Epstein-Barr virus-positive lymphoma after alemtuzumab therapy for B-cell chronic lymphocytic leukemia
Epstein-Barr virus-positive lymphoma after alemtuzumab therapy for B-cell chronic lymphocytic leukemia
复制标题
阿仑单抗治疗 B 细胞慢性淋巴细胞白血病后出现 Epstein-Barr 病毒阳性淋巴瘤
DOI：
10.1080/10428190902838392
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发表时间：
2009
影响因子：
2.6
通讯作者：
A. Venditti
中科院分区：
文献类型：
--
作者：
E. Ammatuna;C. Sarlo;L. Ottaviani;M. Quaresima;F. Buccisano;Selenia Campagna;M. D. del Principe;Gottardo De Angelis;L. Anemona;S. Gumenyuk;S. Amadori;A. Venditti
B细胞慢性淋巴细胞性白血病（B-CLL）是一种惰性淋巴组织增生性疾病，其在骨髓、血液和淋巴组织中具有小的、形态成熟的B淋巴细胞的进行性积聚。Alemtuzumab（MabCampath）是一种靶向CD 52抗原（一种在B-CLL细胞上高度表达的糖基化肽）的IgG 1单克隆抗体（mAb）。该mAb在烷化剂和嘌呤核苷类似物难治性B-CLL患者中具有活性。迄今为止报告的主要不良事件是诱导CD 4和CD 8亚群的深度和长期耗竭，导致免疫缺陷状态和机会性感染的发生[1，2]。最近，在接受阿仑单抗治疗的T和B细胞淋巴增生性疾病患者中报告了EB病毒（EBV）相关淋巴瘤[2-5]。在这里，我们报告了一例继发于阿仑单抗治疗B-CLL的EBV相关淋巴组织增生性疾病。一名53岁的男子在1999年1月诊断为Rai II期经典B-CLL，于2007年6月因疾病进展入住我科。未进行IgVH突变状态分析。然而，外周血流式细胞术分析显示肿瘤细胞表达ZAP-70，但CD 38表达呈阴性。他之前接受过两个周期的氟达拉滨25 mg/m2治疗，无应答。2001年3月，他接受了6剂利妥昔单抗375 mg/m2，获得部分缓解。2005年12月，由于与Coombs阳性自身免疫性溶血性贫血（AHA）相关的疾病进展，患者接受利妥昔单抗、氟达拉滨、环磷酰胺（FCR）治疗6个周期，获得部分缓解，AHA消退。2007年6月至2007年7月，患者接受了12剂Alemtuzumab 30 mg/m2，清除了骨髓肿瘤细胞，并持续累及淋巴结。Alemtuzumab治疗前的CD 4和CD 8水平分别为517/mL和1380/mL。抗CD 52治疗4周后，由于CMV再激活而中断治疗，更昔洛韦成功治疗了CMV再激活。2007年10月，患者出现发热、AHA复发和肝肿大。实验室分析显示LDH水平升高（1299 UI/L）、低白蛋白血症（2.5 g/dL）、肝酶升高（ALT：92 UI/L; AST：87 UI/L）和贫血（Hb 8.4 g/dL）。外周血淋巴细胞计数小于40/mL。CT扫描显示横膈两侧存在多个肿大淋巴结和肝脏肿大。腹部超声心动图显示多个低回声肝脏病变，活检显示大B细胞CD 20 α。EBV-RNA原位杂交呈强阳性，血清EBVDNA病毒载量大于6500拷贝/mL。骨髓评估没有显示任何肿瘤细胞浸润。IV期CD 20受体的诊断
B-cell chronic lymphocytic leukemia (B-CLL) is an indolent lymphoproliferative disorder with a progressive accumulation of small, morphologically mature B lymphocytes in the bone marrow, blood and lymphoid tissues. Alemtuzumab (MabCampath) is a IgG1 monoclonal antibody (mAb) that target the CD52 antigen, a glycosylated peptide highly expressed on B-CLL cells. This mAb is active in patients with B-CLL refractory to alkylating agents and purine nucleoside analogues. The primary adverse event so far reported is the induction of a profound and prolonged depletion of CD4 and CD8 subpopulations leading to an immunodeficient status and the development of opportunistic infections [1,2]. Recently, Epstein-Barr virus (EBV) related lymphoma have been reported in patients with T and B cell lymphoproliferative disorder after treatment with alemtuzumab [2–5]. Here, we report a case of an EBV related lymphoproliferative disorder secondary to alemtuzumab therapy for B-CLL. A 53 years old man diagnosed in January 1999 as having stage Rai II classical B-CLL, was admitted to our department in June 2007 as a consequence of disease progression. Analysis of IgVH mutational status was not performed. However, peripheral blood flow cytometry analysis revealed that tumor cells expressed ZAP-70, but were negative for CD38 expression. He was previously treated with two cycles of fludarabine 25 mg/m with no response. In March 2001, he received six doses of rituximab 375 mg/m obtaining a partial remission. In December 2005, because of disease progression associated with Coombs positive autoimmune hemolytic anemia (AHA) he was treated with rituximabþfludarabineþ cyclophosphamide (FCR) for six cycles obtaining a partial remission with resolution of the (AHA). From June 2007 to July 2007, he received 12 doses of alemtuzumab 30 mg/m, obtaining the clearance of bone marrow neoplastic cells with persistence of lymph nodes involvement. CD4 and CD8 levels prior alemtuzumab therapy were 517/mL and 1380/mL, respectively. After 4 weeks of anti CD52 therapy, treatment was interrupted because of CMV reactivation which was successfully treated with ganciclovir. In October 2007, the patient presented with fever AHA recrudescence and hepatomegaly. Laboratory analysis showed high LDH level (1299 UI/L), hypoalbuminemia (2.5 g/dL), elevated liver enzyme (ALT: 92 UI/L; AST: 87 UI/L) and anemia (Hb 8.4 g/dL). Lymphocyte count on peripheral blood was less than 40/mL. A CT scan revealed the presence of multiple enlarged lymph nodes at both sides of the diaphragm and liver enlargement. An abdominal ecography revealed multiple hypoechogenic liver lesions which were biopsied and showed large B cells CD20þ. In situ hybridisation for EBV-RNA was strongly positive and serum EBV DNA viral load showed more than 6500 copies/mL. Bone marrow evaluation didn’t show any infiltration by neoplastic cells. The diagnosis of stage IV CD20þ