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J. Bond et al.
Table 2. Prognostic impact of DNMT3A genotype on event-free survival.
EFS
Univariate Multivariate
HR 95%CI P HR 95%CI P
Age* 1.03
Log(WBC)* 1.62 Corticosteroid sensitivity 0.52 Early chemosensitivity 0.90 DNMT3A mutation 3.22
1.01 – 1.05
Table 3. Prognostic impact of DNMT3A genotype on overall survival.
0.009 1.02 0.011 1.50 0.003 0.66
0.436 -
1.00 – 1.04
0.071
0.062 0.093 - 0.02
1.12 – 2.34 0.34 – 0.81 0.68 – 1.18 1.81 – 5.72
0.98 – 2.29 0.41 – 1.07 -
1.13 – 4.27
<0.001 2.20
*Continuous variable. Statistically significant differences are highlighted in bold. EFS: event-free survival; HR: hazard ratio; 95% CI: 95% confidence interval; WBC: white blood
cell count..
OS
Age*
Log(WBC)*
Corticosteroid sensitivity Early chemosensitivity DNMT3A mutation
Univariate
HR 95%CI p
Multivariate
HR 95%CI p
1.04 1.01 – 1.06
1.65 1.10 – 2.46 0.59 0.37 – 0.94 0.94 0.71 – 1.24 2.91 1.56 – 5.43
notype, while full immunophenotypic assessment was unfortunately not possible for the other patient. The fac- tors that may dictate the acute leukemic phenotype in clonally mutated cases remain to be clarified. For example, this might be influenced by the differentiation capacity of the cell in which the initial DNMT3A mutation occurs. In addition, it is tempting to speculate that the acquisition of specific cooperative mutations, such as the NOTCH1 mutations observed in these T-ALL cases, might act as lin- eage determinants.
Outcome analyses revealed that DNMT3A mutation cor- related with poor prognosis independently of the patients’ age in bivariate analyses. Multivariable analyses using parameters that were used to stratify treatment in the GRAALL-2003 and -2005 studies showed that DNMT3A genotype independently predicted both event-free survival and cumulative incidence of relapse. DNMT3A mutation status also independently predicted event-free survival and overall survival in bivariable analyses that incorporated our recently described oncogenetic risk classifier37 (Online Supplementary Table S5). These results suggest that DNMT3A mutation is directly linked to aggressive T-ALL biology. As DNMT3A-altered T-ALL had higher mutation rates in other genes included in our targeted sequencing panel, it is also possible that increased genotype complex- ity may contribute to the more aggressive phenotype in these leukemias. This issue may be clarified by more com- prehensive genomic assessment in future studies.
The high rates of treatment failure observed in this study suggest that therapeutic intervention is warranted for DNMT3A-mutated cases, and that treatment intensifi- cation should be considered for the infrequent younger patients with mutations. Indeed, we have previously doc- umented a benefit from allogeneic stem cell transplanta- tion in first complete remission for ETP-ALL,24 which sim- ilarly exhibits high rates of intrinsically treatment-resistant disease. As only three of the 18 DNMT3A-mutated patients in this study underwent allogeneic stem cell
0.002
1.03 1.01 – 1.06
1.63 1.03 – 2.57
0.009
0.037
0.015 0.027
0.001 1.66 0.82 – 3.37 0.160 *Continuous variable. Statistically significant differences are highlighted in bold. OS: overall survival; HR: hazard ratio; 95% CI: 95% confidence interval; WBC: white blood cell
0.79 0.47 – 1.34
0.640 - - -
0.388
count..
transplantation (data not shown), we are unable to estimate the potential benefit of such treatment in this setting. We recently reported that treatment-related toxicity in the GRAALL-2005 study increased in proportion to the patients’ age,38 and further therapy intensification in elder- ly patients must therefore be considered of questionable benefit. The upper age of this study cohort was 60 years, but it is likely that the rate of mutations in older patients who do not tolerate such intensive chemotherapy is high- er. Data reported for patients with AML suggest that DNMT3A mutation confers increased sensitivity to hypomethylating agents,39 providing a rationale for evalu- ation of these drugs in DNMT3A-mutated T-ALL. In the longer term, it is to be hoped that investigation of the molecular mechanisms by which DNMT3A mutation alters T-ALL biology will lead to better treatments and improved outcomes for these high-risk cases.
Acknowledgments
This manuscript was written on behalf of the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), which includes the former France-Belgium Group for Lymphoblastic Acute Leukemia in Adults (LALA), the French Western-Eastern Group for Lymphoblastic Acute Leukemia (GOELAL), and the Swiss Group for Clinical Cancer Research (SAKK). The authors would like to thank all participants in the GRAALL-2003 and GRAALL-2005 study groups for collection and provision of data and samples, and V. Lheritier for collection of clinical data. The GRAALL-2003 study was sponsored by the Hôpitaux de Toulouse, and the GRAALL-2005 study by the Assistance Publique-Hôpitaux de Paris. The SAKK was supported by the Swiss State Secretariat for Education, Research and Innovation (SERI). JB was supported by a Kay Kendall Leukaemia Fund Intermediate Research Fellowship and by the National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland. The Necker Laboratory is supported by the Association Laurette Fugain, La Ligue contre le Cancer and the INCa CARAMELE Translational Research and PhD programs.
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haematologica | 2019; 104(8)