All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit Know AML.
Introducing
Now you can personalise
your AML Hub experience!
Bookmark content to read later
Select your specific areas of interest
View content recommended for you
Find out moreThe AML Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the AML Hub cannot guarantee the accuracy of translated content. The AML Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
Bookmark this article
At the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation, the AML Hub will hold a satellite symposium (August 30, 2020 at 8:30 A.M. CEST) on how measurable residual disease (MRD) impacts the outcome of stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). During this satellite symposium, five international experts, Gert Ossenkoppele, Jacqueline Cloos, Christian Thiede, Adriano Venditti, and Charles Craddock, will discuss the latest developments and remaining challenges of MRD assessments in the context of SCT.
Here, we present an overview of a presentation by Matthieu Duchmann on molecular determinants of patient outcome following allogeneic (allo)-SCT, which was given at this year’s European Hematology Association (EHA) Annual Congress.
Isocitrate dehydrogenase (IDH) is commonly mutated in AML, with 20% of patients carrying a mutation in this gene. The aim of the current study was to evaluate the prognostic significance of covariates in each IDH-subtype and also to assess patient outcomes following allo-SCT. The patients included belonged to non-favorable risk categories according to the European LeukemiaNet (ELN) 2010 guidelines1 and were treated with intensive chemotherapy.
A total of 1,493 patients from three separate trials were retrospectively analyzed. Of these, 1,371 had next generation sequencing data available. In total, 319 (23%) patients carried a single IDH1/2 mutation. Out of these patients, 127 had mutations in IDH1R132, 135 in IDH2R140, and 57 in IDH2R172. These patients were treated in three trials: ALFA 0701 (EudraCT 2007-002933-36), ALFA-0702 (NCT00932412) and ALFA-1200 (NCT01966497). Patient baseline characteristics are shown in Table 1.
It is interesting to note that the majority of patients carrying IDH2R172 mutations were female with low white blood cell counts. These patients demonstrated a greater eligibility for hematopoietic stem cell transplant coupled with a lower risk category.
Table 1. Baseline patient characteristics2
CR1, first complete response; ELN-2010, European LeukemiaNet 2010 guidelines; HSCT, hematopoietic stem cell transplant; IDH, isocitrate dehydrogenase; WBC, white blood cell count |
|||
|
IDH1R132 |
IDH2R140 |
IDH2R172 |
---|---|---|---|
Patients, % |
40 |
42 |
18 |
Age, years (range) |
61 (52−67) |
61 (50−67) |
62 (56−68) |
Sex (male), % |
54 |
55 |
39 |
WBC × 109/L (range) |
4.5 (1.6−20.7) |
8.8 (2.3−31.6) |
1.8 (1.2−2.7) |
Cytogenetics, % |
|
|
|
Normal |
63 |
77 |
52 |
Complex |
8 |
2 |
0 |
ELN-2010 risk, % |
|
|
|
Favorable |
33 |
37 |
0 |
Intermediate-1 |
29 |
39 |
52 |
Intermediate-2 |
22 |
19 |
48 |
Adverse |
16 |
5 |
0 |
HSCT in CR1, % |
|
|
|
Eligible patients |
54 |
57 |
89 |
All patients underwent high-throughput sequencing for 37 genes. Patients with non-favorable criteria (according to ELN 2010 guidelines) that achieved a complete response (CR)/CR with incomplete platelet recovery (CRp) were eligible for allo-SCT if they had a matched unrelated donor or sibling.
Overall, 76% of patients reached a CR/CRp after one round of treatment, with this rising to 83% following a second treatment round. A total of 80% of IDH1-mutated patients achieved a CR/CRp. Out of these, 96% of patients with NPM1 mutations achieved a CR/CRp compared with 66% of those with NPM1 wild type (p < 0.001). Table 2 shows the mutational covariates for each IDH subtype along with the associated survival data. The median follow-up of the whole cohort was 46 months (interquartile range [IQR], 38.0−58.4), median overall survival (OS) was 39.7 months (IQR, 14.7−not reached), and disease-free survival (DFS) was 22.3 months (IQR, 10.8−not reached). It can be noted that the IDH genetic landscape was dominated by mutations in DNMT3A, NPM1, SRSF2, and FLT3-ITD.
Table 2. Significant covariates for IDH subtypes (q < 0.05) 2
BCOR, BCL6 corepressor; FLT3-ITD, FMS-like tyrosine kinase 3-internal tandem duplication; IDH, isocitrate dehydrogenase; NPM1, nucleophosmin 1; NRAS, neuroblastoma RAS proto-oncogene; PHF6, PHD finger protein 6; SRSF2, serine and arginine rich splicing factor 2; WBC, white blood cell count (at diagnosis) |
|
Mutation |
Significant covariates |
---|---|
IDH1 (vs IDH2) |
↑NRAS |
IDH1R132C (vs other IDH) |
↓WBC, FLT3-ITD ↑PHF6, BCOR, and BCORL1 |
IDH1R132H (vs other IDH) |
↑NPM1, FLT3-ITD, and WBC |
IDH2R140 (vs other IDH) |
↑NPM1, FLT3-ITD, SRSF2, WBC, and normal karyotype |
IDH2R172 (vs other IDH) |
↑BCOR ↓NPM1, FLT3-ITD, WBC, and SRSF2 No NPM1 |
Multivariate analysis showed that mutated NPM1 was a predictor of increased OS in patients with IDH1R132 and IDH2R140 mutations (HR, 0.29; CI, 0.16−0.54; p < 0.0001 for both subtypes). For IDH2R140 alone, normal karyotype predicted better OS (HR, 0.38; CI, 0.19−0.78; p = 0.008). The benefit of mutant NPM1 in DFS was only apparent in the IDH2R140 subset without a DNMT3A mutation. Whereas for IDH2R172, only platelet count remained as an independent prognostic factor (HR, 0.19; CI 0.07−0.53; p = 0.002).
A total of 55% patients in first CR received allo-SCT. This treatment was associated with a trend towards prolonged DFS (n = 197; HR, 0.55; CI, 0.34−0.89; p = 0.02) and prolonged OS in eligible patients (HR, 0.60, CI, 0.37−0.96; p = 0.03).
Mutant NPM1 was shown to be the best prognostic factor in patients with IDH1R132 and IDH2R140 mutations and could be used to stratify patients in clinical trials. In IDH2R140, DNMT3A mutations and normal karyotype could be used to refine the prognosis. For IDH2R172, the platelet count was the main prognostic factor. In non-favorable IDH1/2-mutated AML, SCT in the first CR may improve outcome.
Your opinion matters
Subscribe to get the best content related to AML delivered to your inbox