Originally published as JCO Early Release 10.1200/JCO.2008.20.1533 on June 8 2009

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Prospective Minimal Residual Disease Monitoring to Predict Relapse of Acute Promyelocytic Leukemia and to Direct Pre-Emptive Arsenic Trioxide Therapy

From the Department of Medical and Molecular Genetics, King's College London School of Medicine; UCL Cancer Institute, University College London; Blood Sciences; Molecular Oncology Diagnostics Unit, Guy's and St Thomas' National Health Service Foundation Trust London, London; Department of Haematology, Royal Liverpool University Hospital, Liverpool; Birmingham Clinical Trials Unit, Birmingham; and Department of Haematology, University of Wales, Cardiff, United Kingdom; Department of Cellular Biotechnology and Haematology, University La Sapienza; and Department of Biopathology, University Tor Vergata, Rome, Italy.

Corresponding author: David Grimwade, MD, Dept of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, United Kingdom; e-mail: david.grimwade{at}genetics.kcl.ac.uk.

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.

Written on behalf of the National Cancer Research Institute Adult Acute Myeloid Leukaemia Working Group.

Supported by Grants No. 9804, 0153, and 04036 from Leukaemia Research, Great Britain (D.G., E.A.N., D.D., R.F., and J.V.J.); Special Trustees of Guy's Hospital and Cell Therapeutics; Grant No. LSHC-CT-2004-503216 from the European LeukemiaNet (D.G., J.V.J., and A.K.B.); Ministero della Salute (Progetto Integrato Oncologia) and Associazione Italiana per la Ricerca sul Cancro (F.L-C.).

The funding agencies played no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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