The University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, Texas.
The University of Texas MD Anderson Cancer Center, Department of Hematopathology, Houston, Texas.
Blood Cancer Discov. 2023 Jul 5;4(4):276-293. doi: 10.1158/2643-3230.BCD-22-0205.
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.
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.
评估了异柠檬酸脱氢酶 1（IDH1）抑制剂ivosidenib（IVO）与 BCL2 抑制剂 venetoclax（VEN；IVO + VEN）±阿扎胞苷（AZA；IVO + VEN + AZA）联合用于 IDH1 突变髓系恶性肿瘤患者的安全性和有效性（n = 31）。大多数（91%）不良事件为 1 级或 2 级。未达到最大耐受剂量。IVO + VEN + AZA 与 IVO + VEN 的复合完全缓解率分别为 90%和 83%。在可测量残留疾病（MRD）可评估患者中（n = 16），63%的患者获得了 MRD 阴性缓解；接受≥5 个治疗周期的患者（n = 14）中，64%的患者发生 IDH1 突变清除。无事件生存和总生存中位数分别为 36 [94%CI，23-NR]和 42（95%CI，42-NR）个月。信号基因突变患者似乎特别受益于三联疗法。纵向单细胞蛋白质基因组学分析将共存突变、抗凋亡蛋白表达和细胞成熟与 IDH1 突变克隆的治疗敏感性联系起来。未观察到 IDH 同工型转换或第二个 IDH1 突变，表明联合治疗可能克服单一药物 IVO 的既定耐药途径。
IVO + VEN + AZA 对 IDH1 突变髓系恶性肿瘤患者安全且有效。联合治疗似乎克服了单一药物 IDH 抑制剂使用中观察到的耐药机制，具有较高的 MRD 阴性缓解率。单细胞 DNA ± 蛋白质和飞行时间质谱细胞术分析在复发时揭示了复杂的耐药机制，突出了未来治疗干预的关键途径。本文在本期内的特色文章中得到了强调，第 247 页。
