Abstract:
Juvenile myelomonocytic leukemia (JMML), which is classified as a myelodysplastic/myeloproliferative neoplasm, is a rare hematologic malignancy of childhood. Most patients with JMML require allogeneic hematopoietic cell transplantation (HCT) as a curative therapy. A Japanese retrospective analysis demonstrated favorable outcomes for a busulfan (BU) + fludarabine (FLU) + melphalan (MEL) regimen, with an overall survival (OS) of 72% and an event-free survival (EFS) of 53%. To further validate the efficacy and safety of this regimen, the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) conducted a nationwide prospective study, JMML-11. Between July 2011 and June 2017, 28 patients with newly diagnosed JMML were enrolled in JMML11. Low-dose chemotherapy for tumor control before HCT was recommended, and patients treated with AML-type chemotherapy and azacitidine were excluded. The conditioning regimen comprised i.v. BU, 16 doses administered every 6 h, with dose adjustment based on pharmacokinetic (PK) studies on days -11 to -8; FLU, 30 mg/m2/day or 1 mg/kg/day for patients <10 kg or age <1 year on days -7 to -4; and MEL, 90 mg/m2/day or 3 mg/kg/day for patients <10 kg or <1 year on days -3 to -2. The donor was selected by the physician in charge. A family donor was available for 7 patients (3 HLA-matched siblings, 3 HLA-1-antigen mismatched parents, and 1 haploidentical father). Overall, 21 patients received grafts from unrelated donors, including 8 HLA-matched donors and 13 HLA-mismatched donors. The graft source was related bone marrow (BM) for 7 patients, unrelated BM for 14 patients, and unrelated cord blood for 7 patients. Neutrophil engraftment was achieved in 21 of 28 patients (75%), with a median of 20.5 days (range, 11 to 39 days) after transplantation. The 3-year OS, 3-year EFS, 3-year relapse rate, and 3-year transplantation-related mortality were 63% (95% confidence interval [CI], 42% to 78%), 52% (95% CI, 32% to 69%), 18% (95% CI, 6% to 34%), and 21% (95% CI, 9% to 38%), respectively. WBC count before the conditioning regimen (≥7.0 × 109/L) was significantly associated with inferior EFS and OS. Body surface area ≥.5 m2, spleen size <4 cm before conditioning, and HLA-matched unrelated BM donors were significantly associated with better OS. Adverse effects related to the conditioning regimen included febrile neutropenia (86%), diarrhea (39%), hypoxemia (21%), and mucositis (18%). BU-associated toxicity, including sinusoidal obstruction syndrome (SOS) and thrombotic microangiopathy (TMA), occurred in 7 patients (25%; SOS, n = 6; TMA, n = 2). Retrospective analysis of PK data after the first BU dose in 23 patients, including 6 with SOS and 17 without SOS, did not show significant differences between groups. The JMML-11 study confirms the positive results of previous retrospective analyses. BU+FLU+MEL might become a standard conditioning regimen for patients with JMML.
摘要:
背景:幼年型粒单核细胞白血病(JMML),被归类为骨髓增生异常/骨髓增生性肿瘤,是儿童时期罕见的恶性血液病.大多数JMML患者需要异基因造血细胞移植(HCT)作为治愈性治疗。日本回顾性分析显示白消安(BU)+氟达拉滨(FLU)+美法仑(MEL)方案的有利结果,总生存率(OS)为72%,无事件生存率(EFS)为53%。
目的:为了进一步验证该方案的有效性和安全性,日本小儿白血病/淋巴瘤研究组(JPLSG)进行了一项全国性的前瞻性研究JMML-11.
方法:2011年7月至2017年6月,28例新诊断的JMML11患者纳入研究。建议在HCT前进行低剂量化疗以控制肿瘤,并接受AML型化疗和阿扎胞苷治疗的患者。调节方案包括静脉内BU(每6小时施用16剂),在第-11至-8天时根据药代动力学(PK)研究进行剂量调整,在第-7至-4天时使用FLU(30mg/m2/天或1mg/kg/天,对于<10kg或<1岁的患者),在第-3天时使用MEL(90mg/m2/天或3mg/kg/天)供体由主治医师选择。7名患者有一个家庭捐赠者(三名HLA匹配的兄弟姐妹,三个HLA-1抗原错配的父母,和一个单倍体父亲)。总的来说,21名患者接受了来自无关供体的移植物,包括8个HLA匹配的供体和13个HLA不匹配的供体。7例患者的移植物来源为相关骨髓(BM),与14例患者无关的BM,7例患者脐带血无关。
结果:28例患者中有21例(75%)实现了中性粒细胞移植,移植后中位数(范围)为20.5(11-39)天。3年OS,3年EFS,3年复发率,3年移植相关死亡率为63%(42-78),52%(32-69),18%(6-34),21%(9-38),分别。预处理前的白细胞计数(≥7.0×109/L)与下EFS和OS显着相关。体表面积(BSA)(BSA≥0.5m2),预处理方案前的脾脏大小(<4cm)和HLA匹配的无关骨髓供体与更好的OS显著相关。与预处理方案相关的不良反应包括发热性中性粒细胞减少症(86%),腹泻(39%),低氧血症(21%),粘膜炎(18%)。BU相关毒性,包括正弦阻塞综合征(SOS)和血栓性微血管病(TMA),发生在7名(25%)患者中(SOS,n=6;TMA,n=2)。回顾性分析23例患者首次服用BU后的PK数据,包括6个有SOS和17个没有SOS,组间没有显着差异。
结论:JMML-11研究证实了先前回顾性分析的阳性结果。BU+FLU+MEL可能成为JMML患者的标准预处理方案。