Hughes Keira, Evans Kathryn, Earley Eric J, Smith Christopher M, Erickson Stephen W, Stearns Tim, Philip Vivek M, Neuhauser Steven B, Chuang Jeffrey H, Jocoy Emily L, Bult Carol J, Teicher Beverly A, Smith Malcolm A, Lock Richard B
Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.
RTI International, Research Triangle Park, North Carolina, USA.
Pediatr Blood Cancer. 2023 Jun 20:e30503. doi: 10.1002/pbc.30503.
While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high-risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B-lineage ALL (B-ALL). Activating mutations or overexpression of Fms-related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK-659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK-659 against pediatric ALL patient-derived xenografts (PDXs).
SYK and FLT3 mRNA expression was quantified by RNA-seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45 cells (%huCD45 ) in the peripheral blood. TAK-659 was administered per oral at 60 mg/kg daily for 21 days. Events were defined as %huCD45 ≥ 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event-free survival and stringent objective response measures.
FLT3 and SYK mRNA expression was significantly higher in B-lineage compared with T-lineage PDXs. TAK-659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45 was significantly reduced in five out of eight PDXs in TAK-659-treated mice compared with vehicle controls.
TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.
虽然急性淋巴细胞白血病（ALL）患儿的治愈可能性接近90%，但某些高危儿科ALL亚型的预后仍然很差。脾酪氨酸激酶（SYK）是儿科B系ALL（B-ALL）中一种突出的胞质非受体酪氨酸激酶。Fms相关受体酪氨酸激酶3（FLT3）的激活突变或过表达与血液系统恶性肿瘤的不良预后相关。TAK-659（米伐替尼）是一种双重SYK/FLT3可逆抑制剂，已在其他几种血液系统恶性肿瘤中进行了临床评估。在此，我们研究TAK-659对儿科ALL患者来源异种移植瘤（PDXs）的体内疗效。
通过RNA测序对SYK和FLT3 mRNA表达进行定量。通过计数外周血中人CD45细胞的比例（%huCD45）评估NSG小鼠中的PDX植入和药物反应。TAK-659按每日60 mg/kg口服给药，持续21天。事件定义为%huCD45≥25%。此外，对小鼠实施安乐死以评估脾脏和骨髓（BM）中的白血病浸润情况。通过无事件生存期和严格的客观反应指标评估药物疗效。
与T系PDXs相比，B系中FLT3和SYK mRNA表达显著更高。TAK-659耐受性良好，在8个测试的PDXs中有6个显著延长了至事件发生的时间。然而，只有1个PDX达到了客观反应。与赋形剂对照组相比，TAK-659治疗的小鼠中8个PDXs中有5个的最小平均%huCD45显著降低。
TAK-659对代表不同亚型的儿科ALL PDXs表现出低至中等的单药体内活性。
