Leukemia arising out of paroxysmal nocturnal hemoglobinuria

In paroxysmal nocturnal hemoglobinuria (PNH), one or more hematopoietic stem cells that are defective in GPI anchor assembly as a result of mutation in the PIG-A gene preferentially expand in the bone marrow and give rise to peripheral blood elements that are deficient in GPI anchored protein expression. According to current concepts, 5-15% of PNH patients develop leukocyte dyscrasias which invariably are acute myelogenous leukemia (AML). In this review, the literature from 1962 to the present is analyzed regarding the type of leukocyte dyscrasia, incidence, and cytogenetic features of the abnormal cells that have been reported. Among a total of 119 cases that are well-documented, 104 myeloid dyscrasias involving several categories in addition to AML, as well as 15 lymphoid dyscrasias are described. Of 1,760 patients in 15 series that contain 20 or more patients, 16 (1%) are reported as having developed "acute leukemia." However, of 288 listed as having died, 13 (5%) are recorded as having had "acute leukemia." In 32 of the patients with hematological dyscrasias where karyotypes were analyzed, 7 were found to be normal and 25 found to harbor various alterations with the +8 abnormality present in 8. In 5 of 7 instances evidence indicates that the dyscratic cell arises from the PNH clone. Processes potentially involved in the evolution of the dyscratic cells from PNH clones are discussed.     

Angio-immunoblastic lymphadenopathy terminating as Hodgkin's disease.

The clinical course of a 33-year-old man with generalized lymphadenopathy bearing all physical, laboratory and histologic characteristics of "angio-immunoblastic lymphadenopathy with dysproteinemia" (AILD) is described. Therapy was without significant benefit and the patient died 22 months after initial diagnosis. At autopsy in addition to the characteristic cellular polymorphism of AILD, numerous Hodgkin's cells and Sternberg-Reed cells were identified in the lymph nodes and spleen. Pleomorphic cellular infiltrates containing an increased number of immunoblasts and some giant cells were found also in the portal spaces of the liver. The evolution of Hodgkin's disease (H.D.) from AILD suggests that the latter may have represented a reaction to the agent which causes H.D..     

Paroxysmal nocturnal hemoglobinuria: termination in acute monocytic leukemia and reappearance after chemotherapy with N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (PL-AC) and vincristine

Acute monocytic leukemia developed in a 77-year-old woman about 18 months after a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) had been made. The classical features of PNH disappeared with the onset of the leukemia. Chemotherapy with N4-palmitoyl-1-beta-D-arabinosylcytosine and vincristine resulted in the disappearance of leukemic cells in the bone marrow, during which time intravascular hemolysis recurred and the results of a Ham's test were again positive. The anemia and thrombocytopenia, however, were not improved. The present case report suggests the disappearance of the leukemic cells to imply not bone marrow remission but the return of PNH.     

PIG-A mutations in paroxysmal nocturnal hemoglobinuria and in normal hematopoiesis

PIG-A is an X-linked gene that is essential for the first step in the biosynthesis of glycosylphosphatidyl-inositol (GPI) anchors. A rare clonal hematopoietic stem cell disease, paroxysmal nocturnal hemoglobinuria (PNH), is caused by mutations in the PIG-A gene. PNH is an acquired disease that may arise de novo or emanate from aplastic anemia. PNH blood cells have an absence or marked deficiency of all GPI anchored proteins. Interestingly, rare GPI anchor deficient blood and marrow cells that harbor PIG-A mutations can also be found in most healthy controls. This review examines the clinical and biological relevance of PIG-A mutations in PNH, aplastic anemia and healthy controls.     

阵发性睡眠性血红蛋白尿症发病机制、诊断及治疗进展

阵发性睡眠性血红蛋白尿症(PNH)是一种罕见的获得性造血干细胞基因突变引起的疾病.已明确磷脂酰肌醇聚糖A(PIGA)基因突变是PNH患者血管内溶血的分子病因,但克隆性增殖的机制仍有待揭示.PNH与再生障碍性贫血、骨髓增生异常综合征关系密切.流式细胞术检测锚连蛋白缺陷是诊断PNH的金标准,但基于细胞表型诊断的PNH在病因上仍是一组异质性疾病.依库珠单抗可有效减少PNH血管内溶血,显著改善患者的生命质量,但仍属对症治疗.对PNH发病机制的进一步研究有助于正确认识患者的内在病因、提高鉴别诊断能力和改善治疗.文章对结合近年来的研究进展进行综述.     

Severe aplastic anemia associated with paroxysmal nocturnal hemoglobinuria and lymphoplasmacytic lymphoma

An unusual case of aplastic anemia presenting in association with lymphoplasmacytic lymphoma and paroxysmal nocturnal hemoglobinuria is discussed. An insult to the hematological stem cell compartment may result in multiple pathological entities, potentially influencing our approach to the treatment of hematological clonal disorders.     

Biologic relevance of elevated red cell adenosine deaminase activity in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria.

Red cell adenosine deaminase (ADA-RBC) activity in patients with myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria is significantly increased compared to that observed in normal controls. ADA-RBC activity is not related to fetal hemoglobin concentration, but it is significantly correlated with hemoglobin concentration at diagnosis and with the degree of morphologic dysplasia in the erythroid lineage. The results of our study suggest that the observed enzymatic abnormality may constitute a non-specific manifestation of the stem cell alteration that determines these disorders.     

Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients.

In paroxysmal nocturnal hemoglobinuria (PNH), clonal expansion of glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient cells leads to a syndrome characterized by hemolytic anemia, marrow failure, and venous thrombosis. PNH is closely related to aplastic anemia and may share its immune pathophysiology. In vivo expansion of dominant T-cell clones can reflect an antigen-driven immune response but may also represent autonomous proliferation, such as in large granular lymphocytic (LGL)-leukemia. T-cell clonality can be assessed by a combination of T-cell receptor (TCR) flow cytometry and complementarity-determining-region-3 (CDR3) molecular analysis. We studied 24 PNH patients for evidence of in vivo dominant T-cell responses by flow cytometry; TCR-Vbeta-specific expansions were identified in all patients. In four cases, extreme expansions of one Vbeta-subset of CD8+/CD28-/CD56+ (effector) phenotype mimicked subclinical LGL-disease. The monoclonality of these expansions was inferred from unique CDR3-size peak distributions and sequencing of dominant clonotypes. We conclude that the molecular analysis of TCR-beta chain may demonstrate clonal LGL-like expansions at unexpected frequency in PNH patients. Our observations blur the classical boundaries between different bone marrow failure syndromes such as AA, PNH, and LGL, and support the hypothesis that in PNH, the mutant clone may expand as a result of an immune-escape from antigen-driven lymphocyte attack on hematopoietic progenitors.     

异基因造血干细胞移植治疗阵发性睡眠性血红蛋白尿症

目的 探讨异基因造血干细胞移植（allo-HSCT）治疗阵发性睡眠性血红蛋白尿症（PNH）的临床效果及安全性.方法 回顾性分析4例接受allo-HSCT的患者资料,其中3例为难治性PNH,1例为PNH-再生障碍性贫血综合征,均为HLA 6/6相合亲缘供者.预处理均采用白消安（BU）/环磷酰胺（CY）＋抗人T淋巴细胞兔球蛋白（ATG-F）方案,急性移植物抗宿主病（GVHD）预防采用环孢素A（CsA）＋甲氨蝶呤（MTX）,并复习相关文献.结果 移植后4例患者经DNA短串联重复序列多态性分析证明均为完全供者植入,中性粒细胞＞ 0.5×109/L的平均时间为15d（11～18d）,血小板计数＞ 20×109/L的平均时间为19 d（14～28 d）.移植后15～30 d CD55、CD59恢复正常.2例发生Ⅱ度急性GVHD,1例发生慢性GVHD,未发生移植排斥.中位随访时间14个月（7～42个月）,患者均无病生存.结论 allo-HSCT是根治难治性PNH的有效方法.     

Idiopathic hypereosinophilic syndrome terminating as disseminated T-cell lymphoma

The authors describe a case of idiopathic hypereosinophilic syndrome (HES) terminated as a T-cell lymphoma in a 3-year-old girl. The clinical course was chronic and characterized by chronic eczema, persistent peripheral blood eosinophilia, organomegaly, interstitial lung change, and pericarditis. Postmortem examination demonstrated a disseminated T-cell lymphoma involving the inguinal lymph node, liver, lung, and kidney. The findings of the current case suggest a possibility that certain abnormalities in this case of idiopathic HES per se may have triggered the development of malignant lymphoma, and it may represent a transition of idiopathic HES into a T-cell lymphoma. Other possible sequences are discussed. The development of T-cell malignancy in idiopathic HES in a girl is quite an unusual presentation.     

再生障碍性贫血伴阵发性睡眠性血红蛋白尿综合征合并骨髓瘤一例

患者 女性,64岁. 于2001年6月因无明显诱因出现面黄、乏力、齿龈渗血、皮肤出血点、瘀斑入住当地医学院附属医院.血常规示:血红蛋白(Hb)80 g/L,白细胞计数(WBC) 1.4 ×109/L,红细胞计数(RBC)2.30 ×1012/L,血小板计数(Plt)6×109/L. 随后行骨髓象检查结果示:有核细胞增生减低,粒、红两系少见,淋巴细胞相对增多,浆细胞易见,巨核细胞缺如.诊断为再生障碍性贫血(AA).予口服司坦唑醇、环孢素治疗,丙种球蛋白2.0 g×7 d静脉滴注,间断输血及血小板,茵陈蒿汤1剂/d,口服再生胶囊、地黄止血胶囊对症支持治疗,病情控制相对稳定. 2005年7月因间断出现酱油色尿、双目视物不清入院治疗.入院后检查血常规:Hb 32 g/L,WBC 1.2× 109/L,RBC 1.03×1012/L,Plt 16×109/L.随后行骨髓象检查结果示:红系增生活跃,以中晚期幼红细胞红居多,占0.475.溶血试验:酸化溶血试验、蔗糖溶血试验、抗人球蛋白试验均阴性;肝、肾功能:天门冬氨酸氨基转移酶89 U/L、尿素氮13.76 mmol/L、肌酐90.30μmol/L,其他检测项目均正常;流式细胞术检测:外周血粒细胞CD5548.40 %,CD5956.19 %,红细胞CD5571.34 %,CD5968.15 %.诊断为再生障碍性贫血-阵发性睡眠性血红蛋白尿(AA-PNH)综合征. 应用胸腺肽、多抗甲素、达那唑、叶酸、维生素B12等药物治疗,曾给予甲泼尼龙冲击治疗,茵陈蒿汤1剂/d、保肝、抗感染等对症治疗,患者病情平稳出院. 2012年11月患者病情呈进行性加重,再次住院治疗.入院后血常规示:Hb 18 g/L,WBC 2.13×109/L,RBC 0.51×1012/L,Plt 4×109/L,骨髓象检查显示浆细胞增多,占0.195,以成熟浆细胞为主,可见双核浆细胞,成熟红细胞呈缗钱状排列.     

FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria

On March 16, 2007, eculizumab (Soliris; Alexion Pharmaceuticals, Inc. Cheshire, CT), a humanized monoclonal antibody that binds to the human C5 complement protein, received accelerated approval by the U.S. Food and Drug Administration for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Eculizumab was studied in a randomized, double-blind, placebo-controlled clinical trial in 87 RBC transfusion-dependent adult PNH patients and in a supportive single-arm study in 96 patients. The eculizumab dose was 600 mg as a 35-minute i.v. infusion administered weekly for the first 4 weeks followed by 900 mg (week 5) then 900 mg every 14 days thereafter. Hemoglobin stabilized in 21 of 43 (48.8%) eculizumab-treated patients, compared with none of 44 placebo-treated patients. Eculizumab-treated patients required significantly fewer RBC transfusions than placebo-treated patients (median, 0 versus 10 units). There was also a significant reduction in the serum lactate dehydrogenase area under the curve with eculizumab compared with placebo treatment. Results of the phase II supportive study were similar to those of the phase III study. The safety database included 196 adult patients with PNH. Significant findings included the development of human anti-human antibody responses in three patients and serious meningococcal infections in three patients. Patients should undergo meningococcal vaccination at least 2 weeks prior to receiving the first eculizumab treatment and have revaccination according to current medical guidelines. Patients must be monitored and evaluated immediately for early signs of meningococcal infections and treated with antibiotics as indicated.     

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones.

PNH is characterized by expansion of one or more stem cell clones with a PIG-A mutation, which causes a severe deficiency in the expression of glycosylphosphatidylinositol (GPI)-anchored proteins. There is evidence that the expansion of PIG-A mutant clones is concomitant with negative selection against PIG-A wild-type stem cells by an aplastic marrow environment. We studied 36 patients longitudinally by serial flow cytometry, and we determined the proportion of PNH red cells and granulocytes over a period of 1-6 years. We observed expansion of the PNH blood cell population(s) (at a rate of over 5% per year) in 12 out of 36 patients; in all other patients the PNH cell population either regressed or remained stable. The dynamics of the PNH cell population could not be predicted by clinical or hematologic parameters at presentation. These data indicate that in most cases the PNH cell expansion has already run its course by the time of diagnosis. In addition, since in most cases no further expansion takes place, we can infer that the tendency to overgrow normal cells is not an intrinsic property of the PNH clone.