Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy

David Grimwade, Jelena V. Jovanovic, Robert K. Hills, Elizabeth A. Nugent, Yashma Patel, Rajinder Flora, Daniela Diverio, Katy Jones, Hannah Aslett, Elaine Batson, Kristian Rennie, Roger Angell, Richard E. Clark, Ellen Solomon, Francesco Lo-Coco, Keith Wheatley, Alan K. Burnett

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)3650-3658
Number of pages9
JournalJournal of Clinical Oncology
Volume27
Issue number22
DOIs
Publication statusPublished - Aug 1 2009

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Acute Promyelocytic Leukemia
Residual Neoplasm
Recurrence
Therapeutics
Leukemia
Real-Time Polymerase Chain Reaction
arsenic trioxide
Survival
Molecular Pathology
Anthracyclines
Tretinoin
Biomedical Research
Appointments and Schedules
Survival Rate
Bone Marrow

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. / Grimwade, David; Jovanovic, Jelena V.; Hills, Robert K.; Nugent, Elizabeth A.; Patel, Yashma; Flora, Rajinder; Diverio, Daniela; Jones, Katy; Aslett, Hannah; Batson, Elaine; Rennie, Kristian; Angell, Roger; Clark, Richard E.; Solomon, Ellen; Lo-Coco, Francesco; Wheatley, Keith; Burnett, Alan K.

In: Journal of Clinical Oncology, Vol. 27, No. 22, 01.08.2009, p. 3650-3658.

Research output: Contribution to journalArticle

Grimwade, D, Jovanovic, JV, Hills, RK, Nugent, EA, Patel, Y, Flora, R, Diverio, D, Jones, K, Aslett, H, Batson, E, Rennie, K, Angell, R, Clark, RE, Solomon, E, Lo-Coco, F, Wheatley, K & Burnett, AK 2009, 'Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy', Journal of Clinical Oncology, vol. 27, no. 22, pp. 3650-3658. https://doi.org/10.1200/JCO.2008.20.1533
Grimwade, David ; Jovanovic, Jelena V. ; Hills, Robert K. ; Nugent, Elizabeth A. ; Patel, Yashma ; Flora, Rajinder ; Diverio, Daniela ; Jones, Katy ; Aslett, Hannah ; Batson, Elaine ; Rennie, Kristian ; Angell, Roger ; Clark, Richard E. ; Solomon, Ellen ; Lo-Coco, Francesco ; Wheatley, Keith ; Burnett, Alan K. / Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 22. pp. 3650-3658.
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abstract = "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.",
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T1 - Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy

AU - Grimwade, David

AU - Jovanovic, Jelena V.

AU - Hills, Robert K.

AU - Nugent, Elizabeth A.

AU - Patel, Yashma

AU - Flora, Rajinder

AU - Diverio, Daniela

AU - Jones, Katy

AU - Aslett, Hannah

AU - Batson, Elaine

AU - Rennie, Kristian

AU - Angell, Roger

AU - Clark, Richard E.

AU - Solomon, Ellen

AU - Lo-Coco, Francesco

AU - Wheatley, Keith

AU - Burnett, Alan K.

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N2 - 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.

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