Ben Hassine Khalil, Powys Madeleine, Svec Peter, Pozdechova Miroslava, Versluys Birgitta, Ansari Marc, Shaw Peter J
Cansearch Research Platform for Pediatric Oncology and Hematology, Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Blood Transplant and Cell Therapies, Children's Hospital at Westmead, Sydney, NSW, Australia.
Front Pediatr. 2021 Dec 10;9:775485. doi: 10.3389/fped.2021.775485. eCollection 2021.
Total-body irradiation (TBI) based conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT) is generally regarded as the gold-standard for children >4 years of age with acute lymphoblastic leukaemia (ALL). Retrospective studies in the 1990's suggested better survival with irradiation, confirmed in a small randomised, prospective study in the early 2000's. Most recently, this was reconfirmed by the early results of the large, randomised, international, phase III FORUM study published in 2020. But we know survivors will suffer a multitude of long-term sequelae after TBI, including second malignancies, neurocognitive, endocrine and cardiometabolic effects. The drive to avoid TBI directs us to continue optimising irradiation-free, myeloablative conditioning. In chemotherapy-based conditioning, the dominant myeloablative effect is provided by the alkylating agents, most commonly busulfan or treosulfan. Busulfan with cyclophosphamide is a long-established alternative to TBI-based conditioning in ALL patients. Substituting fludarabine for cyclophosphamide reduces toxicity, but may not be as effective, prompting the addition of a third agent, such as thiotepa, melphalan, and now clofarabine. For busulfan, it's wide pharmacokinetic (PK) variability and narrow therapeutic window is well-known, with widespread use of therapeutic drug monitoring (TDM) to individualise dosing and control the cumulative busulfan exposure. The development of first-dose selection algorithms has helped achieve early, accurate busulfan levels within the targeted therapeutic window. In the future, predictive genetic variants, associated with differing busulfan exposures and toxicities, could be employed to further tailor individualised busulfan-based conditioning for ALL patients. Treosulfan-based conditioning leads to comparable outcomes to busulfan-based conditioning in paediatric ALL, without the need for TDM to date. Future PK evaluation and modelling may optimise therapy and improve outcome. More recently, the addition of clofarabine to busulfan/fludarabine has shown encouraging results when compared to TBI-based regimens. The combination shows activity in ALL as well as AML and deserves further evaluation. Like busulfan, optimization of chemotherapy conditioning may be enhanced by understanding not just the PK of clofarabine, fludarabine, treosulfan and other agents, but also the pharmacodynamics and pharmacogenetics, ideally in the context of a single disease such as ALL.
对于4岁以上的急性淋巴细胞白血病（ALL）患儿，异基因造血干细胞移植（HSCT）前基于全身照射（TBI）的预处理通常被视为金标准。20世纪90年代的回顾性研究表明，照射可提高生存率，这在21世纪初的一项小型随机前瞻性研究中得到了证实。最近，2020年发表的大型随机国际III期FORUM研究的早期结果再次证实了这一点。但我们知道，TBI后的幸存者会遭受多种长期后遗症，包括二次恶性肿瘤、神经认知、内分泌和心脏代谢影响。避免TBI的需求促使我们继续优化无照射的清髓预处理。在基于化疗的预处理中，主要的清髓作用由烷化剂提供，最常用的是白消安或曲奥舒凡。白消安与环磷酰胺联合使用是ALL患者中TBI预处理的长期替代方案。用氟达拉滨替代环磷酰胺可降低毒性，但可能效果不佳，这促使添加第三种药物，如噻替派、美法仑，现在还有氯法拉滨。对于白消安，其广泛的药代动力学（PK）变异性和狭窄的治疗窗是众所周知的，治疗药物监测（TDM）已广泛用于个体化给药并控制白消安的累积暴露量。首剂选择算法的开发有助于在目标治疗窗内尽早准确获得白消安水平。未来，与不同白消安暴露量和毒性相关的预测性基因变异可用于进一步为ALL患者量身定制基于白消安的个体化预处理。在小儿ALL中，基于曲奥舒凡的预处理与基于白消安的预处理效果相当，目前无需TDM。未来的PK评估和建模可能会优化治疗并改善结局。最近，与基于TBI的方案相比，在白消安/氟达拉滨中添加氯法拉滨已显示出令人鼓舞的结果。该联合方案在ALL以及AML中均有活性，值得进一步评估。与白消安一样，化疗预处理的优化不仅可以通过了解氯法拉滨、氟达拉滨、曲奥舒凡和其他药物的PK来实现，还可以通过了解药效学和药物遗传学来实现，理想情况下是在单一疾病如ALL的背景下。
