Longitudinal Molecular Profiling in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib
Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6-10% of patients (pts) with acute myeloid leukemia (AML), resulting in production of the oncometabolite D-2-hydroxyglutarate. Ivosidenib (IVO) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) and is FDA-...
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Veröffentlicht in: | Blood 2020-11, Vol.136 (Supplement 1), p.2-3 |
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Sprache: | eng |
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Zusammenfassung: | Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6-10% of patients (pts) with acute myeloid leukemia (AML), resulting in production of the oncometabolite D-2-hydroxyglutarate. Ivosidenib (IVO) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) and is FDA-approved for the treatment of mIDH1 relapsed or refractory (R/R) AML and mIDH1 newly diagnosed (ND) AML in adults ≥ 75 years of age or with comorbidities precluding intensive induction chemotherapy. In a phase 1 study (NCT02074839), durable remissions in pts with mIDH1 ND AML (n = 33) were achieved with IVO, with a complete remission (CR) plus CR with partial hematologic recovery (CRh) rate of 42.4%, and median overall survival of 12.6 months (mo), as of 02Nov2018. The most frequent co-occurring mutations at baseline were ASXL1, DNMT3A, RUNX1, SRSF2, TET2, and NRAS.
Aim: To characterize the longitudinal evolution of gene mutations in pts with mIDH1 ND AML treated with IVO 500 mg once daily, including relapse mechanisms and depth of molecular response for mIDH1 and co-occurring mutations.
Methods: The mIDH1 variant allele frequency (VAF) was assessed in bone marrow mononuclear cells (BMMCs), peripheral blood mononuclear cells (PBMCs), and neutrophils using BEAMing digital polymerase chain reaction (PCR) technology (Sysmex Inostics, Inc.), which has a lower limit of detection for mIDH1 of 0.02-0.04%. Deep IDH1 mutation clearance (MC) was defined as reduction in mIDH1 VAF to below the limit of detection for ≥ 1 on-treatment timepoint. Baseline and longitudinal co-occurring mutation profiling was conducted on BMMC or PBMC samples by next-generation sequencing (NGS; detection sensitivity of 1-5%). Single-cell targeted DNA sequencing (DNA-seq) was performed on PBMCs using a microfluidic platform (Tapestri®). The clinical data cut-off for this analysis was 02Nov2018.
Results: In pts who achieved a best response of CR or CRh, the IDH1-MC rate in BMMCs was 64.3% (9/14), and 72.7% (8/11) in both PBMCs and neutrophils, by sensitive digital PCR (Table). Median time to IDH1-MC was 7.4 mo (BMMCs), 6.9 mo (PBMCs), and 5.1 mo (neutrophils) in pts achieving CR or CRh. IDH1-MC was significantly associated with a best response of CR or CRh (p < 0.001, Table). Overall survival at 12 mo was 88.9% (95% CI 43.3, 98.4) for pts with IDH1-MC in BMMCs (n = 9), as compared with 38.5% (95% CI 17.7, 59.0) for pts who did not achieve IDH1-MC (n = 21). The longitudinal evolution of mIDH1 and c |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2020-136589 |