氟达拉宾对系统性红斑狼疮BXSB小鼠狼疮活动的影响

目的 :探讨氟达拉宾对系统性红斑狼疮BXSB小鼠狼疮活动的影响 ,氟达拉宾治疗重型系统性红斑狼疮的可能性、有效性及其可能的机制。方法 :用 30mg (m2 ·d) ,连续 3天氟达拉宾尾静脉注入BXSB小鼠体内 ,用血液分析仪分析用氟达拉宾前后不同时间小鼠外周血白细胞的变化 ,用ELISA方法测定BXSB小鼠血清抗ds DNA抗体、抗核抗体的变化 ,免疫荧光检查肾组织的病理改变 ,尿蛋白试纸检测用氟达拉宾前后BXSB小鼠的蛋白尿 ,流式细胞仪分析T淋巴细胞表面CD4 + Fas+ 、CD8+ Fas+ 、、CD4 5RO+ Fas+ 表达的变化。结果 :用氟达拉宾后BXSB小鼠外周血白细胞数从第 3天开始下降 ,至第 7天时白细胞下降至最低值〔(0 5± 0 2 )× 10 9L- 1 〕 ,白细胞上升至 1 0× 10 9L- 1 的时间是用药后 19天 ;BXSB小鼠血清抗ds DNA抗体、抗核抗体的水平明显下降 ,分别出现在用氟达拉宾后第 14、2 1天时 ;用药后第 2 8天氟达拉宾组 72 7%的BXSB小鼠肾组织进行免疫荧光病理检查 ,其荧光强度由 +～ ++→± ;用氟达拉宾后第 2 1、2 8天尿蛋白从 ++～ +++转±～ -占 81 8% ;用Flu后BXSB小鼠CD4 + Fas+ 、CD8+ Fas+ 、CD4 5RO+ Fas+ 的表达均明显低于用Flu前。结论 :氟达拉宾可明显减少BXSB小鼠血清抗ds DNA抗体、抗核抗体的水平 ,减少BXSB小     

Treatment of refractory fludarabine induced autoimmune haemolytic with the anti‐cd20 monoclonal antibody rituximab

A patient with cold‐type autoimmune haemolytic anaemia for 8 years developed progressive B cell chronic lymphocytic leukaemia (CLL). Despite the risk of fludarabine induced exacerbation of haemolysis, he was given aggressive anti‐CLL therapy with six courses of FCR (fludarabine 25 mg/m² D1–3, cyclophosphamide 250 mg/m² D2–4 and rituximab 375 mg/m² D1) every 4 weeks. This resulted in a marked acute increase in haemolysis shortly after completing each course of fludarabine. However, haemolysis had settled to its baseline level by the time of subsequent courses of FCR. FCR resulted in complete clinical remission of CLL but residual haemolysis persisted. The patient was then given four weekly infusions of single agent rituximab, resulting in ongoing remission of haemolysis. In this patient, rituximab appears to have controlled fludarabine induced exacerbation of autoimmune haemolysis. In addition, subsequent single agent rituximab therapy resulted in prolonged remission of cold‐type autioimmune haemolytic anaemia. It remains to be seen if the addition of rituximab will allow other patients with a positive direct Coomb's test and/or autoimmune haemolysis to receive fludarabine containing chemotherapy without undue risk of life‐threatening haemolytic anaemia.     

Unrelated-Donor Bone Marrow Transplantation with a Conditioning Regimen Including Fludarabine, Busulfan, and 4 Gy Total Body Irradiation

We investigated the feasibility of reduced-intensity conditioning with 4 Gy total body irradiation, fludarabine (30 mg/m2 for 6 days), and busulfan (4 mg/kg for 2 days) for bone marrow transplantation from a serologically HLA-matched unrelated donor. Seventeen adult patients (median age, 55 years; range, 27-67 years) with various hematologic malignancies (6 in remission, 11 not in remission) were treated. Successful engraftment was achieved in all patients at a median of day 18 (range, day 14-35) after transplantation, although subsequent secondary graft failure was observed in 2 patients. The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV at day 100 was 48%. With a median follow-up of 286 days (range, 56-687 days), the rates of 1-year overall survival, 100-day nonrelapse mortality, and 1-year nonrelapse mortality were 41%, 14%, and 46%, respectively. Eleven patients died, and the causes of death were relapse (n = 4), pulmonary complications (n = 4), acute GVHD (n = 2), and sepsis (n = 1). The remaining 6 patients (at transplantation, 2 were in remission, and 4 were not in remission) are currently still in remission. These results suggest that this regimen reduces the risk of graft failure, but further studies are needed to ameliorate transplantation-related toxicities, primarily GVHD and/or pulmonary complications.     

氟达拉滨治疗慢性淋巴细胞白血病的临床观察

目的:观察氟达拉滨(Fludarabine)治疗慢性淋巴细胞白血病的疗效和不良反应。方法:收集氟达拉滨治疗慢性淋巴细胞白血病15例患者的临床资料,其中10例为首次疗程即使用氟达拉滨单药,5例为COP或CHOP方案1～2疗程或服用苯丁酸氮芥(瘤可宁)半年无效改用氟达拉滨,部分疗程为氟达拉滨和环磷酰胺联合用药;评估CR率和PR率,同时观察不良反应。结果:9例(60%)完全缓解,2例部分缓解,4例无效(1例耐药),总有效率73.3%。不良反应粒细胞减少7例,血小板减少3例,其中1例示ITP,1例发生溶血。结论:氟达拉滨治疗慢性淋巴细胞白血病有较高的疗效;不良反应以骨髓抑制常见,感染、ITP、AIHA最为严重,如在化疗前检查Coombs’test,可能避免发生自身免疫性溶血。     

供鼠细胞经氟达拉滨处理后移植对aGVHD的影响

目的 探讨临床注射用氟达拉滨对大鼠同种异基因骨髓移植(Allo-BMT)后造血重建及急性移植物抗宿主病(aGVHD)的影响.方法 建立大鼠Allo-BMT模型,以清洁级Wistar大鼠为供鼠,清洁级SD大鼠20只随机分为A、B、C三组,受鼠接受全身照射(TBI)6.0Gy作为清髓性预处理.4h后,A组输注生理盐水作为对照组,B组经尾静脉输注供鼠骨髓及脾混合单个核细胞,C组经尾静脉输注用氟达拉滨体外培养24h的供鼠骨髓及脾混合单个核细胞.移植后每天观察三组受鼠造血恢复情况及aGVHD的发生情况.结果 移植后B、C组大鼠的外周血像平均恢复时间分别为(18.50±1.05)和(15.17±1.47)d(P＜0.05).A组大鼠的血像持续降低至死亡.临床aGVHD评分,B组明显高于C组[(7.33±1.63) vs. (4.67±1.23)分,(P＜0.05)].肝脏和结肠病理分级比较,B组以Ⅳ～Ⅴ级、C组以Ⅱ～Ⅲ级aGVHD病理变化为主,两组差异显著(P＜0.05).结论 大鼠Allo-BMT模型中,经氟达拉滨体外培养的供鼠细胞能显著减轻受鼠的aGVHD.     

复发性难治性急性白血病21例临床分析

目的观察氟达拉滨（Flu）、阿糖胞苷（Ara-C）及粒细胞集落刺激因子（G-CSF）（FLAG）方案对复发性难治性急性白血病的疗效与不良反应。方法Flu 30mg·m^-2·d^-1，1～5d；Ara-C1．5g·m^-2·d^-1，5d；在WBC〈1×10^9／L时用G-CSF5μg·kg^-1·d^-1直至WBC〉1．5×10^9／L。治疗21例复发难治急性白血病。结果总有效率81％（17／21），CR57％（12／21），PR24％（5／21），NR14％（3／21）。发生中性粒细胞缺乏16例，持续时间6～18d，血小板〈20×10^9／L 13例，持续时间7～20d。不良反应包括丙氨酸氨基转移酶（ALT）升高、发热、腹泻。结论FLAG方案治疗复发性难治性急性白血病疗效较好，不良反应较少。     

Fatal Bone Marrow Necrosis Following Fludarabine Administration in a Patient with Indolent Lymphoma

We report the first known case of fulminant bone marrow necrosis (BMN) occurring after infusion of fluduabine monophosphate in a patient with recurrent low-grade non-Hodgkin's lymphoma (NHL). Extensive BMN is characterized by the development of fever, bony pain. a leukoerythroblastic peripheral blood film, variable degrees of pancytopenia and elevations in lactate dehydrogcnase and alkaline phosphatase. The diagnosis of BMN is rarely entertained ante-mortem. Although the precise role chemotherapy may have played in triggering fatal BMN remains speculative, we alert clinicians to be aware of this entity as more patients with indolent lymphomas and leukemias are treated with this and other potent nucleoside analogs.     

Fludarabine in comparison to alkylator-based regimen as induction therapy for chronic lymphocytic leukemia: a systematic review and meta-analysis

The superiority of Fludarabine over conventional therapy as primary induction therapy for patients with chronic lymphocytic leukemia (CLL) has been shown in several studies but no studies have yet reported a pooled estimate of the treatment effect. We performed a systematic review of evidence from 5 randomized controlled trials involving approximately 1300 patients with CLL, comparing Fludarabine with several alkylator-based combination regimens in the primary treatment of CLL. Complete response rate was significantly higher for Fludarabine compared to alkylator-based chemotherapy (RR 1.87, 95% CI 1.10 - 3.19, P = 0.02), while overall response, though superior, did not reach statistical significance (RR 1.22, 95% CI = 0.88 - 1.69, P = 0.24). Overall survival was similar for Fludarabine and alkylator-based therapy (the pooled log hazard ratio of death, HR =  - 0.05, 95% CI =  - 0.36 - 0.26, P = 0.75). Infection rate was significantly higher (RR 1.58, 95% CI = 1.10 - 2.27, P = 0.01), but there was no significant difference in the incidence of thrombocytopenia, neutropenia and anemia. Therefore, this meta-analysis supports the findings that Fludarabine as an induction agent for patients with CLL yields a better clinical response with acceptable toxicity when compared with alkylator-based combination therapy, but without a survival benefit by 5 - 6 years of follow up.     

Efficacy and safety of fludarabine and cyclophosphamide combined therapy in patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL)-Polish multicentre study

The aim of this study was to investigate the efficacy of a combination of fludarabine (F) and cyclophosphamide (C) in the treatment of patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL). Between November 1999 and December 2001, 63 patients with B-CLL (median age 60 years) received a regimen that consisted of F 25 mg/m² and C 250 mg/m², days 1 - 3, intravenously, every 4 weeks, for a maximum of 6 courses. Response and toxicity were assessed according to current criteria (NCI-WG and WHO). Complete and partial remissions were achieved in 17.5% and 55.6% of patients, respectively; 19% of patients had stable disease and 7.9% of patients showed disease progression. The median follow-up was 16.5 (range 1.5 - 32) months. The median duration of progression-free survival (PFS) has not been reached among patients treated with FC regimen as second-line therapy.The median PFS was 13 (range 8 - 26) months in the 19 responding patients treated with FC regimen as third-line therapy. The most frequent side-effects were neutropenia (45%), thrombocytopenia (42%) and infections (57%). We conclude that the combination of fludarabine and cyclophosphamide demonstrated significant efficacy in pretreated, advanced B-CLL patients, with tolerable toxicity.     

A sensitive fluorescence assay for quantitation of fludarabine and metabolites in biological fluids

Rapid and quantitative dephosphorylation of the new anticancer nucleotide analogue fludarabine phosphate to its nucleoside 9-β-D-arabinofuranosyl-2-fIuoroadenine (F-ara-A) renders this metabolite the target for pharmacologic investigations. At clinically effective doses of fludarabine phosphate (18–30 mg/m² per day) comprehensive pharmacokinetic analysis of F-ara-A has been limited by the sensitivity of UV based HPLC assays. To address this problem we developed a sensitive test based on the condensation of F-ara-A with chloroacetaldehyde to form the fluorescent derivative, arabinosyl-1, N⁶-etheno-isoguanine. Combined with a solid-phase extraction step prior to derivatization and separation of the reaction products by reverse-phase HPLC, this assay had a quantitation limit of 2 pmol F-ara-A per ml plasma. Slightly modified, the system was also applicable to urine specimens, with a quantitation limit of 1 nmol F-ara-A per ml urine.