Functional cure with single agent olutasidenib in relapsed IDH1/NPM1 co-mutated AML

Abstract

Olutasidenib is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) that was recently approved by the US FDA for adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring mutant IDH1. In the pivotal Phase II trial of olutasidenib, the median duration of complete response (CR) was 28.1 months. Here we report the first patient in the world to receive olutasidenib, for relapsed NPM1 and IDH1 co-mutated AML, who remains in continuous CR for over 7 years on olutasidenib monotherapy. We detail the clinical course as well as the pathologic and genomic evolution of the disease. Furthermore, using a novel single cell measurable residual disease assay and digital PCR and qPCR for the detection of IDH1 and NPM1 mutations, we found no evidence of residual detectable leukemia. To our knowledge, this is the first report of an AML patient functionally cured by IDH1 inhibitor monotherapy.

Fig. 1. Bone marrow biopsy before, during and after treatment with olutasidenib.

Representative sections of bone marrow core biopsy and bone marrow aspirates. a, b Numerous blasts are present in the baseline bone marrow sample. c, d Post-induction bone marrow with persistent but decreased blasts with the presence of myeloid differentiation. e, f Post-therapy bone marrow showing remission with maturing trilineage hematopoiesis.

Fig. 2. Comprehensive analysis of MRD negativity using single cell MRD sequencing in relapsed AML patient post olutasidenib.

a Multimodal heatmap illustrating the detected single nucleotide variants (SNV), copy number variant (CNV) ploidy estimation, and antibody-oligonucleotide conjugated (AOC) normalized counts distribution in the patient post- olutasidenib. Numerous single nucleotide polymorphisms and copy number variants were present, but the previously detected NPM1 and IDH1 AML-associated mutations were notably absent. b Louvain-based clustering identified 8 distinct protein clusters. c, d Noise Corrected and Scaled (NSP)-normalization AOC counts distribution does not indicate any leukemic or AML-associated surface protein expression. The absence of any AML-associated mutant or phenotypic clones at single cell resolution, further verifies the patient’s MRD negativity post-olutasidenib.

Fig. 3. Assessing the presence of NPM1 and IDH1 mutant alleles using digital PCR in an AML patient from relapse to long-term remission.

Digital PCR was performed for NPM1 and IDH1 mutations at the indicated timepoints.