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Phase 1 study of the histone deacetylase inhibitor entinostat plus clofarabine for poor-risk Philadelphia chromosome-negative (newly diagnosed older adults or adults with relapsed refractory disease) acute lymphoblastic leukemia or biphenotypic leukemia
Leukemia Research ( IF 2.1 ) Pub Date : 2021-09-10 , DOI: 10.1016/j.leukres.2021.106707
Hetty E Carraway 1 , Yazeed Sawalha 2 , Ivana Gojo 3 , Min-Jung Lee 4 , Sunmin Lee 4 , Yusuke Tomita 4 , Akira Yuno 4 , Jackie Greer 3 , B Douglas Smith 3 , Keith W Pratz 5 , Mark J Levis 3 , Steven D Gore 6 , Nilanjan Ghosh 7 , Amy Dezern 3 , Amanda L Blackford 3 , Maria R Baer 8 , Lia Gore 9 , Richard Piekarz 6 , Jane B Trepel 4 , Judith E Karp 3
Affiliation  

PURPOSE

Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL.

EXPERIMENTAL DESIGN

Adults >60 years with ND ALL/ABL or >21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m2/day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age >21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy.

RESULTS

Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32%; it was 50% for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined.

CONCLUSION

Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted.



中文翻译:

组蛋白去乙酰化酶抑制剂恩替司他加氯法拉滨治疗低风险费城染色体阴性(新诊断的老年人或患有复发难治性疾病的成人)急性淋巴细胞白血病或双表型白血病的 1 期研究

目的

尽管免疫疗法取得了进展,但费城染色体阴性、新诊断 (ND) 或复发/难治性 (R/R) 急性淋巴细胞白血病/急性双表型白血病 (ALL/ABL) 成人的预后仍然很差。苯甲酰胺衍生物恩替司他抑制组蛋白去乙酰化酶并诱导组蛋白高乙酰化。嘌呤核苷类似物氯法拉滨已获 FDA 批准用于 1-21 岁儿童的 R/R ALL。据报道,低剂量的氯法拉滨可诱导 DNA 低甲基化。我们对患有 ND 或 R/R ALL/ABL 的成人进行了低剂量氯法拉滨和递增剂量恩替司他的 1 期研究。

实验设计

> 60 岁的 ND ALL/ABL 或> 21 岁的 R/R ALL/ABL成人每 3 周接受一次重复周期的恩替司他(第 1 天和第 8 天口服 4 mg、6 mg 或 8 mg)和氯法拉滨(10 mg/m 2 次/天 IV 持续 5 天,第 3-7 天)(A 组)。40-59 岁的 ND ALL/ABL 或首次复发年龄> 21 岁的成年人在第 11 天(B 组)传统化疗前接受恩替司他和氯法拉滨。在治疗前和治疗期间测量 PBMC 中 DNA 损伤、整体蛋白赖氨酸乙酰化、骨髓来源的抑制细胞和单核细胞的变化。

结果

28 名患者接受了三种恩替司他剂量水平的治疗,最大给药剂量为 8 毫克恩替司他。该方案耐受性良好,感染和代谢紊乱在老年人群中比在年轻人群中更常见。在这项小型研究中,没有严重的高血糖症和周围神经病变。有 2 人死亡(1 例败血症,1 例颅内出血)。总体响应率为 32%;ND ALL/ABL 为 50%。Entinostat 增加整体蛋白质乙酰化并抑制免疫抑制单核细胞亚群,而氯法拉滨在所有检查的细胞亚群中诱导 DNA 损伤。

结论

恩替司他加氯法拉滨似乎对患有 ND ALL/ABL 的老年人具有耐受性和活性,但在 R/R 患者中活性较低。似乎有必要在 ND ALL/ABL 中进一步评估该方案。

更新日期:2021-09-10
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