A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies

Abstract

The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n = 31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO + VEN + AZA versus IVO + VEN was 90% versus 83%. Among measurable residual disease (MRD)-evaluable patients (N = 16), 63% attained MRD--negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N = 14). Median event-free survival and overall survival were 36 [94% CI, 23-not reached (NR)] and 42 (95% CI, 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.

Significance: IVO + VEN + AZA is safe and active in patients with IDH1-mutated myeloid malignancies. Combination therapy appears to overcome resistance mechanisms observed with single-agent IDH-inhibitor use, with high MRD-negative remission rates. Single-cell DNA ± protein and time-of-flight mass-cytometry analysis revealed complex resistance mechanisms at relapse, highlighting key pathways for future therapeutic intervention. This article is highlighted in the In This Issue feature, p. 247.

Figure 1.

Overall response rate and measurable residual disease (MRD) clearance rates by multiparameter flow cytometry (MRD-MFC) and IDH1 digital-droplet PCR (ddPCR) in patients treated with IVO + VEN ± AZA. A, Overall response and composite complete response (CRc) rates across the study cohort. B, Timing of MRD-negative response in 10 patients obtaining MRD-MFC–negative CRc. 90% of patients attained MRD-MFC–negative remissions by 4 cycles of treatment. C, Clearance of IDH1 mutation in remission assessed using ddPCR in patients receiving <5 vs. ≥5 cycles of protocol-directed treatment. IDH1 mutation clearance was improved with continued cycles of therapy with IDH1 mutation clearance observed in 64% of patients receiving ≥5 cycles of treatment. IDH1 mutation clearance was observed across all disease types.

Figure 2.

Overall survival in patients treated with IVO + VEN or IVO + VEN + AZA. A, Overall survival across study cohorts. B, Overall survival by disease type. C, Landmark analysis (5-month landmark shown here, remainder in Supplementary Fig. S10) depicting overall survival based upon IDH1 clearance vs. IDH1 persistence in patients attaining CRc. D, Landmark analysis (4-month landmark) demonstrating overall survival based upon the detection or absence of MRD between C1 and C4 using MFC.

Figure 3.

Bulk NGS and single-cell correlates of relapse in patients treated with IVO + VEN ± AZA. A, Bulk next-generation myeloid gene panel sequencing at the time of diagnosis and at relapse in responding patients treated with IVO + VEN or IVO + VEN + AZA who ultimately relapsed following treatment. B, scDNA-seq in a patient with R/R-AML (Accession #15) at the time of remission and relapse identified expanding leukemic clones contributing to relapse. C, scDNA-seq in a patient with ND-AML (Accession #16) demonstrating differing clonal architecture with respect to signaling mutations and variants throughout treatment. Methyl., methylation; T.S., tumor suppressor.

Figure 4.

scDNA + surface protein (DAb-seq) analysis of a patient with ND-AML (accession #20) treated with IVO + VEN + AZA with subsequent deescalation to IVO maintenance therapy revealed dynamic clonal changes secondary to selective pressure of targeted therapy. A–C, Single-cell analysis at diagnosis, in remission [sampled at end of cycle (EOC) 1, 3, 7, and 9] and after relapse (sampled at EOC 26) identified elimination of IDH1-mutated clones following IVO + VEN + AZA treatment, with persistent mutations in background preleukemic genes. D–F, Analysis of the surface proteome revealed a phenotypic shift occurring between diagnosis and relapse (EOC26), with a more primitive immunophenotype identified at relapse following IVO maintenance. G, Paired genotype–phenotype analysis demonstrated the expanding primitive myeloid progenitor clone contributing to relapse did not contain mutated IDH1. H, Bulk next-generation myeloid panel sequencing in this patient identified outgrowth of a RUNX1 mutation at relapse, poorly covered in the scDNA-seq analysis. NK, natural killer.

Figure 5.

Time-of-flight mass cytometry (CyTOF) identifies cellular pathways associated with divergent CD34⁺ populations. A and B, CyTOF of a patient with ND-AML (accession #20) who attained morphologic remission but remained MRD-positive and developed morphologic relapse following cycle 23. PCA clustering of CyTOF performed in remission (end of cycle 7) identified an expanding CD34⁺ cell population with increased MCL-1 levels. C and D, CyTOF of a patient with ND-AML (accession #27) with an ongoing response following 18 cycles of treatment. In contrast to the previous patient, PCA clustering of CyTOF performed at the end of cycle 3 identified marked reductions in CD34⁺ cell populations with increased BCL-2 levels relative to BCL-xL or MCL-1. NA, not applicable.