Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial
Abstract
The optimum chemotherapy schedule for reinduction of patients with high-risk acute myeloid leukemia (relapsed, resistant/refractory, or adverse genetic disease) is uncertain. The MRC AML (Medical Research Council Acute Myeloid Leukemia) Working Group designed a trial comparing fludarabine and high-dose cytosine (FLA) with standard chemotherapy comprising cytosine arabinoside, daunorubicin, and etoposide (ADE). Patients were also randomly assigned to receive filgrastim (G-CSF) from day 0 until neutrophil count was greater than 0.5 × 109/L (or for a maximum of 28 days) and all-trans retinoic acid (ATRA) for 90 days. Between 1998 and 2003, 405 patients were entered: 250 were randomly assigned between FLA and ADE; 356 to G-CSF versus no G-CSF; 362 to ATRA versus no ATRA. The complete remission rate was 61% with 4-year disease-free survival of 29%. There were no significant differences in the CR rate, deaths in CR, relapse rate, or DFS between ADE and FLA, although survival at 4 years was worse with FLA (16% versus 27%, P = .05). Neither the addition of ATRA nor G-CSF demonstrated any differences in the CR rate, relapse rate, DFS, or overall survival between the groups. In conclusion these findings indicate that FLA may be inferior to standard chemotherapy in high-risk AML and that the outcome is not improved with the addition of either G-CSF or ATRA.
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The efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor.
“After decades of studies, the efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor.”
From Unlocking the potential of retinoic acid in anticancer therapy (2014) · cites this paper as Milligan et al, 2006
Other phase 2 studies showed no or non-significant effects of ATRA in non-APL AML.
“However, other phase 2 studies showed no or non-significant effects (Milligan et al, 2006; Burnett et al, 2007).”
From Unlocking the potential of retinoic acid in anticancer therapy (2014) · cites this paper as Milligan et al, 2006
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- Authors
- Milligan, D. W., Wheatley, K., Littlewood, T., Craig, J. I. O., Burnett, A. K., & for the NCRI Haematological Oncology Clinical Studies Group
- Affiliations
- John Radcliffe Hospital (GB)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-06-15
- Volume
- 107
- Issue
- 12
- Pages
- 4614-4622
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1984229644
- Cited by
- 141
- References
- 49
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 4 · 2021: 10 · 2020: 5 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 11 · 2015: 10 · 2014: 7 · 2013: 8 · 2012: 8
- FWCI
- 5.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- high-risk acute myeloid leukemia, fludarabine, cytarabine, daunorubicin, etoposide, filgrastim, granulocyte colony-stimulating factor, all-trans retinoic acid, reinduction chemotherapy, complete remission, disease-free survival, relapse
- MeSH terms
- Filgrastim, Adolescent, Adult, Aged, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Cytarabine, Daunorubicin, Etoposide, Female, Humans, Male, Middle Aged, Recombinant Proteins, Remission Induction, Retrospective Studies, Risk Factors, Tretinoin, Leukemia, Myeloid, Acute, Survival Rate, Granulocyte Colony-Stimulating Factor, Treatment Outcome, Disease-Free Survival
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