a wide variety of diagnoses, including AML (11), CML-BC (1), CMML (2), Hemophagocytic Syndrome (1), ALL (3), Burkitt's Leukemia (1), and CLL (16). A broad range of IC50 values were observed within each diagnosis examined (50/10 nM – 4,000/800 nM). Notably, initial results indicated potent cytotoxicity of CPX-351 against a broad range of leukemia diagnoses, and CPX-351 efficacy was observed in some patients exhibiting clinical features typically associated with disease that is recalcitrant to other forms of therapy. The data establish a rationale for clinical testing of CPX-351 in a broader diversity of leukemia diagnoses. Conclusions: CPX-351 exhibits potent anti-leukemic activity against a wide range of leukemia cell types and continuation of this form of in vitro screening may help to identify specific patient populations most likely to benefit from clinical administration of CPX-351. Combining such in vitro cytotoxicity information with other forms of phenotypic and/or genomic data may also reveal biomarkers that are predictive of response to CPX-351 therapy. In sum, CPX-351 is suggested as a potent anti-leukemic agent for a wide diversity of leukemia diagnoses. Disclosures: Tardi: Celator Pharmaceuticals: Employment, Equity Ownership. Mayer:Celator Pharmaceuticals: Employment, Equity Ownership. Kovacsovics:Celator Pharmaceuticals: Research Funding. Loriaux:Celator Pharmaceuticals: Research Funding.
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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) | 0.000 | 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".