HSCT治疗同一家系儿童XLP-2型合并嗜血细胞综合征——附2例报告并文献复习
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摘要
目的分析1家系2名罕见X-连锁淋巴增殖性疾病XLP-2(XIAP缺乏)合并嗜血细胞综合征(HLH)患儿的临床诊治病案,探讨异基因造血干细胞移植的治疗方案、临床疗效及并发症。方法收治1家系2例XLP-2(XIAP缺乏)并发HLH的患儿,分别以"发热、全血细胞减少、肝功损害"及"脾大"为首发症状,2例患儿经免疫化学治疗使HLH处于完全缓解后,分别行非血缘HLA高分辨全相合外周造血干细胞移植术,采用减低强度的预处理方案(Bu+Cy+Vp16+F-ATG),联合应用CSA,MTX,MMF预防GVHD,熊去氧胆酸、前列腺素E1(凯时)预防肝静脉闭塞病(VOD)。结果胞兄经HLH-2004方案免疫化学治疗HLH完全缓解后,行异基因造血干细胞移植术,移植后11 d中性粒细胞植入,13 d血小板植入,20 d基因嵌合为完全供者型,移植后发生aGVHDⅠ度及晚发性出血性膀胱炎,治疗好转。目前无病生存时间4年。胞弟移植后12 d中性粒细胞植入,8 d并发重度VOD,于12 d家长放弃治疗后出院。结论 HLH-2004方案联合异基因造血干细胞移植是治愈XLP-2合并HLH的有效手段。采用HLH-2004方案治疗使HLH完全缓解后再行减低强度预处理方案的异基因造血干细胞移植是安全可行的,VOD是XLP-2(XIAP缺乏)较为常见和严重的并发症和死因,应加强防范。
Objective Through analysis of clinical diagnosis and treatment of 2 cases of rare X-linked lymphoproliferative syndrometype 2(XIAP deficiency) complicated with hemophagoeytic lymphohistiocytosis(HLH) in a family,we intended to summarize regimens, complications and clinical efficacy during the treatment of above cases using allogeneic stem cell transplantation(allo-HSCT).Methods Two children(two brothers from one family) with XLP-2(XIAP deficiency) complicated with HLH were treated with "fever, pancytopenia, liver function damage" and "splenomegaly" as the first symptoms,respectively.After initial remission of HLH,treated by immunochemotherapy,hematopoietic stem cell transplantations from unrelated donors(URD-HSCT) fully matched with high-resolution HLA typing were performed using a reduced intensity preconditioning regimen(Bu+Cy+Vp16+F-ATG) combined with CSA, MTX, MMF(used to prevent GVHD),ursodeoxycholic acid, and prostaglandin E1(Keshi)to prevent hepatic veno-occlusive disease(VOD).Results After complete remission of HLH with HLH-2004 regimen, allo-HSCT was performed in two brothers. As to the elder brother,neutrophils were implanted on the 11 th day after transplantation, platelets implanted on the 13 th day, and full donor chimerism was restored on the 20 th day. After transplantation, aGVHD Ⅰ and late-onset hemorrhagic cystitis occurredand improved after treatment. Up to now,the elder brother has had a disease-free survival of 4 years. As to the younger brother, neutrophils were implanted on the 12 th day after allo-HSCT but severe VOD occurred 8 days later. His parents gave up the subsequent treatment and he was released from the hospital.Conclusion HLH-2004 regimen combined with allo-HSCT is an effective method to cure XLP-2(XIAP deficiency) complicated with HLH. After complete remission of HLH using HLH-2004 regimen,it is safe and feasible to perfor mallo-HSCT with reduced intensity preconditioning. VOD is a common and serious complication and cause of death in XLP-2(XIAP deficiency), and prevention should be strengthened.
Objective Through analysis of clinical diagnosis and treatment of 2 cases of rare X-linked lymphoproliferative syndrometype 2(XIAP deficiency) complicated with hemophagoeytic lymphohistiocytosis(HLH) in a family,we intended to summarize regimens, complications and clinical efficacy during the treatment of above cases using allogeneic stem cell transplantation(allo-HSCT).Methods Two children(two brothers from one family) with XLP-2(XIAP deficiency) complicated with HLH were treated with "fever, pancytopenia, liver function damage" and "splenomegaly" as the first symptoms,respectively.After initial remission of HLH,treated by immunochemotherapy,hematopoietic stem cell transplantations from unrelated donors(URD-HSCT) fully matched with high-resolution HLA typing were performed using a reduced intensity preconditioning regimen(Bu+Cy+Vp16+F-ATG) combined with CSA, MTX, MMF(used to prevent GVHD),ursodeoxycholic acid, and prostaglandin E1(Keshi)to prevent hepatic veno-occlusive disease(VOD).Results After complete remission of HLH with HLH-2004 regimen, allo-HSCT was performed in two brothers. As to the elder brother,neutrophils were implanted on the 11 th day after transplantation, platelets implanted on the 13 th day, and full donor chimerism was restored on the 20 th day. After transplantation, aGVHD Ⅰ and late-onset hemorrhagic cystitis occurredand improved after treatment. Up to now,the elder brother has had a disease-free survival of 4 years. As to the younger brother, neutrophils were implanted on the 12 th day after allo-HSCT but severe VOD occurred 8 days later. His parents gave up the subsequent treatment and he was released from the hospital.Conclusion HLH-2004 regimen combined with allo-HSCT is an effective method to cure XLP-2(XIAP deficiency) complicated with HLH. After complete remission of HLH using HLH-2004 regimen,it is safe and feasible to perfor mallo-HSCT with reduced intensity preconditioning. VOD is a common and serious complication and cause of death in XLP-2(XIAP deficiency), and prevention should be strengthened.
引文
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[10] Worth AJ,Nikolajeva O,Chiesa R,et al.Successful stem cell transplant with antibody-based conditioning for XIAP deficiency with refractory hemophagocytic lymphohistiocytosis.Blood,2013,121(24):4966-4968.
[11] Dignan FL,Wynn RF,Hadzic N,et al.BCSH/BSBMT guideline:diagnosis and management ofveno-occlusive disease (sinusoidal obstruction syndrome)following haematopoietic stem cell transplantation.British Journal of Haematology,2013,163(4):444-457.
[2] Latour S.Natural killer T cells and X-linked lymphoroliferative syndrome.Current Opinion in Allergy & Clinical Immunology,2007,7(6):5l0-514.
[3] Janka GE,Lehmberg K.Hemophagocytic syndromes-an update.Blood Review,2014,28(4):135-142.
[4] Henter JI,Home AC,Egeler RM,et al.HLH-2004:Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.Pediatric Blood & Cancer,2010,48(2):124-131.
[5] Huck K,Feyen O,Niehues T,et al.Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation.J Clin Invest,2009,119(5):1350-1358.
[6] Yang X,Kanegane H,Imamura T,et al.Clinical and genetic characteristics of XIAP deficiency in Japan.Journal of Clinical Immunology,2012,32(3):411-420.
[7] Rigaud S,Fondanèche MC,Lambert N,et al.XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.Nature,2006,444(7115):110-114.
[8] Schmid JP,Canioni D,Moshous D,et al.Clinical similaritiesand differences of patients with X-linked lymphoproliferativesyndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).Blood,2011,117(5):1522-1529.
[9] Booth C,Gilmour KC,Veys P,et al.X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency:a multicenter study on the manifestations,management and outcome of the disease.Blood,2011,117 (1):53-62.
[10] Worth AJ,Nikolajeva O,Chiesa R,et al.Successful stem cell transplant with antibody-based conditioning for XIAP deficiency with refractory hemophagocytic lymphohistiocytosis.Blood,2013,121(24):4966-4968.
[11] Dignan FL,Wynn RF,Hadzic N,et al.BCSH/BSBMT guideline:diagnosis and management ofveno-occlusive disease (sinusoidal obstruction syndrome)following haematopoietic stem cell transplantation.British Journal of Haematology,2013,163(4):444-457.