Prolonged fever of unknown origin and hemophagocytosis evolving into acute lymphoblastic leukemia

Hemophagocytic syndrome (HPS) is an unusual acute syndrome presenting with fever, hepatosplenomegaly, and cytopenias. The hallmark of HPS is the accumulation of activated macrophages that engulf hematopoietic cells in the reticuloendothelial system. Most cases of HPS in adults are secondary to infection or malignancy, and thus investigation of the underlying disease is necessary. We describe a patient with prolonged fever, HPS, and chromosomal abnormalities in the bone marrow who underwent thorough evaluation for the cause of his symptoms. A final diagnosis of acute lymphoblastic leukemia (ALL) was established in a fourth, repeated bone marrow biopsy performed more than 2 months after the first presenting symptom appeared. This unusual case demonstrates the importance of cytogenetic abnormalities found in cases of HPS and the importance of repeated testing when an underlying disease is suspected.     

Risk of Etoposide-Related Acute Myeloid Leukemia in the Treatment of Epstein-Barr Virus—Associated Hemophagocytic Lymphohistiocytosis

We studied the impact of etoposide on the prognosis of 81 patients (77 of whom were children <15 years old) with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The study group received a median cumulative dose of 1,500 mg/m2 etoposide (range, 0-14,550 mg/m2), with a median follow-up period of 44 months (range, 20-88 months) from the diagnosis. Only 1 patient, who received 3150 mg/m2 etoposide, developed therapy-related acute myeloid leukemia (t-AML), at 31 months after diagnosis. Excluding 9 patients who underwent hemopoietic stem cell transplantation during the course of treatment, the prognosis was poorer for those patients who received less than a 1,000 mg/m2 cumulative dose of etoposide. Our results indicate that the risk of etoposide-related t-AML is low. An appropriate dosage of etoposide for the treatment of EBV-HLH would be in the range of 1,000 to 3,000 mg/m2. However, even at these doses, care must be taken to prevent the rare risk of t-AML.     

Malignancy‐associated haemophagocytic lymphohistiocytosis in children and adolescents

Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M‐HLH) in 21 patients, most of whom had T‐ (n = 12) or B‐cell neoplasms (n = 7), with Epstein–Barr virus as a co‐trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch‐HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M‐ and Ch‐HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M‐HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch‐HLH patients had evidence of active HLH. To overcome HLH, malignancy‐ and HLH‐directed treatments were administered in the M‐HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch‐HLH, treatment ranged from postponement of chemotherapy to the use of etoposide‐containing regimens.     

Laboratory parameters identify familial haemophagocytic lymphohistiocytosis from other forms of paediatric haemophagocytosis

Haemophagocytic lymphohistiocytosis (HLH) is a life‐threatening syndrome of immune dysregulation and is classified as primary or secondary according to the underlying aetiology. The treatment strategies recommended for these two groups differ substantially; however, it is thought to be impossible to predict the underlying causes of HLH using conventional laboratory tests. Recent studies show that serum levels of soluble interleukin‐2 receptor (sIL2R) and ferritin are useful for differentiating some forms of HLH. The present study reports that combinations of common laboratory parameters, such as the percentage of total lymphocytes within the peripheral blood leucocyte population, serum levels of lactate dehydrogenase and the sIL2R/ferritin ratio, are useful for identifying patients with familial haemophagocytic lymphohistiocytosis and for differentiating the underlying aetiology of paediatric HLH during the early course of the disease. These findings suggest that the pathogenesis of HLH differs greatly in terms of innate and adaptive immunity depending on the aetiology and may provide a new approach to unravelling the complex pathophysiology underlying this syndrome.     

儿童噬血细胞综合征11例临床分析

目的探讨儿童噬血细胞综合征(HLH)的临床特点及诊治策略。方法回顾性分析2009至2013年住院治疗的11例HLH患儿的临床资料。结果 11例患儿中,6例为EB病毒感染相关性HLH,1例为T细胞淋巴瘤相关性HLH,2例病因不明,2例为UNC13D基因编码序列突变,分别为c.2459CT/p.A832V(丙氨酸突变为缬氨酸),c.3067CT/p.R1023C(精氨酸突变为半胱氨酸);11例患儿中6例经治疗后病情好转,5例治疗无效死亡。结论儿童HLH临床表现缺乏特异性,病情发展快,须及时诊断、治疗。     

Clonal and non-clonal karyotypically abnormal cells in haemophagocytic lymphohistiocytosis

We studied chromosomes in bone marrow (BM) or peripheral blood cells of nine patients with haemophagocytic lymphohistiocytosis (HLH); three of them had a family history of HLH and four others underwent concurrent Epstein-Barr virus (EBV) infection. In addition to a large population of normal mitotic cells, karyotypically abnormal clonal cells were found in two patients, abnormal clonal cells and a nonclonal (single) abnormal cell in one, and nonclonal abnormal cells in three. All the six patients with chromosome abnormalities died of progressive disease; one of them also had EBV infection and EBV-associated clonal proliferation. Two of three patients with EBV infection and only normal mitotic cells in BM completely recovered from the disease.
Although HLH did not show histological and/or haema-tological evidence of a neoplastic disease, clonal chromosome abnormalities and the fatal clinical outcome found in some of the patients suggest that the disease may be heterogenous and include malignancy. HLH patients with karyotypically abnormal clonal cells in BM should warrant more intensive chemotherapy than that presently being applied to them and should be considered as candidates for BM transplantation.     

Life-threatening hemophagocytic syndrome triggered by disseminated toxoplasmosis in a young patient with previously unknown AIDS

Hemophagocytic syndrome is a rare life-threatening disorder that can be triggered by various conditions such as HIV infection and opportunistic agents. We report a case of disseminated toxoplasmosis complicated with severe hemophagocytic syndrome and revealing an unknown acquired immunodeficiency syndrome. The patient presented with multiple organ failure in intensive care unit. Once diagnosed, he benefitted from etoposide infusion, administration of specific anti-toxoplasmosis treatments and secondary antiretroviral therapy. He was alive at intensive care unit discharge and returned home with little sequalae. This case illustrates both the importance of rapid investigations of hemophagocytic syndrome etiologies in HIV positive patients and the necessity to prompt etoposide and specific treatments in order to improve potentially dramatic outcomes.     

Successful treatment with splenectomy and interferon alpha against recurred hemophagocytic syndrome in remission state of anaplastic large cell lymphoma following high-dose therapy and autologous peripheral blood stem cell transplantation

A 25-yr-old man had been diagnosed as having CD30(+) anaplastic large cell lymphoma associated with hemophagocytic syndrome (HS). He received aggressive frontline chemotherapies and consolidation with autologous peripheral blood stem cell transplantation (PBSCT) following high-dose chemotherapy combined with splenic irradiation (720 cGy in fraction of 180 cGy). However, HS recurred on day 50 of PBSCT without radiologic evidence of lymphoma relapse. On day 56 of PBSCT, splenectomy was performed and pathology showed massive sinusoidal infiltration of histiocytes. On day 68 of PBSCT, administration of interferon alpha was started and maintained for 24 months. HS was completely resolved and he has been alive well and in complete remission (CR), 60 months after initial diagnosis.     

干扰素γ介导噬血细胞综合征血细胞减少的机制研究

目的探讨噬血细胞综合征患者与正常人骨髓CD34＋细胞质量的差异情况,研究干扰素γ对骨髓分化的影响和特点,并观察提高集落刺激因子对干扰素γ抑制骨髓作用的对抗情况。方法采用免疫磁珠法分离纯化骨髓CD34＋造血干细胞。在体外扩增培养中,以干细胞因子（stem cell factor,SCF）和白介素-3（interleukin-3,IL-3）、粒细胞-巨噬细胞集落刺激因子（granulocyte macrophage-colony stimulating factor,GM-CSF）、粒细胞集落刺激因子（granulocyte-colony stimulating factor,G-CSF）、促红细胞生成素（erythropoietin,EPO）集落刺激因子组合对骨髓干细胞诱导分化,以集落形成单位（colony forming units,CFU）的形成数来评价骨髓分化情况,在体系中加入不同浓度梯度的干扰素γ,观察骨髓集落形成情况。在干扰素γ抑制骨髓的最低浓度下增加集落刺激因子浓度,观察骨髓生长情况。结果患者骨髓CD34＋细胞质量与正常人相比差异无统计学意义（P〉0.05）;不同浓度的干扰素γ对骨髓的抑制程度不同,当干扰素γ浓度提高到10 ng/mL以上时,实验组的集落数目相比于未添加干扰素γ的对照组,差异有统计学意义（P〈0.05）;增加培养体系中集落刺激因子浓度可对抗因干扰素γ使骨髓出现的抑制作用情况。结论噬血细胞综合征患者与正常人骨髓质量不存在差异,干扰素γ可以对骨髓生长起抑制作用,提高集落刺激因子浓度可以对抗干扰素γ产生的抑制作用。     

Successful rituximab treatment of refractory hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia associated with systemic lupus erythematosus

Abstract

High-dose steroids, immunosuppressants such as cyclophosphamide and cyclosporine, and high-dose intravenous immunoglobulin have all been used to control hemophagocytic lymphohistiocytosis (HLH) or autoimmune hemolytic anemia (AIHA) associated with systemic lupus erythematosus (SLE); however, some patients are refractory to treatment. Rituximab has successfully resolved many of the refractory manifestations of SLE. Here, we report a case of HLH and AIHA associated with SLE that was refractory or intolerable to conventional therapy, but was successfully treated with rituximab.