利妥昔单抗治疗华氏巨球蛋白血症时的特殊反应

目的：研究抗CD20单克隆抗体利妥昔（rituximab）治疗华氏巨球蛋白血症（Waldenstrom macroglobu-linemia,WM）时血清IgM异常增高现象及其表现和处理,并复习相关文献,推荐处理方法。方法：1例68岁患者通过骨髓细胞学、病理学和免疫固定电泳等检查确诊为WM,并给予利妥昔（375 mg/m2,d1）联合复达拉滨（30mg/m2,i.v.d1-3）作为初始治疗,对治疗前后的血清IgM水平进行监测。结果：在第一疗程RF治疗结束后四周,患者的血清IgM水平从治疗前的34.8g/L增高至115g/L,同时出现头痛和眼底出血,但骨髓浆细胞和淋巴样浆细胞无明显增多。在停用利妥昔,改用FC（复达拉滨和环磷酰胺）方案治疗四疗程后,IgM下降至治疗前水平,然后进一步下降达部分缓解。结论：WM患者在接受以利妥昔为基础的治疗后,血清IgM可明显增高,并导致高黏滞综合征等高IgM相关并发症。尽管此种异常增高并不提示利妥昔单抗治疗失败,但在治疗过程中仍需密切。在治疗开始的前二个疗程中避免使用利妥昔单抗可减少此现象的发生。     

预防性血浆置换联合利妥昔单抗序贯治疗华氏巨球蛋白血症

目的：探讨华氏巨球蛋白血症（WM）的临床特征,提高利妥昔单抗治疗WM的认识。方法：报告1例采用预防性血浆置换后给予利妥昔单抗序贯治疗血清IgM〉50g／L的WM并结合文献进行复习。结果：患者为老年男性。无淋巴结和肝脾肿大,主要表现为血清IgM明显增高（IgM631g／L）、伴有高黏滞血症表现、贫血,骨髓示淋巴细胞弥漫性浸润,免疫分型符合WM。经预防性血浆置换后给予利妥昔单抗为基础的方案治疗,出现轻微IgM反跳,未发生高黏滞血症加重和其他并发症。接受治疗5月后获得主要反应（IgM下降〉50％）、23月后接近非常好的部分缓解水平（IgM下降／〉90％）。结论：WM属于慢性B淋巴细胞增殖性肿瘤,临床少见,多发生于老年,有症状者需接受治疗。接受以利妥昔单抗为基础的治疗后,可发生IgM反跳,严重时可使病情加重,治疗前IgM〉50g／L者尤为明显,IgM反跳并不意味利妥昔单抗治疗失败,预防性血浆置换对降低反跳发生及IgM增高的程度有积极意义。     

华氏巨球蛋白血症研究进展

华氏巨球蛋白血症（WM）是一种B细胞淋巴增殖性疾病,目前仍然难以治愈。近年来,在基础研究方面,针对WM患者依鲁替尼耐药的机制有了进一步探索,二代测序、靶向测序等新技术的应用促进了疾病发生及预后方面的研究进展。在临床研究方面,传统药物的回顾性亚组分析为治疗方案的选择提供了新方向,新型药物如BGB-3111、oprozomib等的临床试验相继开展,将为WM的治疗提供新的选择。就第58届美国血液学会（ASH）年会上关于WM的研究进展进行报道。     

华氏巨球蛋白血症研究进展

华氏巨球蛋白血症(WM)是一种少见的以血清单克隆IgM为主要特征的惰性淋巴细胞肿瘤,首发症状多为发热、体质量减轻、血细胞减少或脏器肿大等.IgM型意义未明单克隆免疫球蛋白血症(IgM MGUS)和冒烟型WM(SWM)是疾病的早期阶段.WM治愈率低,但随着对其发病机制研究的深入以及各种新药的研制,患者预后得到显著改善.研究表明90%以上WM患者存在MYD88基因突变.MYD88基因编码是一种衔接蛋白,该蛋白衔接了TLR9和白细胞介素(IL)-6R信号,进而激活核因子(NF)-κB和mTOR的活性.依布替尼(ibrutinib)是首个被批准用于治疗WM的Bruton酪氨酸激酶抑制剂,对MYD88基因突变的WM具有显著疗效.第60届美国血液学会(ASH)年会关于WM的研究涵盖了多个方面,文章主要就第60届ASH会议关于WM的最新研究进行报道.     

利妥昔单抗治疗Castleman病一例

患者男性,65岁。2011年9月6日因面色苍白2年,加重4个月入院。患者于入院2年余前无明显诱因开始出现面色苍白,不伴头晕,活动后胸闷、心悸、气促,多次体检发现贫血,未进一步诊治。入院前4个月,患者面色苍白加重,偶有头晕,活动后胸闷、气促,休息后可缓解,伴轻度疲乏。     

利妥昔单抗治疗慢性淋巴细胞白血病一例

患者男,80岁。主因确诊慢性淋巴细胞白血病2年余,乏力3个月入院。患者于2001年体检时发现脾脏大,肋下2cm,未诊治。2002年8月,自觉腹胀,左上腹可触及包快。2002年10月上旬就诊我院,查全身浅表淋巴结肿大,脾大平脐,白细胞169×109/L,淋巴细胞0.65。行免疫分型、骨髓穿刺及骨髓活检确诊为慢性淋巴细胞白血病(C期),CHOP方案化疗一疗程,淋巴结基本消退。后口服苯丁酸氮芥(瘤可宁)治疗。2005年3月乏力明显加重,脾脏大入院。查体:中度贫血貌,双下肢皮肤散在出血点,双侧颈部、颌下、腋下、腹股沟均可见肿大的淋巴结,2cm×2cm大小,质软,活动、无压…     

华氏巨球蛋白血症的个体化治疗研究进展

华氏巨球蛋白血症（WM）是一种少见的淋巴瘤,目前的治疗手段仍不能治愈。MYD88和CXCR4基因突变是该病的特征。对WM患者的临床表现、病理及遗传学特征等方面的研究进展,已经催生了一系列极具前景的WM临床治疗方案。现结合第59届美国血液学会（ASH）年会关于WM的个体化治疗相关研究进展的最新报道,对WM患者应用烷化剂、蛋白酶体抑制剂、单克隆抗体及酪氨酸激酶抑制剂（BTK）等药物的安全性和有效性进行综述,探讨以基因组特征为主的基础治疗与现有治疗方案整合治疗WM的可行性。     

利妥昔单抗治疗非霍奇金淋巴瘤9例

[目的]观察利妥昔单抗治疗非霍奇金淋巴瘤的疗效和毒性反应.[方法]9例均为住院患者,用药剂量为375mg/m2,每周1次,连续4～6次,可与化疗方案联用.[结果]CR5例,PR1例,SD1例,PD2例,总有效率(RR)为66.67%,其中Ⅰ A期6例,ⅢB期1例,ⅣB期2例.主要毒副反应为发热、寒战、胸闷、一过性皮疹及短暂的肝功能指标升高等.[结论]利妥昔单抗联合化疗是治疗低度恶性非霍奇金淋巴瘤有效而安全的方案.     

利妥昔单抗在淋巴瘤维持治疗中的新进展

利妥昔单抗是第一个被批准用于淋巴瘤治疗的单克隆抗体。在弥漫大B细胞性淋巴瘤、滤泡淋巴瘤等B细胞非霍奇金淋巴瘤中取得了显著疗效。对于诱导治疗获得缓解后的滤泡淋巴瘤,利妥昔单抗维持治疗可进一步改善患者预后,为治疗指南所推荐。随着淋巴瘤治疗方案的不断改进,如何更好地把握维持治疗的适应症并进一步优化现有的治疗策略,成为研究的热点。本文通过总结分析近年来的相关文献,对利妥昔单抗用于淋巴瘤维持治疗的最新进展进行综述。      

利妥昔单抗相关间质性肺炎四例

 【摘要】　目的　探讨利妥昔单抗相关间质性肺炎的临床特点、诊断及治疗方法。方法 回顾性分析4例利妥昔单抗相关间质性肺炎患者的临床资料,并复习相关文献。结果 4例患者中,男3例,女1例,均为弥漫大B细胞淋巴瘤,在利妥昔单抗应用3～6个周期后出现间质性肺炎,其中2例发生Ⅰ型呼吸衰竭,糖皮质激素治疗有效,无相关死亡。结论 接受利妥昔单抗治疗的患者有必要动态监测胸部CT,出现利妥昔单抗相关间质性肺炎时,应及时应用糖皮质激素治疗。     

Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenstrom's macroglobulinemia.

BACKGROUND: The anti-CD20 monoclonal antibody rituximab is an important therapeutic in Waldenstrom's macroglobulinemia (WM), producing response rates of 50-70%. Responses, which are based on serum IgM levels, have typically been evaluated at 12 weeks. Paradoxically, we have observed that serum IgM levels can abruptly rise following rituximab therapy in patients with WM, and can often lead to morbidity on the basis of hyperviscosity. PATIENTS AND METHODS: Eleven WM patients with CD20+ tumor cells who received rituximab at our Institution and had serum IgM levels measured within a 12-week period following start of therapy were evaluated. Therapy consisted of four weekly infusions of rituximab at 375 mg/m(2). Pre- and post-therapy serum IgM levels were determined by nephelometry and corresponding serum viscosity levels were determined by viscometry. RESULTS: Ten of the 11 patients demonstrated an abrupt rise in serum IgM levels, with a >25% increase occurring in eight (73%) patients. Mean serum IgM levels for all 10 spiking patients rose from 4370 (range, 655-7940) to a peak of 5865 (range, 872-11 800) mg/dl (P=0.004), which occurred at a mean of 4 (range, 1-8) weeks following initiation of therapy. Mean serum viscosity levels also increased from 3.5 to 5.6 centipoise (CP) (P=0.09) in eight patients for whom pre- and post-therapy studies were obtained. A subdural hemorrhage occurred in one patient when serum IgM levels rose from 7530 to 11 800 mg/dl, and serum viscosity increased from 3.9 to 10.1 CP. Two other spiking patients with pre-therapy IgM levels of >5000 mg/dl experienced worsening headaches and/or epistaxis attributed to increasing serum viscosity. CONCLUSIONS: Abrupt increases in serum IgM levels commonly occur following rituximab therapy in WM. Careful clinical and laboratory monitoring is warranted, particularly if patients have pre-therapy serum IgM levels of >5000 mg/dl. The mechanism of this effect is under active investigation, and may be related to CD20 signaling triggered by rituximab.     

原发性巨球蛋白血症15例

目的探讨原发性巨球蛋白血症（WM）的临床特点。方法回顾性分析15例患者临床表现、免疫表型及治疗。结果3例完全缓解（CR）,9例部分缓解（PR）,7例生存,病程最长达79个月。结论WM传统的诊断方法不够完善,免疫表型能够更进一步明确诊断。在治疗方面,WM是不能治愈性疾病,但经积极治疗生存期可延长,应考虑化疗并血浆置换联合治疗。     

原发性巨球蛋白血症1例报告并文献复习

 目的 探讨原发性巨球蛋白血症（Waldenstrom’s macroglobulinemia,WM）的临床特点、免疫表型、遗传学改变及诊疗措施。方法 回顾分析一例原发性巨球蛋白血症患者的临床资料。结果 本病例经血清固定电泳、骨髓形态学、细胞免疫分型等检测结果证实为原发性巨球蛋白血症,患者经过8个疗程的化疗后,恢复良好,目前仍在定期随访之中。结论 WM有特殊的免疫表型及细胞遗传学的改变,在临床工作中如果遇到单克隆IgM增高的病例,建议要考虑到WM的可能性,进一步完善免疫表型和细胞遗传学检测。     

Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease

BACKGROUND:

The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM).

METHODS:

Forty‐three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m² intravenously on day 1 and fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses.

RESULTS:

The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow‐up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the β2‐microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long‐lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow‐up.

CONCLUSIONS:

The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good‐quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration. Cancer 2011;. © 2011 American Cancer Society.     

Survival and prognostic factors after initiation of treatment in Waldenstrom's macroglobulinemia.

BACKGROUND: Waldenstrom's macroglobulinemia (WM) is an unusual lymphoplasmacytoid lymphoma characterized by the presence of a serum monoclonal immunoglobulin M. Although several studies have evaluated possible prognostic factors of this disease, few have focused on the survival and prognosis of symptomatic patients after the initiation of treatment. PATIENTS AND METHODS: Our study included 122 previously untreated patients with a median age of 67 years who required systemic treatment. Multiple variables were analyzed for their prognostic value on survival after initiation of treatment using univariate and Cox regression multivariate analysis. RESULTS: The median overall survival was 106 months. Pretreatment factors associated with shorter survival were age >/=65 years, splenomegaly, B-symptoms (weight loss, fever or night sweats), hemoglobin <10 g/dl, platelets <100 x 10(6)/dl, albumin <3.5 g/dl and bone marrow lymphoplasmacytic infiltrate >/=50%. In the multivariate analysis, the two variables with independent prognostic value were age >/=65 years and hemoglobin <10 g/dl. Furthermore, we were able to divide our patients into three risk groups based on the presence of two, one or none of these two adverse prognostic factors. The median survival times in the high-, intermediate- and low-risk groups were 46 months, 107 months and 172 months, respectively (P <0.0001). DISCUSSION: Our findings suggest that advanced age and anemia appear to be the two dominant prognostic factors for survival after initiation of treatment in patients with WM. These two readily available parameters can stratify the patients into three distinct subgroups and may help the selection of appropriate treatment.     

Successful treatment of multi-agent chemotherapy with rituximab for IgM plasma cell leukemia

A 67-year-old woman presented with impaired general performance, suffering from fatigue, dyspnea on exertion, and paresthesia of the finger tips. The laboratory findings showed increased white blood cells at 11.37 × 10³ cells/μl with 26.5% abnormal cells, low haemoglobin and, elevated creatinine, although serum lactate dehydrogenase and calcium levels were normal. Serum immunofixation was positive for monoclonal IgM-kappa paraprotein. Total serum protein and the IgM component were elevated. X-ray examination of the skeleton was normal. Bone marrow aspiration showed 59.5% infiltration of abnormal cells that were characterized by typical mature plasmacytoid morphology. Abnormal cells expressed surface CD20, surface CD138, and cytoplasmic IgM, but not surface CD56 nor surface IgM by flow cytometric immunophenotyping with CD38 gating. Immunohistochemistry showed surface CD38, surface CD20, and cytoplasmic IgM. The clinical findings led to the diagnosis of the IgM Plasma cell leukemia (PCL). The patient recived multi-agent chemotherapy (VAD and EDAP with rituximab). The clinical symptoms disappeared, leading to the tumor load reduction.

To the best of our knowledge, this is the first report of successful treatment of multi-agent chemotherapy with rituximab for IgM PCL.     

Use of iodine 131I-tositumomab radioimmunotherapy in a patient with Waldenstrom's macroglobulinemia

Waldenstrom's macroglobulinemia is an indolent B-cell malignancy that is characterized by high levels of IgM paraprotein production and is incurable with standard chemotherapy. Iodine ¹³¹I-Tositumomab (iodine-131-labeled murine anti-CD20 monoclonal antibody; Bexxar) is a novel radioimmunotherapeutic agent that has a high response rate in relapsed or chemotherapy refractory, CD20-positive, low grade or transformed B-cell non-Hodgkin's lymphomas. There are no data on the use of radioimmunotherapy in Waldenstrom's macroglobulinemia. We report a patient with Waldenstrom's macroglobulinemia with transformation to a large B-cell lymphoma, who was treated successfully with iodine ¹³¹I-tositumomab. The patient had a complete response to the treatment, including disappearance of any detectable IgM paraprotein. This case report demonstrates the potential for radioimmunotherapy in CD20 positive B-cell malignancies.     

利妥昔单抗联合CHOP方案治疗B细胞非霍奇金淋巴瘤的疗效分析

目的：探讨利妥昔单抗联合CHOP方案治疗B细胞型非霍奇金淋巴瘤（NHL）的临床效果和不良反应。方法选择96例CD20阳性的B细胞NHL患者分为研究组49例和对照组47例,研究组采用利妥昔单抗与CHOP方案联合治疗方案,对照组只采用CHOP化疗方案。应用4个疗程后评价两组疗效及不良反应。结果研究组治疗有效率为90.0%,高于对照组的72.3%,差异有统计学意义（P﹤0.05）。而且两组的白细胞下降、脱发、恶心呕吐、便秘、血小板减少、贫血、肺部感染等不良反应比较,差异无统计学意义（P﹥0.05）。研究组1年、3年、5年无进展生存率（PFS）分别为81.6%、61.2%、26.5%,生存率分别为89.8%、65.3%、30.6%,均高于对照组,差异均有统计学意义（P﹤0.05）。结论采用利妥昔单抗与CHOP联合方案治疗B细胞非霍奇金淋巴瘤,可以提高临床疗效和远期生存率,且不因联合化疗而增加不良反应。