[1]黄小丽,刘林,袁忠涛,等.芦可替尼对慢性移植物抗宿主病患者的疗效及安全性研究[J].第三军医大学学报,2019,41(23):2290-2295.
 HUANG Xiaoli,LIU Lin,YUAN Zhongtao,et al.Clinical efficacy and safety of ruxolitinib in treatment of chronic graft versus host disease[J].J Third Mil Med Univ,2019,41(23):2290-2295.
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芦可替尼对慢性移植物抗宿主病患者的疗效及安全性研究(/HTML )
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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
41卷
期数:
2019年第23期
页码:
2290-2295
栏目:
专题报道
出版日期:
2019-12-15

文章信息/Info

Title:
Clinical efficacy and safety of ruxolitinib in treatment of chronic graft versus host disease
作者:
黄小丽刘林袁忠涛罗乐黎诗琦王三斌
364000 福建 龙岩,福建医科大学附属龙岩市第一医院血液风湿科1;650500 昆明,解放军联勤保障部队第920医院血液科2
Author(s):
HUANG Xiaoli LIU Lin YUAN Zhongtao LUO Le LI Shiqi WANG Sanbin

1Department of Hematology and Rheumatology, Longyan First Hospital, Fujian Medical University, Longyan, Fujian Province, 364000; 2Department of Hematology, No. 902 Hospital of Joint Logistics Support Force, Kunming, Yunnan Province, 650500, China

关键词:
慢性移植物抗宿主病芦可替尼临床疗效安全性
Keywords:
chronic graft versus host disease ruxolitinib clinical efficacy safety
分类号:
R392.1; R617; R977.3
文献标志码:
A
摘要:

目的观察芦可替尼治疗慢性移植物抗宿主病(chronic graft versus host disease,cGVHD)的临床效果,并探讨其安全性。方法收集2017年7月1日至2019年2月1日解放军联勤保障部队第920医院42例cGVHD患者的临床资料,芦可替尼治疗方案分为两种:①当cGVHD患者受累器官为皮肤、口腔、眼睛、关节、生殖道时,在原有免疫抑制剂治疗基础上加用芦可替尼5 mg/d(当患者体质量≤25 kg或当芦可替尼与强效CYP3A4抑制剂或者氟康唑合并给药时总剂量减半);②当cGVHD患者受累器官为肺部、肝脏、胃肠道等,予芦可替尼5 mg/d+甲泼尼龙1 mg·kg-1·d-1治疗。分别于cGVHD患者使用芦可替尼治疗后1、3个月评估患者疗效。同时每周检测患者外周血象、凝血功能、人巨细胞病毒拷贝数及胸部CT。结果42例cGVHD患者使用芦可替尼治疗后1、3个月总体反应疗效评估ORR分别为85.7%(36/42)、95.2%(40/42)。治疗过程中有6例患者出现肺部感染;有4例患者出现出血事件;有12例患者出现人巨细胞病毒感染或病毒拷贝数持续上升;有8例患者出现明显骨髓抑制,均为Ⅰ~Ⅱ级。中位随访时间为4(1~19)个月,无患者失访,随访期间有4例(9.5%,4/42)患者死亡,其死亡原因包括白血病复发、肺部感染及cGVHD病情控制不佳。结论芦可替尼治疗慢性移植物抗宿主病效果显著,不良反应低,可预防、可耐受。

Abstract:

ObjectiveTo study the clinical efficacy and safety of ruxolitinib in the treatment of chronic graft versus host disease (cGVHD). MethodsWe collected the clinical data of 42 cGVHD patients after receiving allogeneic hematopoietic stem cell transplantation from July 1, 2016 to February 1, 2019 in our hospital. There were 2 specific treatment regimens. For the patients diagnosed with the skin, mouth, eyes, joints or genital tract involvement, 5 mg/d ruxolitinib was given (when the patient weighs less than 25 kg, or ruxolitinib is administered in combination with a potent CYP3A4 inhibitor or fluconazole, the total dose is halved) on the basis of the original immunosuppressant therapy. For those diagnosed with lung, liver or gastrointestinal tract involvement, 5 mg/d ruxolitinib and 1 mg/(kg·d) methylprednisolone were given on the basis of the original immunosuppressant therapy. The clinical efficacy was evaluated in 1 and 3 month after treatment. Peripheral blood test, coagulation function, copy number of human cytomegalovirus and chest CT scanning were performed every week. ResultsAmong the 42 cGVHD patients, overall response rates (ORR) were 85.7% (36/42) and 95.2% (40/42) at 1 month and 3 months after treatment, respectively. In the process of this study, 6 patients developed pulmonary infection, and 4 patients experienced bleeding events. There were 12 patients having human cytomegalovirus and epstein-barr virus infection or the virus copy number being continued to rise. Bone marrow suppression at grade of Ⅰ~Ⅱ presented in 8 patients. During the follow-up period of 4 (1~19) months, no one patient was lost, and 4 patients (9.5%, 4/42) died, due to leukemia recurrence, pulmonary infection and poor control of cGVHD. ConclusionRuxolitinib has significant efficacy in the treatment of cGVHD, with low adverse reactions and preventable and tolerable effects.
 

参考文献/References:

[1]PAVLETIC S Z, MARTIN P, LEE S J, et al. Measuring therapeutic response in chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. response criteria working group report[J]. Biol Blood Marrow Transplant, 2006, 12(3): 252-266. DOI:10.1016/j.bbmt.2006.01.008.
[2]ASSOUAN D, LEBON D, CHARBONNIER A, et al. Ruxolitinib as a promising treatment for corticosteroid-refractory graft-versus -host disease[J]. Br J Haematol, 2018, 181(5): 687-689. DOI:10.1111/bjh.14679.
[3]MARTIN P J, STORER B E, INAMOTO Y, et al. An endpoint associated with clinical benefit after initial treatment of chronic graft-versus-host disease[J]. Blood, 2017, 130(3): 360-367. DOI:10.1182/blood-2017-03-775767.
[4]JAGLOWSKI S M, BLAZAR B R. How ibrutinib, a B-cell malignancy drug, became an FDA-approved second-line therapy for steroid-resistant chronic GVHD[J]. Blood Adv, 2018, 2(15): 2012-2019. DOI:10.1182/bloodadvances.2018013060.
[5]ZEISER R, BLAZAR B R. Pathophysiology of chronic graft-versus-host disease and therapeutic targets[J]. N Engl J Med, 2017, 377(26): 2565-2579. DOI:10.1056/nejmra1703472.
[6]IM A, HAKIM F T, PAVLETIC S Z. Novel targets in the treatment of chronic graft-versus-host disease[J]. Leukemia, 2017, 31(3): 543-554. DOI:10.1038/leu.2016.367.
[7]MASCARENHAS J, HOFFMAN R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis[J]. Clin Cancer Res, 2012, 18(11): 3008-3014. DOI:10.1158/1078-0432.CCR-11-3145.
[8]SPOERL S, MATHEW N R, BSCHEIDER M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease[J]. Blood, 2014, 123(24): 3832-3842. DOI:10.1182/blood-2013-12-543736.
[9]JAGASIA M, ZEISER R, ARBUSHITES M, et al. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials[J]. Immunotherapy, 2018, 10(5): 391-402. DOI:10.2217/imt-2017-0156.
[10]JAGASIA M H, GREINIX H T, ARORA M, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. the 2014 diagnosis and staging working group report[J]. Biol Blood Marrow Transplant, 2015, 21(3): 389-401.e1. DOI:10.1016/j.bbmt.2014.12.001.
[11]李小平, 张曦. 慢性移植物抗宿主病二线治疗进展[J]. 中华血液学杂志, 2019,40(2):160-163.DOI:10.3760/cma.j.issn.0253-2727.2019.02.014.
LI X P, ZHANG X. Progress in second-line treatment of chronic graft-versus-host disease[J]. Chin J Hematol, 2019,40(2):160-163.DOI:10.3760/cma.j.issn.0253-2727.2019.02.014.
[12]MA H H, LU C S, ZIEGLER J, et al. Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice[J]. J Clin Invest, 2011, 121(7): 2554-2569. DOI:10.1172/JCI43706.
[13]MA H H, ZIEGLER J, LI C L, et al. Sequential activation of inflammatory signaling pathways during graft-versus-host disease(GVHD): early role for STAT1 and STAT3[J]. Cell Immunol, 2011, 268(1): 37-46. DOI:10.1016/j.cellimm.2011.01.008.
[14]BLAZAR B R, MURPHY W J, ABEDI M. Advances in graft-versus-host disease biology and therapy[J]. Nat Rev Immunol, 2012, 12(6): 443-458. DOI:10.1038/nri3212.
[15]HEINE A, HELD S A, DAECKE S N, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo[J]. Blood, 2013, 122(7): 1192-1202. DOI:10.1182/blood-2013-03-484642.
[16]TAKAHASHI S, HASHIMOTO D, HAYASE E, et al. Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease[J]. Blood, 2018, 131(18): 2074-2085. DOI:10.1182/blood-2017-06-792614.
[17]CHOI J, ZIGA E D, RITCHEY J, et al. IFNγR signaling mediates alloreactive T-cell trafficking and GVHD[J]. Blood, 2012, 120(19): 4093-4103. DOI:10.1182/blood-2012-01-403196.
[18]CHOI J, COOPER M L, ALAHMARI B, et al. Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect[J]. PLoS ONE, 2014, 9(10): e109799. DOI:10.1371/journal.pone.0109799.
[19]CARNITI C, GIMONDI S, VENDRAMIN A, et al. Pharmacologic inhibition of JAK1/JAK2 signaling reduces experimental murine acute GVHD while preserving GVT effects[J]. Clin Cancer Res, 2015, 21(16): 3740-3749. DOI:10.1158/1078-0432.CCR-14-2758.
[20]ZHONG J, YANG P, MUTA K, et al. Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock[J]. PLoS ONE, 2010, 5(3): e9593. DOI:10.1371/journal.pone.0009593.
[21]ZEISER R, BURCHERT A, LENGERKE C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey[J]. Leukemia, 2015, 29(10): 2062-2068. DOI:10.1038/leu.2015.212.
[22]MORI Y, IKEDA K, INOMATA T, et al. Ruxolitinib treatment for GvHD in patients with myelofibrosis[J]. Bone Marrow Transplant, 2016, 51(12): 1584-1587. DOI:10.1038/bmt.2016.256.

更新日期/Last Update: 2019-12-09