Contributions
Abstract: PB1697
Type: Publication Only
Background
The association of NPM1mut and the internal tandem duplication of FLT3 (FLT3-ITD) in de novo AML with intermediate-risk cytogenetics has different prognostic impact according to the FLT3-ITD/FLT3wt ratio, thus affecting clinical decisions about the indication of allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1). DNMT3A mutations (DNMT3Amut) have been suggested to have an adverse prognostic impact in this group of patients; however the effect of this triple mutation association is not well established.
Aims
To evaluate the prognostic value of additional DNMT3Amut in de novo AML with NPM1mut and FLT3-ITD, and its survival impact according to FLT3 ratio.
Methods
Patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were selected from CETLAM database, from our cooperative group protocols AML-2003 and AML-2012. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The Kaplan-Meier test was used to estimate overall survival (OS) and leukemia-free survival (LFS), whereas risk of relapse (RR) was analysed by the cumulative incidence estimator with non-relapse mortality as the competing event.
Results
A total of 114 patients were selected from protocol AML-2003 (n=49) or AML-2012 (n=65). Median age was 51 years (18-71), with 54% females, median leucocyte count 42x10E9/L (1.2-408x10E9/L) and median bone marrow blasts 78% (20-100%). FLT3 status was defined as wild type (n=34) or FLT3-ITD (n=76). High ratio (FLT3high) was considered when ≥0.50(n=43) and low ratio (FLT3low) when <0.5(n=33). DNMT3Amut was detected in 60 patients, the majority in amino acid R882(n=48). In patients with NPM1mut and FLT3-ITD, DNMT3Amut vs DNMT3Awt had no impact in 5 year OS (n=80): 40%±10% vs 56%±6% (p=0.28) or 5 year LFS (n=70): 27%±12.6% vs 55%±1% (p=0.105). Similarly, when divided according to FLT3 status (FLT3wt vs. FLT3low vs. FLT3high) DNMT3Amut had no significant prognostic impact in 5 year OS (n=58) 70%±11% vs 58%±13% vs 28%±13% (p=0.104); 5 year LFS (n=54) 67%±12% vs 44%±13% vs 19%±14% (p=0.073); or RR (n=54) 20.4% (95%CI 2.6%>49.8%) vs 35.6% (95%CI, 11.4%>61.1%) vs 52.2% (95%CI, 24.7%>73.9%) p=0.117. Thirty-six patients of the entire cohort received alloHSCT in CR1. When censoring follow-up at the date of transplant, RR analysis confirmed an increasing risk in DNMT3Amut patients according to FLT3 status: FLT3wt 23.4% (95% CI, 2.8%>55.4%; n=30) vs FLT3low 49.8% (95% CI, 13.8%>78.2%; n=28) and FLT3high 56.6% (95% CI, 23.2%>80.2%; n=32) p=0.0113. DNMT3Amut effect was analysed in FLT3 subgroups, showing impact only in FLT3wt vs FLT3high 23.4% vs. 56.6% (p=0.014), and a trend in FLT3low vs FLT3high 49.8% vs. 56.6% (p=0.077). No significant differences were seen in FLT3wt vs FLT3low 23.4% vs 49.8% (p=0.178).
Conclusion
It has been established that AML with NPM1mut and FLT3low has better outcome than FLT3high. Overall, our study suggests that DNMT3A mutations do not have survival impact in AML with NPM1mut and FLT3-ITD. However, when RR is censored by date of alloHSCT in CR1, DNMT3Amut shows a trend to a higher relapse risk when associated to FLT3-ITD; this could be of clinical relevance in patients with a low FLT3-ITD ratio who are currently not considered for alloHCT in CR1 in our group. These results should be confirmed in future studies that gather a higher number of patients and may include the evaluation of measurable residual disease (MRD) that could anticipate patients with an inadequate MRD clearance who could benefit from alloHCT in an early phase.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): Acute Myeloid Leukemia, mutation analysis, prognosis
Abstract: PB1697
Type: Publication Only
Background
The association of NPM1mut and the internal tandem duplication of FLT3 (FLT3-ITD) in de novo AML with intermediate-risk cytogenetics has different prognostic impact according to the FLT3-ITD/FLT3wt ratio, thus affecting clinical decisions about the indication of allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1). DNMT3A mutations (DNMT3Amut) have been suggested to have an adverse prognostic impact in this group of patients; however the effect of this triple mutation association is not well established.
Aims
To evaluate the prognostic value of additional DNMT3Amut in de novo AML with NPM1mut and FLT3-ITD, and its survival impact according to FLT3 ratio.
Methods
Patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were selected from CETLAM database, from our cooperative group protocols AML-2003 and AML-2012. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The Kaplan-Meier test was used to estimate overall survival (OS) and leukemia-free survival (LFS), whereas risk of relapse (RR) was analysed by the cumulative incidence estimator with non-relapse mortality as the competing event.
Results
A total of 114 patients were selected from protocol AML-2003 (n=49) or AML-2012 (n=65). Median age was 51 years (18-71), with 54% females, median leucocyte count 42x10E9/L (1.2-408x10E9/L) and median bone marrow blasts 78% (20-100%). FLT3 status was defined as wild type (n=34) or FLT3-ITD (n=76). High ratio (FLT3high) was considered when ≥0.50(n=43) and low ratio (FLT3low) when <0.5(n=33). DNMT3Amut was detected in 60 patients, the majority in amino acid R882(n=48). In patients with NPM1mut and FLT3-ITD, DNMT3Amut vs DNMT3Awt had no impact in 5 year OS (n=80): 40%±10% vs 56%±6% (p=0.28) or 5 year LFS (n=70): 27%±12.6% vs 55%±1% (p=0.105). Similarly, when divided according to FLT3 status (FLT3wt vs. FLT3low vs. FLT3high) DNMT3Amut had no significant prognostic impact in 5 year OS (n=58) 70%±11% vs 58%±13% vs 28%±13% (p=0.104); 5 year LFS (n=54) 67%±12% vs 44%±13% vs 19%±14% (p=0.073); or RR (n=54) 20.4% (95%CI 2.6%>49.8%) vs 35.6% (95%CI, 11.4%>61.1%) vs 52.2% (95%CI, 24.7%>73.9%) p=0.117. Thirty-six patients of the entire cohort received alloHSCT in CR1. When censoring follow-up at the date of transplant, RR analysis confirmed an increasing risk in DNMT3Amut patients according to FLT3 status: FLT3wt 23.4% (95% CI, 2.8%>55.4%; n=30) vs FLT3low 49.8% (95% CI, 13.8%>78.2%; n=28) and FLT3high 56.6% (95% CI, 23.2%>80.2%; n=32) p=0.0113. DNMT3Amut effect was analysed in FLT3 subgroups, showing impact only in FLT3wt vs FLT3high 23.4% vs. 56.6% (p=0.014), and a trend in FLT3low vs FLT3high 49.8% vs. 56.6% (p=0.077). No significant differences were seen in FLT3wt vs FLT3low 23.4% vs 49.8% (p=0.178).
Conclusion
It has been established that AML with NPM1mut and FLT3low has better outcome than FLT3high. Overall, our study suggests that DNMT3A mutations do not have survival impact in AML with NPM1mut and FLT3-ITD. However, when RR is censored by date of alloHSCT in CR1, DNMT3Amut shows a trend to a higher relapse risk when associated to FLT3-ITD; this could be of clinical relevance in patients with a low FLT3-ITD ratio who are currently not considered for alloHCT in CR1 in our group. These results should be confirmed in future studies that gather a higher number of patients and may include the evaluation of measurable residual disease (MRD) that could anticipate patients with an inadequate MRD clearance who could benefit from alloHCT in an early phase.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): Acute Myeloid Leukemia, mutation analysis, prognosis