Time to Reconsider the Role of Allogeneic Transplantation for Patients With Acute Myeloid Leukemia and NPM1 Mutation

Patients with acute myeloid leukemia (AML) in first remission are risk stratified using an integrated profile that incorporates response assessment, cytogenetics, and molecular genetic data. The purpose is to identify which patients may benefit from allogeneic transplantation versus chemotherapy alone as postremission therapy (PRT). Patients with high-risk profiles are often referred for transplantation, whereas those with a favorable-risk profile usually receive chemotherapy alone. An increasing number of recurring mutations is being identified in patients with AML, which helps to further refine the risk profile for these patients. This additional genetic information is especially helpful in managing the large number of patients with an intermediate cytogenetic–risk profile; this population of patients is increasingly recognized to be heterogeneous at a genetic level. Adding to the importance of better understanding the risk profile of these patients is a recent decision analysis that demonstrated an improved outcome with allogeneic transplantation for patients with intermediate-risk profiles compared with those receiving conventional chemotherapy. Given the toxicities and benefits of allogeneic transplantation, it is imperative that patients who would not benefit from transplantation are identified and treated with chemotherapy, sparing them the risks of transplantation. In contrast, those patients with a higher risk of relapse may benefit from allogeneic transplantation in first complete remission (CR1). The article by Rollig et al that accompanies this editorial demonstrates an improved relapse-free survival in patients harboring the NPM1 mutation who received transplantation from a sibling donor compared with those who received chemotherapy alone. The trial used a donor versus no donor random assignment and retrospectively looked at the impact of NPM1 mutation on both relapse and overall survival. NPM1 mutations, which are present in a large percentage of patients with AML who have a normal karyotype, are considered a favorable prognostic marker. Mutations of the NPM1 gene in exon 12 result in aberrant cytoplasmic expression of the abnormal nucleophosmin proteins. NPM1 mutation is associated with an increased frequency of FLT-3 expression and CD34 phenotype and also defines a distinctive gene profile. In a subset of 401 patients with AML with a normal karyotype, NPM1 mutations were identified in nearly 53% of patients. In more than 40% of patients with NPM1 mutations, there was also a mutation of FLT3. The presence of the NPM1 mutation alone was associated with improved outcome, with remission rates of 70% versus 55% for those without the NPM1 mutations. A trend toward improved overall survival and progression-free survival has been noted. These results are similar to the high remission rates seen in patients with core binding factor (CBF) mutations. Given these findings, the European LeukemiaNet grouped the patients with mutated NPM1 without FLT3/internal tandem duplication and normal karyotype into the favorable prognostic group. In a validation of the prognostic recommendations from the European LeukemiaNet, patients with CBF mutations had an improved median overall survival of 135 months compared with 23 months for patients with the NPM1 mutation/FLT3-negative genotype, whereas patients with the NPM1/FLT3-negative profile still had a near doubling of overall survival compared with a median overall survival of 13 months for patients with an intermediate-risk 1 or 2 profile. Although this difference justified the continued designation as favorable, the most appropriate PRT remains debatable. Should patients with a normal karyotype and NPM1 mutations be referred for allogeneic transplantation in CR1? The authors of the European LeukemiaNet prognostic validation suggest that transplantation should be considered as an option for these patients. As with patients with CBF mutations, excellent outcomes are seen after transplantation in this group. In a study of 101 patients with the NPM1/ FLT3-negative genotype undergoing transplantation beyond CR1, 2-year overall survival was 81%. There is also a suggestion that the NPM1 phenotype may elicit an enhanced graft-versus-leukemia effect. There are no randomized trials to address the issue of the most effective PRT for patients with NPM1 mutations. A prospective randomized controlled trial is considered the gold standard for trial design to eliminate selection bias. The most obvious potential biases in trials involving transplantation relate to referral of only the young and fit for transplantation, whereas those who are older or with comorbidities and those less likely to withstand the rigors of transplantation may be referred for chemotherapy alone. There are practical concerns as well. Because only 30% of eligible patients will have a sibling donor available to make transplantation an option, the sample size to answer a question involving allogeneic transplantation in a clinical trial becomes too JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 5 FEBRUARY 1