Originally published as JCO Early Release 10.1200/JCO.2008.19.4894 on December 15 2008

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In Reply

Jude Fitzgibbon

Centre for Medical Oncology, Barts and The London School of Medicine, London, United Kingdom

Rosemary Gale

Department of Haematology, University College London, London, United Kingdom

Robert Hills

Department of Haematology, University of Wales College of Medicine, Cardiff University, Cardiff, United Kingdom

Priya Virappane

Centre for Medical Oncology, Barts and The London School of Medicine, London, United Kingdom

Alan Burnett

Department of Haematology, University of Wales College of Medicine, Cardiff University, Cardiff, United Kingdom

T. Andrew Lister

Centre for Medical Oncology, Barts and The London School of Medicine, London, United Kingdom

David Linch

Department of Haematology, University College London, London, United Kingdom

We thank Medeiros for his interest in our recent study of Wilms’ tumor 1 (WT1) mutations in acute myeloid leukemia. The data are broadly similar to an accompanying article by Paschka et al¹ with regard to the frequency of WTI mutations in younger patients with acute myeloid leukemia with a normal karyotype, and to the adverse impact of such mutations independent of the mutational status of NPM1 and FLT3 internal tandem duplications (FLT3-ITDs). As noted by Medeiros, and in contrast to the study of Paschka et al, we chose not to include an analysis of the individual subsets of patients defined by the combination of the mutational status of NPM1 and FLT3-ITDs as part of our original submission. We were reluctant to present this data because we had seen no significant interaction between the impact of a WT1 mutation and the presence of an NPM1 mutation or an FLT3-ITD, and the individual subsets defined by these two parameters included too few patients with a WT1 mutation to facilitate robust interpretation. Nonetheless, we accept the point made by Medeiros that there is a particular interest in the NPM1^mutant/FLT3-ITD^wt (where wt indicates wild type) subgroup, because these patients have a relatively good prognosis and, in some centers, might not be considered for allogeneic transplantation strategies, which are associated with high procedure-related mortality. If, as pointed out by Medeiros, the presence of a WT1 mutation negates the good prognosis in this NPM1^mutant/FLT3-ITD^wt subset, then these patients might be managed differently.

In the report by Paschka et al, there were 70 patients with NPM1^mutant/FLT3-ITD^wt, six of whom (9%) had a WT1 mutation. All six died as a result of resistant disease or after relapse. In our cohort, there were 170 patients in the NPM1^mutant/FLT3-ITD^wt subgroup, 10 of whom (6%) had a WT1 mutation. Patients in this small group had significantly worse outcomes than those patients with NPM1^mutant/FLT3-ITD^wt without a WT1 mutation (Fig 1A), but there were survivors, with an actuarial survival of 40% at 5 years after diagnosis. Only two of the 10 patients had received a transplant; one of these patients died in complete remission from infection 9 months after transplantation; the other was alive in remission at last follow-up more than 15 years after transplantation. The Forest plots (Fig 1B) confirm that there is no significant heterogeneity in the impact of a WT1 mutation in the different molecularly defined risk groups, and therefore, the NPM1^mutant/FLT3-ITD^wt should not be viewed differently in assessing the adverse impact of WT1 mutation.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Kaplan-Meier curve of overall survival in the NPM1mutant/FLT3-ITDwt subgroup stratified according to WTI status. (B) Effect of WT1 on overall and relapse-free survival stratified according to FLT3-ITDs and NPM1 mutational status. ITD, internal tandem duplication; OR, odds ratio; O, observed; E, expected; WT, wild type; NS, not significant.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Written on behalf of the Medical Research Council Adult Leukemia Working Party, United Kingdom.

NOTES

published online ahead of print at www.jco.org on December 15, 2008

REFERENCE

1. Paschka P, Marcucci G, Ruppert AS, et al: Wilms’ tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: A cancer and leukemia group B study. J Clin Oncol 26:4595-4602, 2008[Abstract/Free Full Text]

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