Correspondence
Cytogenetically Normal Acute Myeloid Leukemia
N Engl J Med 2008; 359:651-653August 7, 2008
- Article
To the Editor:
Schlenk and colleagues (May 1 issue)1 found that patients who have cytogenetically normal acute myeloid leukemia (AML) with a genotype other than mutant NPM1 (nucleophosmin gene) without FLT3-ITDs (fms-related tyrosine kinase 3 gene internal tandem duplications) benefit from transplantation of hematopoietic stem cells from HLA-matched related donors. The authors assigned patients with an identified donor to a donor group and the other patients to a no-donor group. This method has been used in a meta-analysis involving 3103 patients.2 However, the donor versus no-donor method must be restricted to HLA-typed patients with a sibling because the two groups are equal with respect to the initial risk and intention to transplant. The inclusion of patients who are not HLA-typed, like all those without siblings, causes bias of unknown magnitude.3 Also, results from “receipt” of a transplant should be supported by data.
3 ReferencesThomas Büchner, M.D.
Wolfgang E. Berdel, M.D.
Joachim Kienast, M.D.
University of Münster, 48129 Münster, Germany
buechnr@uni-muenster.de 1
Schlenk RF ,Dohner K ,Krauter J , et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358:1909-1918
Full Text | Web of Science | Medline2
Cornelissen JJ ,van Putten WLJ ,Verdonck LF , et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 2007;109:3658-3666
CrossRef | Web of Science | Medline3
Gray R ,Wheatley K . How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant 1991;7:Suppl 3:9-12
Web of Science | Medline
To the Editor:
Several important questions about the study reported by Schlenk et al. remain unanswered. First, the authors state that “FLT3-TKD [tyrosine kinase domain] mutations (P=0.03), but not NRAS [neuroblastoma RAS viral oncogene homologue gene] mutations (P=0.46), were significantly associated with NPM1 mutations.” How is this possible when more patients with NPM1 mutations were reported to be carrying NRAS mutations than FLT3-TKD mutations? Second, no data are provided on the putative additional favorable effect of FLT3-TKD mutations on event-free survival in cytogenetically normal AML in association with NPM1 or CEBPA (CCAAT/enhancer binding protein α gene) mutations.1 Third, in contrast to the poor prognosis reported by Schlenk et al. for patients with cytogenetically normal AML who had expression of wild-type NPM1 and CEBPA without FLT3-ITD, a previous gene-expression profile analysis failed to show a significantly worse prognosis for such patients.2 Finally, high expression levels of BAALC (brain and acute leukemia, cytoplasmic gene)3 or ERG (V-ets erythroblastosis virus E26 oncogene homologue gene)4 constitute independent adverse prognostic markers in cytogenetically normal AML. The addition of these markers to the panel tested by Schlenk et al. will probably make the proposed molecular-risk classification of cytogenetically normal AML more robust.
4 ReferencesAlfonso Quintas-Cardama, M.D.
M.D. Anderson Cancer Center, Houston, TX 77030
aquintas@mdanderson.org 1
Bacher U ,Haferlach C ,Kern W ,Haferlach T ,Schnittger S . Prognostic relevance of FLT3-TKD mutations in AML: the combination matters -- an analysis of 3082 patients. Blood 2008;111:2527-2537
CrossRef | Web of Science | Medline2
Valk PJM ,Verhaak RGW ,Beijen MA , et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004;350:1617-1628
Full Text | Web of Science | Medline3
Langer C ,Radmacher MD ,Ruppert AS , et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. Blood 2008;111:5371-5379
CrossRef | Web of Science | Medline4
Marcucci G ,Maharry K ,Whitman SP , et al. High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 2007;25:3337-3343
CrossRef | Web of Science | Medline
To the Editor:
In their analysis, Schlenk et al. applied the principles of mendelian (genetic) randomization. Since having a matched sibling is a function of random distribution of genes, mendelian randomization is often used as a surrogate for classic randomization methods in hematologic-cancer trials.1 Katan was among the first to describe this approach2; and Gray and Wheatley1 were among the first to use this approach in evaluating the role of stem-cell transplantation. Subsequently, Wheatley and Gray3 outlined the pitfalls that one should avoid while conducting mendelian randomization.
Analysis of Fig. 2 in the Supplementary Appendix that accompanies the report by Schlenk et al. (available at www.nejm.org) shows that a lower proportion of subjects in the donor group died or had a relapse before receiving their second course of consolidation therapy or did not receive consolidation therapy at all, as compared with subjects in the no-donor group. The odds ratio for this composite end point was 0.46 (chi-square analyis) in the donor group as compared with the no-donor group (95% confidence interval [CI], 0.21 to 1.01; P=0.05). This post hoc analysis suggests that the two groups were not really comparable, which raises questions about selection bias.
3 ReferencesWael Saber, M.D.
Eliot C. Williams, M.D., Ph.D.
University of Wisconsin School of Medicine and Public Health, Madison, WI 53792
saber@wisc.edu 1
Gray R ,Wheatley K . How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant 1991;7:Suppl 3:9-12
Web of Science | Medline2
Katan MB . Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet 1986;1:507-508
CrossRef | Web of Science | Medline3
Wheatley K ,Gray R . Commentary: Mendelian randomization -- an update on its use to evaluate allogeneic stem cell transplantation in leukaemia. Int J Epidemiol 2004;33:15-17
CrossRef | Web of Science | Medline
To the Editor:
Schlenk et al. found that high-risk patients with cytogenetically normal AML and unfavorable genotypes who did not have an HLA-matched related donor had poor relapse-free survival. Therefore, allogeneic stem-cell transplantation from an unrelated HLA-matched donor for such patients could be an option. Schlenk et al. state that 94 patients received allogeneic stem-cell transplants from unrelated HLA-matched donors after relapse. What were the outcomes for these patients according to genotype?
Hiroto Narimatsu, M.D., Ph.D.
Japan Cancer Society, Tokyo 100-0006, Japan
hiroto-narimatsu@umin.net Author/Editor Response
In our study, we found an inhomogeneous distribution of FLT3-TKD but not RAS mutations in patients with mutant NPM1: among patients with mutant NPM1 and those with wild-type NPM1, the frequencies of FLT3-TKD mutations were 14% (41 of 290 patients) and 8% (20 of 253), respectively, whereas those of RAS mutations were 15% (43 of 292) and 12% (32 of 262), respectively. We observed no prognostic effect of FLT3-TKD mutations. In contrast, Bacher et al.1 recently reported a possible favorable effect of FLT3-TKD mutations in patients with NPM1 and CEBPA mutations; however, their data are derived from univariable analyses and are not supported by multivariable analysis. Whether the expression levels of single genes, such as ERG, BAALC, or MN1 (meningioma 1 gene), provide further prognostic information is under investigation; we therefore believe it would be premature to include these values in a clinically applicable prognostic or predictive marker model.
Two comments relate to the technique of donor versus no-donor comparison that was applied in our study and in a recent meta-analysis by Cornelissen et al.2 We concede that from a statistical point of view, patients without siblings should be excluded from such an analysis. However, this does not reflect clinical reality and — most important — the decision-making algorithms within the clinical trials that provided the basis for our analysis. Matched unrelated donors have now become available for the majority of patients, and there no longer appears to be a difference in outcome between matched related and unrelated donors. As a consequence, in future clinical trials, true randomizations can be made between allogeneic transplantation and conventional intensive consolidation, thereby avoiding potential selection bias due to the procedure of genetic randomization.
Saber and Williams raise the question of a potential imbalance in favor of the donor group in terms of early events. The composite end point in their comment is not well defined. The category “no consolidation” did not automatically translate into an event that was relevant for survival analysis; furthermore, frequency tables cannot substitute for correct assessment of the time dependence of events.
In response to Narimatsu's question: the 3-year survival probabilities for patients who underwent allogeneic transplantation were 60% (95% CI, 36 to 99), 56% (95% CI, 31 to 99), and 43% (95% CI, 29 to 64) for 10 patients with mutant NPM1 without FLT3-ITD, 9 patients with mutant CEBPA, and 38 patients with other genotypes, respectively.
2 ReferencesRichard Schlenk, M.D.
Konstanze Döhner, M.D.
Hartmut Döhner, M.D.
University Hospital of Ulm, 89081 Ulm, Germany
hartmut.doehner@uniklinik-ulm. de 1
Bacher U ,Haferlach C ,Kern W ,Haferlach T ,Schnittger S . Prognostic relevance of FLT3-TKD mutations in AML: the combination matters -- an analysis of 3082 patients. Blood 2008;111:2527-2537
CrossRef | Web of Science | Medline2
Cornelissen JJ ,van Putten WLJ ,Verdonck LF , et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 2007;109:3658-3666
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
S. Schnittger, W. Kern, C. Tschulik, T. Weiss, F. Dicker, B. Falini, C. Haferlach, T. Haferlach. (2009) Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood 114:11, 2220-2231
CrossRef2
Sabine Kayser, Richard F. Schlenk. (2009) Tailored therapeutic approaches in acute myeloid leukaemia. memo - Magazine of European Medical Oncology 2:S1, 18-21
CrossRef3
Richard F Schlenk, Konstanze Döhner. (2009) Impact of new prognostic markers in treatment decisions in acute myeloid leukemia. Current Opinion in Hematology 16:2, 98-104
CrossRef
