The clonal basis of either resistance or response to ivosidenib and venetoclax ± azacitidine is established early in IDH1-mutated myeloid malignancies

A recent phase Ib/II trial of ivosidenib and venetoclax ± azacitidine in patients with IDH1-mutated myeloid malignancies showed a promising 94% response rate. However, relapse was still common. To define the clonal and cellular basis of acquired resistance and sustained response, we performed single-cell studies on longitudinal samples from 8 patients. Whilst all 8 patients initially responded to treatment, 6 relapsed and 2 remained in sustained remission for > 4 years. Therapy-resistant clones were selected early, within 3 treatment cycles, preceding relapse by months or years. Treatment failure was associated with either emerging genetically evolved clones or acquired differentiation arrest of pre-existing clones; in both cases, within small immunophenotypic leukemic stem cell (LSC) populations. In sustained response, all leukemic clones were eradicated and rapidly replaced by clonal and wild type hematopoiesis. If validated in larger cohorts, early clonal assessment of LSCs may be predictive of long-term outcome, providing a clinically relevant endpoint. Plate-based single-cell RNA-seq coupled with single-cell targeted genotyping of genomic loci. Results are from primary human samples