Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy
| Autor: | Kristian Rennie, Keith Wheatley, David Grimwade, Daniela Diverio, Robert Kerrin Hills, Richard E. Clark, Hannah Aslett, Katy Jones, Francesca Lo-Coco, Ellen Solomon, Roger Angell, Alan Kenneth Burnett, E. Nugent, Jelena V. Jovanovic, Yashma Patel, Rajinder Flora, Elaine Batson |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Oncology Cancer Research Neoplasm Residual Oncogene Proteins Fusion trans-retinoic acid adult patients Severity of Illness Index Arsenicals Cohort Studies Arsenic Trioxide Leukemia Promyelocytic Acute fusion gene transcripts Bone Marrow Medicine Cumulative incidence Prospective Studies Acute leukemia Reverse Transcriptase Polymerase Chain Reaction Hazard ratio time rt-pcr Oxides Middle Aged Prognosis Gene Expression Regulation Neoplastic Leukemia Treatment Outcome Female acute myeloid-leukemia Adult Acute promyelocytic leukemia medicine.medical_specialty Tretinoin polymerase-chain-reaction Settore MED/36 - Diagnostica per Immagini e Radioterapia Predictive Value of Tests Internal medicine quantitative pcr Confidence Intervals Humans Clinical significance major molecular responses Aged Monitoring Physiologic Probability Proportional Hazards Models acute lymphoblastic-leukemia clinical-significance business.industry Cancer medicine.disease Survival Analysis Minimal residual disease Surgery Multivariate Analysis Neoplasm Recurrence Local business Blood Chemical Analysis |
| Popis: | Purpose Molecular diagnostics and early assessment of treatment response that use methodologies capable of detecting submicroscopic disease can distinguish subgroups of patients with leukemia at differing relapse risk. Such information is being incorporated into risk-stratified protocols; however, there are few data concerning prospective use of sequential minimal residual disease (MRD) monitoring to identify more precisely those patients destined to experience relapse, which would allow more tailored therapies. Methods Real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts (ie, PML-RARA, RARA-PML) were used to prospectively analyze 6,727 serial blood and marrow samples from 406 patients with newly diagnosed acute promyelocytic leukemia (APL) who were receiving all-trans-retinoic acid and anthracycline-based chemotherapy. Results MRD monitoring according to the recommended schedule successfully identified the majority of patients subject to relapse and provided the most powerful predictor of relapse-free survival (RFS) in multivariable analysis (hazard ratio, 17.87; 95% CI, 6.88 to 46.41; P < .0001); MRD monitoring was far superior to presenting WBC (hazard ratio, 1.02; 95% CI, 1.00 to 1.03; P = .02), which is currently widely used to guide therapy. In patients who were predicted to experience relapse on the basis of MRD monitoring, early treatment intervention with arsenic trioxide prevented progression to overt relapse in the majority, and the RFS rate at 1 year from molecular relapse was 73%. By using this strategy, 3-year cumulative incidence of clinical relapse was only 5% in the Medical Research Council AML15 trial. Conclusion Rigorous sequential RQ-PCR monitoring provides the strongest predictor of RFS in APL and, when coupled with pre-emptive therapy, provides a valid strategy to reduce rates of clinical relapse. This provides a model for development of a more individualized approach to management of other molecularly defined subtypes of acute leukemia. |
| Databáze: | OpenAIRE |
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