Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida.
Sylvester Comprehensive Cancer Center, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida.
Clin Cancer Res. 2021 Apr 1;27(7):1893-1903. doi: 10.1158/1078-0432.CCR-20-4054. Epub 2021 Jan 25.
In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).
Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).
ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34 cell phenotype at baseline, including decreased and expression, compared with nonresponders that exhibited a more proliferative CD34 phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.
These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
在临床前研究中，赖氨酸特异性组蛋白去甲基化酶 1A（LSD1）抑制剂曲安西龙（TCP）与全反式维甲酸（ATRA）联合使用可诱导髓系白血病细胞分化，并损害非急性早幼粒细胞白血病急性髓系白血病（AML）中的髓样前体细胞的存活。我们进行了一项 I 期临床试验（NCT02273102），以评估 ATRA 加 TCP 在复发性/难治性 AML 和骨髓增生异常（MDS）患者中的安全性和活性。
17 名患者接受 ATRA 和 TCP 治疗（三个剂量水平：每天两次 10mg、每天两次 20mg 和每天两次 30mg）。
ATRA-TCP 具有可接受的安全性特征。TCP 的最大耐受剂量为每天两次 20mg。最佳反应包括 1 例形态学白血病无状态、1 例骨髓完全缓解伴血液学改善、2 例稳定疾病伴血液学改善和 2 例稳定疾病。按意向治疗，总缓解率为 23.5%，临床获益率为 35.3%。患者白血病细胞的基因表达谱分析表明，与未应答者相比，应答者在基线时具有更静止的 CD34 细胞表型，包括 表达和 表达减少，而未应答者表现出更具增殖性的 CD34 表型，具有细胞生长信号的基因表达富集。在用 ATRA-TCP 治疗后，我们观察到应答者中显著诱导了维甲酸靶基因的表达，而未应答者中则没有。在 AML 细胞系中，我们证实 ATRA-TCP 通过调节关键基因集的表达，协同增加分化能力和细胞死亡，这些基因集将患者按其临床反应进行分类。
这些数据表明 LSD1 抑制使 AML 细胞对 ATRA 敏感，并可能恢复 MDS 和 AML 患者亚群对 ATRA 的反应性。
