Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

Desiree Kunadt, Sebastian Stasik, Klaus H Metzeler, Christoph Röllig, Christoph Schliemann, Philipp A Greif, Karsten Spiekermann, Maja Rothenberg-Thurley, Utz Krug, Jan Braess, Alwin Krämer, Andreas Hochhaus, Sebastian Scholl, Inken Hilgendorf, Tim H Brümmendorf, Edgar Jost, Björn Steffen, Gesine Bug, Hermann Einsele, Dennis Görlich, Cristina Sauerland, Kerstin Schäfer-Eckart, Stefan W Krause, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Bernhard Wörmann, Michael Kramer, Katja Sockel, Katharina Egger-Heidrich, Tobias Herold, Gerhard Ehninger, Andreas Burchert, Uwe Platzbecker, Wolfgang E Berdel, Carsten Müller-Tidow, Wolfgang Hiddemann, Hubert Serve, Matthias Stelljes, Claudia D Baldus, Andreas Neubauer, Johannes Schetelig, Christian Thiede, Martin Bornhäuser, Jan M Middeke, Friedrich Stölzel, A. M. L. Cooperative Group (AMLCG), Study Alliance Leukemia (SAL), Desiree Kunadt, Sebastian Stasik, Klaus H Metzeler, Christoph Röllig, Christoph Schliemann, Philipp A Greif, Karsten Spiekermann, Maja Rothenberg-Thurley, Utz Krug, Jan Braess, Alwin Krämer, Andreas Hochhaus, Sebastian Scholl, Inken Hilgendorf, Tim H Brümmendorf, Edgar Jost, Björn Steffen, Gesine Bug, Hermann Einsele, Dennis Görlich, Cristina Sauerland, Kerstin Schäfer-Eckart, Stefan W Krause, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Bernhard Wörmann, Michael Kramer, Katja Sockel, Katharina Egger-Heidrich, Tobias Herold, Gerhard Ehninger, Andreas Burchert, Uwe Platzbecker, Wolfgang E Berdel, Carsten Müller-Tidow, Wolfgang Hiddemann, Hubert Serve, Matthias Stelljes, Claudia D Baldus, Andreas Neubauer, Johannes Schetelig, Christian Thiede, Martin Bornhäuser, Jan M Middeke, Friedrich Stölzel, A. M. L. Cooperative Group (AMLCG), Study Alliance Leukemia (SAL)

Abstract

Background: The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K).

Methods: Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal-Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate.

Results: Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002).

Conclusion: In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.

Trial registration: ClinicalTrials.gov NCT03188874 NCT00180115 NCT00180102 NCT00266136 NCT00180167 NCT01382147 NCT00893373.

Keywords: Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; IDH mutations.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Consort diagram of patients’ distributions. Consort diagram of the study cohorts’ distribution according to the type of consolidation strategy (alloHCT vs. chemo-consolidation), IDH mutational status and respective submutational groups
Fig. 2
Fig. 2
Heatmap of frequent co-mutations according to IDH mutation status. Heatmap grouped for epigenetic, signaling, transcription, cohesion and splicing pathways of AML patients achieving CR1 with IDH wildtype (IDH-wt) or mutated IDH (IDH-mut). Only patients from the SAL registry with a full dataset of myeloid panel sequencing were included
Fig. 3
Fig. 3
Overall survival and relapse-free survival according to IDH mutation status and allogeneic hematopoietic cell transplantation in CR1. Simon–Makuch plots for a overall survival and b relapse-free survival of AML patients with IDH wildtype (WT) or mutated (mut) IDH treated with allogeneic hematopoietic cell transplantation (blue for IDHWT and violet for IDHmut) or conventional consolidation (red for IDHWT and green for IDHmut), respectively; p-values were determined with Cox model with time-dependent modeling of alloHCT; time in months
Fig. 4
Fig. 4
Overall survival according to IDH, IDH1 and IDH2 mutational status and allogeneic hematopoietic cell transplantation in CR1. Simon–Makuch plots for a overall survival and b relapse-free survival of AML patients with mutated (mut) IDH, IDH1 and IDH2 treated with allogeneic hematopoietic cell transplantation (blue) or conventional consolidation (red), respectively; p‐values were determined with Cox model with time‐dependent modeling of alloHCT; time in months; ns = not significant
Fig. 5
Fig. 5
Overall survival and relapse-free survival according to IDH1 and IDH2 mutational subgroups and allogeneic hematopoietic cell transplantation in CR1. Simon–Makuch plots for a and c overall survival and b and d relapse-free survival of AML patients with mutated IDH1 R132C, IDH1 R132H, IDH2 R140 and IDH2 R172 mutational subgroups treated with allogeneic hematopoietic cell transplantation (blue) or conventional consolidation (red), respectively; p-values were determined with Cox model with time-dependent modeling of alloHCT; time in months; ns = not significant
Fig. 6
Fig. 6
Multivariable Cox model with single interaction terms. Single interaction terms for a overall survival and b relapse-free survival for IDH submutational groups IDH1 R132C, IDH1 R132H, IDH2 R140Q and IDH2 R172K, other IDH mutational subgroups (other) or IDH wildtype (wt) with either allogeneic hematopoietic cell transplantation (alloHCT) or chemo-consolidation (noHCT); p-values and hazard ratios were determined with Cox model

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