淋巴瘤自体造血干细胞移植的临床实践优化探索与未来展望

doi:10.19401/j.cnki.1007-3639.2022.02.008

摘要/Abstract

摘要：

自体造血干细胞移植（autologous hematopoietic stem cell transplantation,AHSCT）是高度侵袭性和复发/难治性淋巴瘤的有效治疗手段之一,可为患者带来生存获益。近年来,小分子靶向药物、单克隆抗体、细胞治疗和免疫治疗等新药给淋巴瘤患者提供了更多的选择,但AHSCT在淋巴瘤治疗中仍占据重要地位。对AHSCT适应证和治疗时机进行概述,进而详细介绍AHSCT治疗流程、移植后管理及注意事项。AHSCT的适应证和治疗时机与疾病亚型、危险分层及移植前疾病状态紧密相关。行AHSCT前,需对患者进行移植前诱导及疗效评估,诱导方案根据淋巴瘤亚型不同而有所差异,可参考相应指南推荐进行选择;目前临床中广泛使用的疗效评价标准为影像学缓解（CT/MRI评价）和代谢缓解（PET/CT评价）。AHSCT流程的每一个环节都与预后密切相关,整体流程包括干细胞动员及采集、移植前预处理、干细胞回输、合并症管理、植入情况评估。制定良好的动员策略以保证动员效果是最关键的一步,对于淋巴瘤患者,应根据诱导治疗后患者的疾病缓解状态来选择最佳的动员方案,以提高干细胞动员成功率。参考国外造血干细胞动员经验,在疾病稳定状态下,如达到CR1/CR2的患者,可优选稳态动员;针对活动复发的患者,建议优选疾病特异性的非稳态动员。针对干细胞采集目标,过往国内外临床经验多推荐外周血干细胞（peripheral blood stem cells,PBSC）的最佳目标采集量为5×10 ⁶个CD34 ⁺细胞/kg,近期新发表的研究结果提示,骨髓瘤患者PBSC为4.5×10 ⁶~8×10 ⁶ 个CD34 ⁺细胞/kg具有更好的生存获益,淋巴瘤患者PBSC最佳阈值还有待进一步研究。自体移植物质量评价也打破了传统仅评估CD34 ⁺细胞数量的模式,已有研究显示,可将自体移植绝对淋巴细胞计数（autograft absolute lymphocyte count,A-ALC）纳入到自体移植物评估中。AHSCT预处理应采用清髓性预处理方案,BEAM（卡莫司汀、依托泊苷、阿糖胞苷、马法兰）方案在淋巴瘤的AHSCT预处理中较为常用。在干细胞回输上,应提前做好准备以避免出现细胞聚集现象,输注过程中还需加强临床质量控制管理,出现不良事件时应及时进行对症处理。植入后定期监测全血细胞计数等指标直至移植后100 d,以评估植入情况。移植后部分淋巴瘤亚型需行维持治疗以减少复发和治疗失败风险,提高生存率;针对不同淋巴瘤亚型,可采取不同的维持治疗方案,对于移植后复发高危患者,现已有BTK抑制剂、免疫调节剂等多种不同作用机制的新药上市,目前针对新药开展的疗效和安全性研究也在进一步探索中。淋巴瘤患者接受AHSCT治疗后造血恢复需要一定的时间,移植后应采取措施避免并发症的发生,植入成功后也应定期进行疗效评价及随访。对于适合移植的淋巴瘤患者,建议尽早转诊到移植中心行AHSCT治疗,以免延误最佳治疗时机。

关键词: 淋巴瘤, 自体造血干细胞移植, 临床实践

Abstract:

Autologous hematopoietic stem cell transplantation (AHSCT) is one of the effective treatments for highly aggressive and relapsed/refractory lymphoma, which can bring survival benefits to patients. In recent years, with the advent of new drugs such as small molecule targeted drugs, monoclonal antibodies, cell therapy and immunotherapy, more choices are provided for lymphoma patients, however, AHSCT still occupies an important position in the treatment of lymphoma. This paper summarized the indications eligible for AHSCT and its timing, and introduced the treatment process, post transplantation management and precautions of AHSCT in detail. The indications and timing of AHSCT are closely related to disease subtypes, risk stratification and disease status before transplantation. Before AHSCT, patients need to undergo pre-transplant induction and efficacy evaluation. The induction scheme varies according to different lymphoma subtypes, which can be selected according to the recommendations of corresponding guidelines. Currently the widely used clinical efficacy evaluation standard is imaging remission (CT /MRI evaluation) and metabolic remission (PET/CT evaluation). Every step of the AHSCT process is closely related to posttransplant outcome and prognosis. The overall process includes stem cell mobilization and collection, pretreatment prior to transplantation, stem cell reinfusion, comorbidity management and implantation evaluation. Formulating a good mobilization strategy to ensure the smooth development of transplantation is the most critical step. It is reasonable to choose stem cell mobilization regimen according to disease status after induction therapy, which is beneficial to improve mobilization success rate. Referring to the experience of hematopoietic stem cell mobilization abroad, steady-state mobilization is preferred in patients with stable disease, such as patients with CR1/CR2; in terms of stem cell collection, previous clinical experiences domestically and abroad mostly recommend that the optimal target collection of peripheral blood stem cells (PBSC) is 5×10 ⁶ CD34 ⁺ cells/kg. A recently published study suggests that a PBSC of 4.5×10 ⁶-8×10 ⁶ CD34 ⁺ cells/kg in myeloma patients generates significantly better survival, and the optimal PBSC threshold for lymphoma patients needs further study. The evaluation of autograft is now evolving from only CD34 ⁺ cells model, and studies have shown that autograft absolute lymphocyte count (A-ALC) can be introduced in autograft evaluation. Myeloablative pretreatment should be used before AHSCT, BEAM (carmustine, etoposide, cytarabine and melphalan) regimen is commonly used in AHSCT pretreatment of lymphoma. For stem cell reinfusion, preparations should be made in advance to avoid cell aggregation. Clinical quality control and management should be strengthened during infusion, and targeted treatment should be carried out in time in case of adverse events. After implantation, the complete blood count and other indicators were monitored regularly until 100 days after the transplantation to evaluate engraftment. After transplantation, patients with certain lymphoma subtypes need maintenance treatment to reduce the risk of recurrence and treatment failure, and to improve survival rate. Different maintenance treatment schemes can be adopted for different lymphoma subtypes. For patients at high risk of recurrence after transplantation, a variety of new drugs with different action mechanisms such as BTK inhibitors and immunomodulators have been launched into the market. At present, the research on the efficacy and safety of new drugs is also under further exploration. It takes a certain amount of time for lymphoma patients to get hematopoiesis recovery after AHSCT treatment. After transplantation, measures should be taken to avoid complications. After successful engraftment, curative effect evaluation and follow-up should be performed regularly. Lymphoma patients eligible for transplantion should be transferred to transplantion centers for AHSCT treatment at an early stage, to avoid missing the best AHSCT timing.

Key words: Lymphoma, Autologous hematopoietic stem cell transplantation, Clinical practice

中图分类号:

R733.4

金正明. 淋巴瘤自体造血干细胞移植的临床实践优化探索与未来展望[J]. 中国癌症杂志, 2022, 32(2): 161-171.

JIN Zhengming. Clinical practice optimization exploration and future prospects of autologous hematopoietic stem cell transplantation for lymphoma[J]. China Oncology, 2022, 32(2): 161-171.

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Adverse events	Management strategies
Nausea/vomiting	Antiemetics
Diarrhea	Antidiarrheals and fluids to prevent dehydration
Loss of appetite	Dexamethasone to stimulate appetite
Altered taste sensation	Zinc tablets or lemon candy
Mucositis	Pelifermin, anesthetic mouth wash, supersaturated calcium phosphate
	oral rinse, opioid analgesic, parenteral nutrition in severe case
Myelosuppression	G-CSF, blood component transfusions
Fevers	Evaluate for infections, antipyretics
Fatigue	Exercise
Infections (bacterial, viral, fungal, etc.)	Symptomatic and supportive care as appropriate based on etiological analysis with reference to international guidelines. For patients with pneumocystis jiroveci pneumonia, recommend dapsone 50 mg and atovaquone 750 mg orally daily as 2 divided doses
Clostridium difficile diarrhea	Hand washing/metronidazole, oral vancomycin
Hemorrhagic cystitis	Mesna for prophylaxi
Cataracts	Topical corticosteroids or emollients
Parotitis	Chewing gums, lemon drops
Infertility	Sperm or oocyte cryopreservation
Hypothyroidism/osteoporosis	Avoid TBI
Flushing/hypotension/breath odor due to DMSO/allergic reactions/ chest tightness/dyspnea	Slow down infusion rate or give acetaminophen, histamine blockers, corticosteroids
Atrial fibrillation	Beta-blockers and calcium channel blockers should be used for rhythm management; anticoagulation therapy to prevent stroke and potential risk factors management