儿童急性髓系白血病造血干细胞移植后复发的预防和治疗

doi:10.12372/jcp.2022.22e1591

摘要/Abstract

摘要：

急性髓系白血病约占儿童白血病的15%~20%，规范化疗后仍有近40%的儿童复发，异基因造血干细胞移植是预防其复发的强有力手段，但仍有部分患者复发，此类患者2年的总生存率不足20%，部分复发患者无法耐受传统化疗或对化疗不敏感。复发是移植后死亡的主要原因，因此预防移植后复发应该着手于移植前，优化移植链条的各个环节，严格随访监测。近年来新涌现的分子靶向药物、新型免疫治疗、CRISPR基因编辑造血干细胞疗法等也为移植后复发的儿童患者提供了更多的治疗策略。文章根据移植链条的流程，总结了各环节的预防措施及移植后复发的治疗选择，以期为临床提供方向和策略。

关键词: 急性髓系白血病, 造血干细胞移植, 复发, 儿童

Abstract:

Acute myeloid leukemia accounts for about 15%-20% of childhood leukemia, and nearly 40% of pediatric patients still relapse after standard chemotherapy. Allogeneic hematopoietic stem cell transplantation is a powerful means to prevent its recurrence. However, some patients still relapse, and the 2-year survival rate of these patients is less than 20%. Some patients with relapse cannot tolerate or are insensitive to conventional chemotherapy. Recurrence is the main cause of death after transplantation. The prevention of relapse after transplantation ought to start before transplantation, optimize each part of the transplantation chain, and strictly follow the follow-up monitoring. In recent years, new molecular targeted drugs, new immunotherapy and CRISPR genome-edited hematopoietic stem cell therapy have also provided more treatment strategies for pediatric patients with AML relapse after transplantation. According to the procedure of transplantation chain, this paper summarized the preventive measures of each link and the treatment options of post-transplantation recurrence, in order to provide the direction and strategy for the clinic.

Key words: acute myeloid leukemia, hematopoietic stem cell transplantation, relapse, child

赵明一, 李嘉华, 江华. 儿童急性髓系白血病造血干细胞移植后复发的预防和治疗[J]. 临床儿科杂志, 2023, 41(3): 167-174.

ZHAO Mingyi, LI Jiahua, JIANG Hua. Prevention and treatment of relapse after hematopoietic stem cell transplantation in children with acute myeloid leukemia[J]. Journal of Clinical Pediatrics, 2023, 41(3): 167-174.

图/表 2

参考文献 50

[1]	Newell LF, Cook RJ. Advances in acute myeloid leukemia[J]. BMJ, 2021, 375: n2026.
[2]	Luo Y, Xu Y, Li X, et al. A prognostic model of seven immune genes to predict overall survival in childhood acute myeloid leukemia[J]. Biomed Res Int, 2022, 2022: 7724220.
[3]	Creutzig U, Kutny MA, Barr R, et al. Acute myelogenous leukemia in adolescents and young adults[J]. Pediatr Blood Cancer, 2018, 65(9): e27089. doi: 10.1002/pbc.27089
[4]	Dohner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN[J]. Blood, 2022, 140(12): 1345-1377. doi: 10.1182/blood.2022016867
[5]	Taga T, Tomizawa D, Takahashi H, et al. Acute myeloid leukemia in children: current status and future directions[J]. Pediatr Int, 2016, 58(2):71-80. doi: 10.1111/ped.12865 pmid: 26645706
[6]	Bejanyan N, Weisdorf DJ, Logan BR, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study[J]. Biol Blood Marrow Transplant, 2015, 21(3): 454-459. doi: 10.1016/j.bbmt.2014.11.007
[7]	Kohler N, Ruess DA, Kesselring R, et al. The role of immune checkpoint molecules for relapse after allogeneic hematopoietic cell transplantation[J]. Front Immunol, 2021, 12: 634435. doi: 10.3389/fimmu.2021.634435
[8]	Christopher MJ, Petti AA, Rettig MP, et al. Immune escape of relapsed AML cells after allogeneic transplantation[J]. N Engl J Med, 2018, 379(24): 2330-2341. doi: 10.1056/NEJMoa1808777
[9]	Zeiser R, Vago L. Mechanisms of immune escape after allogeneic hematopoietic cell transplantation[J]. Blood, 2019, 133(12): 1290-1297. doi: 10.1182/blood-2018-10-846824 pmid: 30578254
[10]	Wang D, Sun Z, Zhu X, et al. GARP-mediated active TGF-beta1 induces bone marrow NK cell dysfunction in AML patients with early relapse post-allo-HSCT[J]. Blood, 2022, 140(26): 2788-2804.
[11]	Zhang XH, Chen J, Han MZ, et al. The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update[J]. J Hematol Oncol, 2021, 14(1): 145. doi: 10.1186/s13045-021-01159-2
[12]	Peters C, Cornish JM, Parikh SH, et al. Stem cell source and outcome after hematopoietic stem cell transplantation (HSCT) in children and adolescents with acute leukemia[J]. Pediatr Clin North Am, 2010, 57(1): 27-46. doi: 10.1016/j.pcl.2010.01.004
[13]	Zheng FM, Zhang X, Li CF, et al. Haploidentical- versus identical-sibling transplant for high-risk pediatric AML: a multi-center study[J]. Cancer Commun (Lond), 2020, 40(2-3): 93-104.
[14]	Bitan M, He W, Zhang MJ, et al. Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens[J]. Blood, 2014, 123(10): 1615-1620. doi: 10.1182/blood-2013-10-535716 pmid: 24435046
[15]	Dandoy CE, Davies SM, Woo Ahn K, et al. Comparison of total body irradiation versus non-total body irradiation containing regimens for de novo acute myeloid leukemia in children[J]. Haematologica, 2021, 106(7): 1839-1845. doi: 10.3324/haematol.2020.249458
[16]	Saraceni F, Beohou E, Labopin M, et al. Thiotepa, busulfan and fludarabine compared to busulfan and cyclophosphamide as conditioning regimen for allogeneic stem cell transplant from matched siblings and unrelated donors for acute myeloid leukemia[J]. Am J Hematol, 2018, 93(10): 1211-1219. doi: 10.1002/ajh.25225 pmid: 30033639
[17]	Versluijs AB, Lankester AC, et al. Clofarabine-fludarabine-busulfan in HCT for pediatric leukemia: an effective, low toxicity, TBI-free conditioning regimen[J]. Blood Adv, 2022, 6(6): 1719-1730. doi: 10.1182/bloodadvances.2021005224
[18]	Zhang N, Shao J B, Li H, et al. Re-induction with modified CLAG regimen in relapsed or refractory acute myeloid leukemia in children bridging to allogeneic hematopoietic stem cell transplantation[J]. World J Pediatr, 2020, 16(2): 152-158. doi: 10.1007/s12519-019-00321-8 pmid: 31748985
[19]	Ye P, Pei R, Jin J, et al. Modified cladribine, cytarabine, and G-CSF as a salvage regimen in patients with relapsed/refractory acute myeloid leukemia: a bridge to myeloablative allogeneic hematopoietic stem cell transplantation[J]. Ann Hematol, 2019, 98(9): 2073-2080. doi: 10.1007/s00277-019-03723-w pmid: 31201514
[20]	Zhang H, Bu C, Peng Z, et al. Characteristics of anti-CLL1 based CAR-T therapy for children with relapsed or refractory acute myeloid leukemia: the multi-center efficacy and safety interim analysis[J]. Leukemia, 2022, 36(11): 2596-2604. doi: 10.1038/s41375-022-01703-0 pmid: 36151140
[21]	Tischer J, Engel N, Fritsch S, et al. Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings[J]. Ann Hematol, 2015, 94(10): 1677-1688. doi: 10.1007/s00277-015-2423-y pmid: 26055139
[22]	Sheikh IN, Alqahtani S, Ragoonanan D, et al. Post-transplant cyclophosphamide after matched sibling and unrelated donor hematopoietic stem cell transplantation in pediatric patients with acute myeloid leukemia[J]. Int J Mol Sci, 2022, 23(15): 8748. doi: 10.3390/ijms23158748
[23]	Alanazi W, Chen S, Lipton J H, et al. Post-transplant cyclophosphamide combined with anti-thymocyte globulin as graft-versus-host disease prophylaxis for allogeneic hematopoietic cell transplantation in high-risk acute myeloid leukemia and myelodysplastic syndrome[J]. Acta Haematol, 2021, 144(1): 66-73. doi: 10.1159/000507536
[24]	Cruijsen M, Hobo W, van der Velden W, et al. Addition of 10-day decitabine to fludarabine/total body irradiation conditioning is feasible and induces tumor-associated antigen-specific T cell responses[J]. Biol Blood Marrow Transplant, 2016, 22(6): 1000-1008. doi: 10.1016/j.bbmt.2016.02.003
[25]	Ma Y, Qu C, Dai H, et al. Maintenance therapy with decitabine after allogeneic hematopoietic stem cell transplantation to prevent relapse of high-risk acute myeloid leukemia[J]. Bone Marrow Transplant, 2020, 55(6): 1206-1208. doi: 10.1038/s41409-019-0677-z
[26]	Tamura A, Ishida T, Saito A, et al. Low-dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high-risk pediatric acute myeloid leukemia[J]. Pediatr Blood Cancer, 2018, 65(10): e27284. doi: 10.1002/pbc.27284
[27]	Xuan L, Wang Y, Huang F, et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial[J]. Lancet Oncol, 2020, 21(9): 1201-1212. doi: S1470-2045(20)30455-1 pmid: 32791048
[28]	Pham B, Hoeg R, Krishnan R, et al. Safety and tolerability of lenalidomide maintenance in post-transplant acute myeloid leukemia and high-risk myelodysplastic syndrome[J]. Bone Marrow Transplant, 2021, 56(12): 2975-2980. doi: 10.1038/s41409-021-01444-1
[29]	Jedlickova Z, Schmid C, Koenecke C, et al. Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation[J]. Bone Marrow Transplant, 2016, 51(5): 663-667. doi: 10.1038/bmt.2015.234
[30]	Yan CH, Liu QF, Wu DP, et al. Prophylactic donor lymphocyte infusion (DLI) followed by minimal residual disease and graft-versus-host disease-guided multiple DLIs could improve outcomes after allogeneic hematopoietic stem cell transplantation in patients with refractory/relapsed acute leukemia[J]. Biol Blood Marrow Transplant, 2017, 23(8): 1311-1319. doi: 10.1016/j.bbmt.2017.04.028
[31]	Bazarbachi A, Labopin M, Battipaglia G, et al. Sorafenib improves survival of FLT3-mutated acute myeloid leukemia in relapse after allogeneic stem cell transplantation: a report of the EBMT Acute Leukemia Working Party[J]. Haematologica, 2019, 104(9): e398-e401. doi: 10.3324/haematol.2018.211615
[32]	Miyamoto T, Fukuda T, Nakashima M, et al. Donor lymphocyte infusion for relapsed hematological malignancies after unrelated allogeneic bone marrow transplantation facilitated by the Japan Marrow Donor Program[J]. Biol Blood Marrow Transplant, 2017, 23(6): 938-944. doi: 10.1016/j.bbmt.2017.02.012
[33]	Schroeder T, Rautenberg C, Kruger W, et al. Treatment of relapsed AML and MDS after allogeneic stem cell transplantation with decitabine and DLI-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group[J]. Ann Hematol, 2018, 97(2): 335-342. doi: 10.1007/s00277-017-3185-5 pmid: 29151133
[34]	Zhao P, Ni M, Ma D, et al. Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation[J]. Ann Hematol, 2022, 101(1): 119-130. doi: 10.1007/s00277-021-04674-x
[35]	Lamure S, Paul F, Gagez A L, et al. A retrospective comparison of DLI and gDLI for post-transplant treatment[J]. J Clin Med, 2020, 9(7) :2204. doi: 10.3390/jcm9072204
[36]	Shah N, Rakszawski K, Nickolich M, et al. Improved outcome in AML relapse after allogeneic transplant with high-intensity chemotherapy followed by 2nd allogeneic stem cell transplant or donor lymphocyte infusion[J]. Ann Hematol, 2021, 100(10): 2585-2592. doi: 10.1007/s00277-021-04616-7
[37]	Craddock C, Slade D, De Santo C, et al. Combination lenalidomide and azacitidine: a novel salvage therapy in patients who relapse after allogeneic stem-cell transplantation for acute myeloid leukemia[J]. J Clin Oncol, 2019, 37(7): 580-588. doi: 10.1200/JCO.18.00889 pmid: 30653424
[38]	O'Brien MM, Alonzo TA, Cooper TM, et al. Results of a phase 2, multicenter, single-arm, open-label study of lenalidomide in pediatric patients with relapsed or refractory acute myeloid leukemia[J]. Pediatr Blood Cancer, 2021, 68(7): e28946.
[39]	Mo X, Zhang X, Xu L, et al. Interferon-alpha salvage treatment is effective for patients with acute leukemia/myelodysplastic syndrome with unsatisfactory response to minimal residual disease-directed donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation[J]. Front Med, 2019, 13(2): 238-249. doi: 10.1007/s11684-017-0599-3
[40]	Cui Q, Qian C, Xu N, et al. CD38-directed CAR-T cell therapy: a novel immunotherapy strategy for relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation[J]. J Hematol Oncol, 2021, 14(1): 82. doi: 10.1186/s13045-021-01092-4
[41]	Zhang H, Wang P, Li Z, et al. Anti-CLL1 chimeric antigen receptor T-Cell therapy in children with relapsed/refractory acute myeloid leukemia[J]. Clin Cancer Res, 2021, 27(13): 3549-3555. doi: 10.1158/1078-0432.CCR-20-4543 pmid: 33832948
[42]	Tang X, Yang L, Li Z, et al. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia[J]. Am J Cancer Res, 2018, 8(6): 1083-1089. pmid: 30034945
[43]	Duncan C N, Majhail N S, Brazauskas R, et al. Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes[J]. Biol Blood Marrow Transplant, 2015, 21(1): 151-158. doi: 10.1016/j.bbmt.2014.10.006
[44]	Taga T, Murakami Y, Tabuchi K, et al. Role of second transplantation for children with acute myeloid leukemia following posttransplantation relapse[J]. Pediatr Blood Cancer, 2016, 63(4): 701-705. doi: 10.1002/pbc.25866 pmid: 26670954
[45]	Yaniv I, Krauss AC, Beohou E, et al. Second hematopoietic stem cell transplantation for post-transplantation relapsed acute leukemia in children: a retrospective EBMT-PDWP study[J]. Biol Blood Marrow Transplant, 2018, 24(8): 1629-1642. doi: 10.1016/j.bbmt.2018.03.002
[46]	Cho HW, Ju HY, Hyun JK, et al. Conditioning with 10 Gy total body irradiation, cyclophosphamide, and fludarabine without ATG is associated with improved outcome of cord blood transplantation in children with acute leukemia[J]. J Korean Med Sci, 2021, 36(19): e128. doi: 10.3346/jkms.2021.36.e128 pmid: 34002548
[47]	罗荣牡, 田正芹, 张晓妹, 等. 进展期儿童急性白血病行挽救性造血干细胞移植的疗效分析[J]. 中国小儿血液与肿瘤杂志, 2022, 27(3): 178-183.
[48]	贾晨光, 周翾, 王彬, 等. 异基因造血干细胞移植治疗儿童急性髓系白血病的临床观察[J]. 首都医科大学学报, 2019, 40(2): 163-168.
[49]	Beelen DW, Trenschel R, Stelljes M, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome: a randomised, non-inferiority, phase 3 trial[J]. Lancet Haematol, 2020, 7(1): e28-e39. doi: 10.1016/S2352-3026(19)30157-7
[50]	Sauer MG, Lang PJ, Albert MH, et al. Hematopoietic stem cell transplantation for children with acute myeloid leukemia-results of the AML SCT-BFM 2007 trial[J]. Leukemia, 2020, 34(2): 613-624. doi: 10.1038/s41375-019-0584-8 pmid: 31578451

预处理方案	药物	剂量	用药时机	供者类型	文献
Clo/Flu/Bu	Clo Flu Bu（iv）或ATG	30 mg·m^-2·d^-1 10 mg·m^-2·d^-1 AUC=85~95 mg·h^-1·L^-1 6 mg·kg^-1（>40 kg）	－5 d to －2 d －5 d to －2 d / －9 d to －6 d	allo-HSCT	Versluijs等^[17]
TBI/Flu/Cy	TBI Flu Cy	333 cGy 25 mg·m^-2·d^-1 60 mg·m^-2·d^-1	－7 d to －5 d －4 d to －2 d －3 d，－2 d	CB-HSCT	Cho 等^[46]
Bu/Cy/ATG	Bu Cy ATG	3.2~4.8 mg·kg^-1·d^-1 40~60 mg·kg^-1·d^-1 8~10 mg·kg^-1·d^-1 or 10~15 mg·kg^-1·d^-1	－8 d to －6 d －5 d to －4 d －5 d to －2 d －3 d to －1 d	MUD, HID, MSD-HSCT	罗荣牡，等^[47]
Ara-C/Bu/Cy/CCNU	Ara-C Bu Cy CCNU	4 g·m^-2·d^-1 3.2 g·m^-2·d^-1 1.8 g·m^-2·d^-1 250 mg·m^-2·d^-1	－10 d to －9 d －8 d to －6 d －5 d to －4 d －1 d	MUD-HSCT	贾晨光，等^[48]
treosulfan/Flu/TBI	treosulfan Flu TBI	10~14 mg·m^-2·d^-1 30 mg·m^-2·d^-1 200 cGy	－6 d to －4 d －6 d to －2 d －1 d	allo-HSCT	Beelen等^[49]
Bu/Cy/Mel	Bu Cy Mel	3.2~4.8 mg·kg^-1 60 mg·kg^-1 140 mg·m^-2	－7 d to －4 d －3 d，－2 d －1 d	MUD, MSD-HSCT	Sauer等^[50]