For patients with acute myeloid leukemia (AML), acquired chromosomal abnormalities present at diagnosis are the most important independent predictors of complete remission, disease-free survival, and overall survival.1-3 Chromosomal analysis is used to determine outcome risk and direct treatment strategies for patients, including allogeneic stem cell transplantation (SCT) in first complete remission. However, in 40% to 50% of patients, chromosome aberrations are not detected, making it difficult to similarly define risk in patients with cytogenetically normal (CN) AML. However, with the discovery of recurrent somatic mutations, patients with CN-AML are now categorized into molecularly defined subgroups with distinct clinical outcomes. The WHO, European LeukemiaNet (ELN), and NCCN now include recurrent molecular markers along with cytogenetics in their respective classification schemas.4-6
Within CN-AML, the prognostic significance of mutations in FLT3, NPM1, and CEBPA has been consistently demonstrated. Internal tandem duplications (ITDs) of the FLT3 gene occur in 25% to 35% of patients with CN-AML and confer an increased risk for relapse and death when compared with patients without FLT3-ITD.7-9 It seems that not only the presence of the mutation but also the level of the mutated allele is important, as patients with a low allelic ratio (ratio of mutant to wild-type FLT3) have an outcome similar to those without FLT3-ITD mutations.10 Because of its association with an unfavorable outcome, allogeneic SCT during first complete remission is recommended in patients with an FLT3-ITD mutation who are not enrolled in a clinical trial.8 Mutations arising within the tyrosine kinase domain (TKD) of the FLT3 gene occur in 5% to 10% of all patients with AML; however, the prognostic relevance of these mutations is controversial, and genetic risk based on TKD mutational status has not been included in classification systems to date.11-13
NPM1 mutations are the most common molecular mutations, found in 45% to 60% of patients with CN-AML, and are associated with achievement of complete remission and an overall favorable outcome in younger and select older patients.8,14-16 An interaction between FLT3 and NPM1 has been observed, wherein patients with FLT3-ITD wild-type (wt)/NPM1 mutated (mut) disease have the highest remission rate and most favorable overall survival, and do not seem to benefit from allogeneic SCT in first complete remission.15 Assessment of minimal residual disease with real-time quantitative polymerase chain reaction (RQ-PCR) of NPM1-mut transcript levels has been used to further refine risk and predict relapse in this group of patients with favorable risk.17 Patients with RQ-PCR negativity after induction chemotherapy had a lower cumulative incidence of relapse and improved overall survival, whereas increasing transcript levels were associated with a higher risk for relapse.17
CN-AML with mutations in CEBPA, which occur in approximately 10% to 15% of patients, is also associated with a favorable outcome. This led the ELN and NCCN to reclassify patients with either FLT3-ITD-wt/NPM1-mut or CEBPA-mut CN-AML from intermediate to favorable risk and to recommend chemotherapy alone as postremission treatment, reserving allogeneic SCT until relapse.4,5 However, more recently it has been demonstrated that the prognostic impact of CEBPA mutations depends on the presence of a mutation in both alleles. Patients with one affected allele have an outcome indistinguishable from wt cases and express a gene expression profile different from that of patients with 2 affected alleles who have a favorable outcome.18,19
Despite improvements in risk stratification, uncertainty remains regarding the optimal post-remission treatment for patients with CN-AML who have neither favorable nor unfavorable molecular markers (ie, FLT3-ITD-wt/NPM1-wt/CEBPA-wt CN-AML). Current NCCN recommendations for these patients include matched sibling or alternate-donor allogeneic SCT, 1 to 2 cycles of dose-intensive cytarabine followed by autologous SCT, or multiple courses of intermediate or high-dose cytarabine.5 Although a potentially curative option, allogeneic SCT is associated with higher treatment-related mortality than intensive chemotherapy or autologous SCT, and this risk may influence use of allogeneic SCT in first complete remission in this molecular subgroup.
This article reviews reported outcomes after postremission therapies for patients with CN-AML who have neither favorable nor unfavorable molecular markers, discusses the role of recently discovered molecular mutations that may help further risk-stratify this group, and finally, suggests factors to consider when choosing postremission therapy for individual patients.
Postremission Therapy for Patients With FLT3-ITD-wt/NPM1-wt CN-AML
Initial reports describing the frequency, clinical features, and prognostic significance of FLT3 and NPM1 mutations included treatment outcomes of patients with CN-AML without either mutation.15,20,21 Schlenk et al8 reported the mutational status and clinical outcomes of 872 patients (age <60 years) with newly diagnosed CN-AML treated on German-Austrian Acute Myeloid Leukemia Study Group trials. All patients received a double induction with idarubicin, cytarabine, and etoposide followed by a cycle of consolidation chemotherapy with high-dose cytarabine. As part of a donor-versus-no donor comparison, patients with an HLA-matched related donor were assigned to undergo allogeneic SCT, whereas those without a suitable donor received high-dose cytarabine-based chemotherapy or autologous SCT. The overall 4-year relapse-free survival rate for patients with a triple-negative genotype (NPM1-wt/CEBPA-wt/without FLT3-ITD) was 25%, similar to the 24% relapse-free survival rate observed in patients with FLT3-ITD CN-AML.8 Patients with either a FLT3-ITD mutation or a triple-negative genotype and a donor had improved relapse-free survival compared with those without a donor (P=.003), suggesting an advantage to allogeneic transplantation for this group as a whole.8 Although the relapse-free and overall survivals of patients with a triple-negative genotype after high-dose cytarabine chemotherapy or autologous SCT were not individually reported, no significant difference was seen in these outcome measures after either form of postremission therapy for the cohort overall. These findings support allogeneic transplantation in first complete remission for patients with NPM1-wt/CEBPA-wt/without FLT3-ITD CN-AML who have an HLA-matched related donor.
Gale et al20 also described the impact of FLT3-ITD and its interaction with NPM1 mutations in a larger group of 1425 younger patients (age <60 years) with AML treated on the United Kingdom Medical Research Council AML 10 and 12 trials. All patients received cytarabine- and anthracycline-based induction chemotherapy followed by randomization to allogeneic transplantation if a suitable donor existed (HLA-matched related or unrelated). If no donor was available, patients received additional chemotherapy followed by autologous transplant, a design similar to that of trials reported by Schlenk et al8 aside from the allowable donor sources. Of the 550 patients with CN-AML, 154 were molecularly classified as NPM1-wt/FLT3-ITD-wt. The relapse and overall survival rates at 5 years for this group were 57% and 38%, respectively, similar to the 61% relapse rate and 37% overall survival rate observed in patients with NPM1-mut/FLT3-ITD-mut CN-AML.20 The proportion of patients with NPM1-wt/FLT3-ITD-wt CN-AML who received an allogeneic SCT was not reported, and therefore drawing conclusions about its role as postremission therapy is difficult. However, these findings may suggest that proceeding with an allogeneic SCT based on donor availability offers patients with NPM1-wt/FLT3-ITD-wt CN-AML an overall survival similar to that of patients with FLT3-ITD-mut CN-AML.
In a study of 1485 patients with newly diagnosed AML treated on the AML96 protocol of the Deutsche Studieninitiative Leukamie, 709 patients with CN-AML were identified, 117 with NPM1-wt/FLT3-ITD-wt disease.21 Patients with CN-AML received cytarabine- and anthracycline-based induction chemotherapy followed by allogeneic SCT if a suitable HLA-matched sibling donor was available. If not, they received additional chemotherapy followed by autologous SCT. Although the primary findings focused on the impact of NPM1 mutations on treatment outcome, a multivariate analysis found no difference in overall or disease-free survival for patients with NPM1-wt/FLT3-ITD-wt AML when compared with patients with NPM1-mut/FLT3-ITD-mut AML, similar to observations made by both Schlenk et al8 and Gale et al.20 Interestingly, of those with CN-AML, more patients with FLT3-wt/NPM1-wt underwent allogeneic SCT (n=32) than those with FLT3-ITD mutations (n=22) in this study, which may have been due to donor availability or other patient-specific factors. This may suggest that allogeneic SCT in this group does not impact disease-free or overall survival, although given the small numbers of patients included in each group, a definitive conclusion cannot be drawn.
Meta-analyses of prospective trials that have included adults with newly diagnosed AML assigned to receive an allogeneic SCT in first complete remission versus consolidation chemotherapy and/or autologous SCT have been performed to further evaluate the impact of postremission therapy for patients with intermediate genetic risk.22,23 Meta-analyses have known limitations, including use of abstracted data and publication biases that may lead to incomplete data reporting; however, they offer an opportunity to more powerfully evaluate the effect of allogeneic SCT than is possible with a single study. In AML, meta-analyses of trials that include a donor-versus-no donor randomization are limited by incomplete compliance with the assigned treatment (eg, patient refusal, disease recurrence), which may lead to underestimations of the effect of allogeneic SCT, although an intention-to-treat analysis does attempt to overcome this.
A small meta-analysis of 5 AML studies that randomized patients in first complete remission to allogeneic SCT based on donor availability confirmed that the benefit of allogeneic SCT was dependent on cytogenetic risk, namely for those with poor-risk AML, and that it had no clear benefit over autologous SCT or chemotherapy for patients with intermediate genetic risk.23 Notably, intermediate genetic risk included normal karyotype and chromosomal abnormalities, such as trisomy 8, del(12p), and others, which may have impacted the outcomes observed.
Koreth et al22 performed a larger meta-analysis of 24 trials that compared allogeneic SCT versus nonallogeneic SCT in first complete remission, and concluded that survival benefit varies by cytogenetic risk. However, an improved comparative absolute overall survival rate was seen for patients with intermediate genetic risk (not confined to patients with CN-AML) who received an allogeneic SCT versus nonallogeneic SCT treatment (54% vs 45%, respectively). Both analyses are limited by the heterogeneity of the cytogenetic criteria used in each of the trials, and not all patients with CN-AML were molecularly defined, which limits specific application of either conclusion to patients with NPM1-wt/FLT3-ITD-wt CN-AML.
Although consistent data are currently limited regarding the role of allogeneic SCT in first complete remission for patients with NPM1-wt/FLT3-wt CN-AML, some evidence seems to suggest benefit. Therefore, for patients who are not eligible to participate in a clinical trial and have an HLA-matched donor, proceeding to allogeneic SCT in first complete remission should be considered as a postremission therapy. Autologous SCT does not seem to confer a superior benefit over chemotherapy in this group.
New Recurrent Mutations in CN-AML
Recent studies have identified additional recurrent somatic mutations in patients with CN-AML that have prognostic relevance and may help further define risk in this subset of patients. A complete review of all new mutations, dysregulated genes, and microRNAs is beyond the scope of this article, but a recent review of molecular genetics in AML was recently published.24 This article discusses the prognostic significance of DNMT3A, TET2, IDH1/IDH2, and ASXL1 mutations, and how each might improve risk stratification for patients with FLT3-wt/NPM1-wt CN-AML.
DNA Methyltransferase 3A Mutations
Mutations in DNA methyltransferase 3A (DNMT3A), 1 of 3 isoforms of the DNA methyltransferase enzyme responsible for maintenance of methylation patterns, occur in 27% to 33% of patients with CN-AML and are associated with a worse overall survival in patients receiving cytarabine- and anthracycline-based induction chemotherapy.25-28 In addition to evaluating the prognostic impact of DNMT3A mutations based on age and the type of mutation present, the authors evaluated its association with FLT3 and NPM1 mutations in patients with CN-AML.26 Younger patients (age <60 years) with R882-DNMT3A mutations more often had both NPM1 mutations and FLT3-ITD mutations, whereas those with non-R882-DNMT3A mutations more frequently had NPM1 mutations. Only non-R882 mutations were associated with a shorter disease-free survival in younger patients (20% vs 49%; P=.001). Conversely, R882-DNMT3A mutations did not seem to be associated with either NPM1 or FLT3 mutations in older patients (age ≥60 years), and these patients had significantly shorter disease-free (3% vs 21%; P=.006) and overall survivals (4% vs 24%; P=.01) than DNMT3A-wt patients.26 This suggests that the presence of R882-DNMT3A mutations in older patients with FLT3-wt/NPM1-wt CN-AML confers adverse risk, and that this genetic subset may require more-intensive postremission therapy. Non-R882-DNMT3A mutations are associated with NPM1 mutations in older patients but did not have an effect on disease-free or overall survivals.
In a study of 415 younger patients (age <60 years) with newly diagnosed AML treated with cytarabine- and anthracycline-based induction chemotherapy according to HOVON AML protocols, DNMT3A mutation analysis identified mutations in 23.1% of the cohort.27 Interestingly, in patients with either FLT3-wt/NPM1-wt CN-AML or FLT3-wt/NPM1-wt/CEBPA-wt CN-AML, the presence of a DNMT3A mutation predicted for significantly inferior overall (P=.017) and relapse-free survivals (P=.016) compared with patients without the mutation, but did not have predictive value in patients with FLT3-wt/NPM1-mut or FLT3-ITD/NPM1-mut AML. Outcomes for patients with CN-AML based on postremission therapy were not reported. Thol et al28 also reported a worse overall survival in patients with FLT3-wt/NPM1-wt CN-AML with DNMT3A mutations compared with DNMT3A-wt patients (P<.001), but did not observe an effect of DNMT3A mutations in patients with FLT3-wt/NPM1-mut AML.
Based on these findings, DNMT3A mutational status does seem to have a negative prognostic impact in patients with FLT3-wt/NPM1-wt AML, and consideration of allogeneic SCT in first complete remission is recommended. However, additional studies are needed to assess the impact of specific postremission therapy in patients with FLT3-wt/NPM1-wt CN-AML and DNMT3A mutations.
TET2 Mutations
TET proteins are necessary for the conversion of 5-methylcytosine to 5-hydroxymethylcytosine and play a role in demethylation processes within the cell.29 TET2 mutations have been reported in 7% to 12% of patients with AML and 10% to 23% of patients with CN-AML.30-33 Metzeler et al32 described a significant impact of this mutation in patients with ELN favorable-risk CN-AML (mutated CEBPA and/or FLT3-wt/NPM1-mut). Patients with TET2 mutations and favorable-risk CN-AML had shorter disease-free and overall survivals than those with TET2-wt (P=.003 and P=.001, respectively); however, no impact was seen on outcome of TET2 mutations in patients with FLT3-wt/NPM1-wt.32
Gaidzik et al31 also described the impact of TET2 mutations according to ELN classification but did not observe a significant difference in the incidence of relapse, relapse-free survival, or overall survival in the favorable-risk group. These differences in outcome may be due to differences in the age of the patients enrolled on each study or the therapy received, but in both cases, TET2 mutations did not seem to impact the outcome of patients with FLT3-wt/NPM1-wt CN-AML. However, Patel et al34 found that, when included as part of an integrated mutational analysis, patients with NPM1-wt/FLT3-wt/TET2-mut AML had worse overall survival. Notably, this group was cytogenetically diverse. Additional studies that evaluate TET2 mutations as part of an integrated analysis in patients with CN-AML are needed.
IDH1/IDH2 Mutations
Mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) have been identified in 25% to 30% of patients with CN-AML and are associated with an unfavorable prognosis in specific subsets of patients.35-37 In a group of 358 patients with de novo CN-AML reported by the CALGB, no difference was seen in outcome when comparing all patients with IDH1 mutations and IDH1/IDH2-wt. However, in younger patients (age <60 years) with FLT3-wt/NPM1-mut AML, IDH1 mutations were associated with a shorter disease-free survival.36 No associations with IDH mutations were seen in patients with FLT3-wt/NPM1-wt AML. A larger study reported by Paschka et al37 confirmed both the negative prognostic impact of IDH1 mutations in patients with FLT3-wt/NPM1-mut CN-AML and the lack of association with FLT3-wt/NPM1-wt CN-AML. When included within an integrated mutational analysis, IDH1/IDH2 mutations in combination with mutated NPM1 conferred favorable risk in patients with intermediate risk cytogenetics.34 Currently, IDH mutations do not seem have prognostic impact in patients with FLT3-wt/NPM1-wt CN-AML, and the authors recommend reserving allogeneic SCT for when relapse occurs until additional studies in this subset of patients are completed.
ASXL1 Mutations
Mutations in the additional sex combs like-1 (ASXL1) gene occur in 9% to 10% of patients with CN-AML and have been associated with an inferior outcome.38,39 Metzeler et al39 reported the impact of ASXL1 mutations in approximately 400 patients with CN-AML who received cytarabine- and daunorubicin-based induction chemotherapy. Overall, ASXL1 mutations rarely occurred concurrently with NPM1 or FLT3 mutations but were associated with a lower complete remission rate and shorter disease-free and overall survival times when compared with ASXL1-wt mutations in older patients. Patients with ASXL1 mutations tended to fall into the ELN intermediate-I category, which includes patients with FLT3-wt/NPM1-wt CN-AML, although the presence of the ASXL1 mutation did not impact disease-free or overall survival in this group. The small sample size and inherent molecular heterogeneity of patients included in the ELN intermediate-I category (ie, those with CEBPA-wt/NPM1-wt with or without FLT3-ITD, or NPM1-mut/FLT3-ITD) prevent specific conclusions about the impact of this mutation in patients with FLT3-wt/NPM1-wt CN-AML. Nonetheless, given that these mutations are associated with FLT3-wt and NPM1-wt genotypes, additional study in larger groups of patients will be important to determine its independent impact and its impact in combination with other molecular markers before using ASXL1 mutational status as an indication for allogeneic transplantation.
Integrated Mutational Analysis
Choosing which mutations provide the most relevant prognostic information and then determining how best to account for their interrelationships has become a critical part of risk stratification for patients with AML. Patel et al34 reported results of a mutational analysis of 18 genes in a cohort of 398 younger patients (age <60 years) randomized to receive high- or low-dose daunorubicin during induction chemotherapy in the ECOG E1900 trial. In this analysis, all patients with CN-AML were included in the intermediate-risk cytogenetic group. With respect to those with FLT3-wt/NPM1-wt CN-AML, patients with mutated TET2 or ASXL1 had the worst overall survival of all patients with FLT3-wt CN-AML. Additional mutations associated with worse overall survival in patients with FLT3-wt/NPM1-wt CN-AML were partial tandem duplications (PTDs) of the MLL gene and PHF6 mutations. MLL-PTD rearrangements had been previously associated with an unfavorable outcome unless the patient was treated with intensive chemotherapy and autologous SCT,40 and PHF6 mutations were only recently identified in AML41; the study by Patel et al34 provided the first report of the prognostic significance of these mutations. Interestingly, the investigators did not find that DNMT3A mutations were associated with adverse outcome, and in fact patients with DNMT3A mutations who received a higher dose of daunorubicin (90 mg/m2), during induction chemotherapy had an improved rate of survival compared with those with DNMT3A-wt, suggesting a possible relationship between treatment intensity and DNMT3A mutational status.
In the study by Patel et al,34 combining mutational and cytogenetic analyses led to a decrease in the percentage of patients originally classified as intermediate risk (from 63% to 35%), and an increase in the percentage of patients in both the favorable and unfavorable risk groups (from 19% to 26%, and 18% to 39%, respectively). These data show that incorporating additional mutations improves risk stratification models. If verified in additional studies of molecular and cytogenetically well-characterized patients, models such as this will help better guide postremission therapy in the FLT3-wt/NPM1-wt CN-AML group.
Proposed postremission treatment for patients with cytogenetically normal acute myeloid leukemia (CN-AML) and FLT3-ITD-wt/NPM1-wt/CEBPA-wt and select molecular mutations.
Abbreviations: CR1, first complete remission; DFS, disease-free survival; ITD, internal tandem duplication; OS, overall survival; PTD, partial tandem duplication; SCT, stem cell transplant; wt, wild-type.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 4; 10.6004/jnccn.2014.0057
Conclusions
The integration of mutational and cytogenetic analyses as a way to refine classification systems and improve risk stratification will continue to evolve as new mutations are identified. Mrozek et al42 recently reported the prognostic utility of the ELN classification in a cohort of 1550 patients with de novo AML treated with cytarabine- and daunorubicin-based chemotherapy on CALGB frontline protocols. Rates of complete remission and disease-free and overall survival differed significantly across the ELN groups, confirming that the ELN classification allows for prognostic grouping of patients. These findings also validate the incorporation of molecular markers with cytogenetics as a way to improve risk stratification of patients with AML.
Perhaps in no other group is this needed than in those with FLT3-wt/NPM1-wt CN-AML. The identification of recurrent, prognostically significant mutations such as DNMT3A, TET2, IHD1/IDH2, and ASXL1 (Figure 1) has helped further define outcome risk in this group and may help determine postremission therapy in the future. However, routine assessment of these mutations has yet to enter clinical practice and currently remains investigational. Therefore, the authors recommend consideration of allogeneic SCT in first complete remission based on patient-related factors (ie, performance status, organ function) and donor availability for younger patients (age <60 years) with FLT3-wt/NPM1-wt CN-AML. Similarly, older patients (age ≥60 years) should be considered for reduced-intensity allogeneic SCT if they have experienced remission after induction chemotherapy.
Despite progress in the development of classification systems, a greater understanding of initiating and disease-promoting events in AML is needed. Interestingly, all of the new recurrent mutations mentioned herein are involved in epigenetic regulation, suggesting that epigenetic regulators are important in normal hematopoiesis, likely play a role in leukemogenesis, and may be possible targets for therapeutic intervention. Future discoveries in AML will depend on patient enrollment in clinical trials that also include collection of tissue samples for future analysis, and ultimately will be the only way to improve the overall outcome for patients with this disease.
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