Children's Cancer Centre, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
Department of Pediatrics, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Cancer Res Commun. 2024 Sep 1;4(9):2553-2564. doi: 10.1158/2767-9764.CRC-24-0338.
Patients with anaplastic lymphoma kinase (ALK)-driven neuroblastoma may respond to tyrosine kinase inhibitors, but resistance to treatment occurs and methods currently used for detection of residual disease have limited sensitivity. Here, we present a national unselected cohort of five patients with relapsed or refractory ALK-driven neuroblastoma treated with lorlatinib as monotherapy and test the potential of targeted circulating tumor DNA (ctDNA) analysis as a guide for treatment decisions in these patients. We developed a sequencing panel for ultrasensitive detection of ALK mutations associated with neuroblastoma or resistance to tyrosine kinase inhibitors and used it for ctDNA analysis in 83 plasma samples collected longitudinally from the four patients who harbored somatic ALK mutations. All four patients with ALK p.R1275Q experienced major responses and were alive 35 to 61 months after starting lorlatinib. A fifth patient with ALK p.F1174L initially had a partial response but relapsed after 10 months of treatment. In all cases, ctDNA was detected at the start of lorlatinib single-agent treatment and declined gradually, correlating with clinical responses. In the two patients exhibiting relapse, ctDNA increased 9 and 3 months, respectively, before clinical detection of disease progression. In one patient harboring HRAS p.Q61L in the relapsed tumor, retrospective ctDNA analysis showed that the mutation appeared de novo after 8 months of lorlatinib treatment. We conclude that some patients with relapsed or refractory high-risk neuroblastoma show durable responses to lorlatinib as monotherapy, and targeted ctDNA analysis is effective for evaluation of treatment and early detection of relapse in ALK-driven neuroblastoma.
We present five patients with ALK-driven relapsed or refractory neuroblastoma treated with lorlatinib as monotherapy. All patients responded to treatment, and four of them were alive after 3 to 5 years of follow-up. We performed longitudinal ctDNA analysis with ultra-deep sequencing of the ALK tyrosine kinase domain. We conclude that ctDNA analysis may guide treatment decisions in ALK-driven neuroblastoma, also when the disease is undetectable using standard clinical methods.
具有间变性淋巴瘤激酶（ALK）驱动的神经母细胞瘤的患者可能对酪氨酸激酶抑制剂有反应，但治疗会产生耐药性，并且目前用于检测残留疾病的方法敏感性有限。在这里，我们提出了一个由五个患有复发性或难治性 ALK 驱动的神经母细胞瘤的患者组成的全国性未选择队列，这些患者接受了 lorlatinib 作为单一疗法治疗，并测试了靶向循环肿瘤 DNA（ctDNA）分析作为指导这些患者治疗决策的潜力。我们开发了一个用于超灵敏检测与神经母细胞瘤相关或对酪氨酸激酶抑制剂耐药的 ALK 突变的测序面板，并在从携带体细胞 ALK 突变的四名患者中纵向收集的 83 个血浆样本中使用该面板进行 ctDNA 分析。所有四名患有 ALK p.R1275Q 的患者均经历了重大反应，并在开始 lorlatinib 治疗后 35 至 61 个月时存活。一名患有 ALK p.F1174L 的第五名患者最初有部分反应，但在治疗 10 个月后复发。在所有情况下，在开始 lorlatinib 单药治疗时检测到 ctDNA，并随着临床反应逐渐下降。在表现出疾病复发的两名患者中，ctDNA 分别在临床检测到疾病进展前 9 个月和 3 个月增加。在一名患有复发性肿瘤中 HRAS p.Q61L 的患者中，回顾性 ctDNA 分析显示该突变在 lorlatinib 治疗 8 个月后新出现。我们得出结论，一些患有复发性或难治性高危神经母细胞瘤的患者对 lorlatinib 单药治疗有持久反应，并且靶向 ctDNA 分析可有效评估治疗效果并早期检测 ALK 驱动的神经母细胞瘤复发。
我们提出了五例接受 lorlatinib 单药治疗的 ALK 驱动的复发性或难治性神经母细胞瘤患者。所有患者均对治疗有反应，其中 4 例在随访 3 至 5 年后仍存活。我们进行了 ALK 酪氨酸激酶结构域的超深度测序纵向 ctDNA 分析。我们得出结论，ctDNA 分析可能指导 ALK 驱动的神经母细胞瘤的治疗决策，即使使用标准临床方法无法检测到疾病也是如此。
