不同分期慢性淋巴细胞白血病患者淋巴细胞亚群特点及氟达拉滨对其的影响

Objective To study the feature of the subgroup of lyrnphocytes from patients with chronic lymphocytic leukemia(CLL)at different stages,and the changes in the treatment by the chemotherapy based on fludarabine.Methods The subgroup of T lyrnphocytes and NK cell were detected by flow cytometry during treatment which based on fludarabine from patients with CLL and normal people.Results The total of T.help T cells and ratio of CD4/CD8 of patients were significantly lower than that in normal people,especially in stage Ⅲ-Ⅳ(P＜0.01),and the NK cells in stage 0～Ⅱis higher than that in normal(P＞0.05),which is lower in stage Ⅲ-Ⅳ(P＜0.05).Four weeks after the chemotherapy mainly based on fludarabine,the total T,help T cell and ratio of CD4/CD8 of patients with CLL was significantly raised(P＜0.01),and meanwhile the NK cell was clearly raised (P＜0.05).Conclusion The cell mediated immunological regulation abnormal exists in patients with CLL,and the immune function correlated closely with the morbid state.Observation on the changes of T lymphocyte subsets and its ratio of NK cells,which were is helpful for the assement of the patient's condition,and also can evaluate the therapeutic effect.The cellular immune function was obviously improved in patients who are effective to fludarabine.whether there exists noticeable immune suppression shortly after chemotherapy should be studied in further clinical observation.     

氟达拉滨治疗慢性淋巴细胞白血病的近期疗效评价

 目的 研究以氟达拉滨为主的化疗方案对慢性淋巴细胞性白血病（CLL）的近期疗效。方法 24例患者中CLL／SLL 16例，CLL 4例，多毛细胞白血病1例，CLL／PLL 1例，PLL 2例。给予FC(氟达拉滨+环磷酰胺)方案，共1 ~ 4个疗程。结果 总有效率（OR）为66.67 %（16／24），完全缓解率（CR）为50 %（12／24），部分缓解（PR）为12.5 %（3／24），主要不良反应为骨髓抑制和轻度胃肠道反应，白细胞下降发生率58.33 %，血红蛋白下降发生率62.5 %，血小板下降发生率58.33 %，肝功能损害12.5 %，恶心呕吐25 %，2例死于基础疾病。结论 以氟达拉滨为主的化疗方案对CLL的近期疗效好，不良反应轻，值得近一步推广和研究。     

慢性淋巴细胞白血病患者外周血T淋巴细胞亚群及NK细胞亚群分析及临床意义

目的研究慢性淋巴细胞白血病(CLL)患者血淋巴细胞亚群与临床分期的关系。方法采用流式细胞仪检测患者及正常成人血中淋巴细胞亚群比例、CD4/CD8比值。结果与正常成人比较,Ⅰ～Ⅱ期CLL患者血中总T、T辅助细胞、CD4/CD8略降低,T抑制细胞略增高(P>0.05);而NK细胞略增高(P>0.05)。Ⅲ期CLL总T、T辅助细胞及CD4/CD8明显下降(P<0.05),NK细胞明显降低(P<0.05)。与Ⅰ～Ⅱ期比较,Ⅲ期患者的总T、T辅助细胞、CD4/CD8和NK细胞明显下降(P<0.05)。结论淋巴细胞亚群的分析有助于CLL病情的判断。     

口服氟达拉滨治疗慢性淋巴细胞白血病小淋巴细胞淋巴瘤的疗效观察

目的:评价口服氟达拉滨治疗慢性淋巴细胞白血病/小淋巴细胞性淋巴瘤（CLL/SLL）的疗效和不良反应。方法:15例CLL/SLL 患者中CLL 10例,SLL 5 例,中位年龄63岁。CLL 患者按照Rai分期分为Ⅱ期5 例,Ⅲ期2 例,Ⅳ期3 例。SLL 患者临床分期为Ⅲ期4 例,Ⅳ期1 例。11例为初治患者,4 例为复治患者。所有患者均口服氟达拉滨片40mg/（m2·d）,持续5 天,每4 周1 疗程,至少连用4 个疗程。12例患者完成4 个疗程,3 例患者4 个疗程后分别又巩固1～2 个疗程。结果:15例患者平均完成4.3 个周期。完全缓解率66.7%（10/15）,部分缓解率26.6%（4/15）,1 例（6.7%）无效,总有效率93.3%（14/15）。 11例初治患者完全缓解9例,部分缓解1 例,1 例由于疾病进展死亡。4 例复治患者1 例完全缓解,3 例部分缓解。不良反应主要为骨髓抑制和感染,5 例（33.3%）出现中性粒细胞下降,1 例Ⅰ级,3 例Ⅱ级,1 例Ⅲ级。感染3 例（20%）。 非血液系统毒性轻微,不良反应均可恢复。结论:口服氟达拉滨治疗CLL/SLL 用药方便,疗效较理想,对既往治疗过的患者亦有较好疗效,不良反应较轻,对于CLL/SLL 患者是值得推荐的治疗方案。      

口服磷酸氟达拉滨对复治慢性淋巴细胞性白血病的治疗

比利时、加拿大、法国、德国、英国、意大利、荷兰、西班牙和瑞典共同了进行一项前瞻性、多中心性、开放性的Ⅱ期临床试验 ,其目的是评估口服磷酸氟达拉滨对慢性淋巴细胞性白血病 (ＣＬＬ)的疗效及安全性。疗效评价标准采用慢性淋巴细胞性白血病国际专题部(ＩＷＣＬＬ)和国立癌症研究所 (ＮＣＩ)关于完全缓解(ＣＲ)、部分缓解 (ＰＲ )、病情稳定 (ＳＤ )和病情进展(ＰＤ)的标准进行 ;安全评估标准采用世界卫生组织(ＷＨＯ)毒性级别标准进行。共有 78例以前接受过治疗的Ｂ ＣＬＬ病人入选。年龄 18～ 75岁 ;以前对至少一种烷化剂治疗无效或者…     

氟达拉滨联合环磷酰胺方案治疗慢性淋巴细胞白血病21例

 【摘要】　目的　观察氟达拉滨联合环磷酰胺（FC）方案治疗慢性淋巴细胞白血病（CLL）的疗效和不良反应。方法　回顾性分析21例经FC方案治疗的CLL患者的临床资料,评估患者临床分期及近期疗效,同时观察患者对药物的不良反应。结果　21例患者中完全缓解（CR）21例（28.57 %）,部分缓解（PR）6例（28.57 %）,总有效率 57.14 %,Ⅲ期与Ⅳ期患者的总CR率明显低于Ⅰ期与Ⅱ期患者（8.33 %比55.56 %）（Fisher精切概率法,P＜0.05）。治疗相关主要不良反应为骨髓抑制和感染。结论　FC方案是目前治疗CLL较有效方案,其安全性好。     

氟达拉滨耐药的慢性淋巴细胞白血病治疗进展

对嘌呤类药物发生耐药为慢性淋巴细胞白血病(CLL)患者预后差的特征.虽然近年来免疫化疗联合应用如氟达拉滨(Fludarabine,Flu)、环磷酰胺(CTX)和利妥昔单抗(rituximab)已导致初治患者反应率达95%和无失败生存率增加,但因为缺乏治疗反应和对Flu耐药许多慢淋患者仍不能治愈.补救治疗的策略包括含阿来组单抗(alemtuzumab)的方案、靶向药物和异基因造血干细胞移植(allo-SCT).单药alemtuzumab治疗Flu耐药的CLL患者反应率高达40%,但反应并不持久,中数生存期约1-2年.耐Flu-CLL患者亦可采用alemtuzumab与Flu、CTX和/或利妥昔单抗,或其他药物如雷利度胺(lenalidomide)、flavopiridol和靶向药物联用进行补救性治疗.包括alemtuzumab和/或利妥昔的免疫化疗方案和allo-SCT或可改善该病的预后,但对新的、更有效的治疗仍需要继续研究.     

含氟达拉滨的联合化疗方案治疗慢性淋巴细胞白血病／小淋巴细胞性淋巴瘤

目的：评价以氟达拉滨为主的化疗方案治疗慢性淋巴细胞白血病／小淋巴细胞淋巴瘤（CLI／SLL）的疗效和不良反应。方法：采用氟达拉滨为主的化疗方案，FC方案：氟达拉滨＋环磷酰胺；FMD方案：氟达拉滨＋米托蒽醌＋地塞米松；FMC方案：氟达拉滨＋米托蒽醌＋环磷酰胺，共治疗18例CLL／SLL患者，其中初发9例，复发、难治9例。结果：18例患者平均完成4．2个周期，完全缓解（CR）率61．1％，部分缓解（PR）率22．2％，总的有效（OR）率83．3％。初发组CR率66．7％。PR率33．3％，OR率100％；复发、难治组CR率55．6％，PR率11．1％，OR率66．7％，两组CR、OR率无显著性差异（P〉0．05）。FC方案和FMD方案治疗组CR、OR率无显著性差异（P〉0．05）。主要不良反应为骨髓抑制和免疫功能抑制，27．8％的患者出现Ⅲ～Ⅳ级粒细胞减少，22．2％的患者出现Ⅲ～Ⅳ级血小板减少。5例患者出现感染、发热，其中1例死亡。其它毒性包括恶心、呕吐，轻度肝肾功能损害，自身免疫性溶血性贫血。中位随访时间24月（1～40月），2年生存率88．9％，2年PFS率81．8％。初发组2年生存率100％，2年PFS率100％；难治组2年生存率83．3％，2年PFS率66．7％，两组无显著性差异（P〉0．05）。结论：氟达拉滨为主的联合化疗方案对CIL／SLL疗效好，同时患者对其耐受性亦较佳。     

利妥昔单抗联合氟达拉滨、环磷酰胺治疗慢性淋巴细胞白血病17例

 目的　评价利妥昔单抗联合氟达拉滨、环磷酰胺（FCR方案）治疗慢性淋巴细胞白血病（CLL）患者的疗效和安全性。方法　选取年龄＜70岁且CD20阳性的初治或既往仅用苯丁酸氮芥治疗的CLL患者,应用FCR方案治疗,利妥昔单抗375 mg／m2,第1天,静脉滴注;氟达拉滨25 mg／m2,第2天至第4天,静脉滴注;环磷酰胺250 mg／m2,第2天至第4天,静脉滴注。28 d为1个疗程,治疗4～6个疗程,治疗结束后评价疗效。结果　共入组17例患者,总有效率为94.12 %（16／17）,完全缓解率为35.29 %（6／17）。Ⅲ～Ⅳ级不良反应主要为中性粒细胞减少,白细胞减少。结论　FCR方案治疗CLL疗效确切,患者耐受良好,可以作为初治患者的一线治疗方案。     

氟达拉滨治疗慢性淋巴细胞白血病合并糖尿病一例

患者男,72岁,主诉"面色苍白伴腹胀、反复皮肤青紫块2年,加剧1个月余"于2005年8月25日入院.患者2年前因面色苍白进行性加重、腹胀、反复皮肤青紫块,肝大于右肋下可缮及,巨脾,经血象骨髓象检查,参照张之南《血液病诊断与治疗标准》确诊为:慢性淋巴细胞白血病(CLL).     

慢性淋巴细胞白血病分层治疗的长期疗效观察

 目的　分析慢性淋巴细胞白血病（CML）按照分期接受不同治疗方法的临床疗效。方法　对1990年至2007年收治的35例CLL患者的资料进行回顾和随访。35例患者按照Binet分期的不同,A期予干扰素300～600万U／d,每周5次皮下注射;观察6个月,若病情稳定无进展则予300万U每周2～3次长期维持。B、C期患者直接给予FC／FC-R或CHOP／COP方案化疗。化疗间歇期、完全缓解（CR）或部分缓解（PR）后予干扰素长期维持。结果　A期20例患者经干扰素治疗6个月后无一例CR,5例（25 %）达PR,14例（70 %）病情稳定（SD）,1例（5 %）进展到B期。5例PR的患者中有3例在平均36.3个月后复发。在14例SD患者中,8例平均在74个月后进展到B期。27例B、C期患者接受化疗,FC／FC-R化疗组CR 41.2 %,总有效率74.6 %明显优于CHOP／COP组（CR 12.5 %）。A、B、C期患者平均生存时间分别为155.2、100.1、82.9个月,经Kaplan-Meier检验具有统计学意义（P＝0.032）。死亡10例,其中A期2例,B期4例,C期4例。9例死于感染,1例死于大出血。结论　CLL患者应视患者疾病分期及其他预后指标给予个性化治疗,早期患者可予干扰素治疗。长期应用干扰素可能减少感染的发生。     

慢性淋巴细胞白血病外周血T细胞亚群及免疫球蛋白研究

 目的　分析慢性淋巴细胞白血病（CLL）患者的免疫状态及其与疾病分期的关系。方法　应用流式细胞术（FCM）分析60例B-CLL患者外周血T淋巴细胞亚群的变化，用免疫速率比浊法分析其中37例患者血清中IgG、IgA和IgM的变化，比较各Binet分期患者免疫功能的变化。结果　与正常对照组相比，60例B-CLL患者外周血中CD+3、CD+4和CD+8细胞比率均明显降低（P＜0.01），Binet B、C期组患者CD+4／CD+8比值也明显低于Binet A和正常对照组（P＜0.01）。37例B-CLL患者中有21例患者（56.8 %）出现有免疫球蛋白（Ig）减低的情况。Binet C期组Ig减低发生率高于Binet A和B期（P＜0.05），Binet C期组IgG、IgA、IgM的平均水平明显低于Binet A和B期组（P＜0.05）。结论　CLL患者存在细胞免疫和体液免疫功能的低下，与CLL病程密切相关。检测CLL患者外周血T细胞亚群及Ig水平的变化，对了解CLL免疫功能状态，从而判断病情具有重要作用。     

Natural killer cell activity in chronic lymphocytic leukemia patients treated with fludarabine

 Fludarabine, the 5′-monophosphate of 9-β-D-arabinofuranosyl-2-fluoroadenine (FaraAMP), is effective in the treatment of chronic lymphocytic leukemia (CLL) and has been demonstrated to increase natural killer (NK) cell lytic activity (NK_a) in humans and mice. To determine the effect of FaraAMP on NK cells in CLL, we analyzed NK_a toward K562 targets after in vitro incubation with FaraAMP and after in vivo exposure to fludarabine. Pretreatment analysis of peripheral blood from 12 CLL patients (9 untreated) revealed: median number of NK cells 500/μl (range 290–1160); median NK_a lytic unit₃₀/10⁶ cells (range 5–80). These results were similar to those from healthy adult donors. After exposure to 3, 30, or 300 μM FaraAMP, the median maximum stimulation index (NK_a FaraAMP/NK_a) was 1.2 (range 0.9–1.5), within the range observed in normal adults. FaraA also stimulated NK_a in vitro toward autologous CLL cells in two of five patients as measured by a dye-exclusion assay. In three patients following three or more treatment courses of fludarabine (30 mg/m² per day for 5 days) the NK cell number and NK_a were maintained near pretreatment values. Phenotypic analysis of the peripheral mononuclear cells in 34 consecutive CLL patients revealed a marked reduction in CD5/CD20 and CD4 cell numbers after three courses of fludarabine with less effect on CD8 and CD56 cells. These results indicate that fludarabine spares NK cells and may stimulate NK_a in some CLL patients. Received: 22 December1994/Accepted: 14 May 1995     

Combined fludarabine and rituximab for low grade lymphoma and chronic lymphocytic leukemia

As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m 2 on days 1-4 and rituximab 125, 250 or 375 mg/m 2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.     

慢性淋巴细胞白血病503例临床及实验室特征回顾性分析

目的 探讨慢性淋巴细胞白血病(CLL)患者的临床及主要实验室特征.方法 回顾性分析1998年10月至2015年2月收治的503例CLL患者的临床及实验室检查资料,应用χ2检验进行差异性检验,并利用Log-rank法检验各组患者生存率的差异.结果 503例CLL患者中位年龄58岁(26~86岁),男性335例,女性168例.初诊时临床分期以Binet A期为主,为204例(40.5%),其次为Binet B期和C期,分别为148例(30.1%)和151例(29.3%).初诊时108例(21.1%)患者存在贫血(血红蛋白<100 g/L);427例进行血清乳酸脱氢酶检测的患者中,有113例(26.5%)升高;344例进行CD38检测的患者中有100例(29.1%)表达阳性.330例具有完整荧光原位杂交(FISH)资料的患者中,156例(47.3%)伴13q缺失(13q-),为检出率最高的细胞遗传学异常;其次为IgH易位(22.4%),12号染色体三体(+12,21.2%)和17p缺失(17p-,14.5%).在230例进行免疫球蛋白重链可变区(IGHV)突变状态检测的患者中,165例(71.7%)IGHV为突变状态,表达V4-34基因的患者比例最高,占12.4%(28例).中位无进展生存(PFS)时间为89.0个月(95%CI 75.0~103.0个月),中位总生存(OS)时间为129.0个月(95%CI 106.9~151.1个月).结论与欧美国家的CLL患者相比,本组CLL患者发病年龄偏低,总体生存期较长,一定程度上反映了我国CLL患者的特点.     

微RNA在慢性淋巴细胞白血病中的研究进展

微RNA(miRNA)是一类长约19~25 nt的单链非编码小RNA,在各种生物体细胞的生长、分化、增殖和凋亡、脂肪代谢等生理进程中发挥重要作用.大量研究表明,miRNA失调与慢性淋巴细胞白血病(CLL)的进展、预后和耐药相关.miR-15a/16-1、miR-34b/c、miR-181b、miR-29、miR-3676、miR-17/92以及miR-155家族成员调节重要基因的表达,是CLL中最易发生失调的miRNA.为了进一步阐明CLL发生发展的分子机制,文章综述了相关miRNA的调控网络以及同其他调控因子的整合.     

U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia

Purpose.

To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL).

Materials and Methods.

The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS).

Results.

The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL.

Conclusions.

On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.