Secondary acute myelocytic leukemia after successful chemotherapy with etoposide for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis
Secondary acute myelocytic leukemia after successful chemotherapy with etoposide for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis
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DOI：
10.1002/mpo.1189
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发表时间：
2001-08-01
期刊：
影响因子：
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通讯作者：
Imashuku, S
中科院分区：
文献类型：
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作者：
Kitazawa, J;Ito, E;Imashuku, S
EB病毒相关性噬血细胞淋巴组织细胞增多症(EBV-HLH)的预后仍不确定，但大量报告表明，在相当大比例的病例中它也可能是致命的[1]。最近的一篇文章记录了使用类固醇、依托泊苷和环孢素A组成的免疫化疗对大多数EBV-HLH病例的有效控制[2]。然而，免疫化疗的长期安全性仍有待确定。为此，我们报告了一例EBV-HLH患者，根据HLH94方案免疫化疗后发展为继发性急性髓细胞白血病(SAML)[3]。她是一名5岁的女孩，在1996年12月19日开始持续高烧之前一直很健康。她的个人和家族历史与此无关。体格检查显示高烧，颈淋巴肿大，肝脾肿大。血常规检查显示全血细胞减少，乳酸脱氢酶(1500IU/L)、铁蛋白(111,000 ng/ml)、可溶性白介素2受体(12,000U/ml)、干扰素-γ(19.1U/ml)和IL-6(69.3pg/ml)升高。骨髓抽吸示骨髓发育不良，异型淋巴细胞少于30%，吞血性组织细胞增多。颈淋巴组织活检显示淋巴结结构破坏，CD3阳性未成熟淋巴细胞和噬血组织细胞明显增殖。原位杂交显示T区未成熟淋巴细胞EBER转录本阳性。用EBV基因组探针进行的Southern杂交分析显示，患者的淋巴和骨髓细胞中存在单一条带。此外，在淋巴结细胞中还检测到T细胞受体-γ(TcR-γ)基因重排。这些结果表明，EB病毒感染的T细胞在淋巴结和骨髓细胞中呈单克隆性增殖。因此，她被诊断出患有EBV-HLH，并根据HLH94方案接受了依托泊苷治疗[3]。总体而言，在9个月的时间里，她的依托泊苷累积剂量为3150 mg/m2。在停止所有治疗大约两年后，她定期体检的血液检查显示轻度全血细胞减少，没有任何症状。骨髓检查显示正常骨髓，约50%的细胞为原始细胞，过氧化物酶染色阳性，胞浆中有Auer棒。表面标志物CD13、CD33和人类白细胞抗原(HLA)-DR均为阳性。诊断为急性髓系白血病(FAB M2)。染色体分析未发现核型异常。未检测到MLL和AML1基因重排。TcR-γ基因为生殖系，未检测到EB病毒基因组的单克隆性。根据BFM AML方案[4]进行强化化疗后，她获得了完全缓解。1998年9月4日，一例非血缘关系相合供者的骨髓移植手术成功。然而，她在骨髓移植后1年出现骨髓复发，对再次诱导强化化疗无效。患者随后于1999年11月15日接受了来自非血缘关系供者的第二次脐带血移植，并于2000年1月11日死于血栓性微血管病。我们的患者在9个月期间接受了累积剂量为3,150 mg/m2的依托泊苷，联合地塞米松和环孢素A。先前在一名接受EBV-HLH治疗的患者中发现了与依托泊苷相关的SAML[5]。尽管有报道称，当依托泊苷的总剂量为…时，发生SAML的风险会增加
The prognosis of Epstein±Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) remains uncertain, but numerous reports indicate that it can also be fatal in a substantial proportion of cases [1]. A recent article recorded effective control of most EBV-HLH cases with immunochemotherapy consisting of steroid, etoposide, and cyclosporin A [2]. However, the safety of immunochemotherapy on a long-term basis remains to be established. For this reason, we report a patient with EBV-HLH, who developed secondary acute myelocytic leukemia (sAML) following immunochemotherapy according to the HLH94 protocol [3]. She was a 5-year-old girl who had been in good health until persistent high fever began on December 19, 1996. Her personal and family histories were not contributory. Physical examination showed high fever, cervical lymph node swelling, and hepatosplenomegaly. Blood examination showed pancytopenia, and high values of lactate dehydrogenase (1,500 IU/L), ferritin (111,000 ng/ml), soluble interleukin-2 (IL-2) receptor (12,000 U/ml), interferon-γ (19.1 U/ml), and IL-6 (69.3 pg/ml). Bone marrow aspiration showed hypoplastic marrow with less than 30% of atypical lymphocytes and an increased number of hemophagocytic histiocytes. Cervical lymph node biopsy showed destroyed lymph node structure with a marked proliferation of CD3-positive immature lymphocytes and hemophagocytic histiocytes. In situ hybridization revealed that the immature lymphocytes in the T-zone were positive for EBER transcripts. Southern hybridization analysis with a probe for the EBV genome showed the presence of a single band in the patient's lymph node and bone marrow cells. Furthermore, the rearrangement of T-cell receptor-γ (TCR-γ) genes were detected in lymph node cells. These results indicate monoclonal proliferation of EBV-infected T-cells in lymph nodes and bone marrow cells. She therefore was diagnosed with EBV-HLH, and was treated with etoposide according to the HLH94 protocol [3]. In total, her cumulative dose of etoposide was 3,150 mg/m2 during a9-month period. Approximately 2 years after all therapy was discontinued, her blood examination on regular check-up showed mild pancytopenia without any symptoms. Bone marrow examination showed normoplastic marrow with approximately 50% of cells being blast cells that stained positive with peroxidase, which included Auer rods in their cytoplasm. Surface markers were positive for CD13, CD33, and human leukocyte antigen (HLA)-DR. A diagnosis of AML (FAB M2) was made. Chromosomal analysis showed no karyotype abnormalities. No gene rearrangements for MLL and AML1 were detected. TCR-γ gene was germline and EB virus genome monoclonality was not detected. After intensive chemotherapy according to the BFM AML protocol [4], she achieved complete remission. Bone marrow transplantation (BMT) from an HLA-matched unrelated donor was successfully performed on September 4, 1998. However, she had a bone marrow relapse 1 year after BMT, which was refractory to reinduction intensive chemotherapy. The patient subsequently received cord blood as a second transplantation from an HLA-two locus mismatched unrelated donor on November 15, 1999, and died of thrombotic microangiopathy on January 11, 2000. Our patient received 3,150 mg/m2 cumulative dose of etoposide during a 9-month period, in combination with dexamethasone and cyclosporin A. Etoposide-related sAML was previously documented in a patient treated for EBV-HLH [5]. Although it has been reported that the risk of sAML increases when the total dose of etoposide is …