异基因造血干细胞移植治疗儿童先天性角化不良3例并文献复习

doi:10.12372/jcp.2024.23e0266

Abstract

Abstract:

Objective To investigate the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of children with dyskeratosis congenita (DKC), and to provide a basis for exploring the optimal transplantation program. Methods The clinical data of 3 children with DKC treated by HSCT in our hospital from June 2019 to June 2022 were retrospectively analyzed and the related literatures were reviewed. Results Three patients all underwent HSCT with a fludarabine-based reduced-intensity conditioning (RIC) regimen. The median count of mononuclear cells (MNC) and CD34⁺ cells was 13.7(8.3-17.3)×10⁸/kg and 8.2(6.3-13.1)×10⁶/kg respectively. A combination of methotrexate, cyclosporin A and mycophenolate mofetil was used to prevent graft-versus-host disease (GVHD). All 3 patients were able to tolerate the HSCT pretreatment. The median time of neutrophil implantation was 11(10-11) days, and the median time of platelet implantation was 11(10-13) days, and no primary implantation failure occurred. Two patients developed acute GVHD of different severity, 1 developed chronic GVHD, and 1 developed reversible posterior leukoencephalopathy syndrome (RPLS) after transplantation. The follow-up was completed in January 2023 and the median follow-up time was 19(11-42) months. All 3 patients survived, and 1 had chronic GVHD. At present, all 3 children were free from blood transfusion, and no DKC-related gene mutation was detected in blood cells after transplantation. The growth and development of the patients was similar to that of normal children of the same age, and no combined solid tumor has been found. Conclusions The pretreatment regimen of " Flu+low-dose cyclophosphamide (CTX) + anti-thymocyte globulin (ATG)" for HSCT treatment in DKC patients was tolerable, and no primary implantation failure occurred. GVHD is still the main factor affecting the survival of children, and it is necessary to explore the clinical study of individualized treatment for DKC.

Key words: dyskeratosis congenita, hematopoietic stem cell transplantation, graft versus host disease, low intensity conditional regimen, child

WANG Yingjie, CHEN Zhiwei, MAI Yumiao, SUN Pan, JING Zhaohe, DONG Pengpeng, LIU Jian. Allogeneic hematopoietic stem cell transplantation for treatment of dyskeratosis congenita: a report of 3 cases and literature review[J].Journal of Clinical Pediatrics, 2024, 42(3): 243-248.

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References 23

[1]	Alsabbagh MM. Dyskeratosis congenita: a literature review[J]. J Dtsch Dermatol Ges, 2020, 18(9): 943-967. doi: 10.1111/ddg.14268 pmid: 32930426
[2]	Dokal I, Vulliamy T, Mason P, et al. Clinical utility gene card for: dyskeratosis congenita-update 2015[J]. Eur J Hum Genet, 2015, 23(4).doi: 10.1038/ejhg.2014.170.
[3]	Snowden JA, Sanchez-Ortega I, Corbacioglu S, et al. Indications for haematopoietic cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2022[J]. Bone Marrow Transplant, 2022, 57(8): 1217-1239. doi: 10.1038/s41409-022-01691-w
[4]	Agarwal S. Evaluation and management of hematopoietic failure in dyskeratosis congenita[J]. Hematol Oncol Clin North Am, 2018, 32(4): 669-685. doi: 10.1016/j.hoc.2018.04.003
[5]	Sharma A, Myers K, Ye Z, et al. Dyskeratosis congenita caused by a novel TERT point mutation in siblings with pancytopenia and exudative retinopathy[J]. Pediatr Blood Cancer, 2014, 61(12):2302-2304. doi: 10.1002/pbc.25161 pmid: 25067791
[6]	Savage SA, Bertuch AA. The genetics and clinical manifestations of telomere biology disorders[J]. Genet Med, 2010, 12(12): 753-764. doi: 10.1097/GIM.0b013e3181f415b5
[7]	Revesz T, Fletcher S, Al-Gazali LI, et al. Bilateral retinopathy, aplastic anaemia, and central nervous system abnormalities: a new syndrome?[J]. J Med Genet, 1992, 29(9): 673-675. pmid: 1404302
[8]	Walne A J, Vulliamy T, Kirwan M, et al. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita[J]. Am J Hum Genet, 2013, 92(3): 448-453. doi: 10.1016/j.ajhg.2013.02.001 pmid: 23453664
[9]	Savage SA. Dyskeratosis congenita and telomere biology disorders[J]. Hematology Am Soc Hematol Educ Program, 2022, 2022(1): 637-648. doi: 10.1182/hematology.2022000394 pmid: 36485133
[10]	Toufektchan E, Lejour V, Durand R, et al. Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance[J]. Sci Adv, 2020, 6(15): eaay3511. doi: 10.1126/sciadv.aay3511
[11]	Vieri M, Kirschner M, Tometten M, et al. Comparable effects of the androgen derivatives danazol, oxymetholone and nandrolone on telomerase activity in human primary hematopoietic cells from patients with dyskeratosis congenita[J]. Int J Mol Sci, 2020, 21(19): 7196. doi: 10.3390/ijms21197196
[12]	Gadalla SM, Sales-Bonfim C, Carreras J, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita[J]. Biol Blood Marrow Transplant, 2013, 19(8): 1238-1243. doi: 10.1016/j.bbmt.2013.05.021
[13]	Fioredda F, Iacobelli S, Korthof ET, et al. Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita[J]. Br J Haematol, 2018, 183(1): 110-118. doi: 10.1111/bjh.2018.183.issue-1
[14]	Ayas M. Hematopoietic cell transplantation in Fanconi anemia and dyskeratosis congenita: a minireview[J]. Hematol Oncol Stem Cell Ther, 2017, 10(4): 285-289. doi: 10.1016/j.hemonc.2017.05.014
[15]	Ayas M, Nassar A, Hamidieh AA, et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure[J]. Bone Marrow Transplant, 2013, 48(9): 1168-1172. doi: 10.1038/bmt.2013.35
[16]	Nelson AS, Marsh RA, Myers KC, et al. A reduced-intensity conditioning regimen for patients with dyskeratosis congenita undergoing hematopoietic stem cell transplantation[J]. Biol Blood Marrow Transplant, 2016, 22(5): 884-888. doi: 10.1016/j.bbmt.2016.01.026
[17]	Bhoopalan SV, Wlodarski M, Reiss U, et al. Reduced-intensity conditioning-based hematopoietic cell transplantation for dyskeratosis congenita: single-center experience and literature review[J]. Pediatr Blood Cancer, 2021, 68(10):e29177. doi: 10.1002/pbc.v68.10
[18]	Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation[J]. Blood, 2009, 113(20): 4992-5001. doi: 10.1182/blood-2008-09-178046 pmid: 19264919
[19]	Bhoopalan SV, Cross SJ, Panetta JC, et al. Pharmacokinetics of alemtuzumab in pediatric patients undergoing ex vivo T-cell-depleted haploidentical hematopoietic cell transplantation[J]. Cancer Chemother Pharmacol, 2020, 86(6):711-717. doi: 10.1007/s00280-020-04160-7
[20]	Imanguli MM, Pavletic SZ, Guadagnini JP, et al. Chronic graft versus host disease of oral mucosa: review of available therapies[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2006, 101(2): 175-183. doi: 10.1016/j.tripleo.2005.08.028 pmid: 16448918
[21]	Giri N, Ravichandran S, Wang Y, et al. Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder[J]. ERJ Open Res, 2019, 5(4): 00209-2019.
[22]	Alter BP, Giri N, Savage SA, et al. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up[J]. Haematologica, 2018, 103(1): 30-39. doi: 10.3324/haematol.2017.178111 pmid: 29051281
[23]	Zhang J, Li M, Yao Z. Updated review of genetic reticulate pigmentary disorders[J]. Br J Dermatol, 2017, 177(4): 945-959. doi: 10.1111/bjd.15575 pmid: 28407215

项目	例1	例2	例3
入院日期	2017年11月	2017年10月	2019年3月
确诊时年龄/岁	3.2	4.8	8.7
性别	男	女	男
首发症状	面色苍白	出血点	间断鼻衄
皮肤黏膜异常	指甲萎缩、结膜炎	指甲萎缩，皮肤网状灰棕色色素沉着、龋齿，双眼周边视网膜血管异常、双下泪小点闭锁、双眼结膜充血	无
血常规	WBC 1.14×10⁹/L，Hb 31.6g/L，PLT 2×10⁹/L，ANC 0.24×10⁹/L	WBC 2.94×10⁹/L，Hb 83g/L，PLT 1×10⁹/L，ANC 0.94×10⁹/L	WBC 2.06×10⁹/L，Hb 61g/L，PLT 21×10⁹/L，ANC 0.82×10⁹/L
骨髓细胞学	骨髓增生重度减低，粒系占5％；红系占0％，比值缺如，成熟红细胞大小不等，色素充盈欠佳；淋巴细胞比值增高；全片未见巨核细胞，可见成堆及散在血小板；全片易见网状细胞及网状细胞团	骨髓增生减低，粒系比例减低；红系比例大致正常，成熟红细胞大小不一；全片共见巨核细胞6个，血小板少见。骨髓小粒细胞面积10-20％，以非造血细胞为主，可见浆细胞。	骨髓增生减低，脂肪组织广泛增生，粒系比例减低；红系比例大致正常，成熟红细胞大小不一；全片未见巨核细胞，可见散在血小板。
基因变异	TINF2: c.845G>A:p.R282H	TINF2: c.845G>A:p.R282H	RTEL1: c.1489G>A:p.A497T
移植前用药（时间）	CsA、司坦唑醇（18个月）	司坦唑醇（4个月）	CsA（33个月）
移植前1月输血史RBC/PLT（U/治疗量）	3/8	1/7	7/4

患者	移植时年龄/岁	供体，HLA配型	供受者血型	MNC×10⁸/kg	CD34⁺×10⁶/kg	预处理方案	GVHD预防方案
1	4.8	MUD10/10	O供O	13.7	8.22	Flu+CTX+ATG	CsA+MMF+小剂量MTX
2	9.0	MMUD 9/10	AB供B	17.32	13.05	Flu+CTX+ATG	CsA+MMF+小剂量MTX
3	11.4	MSD10/10	A供B	8.3	6.3	Flu+CTX+ATG	CsA+MMF+小剂量MTX

Allogeneic hematopoietic stem cell transplantation for treatment of dyskeratosis congenita: a report of 3 cases and literature review

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