Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: Results from a large multicenter study

Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are amongst the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Among 4930 patients (median age 56 years, interquartile range 45-66) with newly diagnosed, intensively treated AML, we have identified IDH1 mutations (mIDH1) in 423 (8.6%) and IDH2 mutations (mIDH2) in 575 (11.7%) patients. Overall, there were no differences in response rates or survival for patients with mIDH1 or mIDH2 compared to patients without mutated IDH1/2. However, distinct clinical and co-mutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with significantly increased age, lower white blood cell count (WBC), less frequent co-mutation of NPM1 and FLT3-ITD as well as lower rate of complete remissions and a trend for reduced overall survival (OS) compared to other mIDH1 variants and wtIDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC, more karyotype abnormalities, and less frequent co-mutations of NPM1 and/or FLT3-ITD. Among patients within the ELN2017 intermediate- and adverse-risk groups, RFS and OS were significantly better for patients with IDH2-R172K compared to wtIDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific co-mutation pattern and favorable outcome. In summary, the presented data from a large cohort of IDH1/2 mutant AML patients indicate novel and clinically relevant findings for the most common IDH-mutation subtypes.

Involvement of subventricular zone shortened the survival of pediatric glioblastoma

PURPOSE Glioblastoma involved with subventricular zone (SVZ) predicted a worse outcome in adult, but we know less about it based on children population due to the rarity of pediatric glioblastoma (pGBM). We performed this study to probe into the clinical and prognostic features of glioblastoma involved with SVZ in children. METHODS We selected thirty-one patients diagnosed with pediatric supratentorial glioblastoma at our department between January 2015 and January 2020. Clinical data and prognostic results were reviewed retrospectively. RESULTS Involvement of SVZ was associated with larger tumor volume (p = 0.007), lower edema index (EI) (p = 0.010), passive adjuvant therapy (p = 0.029), worse progression-free survival (PFS) (p = 0.001) and overall survival (OS) (p < 0.001), it didn’t correlate to age, sex, preoperative KPS, extent of resection (EOR), tumor side, Ki-67, expression of P53 and ATRX and mutation of IDH1 and IDH2 genes. Independent of EOR and adjuvant therapies, involvement of SVZ was a prognostic factor of PFS and OS in pGBM. CONCLUSION Involvement of SVZ was an independent prognostic factor of PFS and OS in pGBM, and it associated with large volume, mild edema and passive adjuvant therapy. More research should be developed to optimize the treatment strategy of pGBM involved with SVZ.

Serum 2-Hydroxyglutarate Level Can Predict IDH2 Mutation in Myeloid Sarcoma

Myeloid sarcoma (MS) is defined as a tumor mass consisting of myeloid blasts with or without maturation occurring at an anatomical site other than bone marrow (BM). MS may occur before, concurrently or after a characterized acute myeloid leukemia (AML). Cytogenetic abnormalities are found in 50% of the cases but molecular alterations are less well described and involved FLT3 and/or NPM1 mutations. Mutations in IDH1 and IDH2 genes are found in 15% to 20% of patients with AML but have never been described in MS. Mutated IDH enzymes produce in vast excess D-2-hydroxyglutarate (2-HG) in leukemic cells, which can act as a biomarker predictive of the presence of IDH1 and IDH2 mutations. As availability of DNA sequencing techniques on paraffin samples are limited, molecular characterization of MS remained difficult. We asked whether in MS, serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis, and could provide a biomarker for follow up. Tissue samples and serum samples from 8 patients with a MS diagnosis were analyzed. High quality genomic DNA was extracted from frozen MS samples using conventional phenol/chloroforme extraction procedures. Exon 4 of IDH1 and IDH2 genes (IDH1/R132 and IDH2/R140 and /R172 codons) was amplified by PCR using HotStar Taq polymeraze (Qiagen) and primers. Direct sequencing was performed using the Sanger method as previously described. In case of MS relapse or AML evolution, IDH1 and IDH2 genes were analyzed in the same way from frozen tissue sample or bone marrow sample. Serum samples at MS diagnosis were analyzed for total 2-HG, D-2-HG and L-2-HG by reverse-phase liquid chromatography coupled to mass spectrometry. In case of myeloid sarcoma with IDH1/2 mutation, 2-HG values were compared to 18F-FDG-PET results when available during remission phase and at relapse. Three patients (3/8; 37.5%) had an IDH2 R140Q mutation at diagnosis of MS localized to lymph node, soft tissue, skin or pharynx. At MS diagnosis, serum total 2-HG, D-2-HG and ratio D/L-2-HG were significantly higher in case of myeloid sarcoma with IDH2 R140Q mutation compared to patients with no IDH mutation (Table 1). Serum total 2-HG level ≥2µM or D-2-HG level ≥1.8µM or ratio D/L 2-HG >2.5 were significantly associated with the presence of IDH2 mutation (Fisher's exact test P≤0.02). Table 1. Myeloid sarcoma with IDH2 R140Q mutation (N=3) Myeloid sarcoma without IDH2 R140Q mutation (N=5) Median total 2-HG (µM) 4.1 (range: 3.1-30.1) 1.4 (range: 1-1.6) Median D-2-HG (µM) 3.7 (range: 2.3-28) 0.6 (range: 0.5-0.8) Median L-2-HG (µM) 0.8 (range: 0.4-2.1) 0.8 (range: 0.4-0.8) Median ratio D/L 2-HG 8.3 (range: 2.9-18.8) 1 (range: 0.7-1.7) All 3 patients with IDH2 R140Q mutated MS received intensive chemotherapy treatment and achieved complete remission (CR). Two patients relapsed: one experienced isolated extramedullary relapse (thigh muscle); one had a bone marrow relapse. IDH2 R140Q mutation was found at the site of relapse in both cases. When available, serum 2-HG values and 18F-fluorodeoxyglucose-positron-emission tomography (FDG-PET) were compared at different time points (at diagnosis, remission and relapse; Table 2). Table 2. Patient #1 Patient #2 Patient #3 FDG-PET at diagnosis (SUVmax) - 17 5.25 Serum 2-HG at diagnosis (µM) 4.1 3.1 30.1 FDG-PET in remission (SUVmax) 0 - 9.6 (N=4) 0 (N=4) - Serum 2-HG in remission (µM) 0.5 - 1.1 (N=4) 0.6 - 3.1 (N=4) 3.4 - 17.9 (N=3) FDG-PET at MS relapse/evolution to AML (SUVmax) 6.1 - 0 Serum 2-HG at MS relapse/evolution to AML (µM) 2.3 - 16.7 Time between diagnosis and MS relapse/evolution to AML (months) 30 - 9 Serum 2-HG values were in accordance with FDG-PET interpretations except in patient #1 who presented a transient hypermetabolic splenic nodule (SUVmax 9.6) without serum 2-HG increase. Patient #2 remained in CR but had recently increased 2-HG values without overt relapse. Patient #3 presented relapse as a refractory anemia with excess of blast without extra-medullary localization. FDG-PET didn't find any abnormality contrary to the persistent increased value of serum 2-HG (total 2-HG: 16.7µM). These data show that myeloid sarcoma can be associated with IDH2 R140Q mutation and suggest that 2-HG measurement in the serum predicts the presence of IDH1/2 mutations at diagnosis. During follow-up, serum 2-HG values could be representative of the disease status. Because of IDH inhibitors promising results in AML, 2-HG screening at MS diagnosis could be useful. Disclosures Ribrag: Celgene: Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. De Botton:Agios pharmaceuticals: Research Funding.