University of California San Francisco, Benioff Children's Hospital, San Francisco, CA.
Notable Labs, Foster City, CA.
JCO Precis Oncol. 2023 Sep;7:e2300302. doi: 10.1200/PO.23.00302.
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric malignancy with myelodysplastic and myeloproliferative features. Curative treatment is restricted to hematopoietic stem-cell transplantation. Fludarabine combined with cytarabine (FLA) and 5-azacitidine (AZA) monotherapy are commonly used pre-transplant therapies. Here, we present a drug screening strategy using a flow cytometry-based precision medicine platform to identify potential additional therapeutic vulnerabilities.
We screened 120 dual- and 10 triple-drug combinations (DCs) on peripheral blood (n = 21) or bone marrow (n = 6) samples from 27 children with JMML to identify DCs more effectively reducing leukemic cells than the DCs' components on their own. If fewer leukemic cells survived a DC ex vivo treatment compared with that DC's most effective component alone, the drug effect was referred to as cooperative. The difference between the two resistant fractions is the effect size.
We identified 26 dual- and one triple-DC more effective than their components. The differentiation agent tretinoin (TRET; all-trans retinoic acid) reduced the resistant fraction of FLA in 19/21 (90%) samples (decrease from 15% [2%-61%] to 11% [2%-50%] with a mean effect size of 3.8% [0.5%-11%]), and of AZA in 19/25 (76%) samples (decrease from 69% [34%-100+%] to 47% [17%-83%] with a mean effect size of 16% [0.3%-40%]). Among the resistant fractions, the mean proportion of CD38 cells increased from 7% (0.03%-25%; FLA) to 17% (0.3%-38%; FLA + TRET) or from 10% (0.2%-31%; AZA) to 51% (0.8%-88%; AZA + TRET).
TRET enhanced the effects of FLA and AZA in ex vivo assays with primary JMML samples.
幼年型粒单核细胞白血病（JMML）是一种具有骨髓增生异常和骨髓增殖性特征的侵袭性儿科恶性肿瘤。治愈性治疗仅限于造血干细胞移植。氟达拉滨联合阿糖胞苷（FLA）和 5-氮杂胞苷（AZA）单药治疗是移植前常用的治疗方法。在这里，我们使用基于流式细胞术的精准医学平台进行药物筛选策略，以确定潜在的额外治疗弱点。
我们对 27 名 JMML 患儿的外周血（n=21）或骨髓（n=6）样本进行了 120 种双药和 10 种三药组合（DC）的筛选，以确定比自身成分更有效地减少白血病细胞的 DC。如果与 DC 最有效的成分单独治疗相比，DC 体外处理后存活的白血病细胞更少，则药物作用被称为协同作用。两个耐药分数之间的差异是作用大小。
我们确定了 26 种双药和一种三药比其成分更有效。分化剂维甲酸（TRET；全反式维甲酸）降低了 19/21（90%）样本中 FLA 的耐药分数（从 15%[2%-61%]降至 11%[2%-50%]，平均作用大小为 3.8%[0.5%-11%]），并降低了 19/25（76%）样本中 AZA 的耐药分数（从 69%[34%-100+%]降至 47%[17%-83%]，平均作用大小为 16%[0.3%-40%]）。在耐药分数中，CD38 细胞的平均比例从 7%（0.03%-25%；FLA）增加到 17%（0.3%-38%；FLA+TRET）或从 10%（0.2%-31%）增加到 51%（0.8%-88%；AZA+TRET）。
TRET 增强了原代 JMML 样本中 FLA 和 AZA 的体外试验效果。
