Page 95 - Haematologica-5

Figure 4. Kaplan-Meier estimates of (A) disease-free survival and (B) overall survival according to the type of IDH1/2 mutation. AB
Figure 5. Prognostic analysis according to post-induction IDH1/2 mutant allele fraction. Kaplan-Meier estimates of (A) disease-free survival and (B) overall survival according to IDH1/2 variant allele fraction (IDH1/2-VAF). MRD+ denotes IDH1/2-VAF ≥0.2% and MRD- denotes IDH1/2-VAF <0.2%.
IDH1/2 mutant allele burden in AML
However, despite technical optimizations, we were not able to reach the 0.01% or even 0.1% threshold that we would expect as the quantitative detection limit with the specific ddPCR assays. This problem was due to a relative- ly high background observed in negative controls, which always consisted of double-positive (actually false-posi- tive) droplets. Polymerase errors occurring during the PCR amplification step seem to be responsible for the genera- tion of these false-positive signals.
The present study is the first to quantify IDH1/2 muta- tion levels in a large cohort of AML patients. Previous studies using Sanger sequencing,23 qPCR,24 or next-genera- tion sequencing technology25 suggested that the presence or the level of IDH1/2 mutations was correlated to disease status in most patients with AML, but the small number of IDH1/2-mutated patients included in these studies pre- cluded statistical analysis. Our study revealed that a posi- tive IDH1/2-VAF after induction chemotherapy was asso- ciated with a shorter disease-free survival. Whether patients with residual IDH1/2 mutations in complete remission may benefit from allogeneic stem cell transplan- tation remains to be addressed by future studies. In clinical
practice, IDH1/2-VAF assessment during and after treat- ment could be especially valuable in AML patients with- out recurrent fusion genes or NPM1 mutations, which are both leukemia-specific and more sensitive MRD markers. Keeping in mind the caveat that IDH1/2 mutations can be present in the pre-leukemic clone in some cases, one could argue that these mutations could be good MRD markers for those patients in whom MRD becomes undetectable after induction or at early follow-up time-points. However, sequential monitoring of IDH1/2-VAF after con- solidation therapy or allogeneic stem cell transplantation could still help to detect disease persistence and guide pre- emptive therapy to prevent hematologic relapse, as sug- gested in a recent study.26 An alternative approach to MRD monitoring in IDH1/2-mutated patients is to quantify the oncometabolite 2-HG.27,28 A previous study from the ALFA group showed that total 2-HG serum levels <2 μmol/L after induction were associated with better disease-free survival and overall survival.29 We were not able to corre- late IDH1/2-VAF and 2-HG levels in this study because of the lack of serum samples.
We found that 7/103 (7%) patients had an IDH1/2
AB
haematologica | 2018; 103(5)
827