IDH1 Mutations Are Detected in 9.3% of All AML and Are Strongly Associated with Intermediate Risk Karyotype and Unfavourable Prognosis: a Study of 999 Patients
Authors: Schnittger Susanne , Haferlach Claudia , Ulke Madlen , Kaya Leyla , Weiss Tamara , Kern Wolfgang , Haferlach Torsten 
Published: October 2019

Abstract
Abstract LBA-3

Introduction:
IDH1 is the gene coding for the soluble isocitrate dehydrogenease 1 (NADP+), which catalyzes the oxidative decaroxylation of isocitrate to 2-oxoglutarate. The gene has been shown to be frequently mutated in high-grade gliomas at residue p.R132, which is located in the substrate binding site of IDH1. So far, several other tumors have been analyzed without detection of the respective mutation (Bleeker et al., Human Mutation 2009). However, recently a next generation sequencing project found IDH1 mutated in 8.5% of AML with normal karyotype (Mardis et al., NEJM, 2009).

Aim:
To further evaluate the importance of IDH1R132 (IDH1mut) in AML we have analyzed a cohort of 999 comprehensively characterized AML cases.

Methods:
The respective base exchange was analysed by a LightCycler based melting curve assay with subsequent sequencing of the positive samples.

Results:
The cohort was comprised of 536 male and 463 female patients (median age: 65.9 years; range: 17.1- 93.3 years). 833 had de novo AML (83.4%), 122 AML following MDS (s-AML,12.1%) and 44 AML after previous treatment of different malignancies (t-AML, 4.4%). Karyotype was available in all cases: 681 had a normal karyotype (NK) AML, and 319 had chromosomal aberrations (t(15;17): n=29; inv(16): n=12, t(8;21): n=23, t(11q23): n=10, t(6;9): n=4, inv(3): n=3; -7: n=27, +8: n=29, +13: n=11, -Y: n=4; complex aberrant: n=60, others: n=106). Overall, in 93 pts IDH1 p.R132 mutations were detected (9.3%). Five different amino acid exchanges were observed: R132C (n=49), R132L (n=22), R132 H and G (n=7, each), and R132S (n=5). With respect to history of the patient IDH1mut were found in 80/833 of de novo AML (9.6%), 11/122 (9.0%) of s-AML, and 2/44 (4.5%) of t-AML, respectively (n.s.). More females (57/463, 12.3%) than males (36/536; 6.7%) had IDH1mut (p=0.003). Age was slightly higher in the mutated cases (63.9 vs. 61.9 years, n.s.). No differences were found for WBC count. IDH1mut were distributed differently between karyotypes: in NK 69/681 (10.1%) and in aberrant karyotypes 24/318 (7.5%). However, IDH1 was never mutated in inv(16), t(8;21), t(6;9), t(11q23), inv(3), or in complex aberrant karyotypes (n=112). In 2 of 27 cases (7.4%) with t(15;17) an IDH1 mutation was detected. Thus, the IDH1 mututations clustered in the intermediate risk karyotype group in comparison to the good or poor risk groups (91/771; 11.8% vs 2/134 (1.5%), p<0.001). The cohort was also characterized for several other molecular mutations. FLT3-ITD was present in 22% (212/954), FLT3-TKD in 6.7% (33/496), NPM1 in 35.4% (329/929), NRAS in 14.6% (48/328), MLL-PTD in 6.9% (64/932), CEBPA mutations in 7.4% (48/645) and RUNX1 mutations in 33.0% (99/299) of analysed cases, respectively. IHD1 mutations were found to be more frequent in NPM1 mutated than in NPM1wt cases (41/329; 12.4% vs 48/598; 8.0%, p= 0.019) and in those with MLL-PTD (11/64; 17.2% vs 77/867; 8.9%, p= 0.031). With lower frequencies IDH1mut were also detected together with RUNX1 mutations (n=8/99), CEBPA mutations (n=2/48), NRAS mutations (n=7/48), and FLT3-TKD (n=1/33). IDH1 was similarly distributed between FLT3-ITD mutated and unmutated cases (18/212; 8.5% vs. 72/744; 9.7%). In 22 (23.7%) of all IDH1mut AML no additional mutation was detected, whereas in 48 (51.6%) one additional, in 22 (23.7%) two additional and in one case three additional mutations were found. An unfavourable effect of IDH1mut on event free survival (EFS) was observed in the total group (median: 272 vs. 456 days; p=0.007) as well as in those with intermediate risk karyotype (median: 272 vs. 449 days; p=0.008). A shorter EFS of the IDH1mut was particularly seen in the NPM1wt cohort (median: 244 vs. 375 days; p=0.038) with a strong trend for an independent effect in a multivariate analysis (p=0.089).

Conclusions:
IDH1 mutations are frequent in AML and are prognostically unfavourable especially in the NPM1wt cohort. IDH1 mutations seem to be a new class of mutation probably complementing with the classical type 1 and type 2 mutations.

Disclosures:
Schnittger: MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Ulke:MLL Munich Leukemia Lab: Employment. Kaya:MLL Munich Leukemia Lab: Employment. Weiss:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.