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Y. Ferret et al.
as well as IDH1/2-VAF, had no impact on overall survival (Table 3; Figure 5).
Discussion
In this study including 103 adult patients with primary IDH1/2 mutant AML who were intensively treated, we showed the feasibility of IDH1/2-VAF monitoring using ddPCR and its prognostic relevance after induction thera- py, independently of pretreatment risk factors. Our find- ings also suggest that patients with persistent IDH1/2- mutated clonal hematopoiesis may be at high risk of dis- mal hematologic evolution.
The prognostic value of IDH1/2 mutations is still a mat- ter of debate9 and may be influenced by the type of muta- tions, as we previously reported,20,21 or the profile of con-
comitant mutations, such as NPM1 or DNMT3A muta- tions.17,22 The present study, which only included patients with IDH1/2 mutations, was not designed to explore the prognostic significance of IDH1/2 mutations.
The role of MRD in the management of AML patients is growing. Because of the marked heterogeneity of AML, no single MRD marker can be applied to all patients. Additionally, the optimal method for measuring clearance of leukemia cells after chemotherapy remains to be deter- mined. Here, we focused on IDH1/2 mutations because they are recurrent genetic events in AML, mostly in nor- mal karyotype AML, and now represent druggable targets. The digital PCR technique had been previously shown to allow absolute quantification of a nucleic acid target with high precision and sensitivity.12 Our data provide evidence that measurement of IDH1/2-VAF by ddPCR is feasible.
Table 2. Clinical and biological characteristics of the seven patients with persistent clonal hematopoiesis with IDH1/2 mutations.
UPN1 UPN2 UPN3 UPN4 UPN5 UPN6 UPN7
Age(years) 50 55 55 50 68 60 63
Gender F M M M F F F
WBC count, x 109/L
Cytogenetics
NPM1 mutation
FLT3-ITD Pos. Neg. Neg. Pos. Pos.
100
Normal
Pos.
Neg.
Neg.
Neg.
Neg.
Neg.
IDH1 p.R132C (48%)
8.2%
NA
Relapse 1.5 year after AML diagnosis
3.2
Normal
Neg.
Neg.
Neg.
Neg.
Neg.
Neg.
IDH1 p.R132C (43%)
NA
27.1%
MDS 2.5 years after AML diagnosis
28 2.4 Normal Trisomy 8 Pos. Neg.
4.7 43 Normal Normal Pos. Neg.
34 Failure Pos.
FLT3-TKD mutation
CEBPA mutation
DNMT3A mutation
TET2 mutation
IDH1/2 mutation (VAF at diagnosis)
IDH1/2-VAF in CR after induction
IDH1/2-VAF in CR after consolidation
Clinical outcome
Pos.
Neg.
NA
NA
IDH2 p.R140Q (44%)
28.5%
28.1%
Alive in CR1 2 years after AML diagnosis
Neg.
NA
p.R882H (VAF 26%)
Neg.
IDH2 p.R140Q (43%)
0.76%
7.2%
Relapse 4 years after AML diagnosis
Neg.
Neg.
NA
NA
IDH2 p.R140Q (39%)
4.87%
42.9%
MDS 1 year after AML diagnosis
Neg.
Neg.
p.R882H (VAF 48%)
Neg.
IDH2 p.R140Q (47%)
28.1%
39.9%
Relapse 1.5 year after AML diagnosis
Neg.
Neg.
Neg.
Neg.
IDH1 p.R132G (44%)
NA
43.5%
Death after allo-SCT
UPN: unique patient number; F: female; M: male; WBC: white blood cell; Pos.: positive; Neg.: negative; ITD: internal tandem duplication; TKD: tyrosine kinase domain; NA: not available; VAF: variant allele fraction; CR: complete remission; AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; allo-SCT: allogeneic stem cell transplantation.
Table 3. Prognostic analysis for disease-free survival and overall survival.
Disease-free survival Overall survival Multivariate Univariate
Univariate
HR 95%CI P HR 95%CI P HR 95%CI P
Variable
Age* 1.04
Log10 (white blood cell count)* 1.00
NPM1 mutation 0.23
Normal karyotype 0.26
FLT3 internal tandem duplication 1.11
FLT3 tyrosine kinase domain mutation 0.20
DNMT3A mutation 1.42
TET2 mutation 2.66
IDH2 p.R172K mutation 2.04
0.98 1.10
0.99 1.01 0.11 0.50 0.12 0.59 0.33 3.70 0.03 1.48 0.61 3.31 0.58 12.30 0.90 4.61 0.15 0.69
0.202 ----
0.537 ----
1.13 1.00 1.27
1.00 0.99 1.01 0.19 0.05 0.72 0.24 0.07 0.76 1.00 0.12 8.08 - - - 2.42 0.64 9.15
0.047
0.698 0.014 0.016 1.000 0.078 0.192 0.014 0.586 0.208
<0.001 0.001 0.865 0.115 0.413 0.209 0.088 0.004
0.32 0.12 0.88 0.027 0.41 0.17 0.99 0.046 ---- ---- ----
IDH1/2-VAF after induction <0.2% 0.32
HR: hazard ratio; CI: confidence interval;VAF: variant allele fraction; *: continuous variable.
---- 12.59 1.68 94.62 0.85 0.31 2.32 0.751 1.44 0.39 5.34 0.40 0.18 0.90 0.026 0.46 0.14 1.54
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