Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia

BACKGROUND: Severe aplastic anemia is a life-threatening bone marrow failure disorder. High-dose cyclophosphamide therapy followed by allogeneic bone marrow transplantation cures the disease. However, it requires a suitable donor and carries the risk for graft-versus-host disease. A small pilot study demonstrated that high-dose cyclophosphamide therapy without bone marrow transplantation leads to durable, treatment-free complete remission. OBJECTIVE: To confirm the safety and efficacy of high-dose cyclophosphamide therapy alone in patients with severe aplastic anemia. DESIGN: Uncontrolled clinical trial. SETTING: Three tertiary care hospitals. PATIENTS: 19 patients with untreated severe aplastic anemia. INTERVENTION: Cyclophosphamide, 50 mg/kg of body weight per day for 4 consecutive days. MEASUREMENTS: Probability of response and overall survival were measured. Complete remission was defined as normal blood count for age and sex. Partial remission was defined as independence from transfusion and an absolute neutrophil count greater than 0.5 x 10(9) cells/L without growth factor support. Nonresponders were patients who remained transfusion dependent or died. Relapse was defined as no longer meeting criteria for partial or complete remission. RESULTS: The median time to an absolute neutrophil count of 0.5 x 10(9) cells/L was 49 days. The probability of survival was 84% (95% CI, 59% to 95%) at 24 months. The probability of achieving treatment-free remission was 73% (CI, 51% to 91%) at 24 months, and the probability of achieving complete remission was 65% (CI, 39% to 89%) at 50 months. No responding patients have had relapse or have developed secondary clonal disorders. CONCLUSIONS: High-dose cyclophosphamide therapy without bone marrow transplantation produces durable treatment-free remission in severe aplastic anemia. This approach deserves further study in patients with severe aplastic anemia who are not suitable candidates for allogeneic bone marrow transplantation.     

Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation

Severe aplastic anemia (SAA) can be successfully treated with allogeneic bone marrow transplantation (BMT) or immunosuppressive therapy. However, the majority of patients with SAA are not eligible for BMT because they lack an HLA-identical sibling. Conventional immunosuppressive therapy also has major limitations; many of its remissions are incomplete and relapse or secondary clonal disease is common. Cyclophosphamide is a potent immunosuppressive agent that is used in all BMT conditioning regimens for patients with SAA. Preliminary evidence suggested that high-dose cyclophosphamide, even without BMT, may be beneficial to patients with SAA. Therefore, 10 patients with SAA and lacking an HLA-identical sibling were treated with high-dose cyclophosphamide (45 mg/kg/d) for 4 consecutive days with or without cyclosporine. A complete response (hemoglobin level, > 13 g/dL; absolute neutrophil count, > 1.5 x 10(9)/L, and platelet count > 125 x 10(9)/L) was achieved in 7 of the 10 patients. One of the complete responders died from the acquired immunodeficiency syndrome 44 months after treatment with high-dose cyclophosphamide. The 6 remaining patients are alive and in continuous complete remission, with a median follow-up of 10.8 years (range, 7.3 to 17.8 years). The median time to last platelet transfusion and time to 0.5 x 10(9) neutrophils/L were 85 and 95 days, respectively. None of the complete responders has relapsed or developed a clonal disease. These results suggest that high-dose cyclophosphamide, even without BMT, may be more effective than conventional immunosuppressive therapy in restoring normal hematopoiesis and preventing relapse or secondary clonal disorders. Hence, further studies confirming the efficacy of this approach in SAA are indicated.     

High-dose cyclophosphamide as salvage therapy for severe aplastic anemia

OBJECTIVE: The treatment options for patients with aplastic anemia who do not respond to conventional immunosuppression are limited. The aim of this study was to evaluate high-dose cyclophosphamide in patients with refractory severe aplastic anemia (SAA). MATERIALS AND METHODS: We treated 17 SAA patients with high-dose cyclophosphamide (50 mg/kg/day for 4 consecutive days) who previously did not respond to one or more courses of immunosuppressive therapy. Median age was 31 years (range 6-58); median disease duration was 14 months (range 6-58), and 8 patients met criteria for very severe aplastic anemia (absolute neutrophil count <0.2 x 10(9)/L) at the time of treatment. RESULTS: At median follow-up of 29 months, 10 patients (59%) are alive. Nine patients (53%) achieved a drug-free remission after high-dose cyclophosphamide; 4 patients achieved a complete remission and 5 patients currently meet criteria for a partial remission but continue to improve. One nonresponder to high-dose cyclophosphamide developed paroxysmal nocturnal hemoglobinuria; another nonresponder developed a myelodysplastic syndrome. In responding patients, median time to 500 neutrophils was 54 days (range 35-119), median time to the last platelet transfusion was 99 days (range 51-751), and median time to the last red cell transfusion was 125 days (range 63-796). CONCLUSION: High-dose cyclophosphamide shows promise for salvaging patients with refractory SAA.     

肺炎克雷伯菌肝脓肿的临床特征分析

目的分析肺炎克雷伯菌肝脓肿(KPLA)的临床资料,为早期诊断、合理治疗提供参考。方法回顾性分析2009年3月~(-2)015年7月于南京医科大学第一附属医院住院的156例血培养或脓液培养阳性的细菌性肝脓肿(BLA)患者的病原学特征,根据培养结果,将BLA患者分为KPLA组(n=81)和非肺炎克雷伯菌肝脓肿(NKPLA)组(n=61),另有14例患者肺炎克雷伯菌培养阳性的同时还获得了大肠埃希菌等其他阳性菌株。比较KPLA和NKPLA的临床、实验室及影像学资料。符合正态分布的计量资料组间比较采用t检验,偏态分布组间比较采用Mann-Whitney U检验;计数资料组间比较采用χ~2检验或Fisher精确检验。结果 BLA最常见的致病菌为肺炎克雷伯菌。与NKPLA相比,KPLA更好发于男性(χ~2=4.50,P=0.03),多有糖尿病的基础(χ~2=27.28,P0.001),患者诉腹痛的比例较低(χ~2=5.24,P=0.02),而NKPLA组患者较KPLA组在基础疾病方面多有胆道疾病、腹部手术史及腹腔内肿瘤史,差异有统计学意义(χ~2值分别为18.38、20.87、21.68,P值均0.001)。实验室检查方面,与KPLA组相比,NKPLA组患者的血红蛋白降低更为明显,差异有统计学意义(t=4.903,P0.001)。2组患者在影像学检查上均以右侧、单发多见,但KPLA患者出现分隔形成的比例较高,差异有统计学意义(χ~2=4.16,P=0.04)。2组患者均出现了肺部感染、胸腔积液、肾周感染等并发症。2组患者均以抗生素联合穿刺治疗为主,其中KPLA组的治疗有效率(93.83%)高于NKPLA组(80.33%),差异有统计学意义(χ~2=6.02,P=0.01)。结论 BLA的主要致病菌为革兰阴性杆菌,尤其是肺炎克雷伯菌。KPLA好发于男性,患者多有糖尿病基础,临床表现常不明显,易出现胸腔积液、肺部感染等并发症,应尽早行影像学检查,及时给予相应治疗。     

肺炎克雷伯杆菌肝脓肿与非肺炎克雷伯杆菌肝脓肿的临床比较

目的:总结分析肺炎克雷伯杆菌肝脓肿与非肺炎克雷伯杆菌肝脓肿在临床方面的差异,为临床医生早诊断、早治疗提供依据．方法:总结2000-01／2005-01细菌性肝脓肿住院患者162例,利用统计学方法比较肺炎克雷伯杆菌与非肺炎克雷伯杆菌引起的肝脓肿在自然情况、伴发基础疾病、临床表现及实验室检查、肝脓肿特点、治疗方法及结果等方面的差异．结果:肺炎克雷伯杆菌肝脓肿112例(69．1％), 非肺炎克雷伯杆菌肝脓肿50例(30．9%),两组在年龄上存在统计学差异(P<0．05);两组患者在伴发糖尿病(66．1％vs 38．0％,P<0．01)、胆道疾患(14．3％vs 28．0％,P<0．05)、腹部创伤 (5．4％vs 16．0％,P<0．05)上存在统计学差异; 两组患者在贫血上存在统计学差异(60．7％vs 78％,P<0．05)．肺炎克雷伯杆菌肝脓肿多为单发脓肿,且多为单一病原体,两组间存在统计学差异(75．9％vs 58％,P<0．05;85．7％vs 64％, P<0．01)．两组间在迁徙性感染、死亡率上存在统计学差异(20．5％vs 6％,P<0．05;8．9％vs 26．0％,P<0．01)．结论:与非肺炎克雷伯杆菌肝脓肿组相比,肺炎克雷伯杆菌肝脓肿组发病年龄较低,伴发糖尿病的比例高,多为单发,单病原体,易形成迁徙性感染,死亡率较低．     

Klebsiella pneumoniae liver abscess associated with septic endophthalmitis

Metastatic septic bacterial endophthalmitis is a rare, but devastating disease. We encountered seven cases of pyogenic liver abscess associated with septic endophthalmitis during a recent four-year period. The causative organism was a pure culture of Klebsiella pneumoniae. The diagnosis was made by results of a blood culture in seven of the cases, liver aspirate culture in four, and eye contents or conjunctival culture in four. Chest roentgenographic examination showed pulmonary embolization in four patients, purulent meningitis in one patient, and suspicious prostatic abscess in one patient. Despite diligent antibiotic therapy, six patients lost their vision and one had impaired vision. This poor outcome for septic endophthalmitis seems to result from delayed diagnosis and lack of scheduled periocular injections of antibiotics. A combination course of treatment by the internist and ophthalmologist acting aggressively, both diagnostically and therapeutically, is needed in the future. To have seven cases of K pneumoniae liver abscess complicated by septic endophthalmitis during a period of four years in one hospital is very unusual. To our knowledge, it has never been reported in the literature.     

Cryptogenic invasive Klebsiella pneumoniae liver abscess syndrome.

BACKGROUND: Klebsiella pneumoniae-associated liver abscesses have distinct clinical and epidemiologic features. METHODS: We report the unusual case of an American patient with a K. pneumoniae-associated liver abscess and septic spread to other organs. We additionally present a comprehensive review of K. pneumoniae-associated liver abscess syndromes in adults. RESULTS: We identified three distinct K. pneumoniae liver abscess syndromes: the polymicrobial liver abscess, the monomicrobial cryptogenic noninvasive liver abscess, and the monomicrobial cryptogenic invasive K. pneumoniae-associated liver abscess (CIKPLA) syndromes, with distinct clinical, epidemiologic and outcome features. CIKPLA syndrome typically affects diabetic patients, mainly in Southeast Asia, and is complicated by septic spread to other organs. CONCLUSIONS: The community-acquired, monomicrobial, K. pneumoniae-associated liver abscess syndromes that typically occur in the USA are mainly noninvasive and affect Asian or Hispanic persons. However, this report provides an alert that CIKPLA syndrome can occur in North America, and physicians need to be aware of it.     

Secondary leukemia after severe aplastic anemia

Summary We describe a patient with acute myeloid leukemia (AML) occurring 5 years after successful treatment of severe aplastic anemia (SAA) with antilymphocyte globulin (ALG). Four years after ALG, SAA had relapsed. A second remission of SAA was achieved, but was followed by transformation of the myelodysplastic syndrome into overt AML. After 2 courses of high-dose cytosine arabinoside and VP-16 complete remission occurred. This case shows that chemotherapy of secondary leukemia after SAA is feasible, and that ex-aplastic bone marrow is capable of complete recovery from chemotherapy-induced aplasia. Morphological anomalies of bone marrow noticed early during remission of SAA might predict a late transformation in leukemia.     

Pyogenic liver abscess caused by hypermucoviscous Klebsiella pneumoniae

Community-acquired primary pyogenic liver abscess (PLA) caused by Klebsiella pneumoniae is an emerging infectious entity, with cases reported in the scientific literature over the past 15 y mainly from Taiwan and Asia, but also from Europe and North America. We describe a case of PLA caused by the hypermucoviscous, K1 capsular serotype of Klebsiella pneumoniae in a Canadian man and highlight the unique features of this increasingly common cause of liver abscess.     

Klebsiella pneumoniae primary liver abscess associated with ruxolitinib

Annals of Hematology -     

Pregnancy after bone marrow transplantation for severe aplastic anemia

Two women suffering from severe aplastic anemia were treated by bone marrow transplantation (BMT). They became pregnant 17 and 40 months after the procedure. During the first 20 weeks of pregnancy, one of them continued to receive cyclosporin A (CSA) to prevent graft-versus-host disease. Her CSA serum levels during these first 4 months ranged from 35 to 280 ng/ml. The course of pregnancy was uneventful and a healthy boy was delivered at term by Cesarean section. The other patient was shown to have rejected the transplanted marrow 4 months after BMT; autologous regeneration had occurred. During the last 2 months of her pregnancy, the hemoglobin and platelet numbers decreased again. Nevertheless, a healthy girl was delivered at term. Three months after delivery this patient's hematologic parameters are almost back to normal.     

Veno-occlusive disease of the liver after allogeneic bone marrow transplantation for severe aplastic anemia

There are few reports about the occurrence of hepatic VOD after BMT for severe aplastic anemia (SAA). We prospectively studied 17 patients with SAA after allogeneic BMT for the occurrence and severity of VOD. Plasma levels of protein C, protein S, antithrombin III, vWF, t-PA and PAI-1 were determined before preparative chemotherapy, on the day of marrow infusion, and on days 7, 14 and 21. VOD occurred in seven patients (41.2%) at a median of day 1 (range, day -2 to 15). Five had mild, and two moderate VOD. Platelet transfusion requirements were higher in the patients with VOD. The plasma levels of natural anticoagulants such as protein C, free protein S and antithrombin III decreased significantly on day 0 from the baseline levels. Plasma levels of t-PA, PAI-1 and vWF increased significantly in the early post-transplant period compared to the baseline levels. The mean plasma levels of t-PA on day 7 (P = 0.016) and PAI-1 on days 0 and 7 (P = 0.016, 0.032) were higher in the patients with VOD. In summary, we observed hypercoagulability and a high incidence of VOD after allogeneic BMT for SAA. Levels of t-PA and PAI-1 were significantly higher in the patients with VOD after BMT.     

Septic endophthalmitis and meningitis associated with Klebsiella pneumoniae liver abscess

We report a female case of septic endophthalmitis and meningitis associated with Klebsiella pneumoniae liver abscess which was thought to be caused by duodeno-biliary reflux related to choledochoduodenostomy. We treated this patient by ultrasonography-guided percutaneous abscess drainage and intravenous administration of third generation antibiotics. However, the visual function of her left eye was eventually lost. Reports of liver abscess with metastatic lesions are rare, and our experience suggests that more physicians should be alert to septic metastatic lesions such as K. pneumoniae liver abscess or bacteremia with complaints of ocular or central nervous system symptoms.