Pharmacologic Monitoring of Dasatinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CP-CML) Identifies Patients At Higher Risk of Pleural Effusion: A Sub-Analysis of the OPTIM-Dasatinib Trial
Bibliographic record
Abstract
Abstract Abstract 3770 Background: Second generation tyrosine kinase inhibitors such as dasatinib (Sprycel®, Bristol-Myers Squibb) induce significantly higher levels of cytogenetic and molecular responses than imatinib when given as frontline therapy for chronic phase chronic myelogenous leukemia (CP-CML) (DASISION trial, Kantarjian et al., NEJM 2010). Dasatinib is associated with the occurrence of pleural effusions (PE). The cumulative incidence of all grades PE in DASISION trial was reported to be 10% by 12 months and 14% by 24 months. Aims: To analyse efficacy of dasatinib first line and to test risk factors associated with the occurrence of PE. (EudraCT 2008–006854–17). Methods: Newly diagnosed CP-CML patients (pts) were assigned to dasatinib 100 mg/d. Dasatinib Cmin levels were assessed 24+/−2h after intake by tandem mass spectrometry after 2 weeks of therapy and every 3 months during 12 months thereafter. Pts with high Cmin values (Cmin ≥ 3 nM) at day 15 were randomized between dasatinib dose reduction or not. As the trial is still recruiting, the effect of randomization (treatment adaptation) was not analysed. For the purpose of this study, patients with at least 12 months follow-up were analysed for efficacy and all enrolled patients were analysed for safety. Molecular assessments were expressed as BCR-ABL/ABL (IS) in %. Results: Efficacy. In March 2012, 125 pts out of 191 pts enrolled in the trial had at least 12 months follow-up. Sokal scores were high for 18%, intermediate for 36% and low for 46% of pts. The median age was 52 (18–89) years. The rates of complete cytogenetic responses (CCyR) at 3, 6, and 12 months were 74%, 87%, and 97% respectively on evaluable samples, and 60%, 82%, and 95% when results were analysed according to the intention-to-treat principle taking into account missing values. The cumulative incidences of major molecular response (MMR) by 3, 6, 9 and 12 months were 21%, 46%, 56%, and 62% respectively. Of note 11 pts (9%) did not have a BCR-ABL (IS) ≤10% at 3 months. None of these patients reached a MMR by 12 months compared to a 68% (95% CI: 60–77) cumulative incidence of MMR in the other 114 pts. At 12 months, molecular response 4.5 (MR4.5) rate was 25%, including 80% of the pts with undetectable BCR-ABL transcript (sensitivity 4 to 5 log). Safety. 12 pts out of 191 (6.3%) presented a PE corresponding to a cumulative incidence of 9% by 24 months. 95 pts had at least one high Cmin value during the pharmacokinetic follow-up and 10 pts developed PE as compared to 2 out of the 96 remaining pts (p= 0.018). Cumulative incidence of PE by 24 months was 13.4% in high Cmin group as compared to 4.8% in low Cmin group (p=0.04). We next analysed whether the measurement of dasatinib Cmin at day 15 could predict the risk to develop a PE. Fifty pts (26%) had a high Cmin value at day 15 (group A) and 141 had a low Cmin (group B). The cumulative incidence of PE by 24 months was 17.4% in group A compared to 6.9% in group B (p=0.021) (fig 1). We next search for clinical factors influencing Cmin value at day15 of dasatinib 100 mg/d. Median Cmin values were significantly higher in patients aged 50 and over as compared to younger patients (2.5 nM versus 1.6 nM, p=0.0032). As expected, age 50 and over was also associated with an increased risk of pleural effusion. Conclusion: Current data demonstrate efficacy of dasatinib 100 mg/d similar or even better to that reported in other frontline trials such as the DASISION trial. We provide evidences suggesting that a high Cmin (>3nM) at day 15 and/or age 50 and over identify patients treated with dasatinib 100 mg/d with a high risk of PE. The benefit of dasatinib dose reduction is randomly tested for this group of patients in the OPTIM-Dasatinib trial and may be a major issue in elderly patients. Disclosures: Rousselot: BMS, Novartis: Research Funding. Nicolini:BMS, Novartis: Consultancy, Research Funding. Coiteux:Novartis, BMS: Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Roy:Novartis, BMS: Speakers Bureau. Dartigeas:Roche: Consultancy. Guilhot:ARIAD: Honoraria. Mahon:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy.
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".