Single-agent rituximab in treatment-refractory or poor prognosis patients with chronic lymphocytic leukemia

Abstract

Objective:

Rituximab in combination with fludarabine and cyclophosphamide has significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL) and an improvement in overall survival has recently been shown for the first time in the history of CLL treatment. However, the chemotherapy portion of this regimen may be unsuitable for elderly patients or those with significant comorbidities. We investigated the safety and tolerability of single-agent rituximab in 23 consecutive patients presenting with CLL at a single institution.     

Therapy of elderly/comorbid patients with chronic lymphocytic leukemia

Treatment of chronic lymphocytic leukemia (CLL) has recently undergone revolutionary changes. Two large randomized trials demonstrated superiority of chemoimmunotherapy combining fludarabine and cyclophosphamide with monoclonal anti-CD20 antibody rituximab (FCR) over fludarabine and cyclophosphamide (FC) alone in first line and relapse; this lead to establishment of FCR regimen as new gold standard in younger and physically fit patients. However, elderly and/or comorbid patients may not tolerate such aggressive approach due to high risk of unacceptable toxicity. To date, no randomized trials in this patient population have improved therapeutic results over chlorambucil; therefore, this agent remains the backbone of treatment against which the new protocols should be tested. Indeed, several currently running large trials investigate whether addition of an anti-CD20 monoclonal antibody (rituximab, obinutuzumab, ofatumumab) to chlorambucil yields better results. Performance status, biological age and number/severity of comorbid conditions should be incorporated into decision-making process with regard to intensity of treatment. Other emerging treatment alternatives for this patient population include fludarabine-based regimens in attenuated doses as well as protocols containing bendamustine or lenalidomide. Highdose steroids combined with rituximab might be a promising in relapsed/refractory CLL but infectious toxicity is serious. Finally, ofatumumab has been recently approved for the treatment of fludarabine and alemtuzumab-refractory patients. This article provides an overview of the current and future possibilities in the treatment of elderly and comorbid patients with CLL.     

Pharmacotherapy of relapsed/refractory chronic lymphocytic leukemia

Introduction: The treatment of relapsed/refractory (RR) CLL has been revolutionized by the advent of the new oral inhibitors of B-cell receptor (BCR) signaling and the pro-survival protein, B-cell lymphoma 2 (BCL2). Additionally, new and more potent monoclonal antibodies against CD20 have replaced/may replace rituximab in many settings.

Areas covered: Herein, we review the entire therapeutic landscape of RR CLL, with particular attention to the new small-molecule kinase inhibitors and BH3-mimetics. We discuss preclinical data with these agents in CLL, cover available efficacy and safety information, and examine potential resistance mechanisms and possible rational combinations to circumvent them.

Expert opinion: The availability of potent and selective inhibitors of BCR signaling and of the anti-apoptotic functions of BCL2 has enormously enhanced our therapeutic armamentarium, with unprecedented efficacy now observed in patients who historically had poor outcomes with chemoimmunotherapy (CIT), e.g., those with deletion 17p/11q and/or IGHV-unmutated disease. The next challenge is to optimally sequence these agents and develop rational combinations that will hopefully lead to deeper and more durable remissions than ever seen before. Indeed, long term relapse free survival, already achievable with CIT in patients with genetically favorable-risk disease, now appears to be a realistic possibility for most patients with CLL.     

桂枝茯苓丸对子宫内膜异位症患者血清中IL-10和IL-17的影响

目的：了解桂枝茯苓丸对子宫内膜异位症（EMS）患者血清IL-10和IL-17水平的影响。方法：选取2013～2014年晋江市内坑卫生院妇产科子宫内膜异位症患者40例,所有患者均接受桂枝茯苓丸治疗,连续治疗1个月,应用ELISA法检测治疗前后患者血清中IL-10和IL-17表达的变化。结果：与治疗前比较,桂枝茯苓丸治疗后患者血清中IL-10和IL-17的表达水平明显下降（P<0.05）。结论：桂枝茯苓丸可能通过抑制IL-10和IL-17的表达从而起到对子宫内膜异位症的治疗作用。     

慢性心力衰竭与白细胞介素-17及白细胞介素-10的相关性研究

目的 探讨慢性心力衰竭与白细胞介素(IL)-17、IL-10的相关性.方法 采用酶联免疫吸附试验(ELISA)检测37例慢性心力衰竭患者(慢性心衰组)和34例健康体检者(对照组)血浆IL-17和IL-10水平,并进行相关性分析.结果 慢性心衰组血浆IL-17水平高于对照组[(46.37±10.57) ng/L vs(32.45±4.55)ng/L],IL-10水平低于对照组[(27.49±4.19) ng/L vs(32.71±4.38) ng/L],差异均有统计学意义(t=7.09,5.46,P＜0.01);慢性心力衰竭患者血浆IL-17与IL-10呈负相关(r=-0.63,P＜0.01).结论 慢性心力衰竭的发病可能与体内IL-17、IL-10的水平失衡存在相关.     

含铋剂的序贯疗法对消化性溃疡患者血清白细胞介素-10和白细胞介素-17的影响

目的 观察采用含铋剂的序贯疗法对消化性溃疡患者血清IL-10和IL-17的影响.方法 162例消化性溃疡患者按数字表法随机分为观察组81例和对照组81例.观察组采用含铋剂的序贯疗法治疗,对照组采用传统三联疗法治疗.治疗前后测定患者血清IL-10和IL-17的表达.结果 观察组总有效率为97.5%,对照组总有效率为87.7%,两组总有效率差异有统计学意义（X^2 =3.96,P＜0.05）.观察组幽门螺杆菌（Hp）根除率为96.3%,对照组Hp根除率为80.2%,两组差异有统计学意义（X^2=4.17,P＜0.05）.两组治疗后血清IL-10和IL-17均明显降低,与对照组比较,观察组降低程度更明显（t=3.7244、9.3422,均P＜0.05）.结论 采用含铋剂的序贯疗法明显降低消化性溃疡患者血清IL-10和IL-17.     

PHA、IL-2和PHA/IL-2在慢性淋巴细胞性白血病染色体研究中的应用

目的 探讨植物血凝素(PHA)、白细胞介素2(IL-2)和PHA／IL-2作为有丝分裂原对提高慢性淋巴细胞性白血病(慢淋,CLL)有丝分裂相的数量及染色体异常检出率的价值。方法 分别用PHA、IL-2和PHA IL-2作为有丝分裂原,对25例CLL患的外周血或骨髓细胞进行短期培养后,按常规收获并制备染色体标本,然后进行R显带核型分析。同时做美洲商陆(PWM)平行培养作为对照。比较各组的有丝分裂指数和异常核型的类型及其检出率。结果 CLL经各种丝裂原刺激后,平均有丝分裂指数分别为：PWM5．03‰,PHA8．5‰,IL-25．33‰,PHA／IL-29．24‰;染色体异常核型检出率为：PWM4％(1／25),PHA32％(8／25),IL-2(8／25),PHA／IL-232％(8／25);染色体异常总检出率为44％(11／25)。结论 与PWM相比,PHA、IL-2和PHA IL-2均可有效地刺激CLL白血病细胞分裂并提高其染色体异常检出率。     

Lenalidomide in the treatment of chronic lymphocytic leukemia

Introduction: Lenalidomide is an immunomodulatory drug (IMiD) with a unique mode of action (MOA) that may vary across disease-type. It is currently approved in multiple myeloma (MM), myelodysplastic syndrome (MDS) and mantle cell lymphoma (MCL), yet is also clinically active in a host of lymphoproliferative diseases, including chronic lymphocytic leukemia (CLL). Due to its protean effects on the immune system, lenalidomide may be particularly appealing in CLL, which is distinct in its ability to evade immune recognition and cause immunosuppression.

Areas covered: This review recaps the biological mechanisms of lenalidomide specific for CLL, and summarizes the clinical data in previously untreated and relapsed/refractory (R/R) CLL patients, with emphasis on toxicity. Moreover, lenalidomide treatment is put into the context of the highly effective targeted agents that are drastically changing the therapeutic approach in CLL.

Expert opinion: Lenalidomide is a potent drug in CLL, both in first line and relapse. However, in comparison to other newly available agents, lenalidomide has slow onset of efficacy and notable toxicity profile that limits both its single agent use and combinations with chemotherapy. Future trials will hopefully direct our ability to harness lenalidomide MOA to best incorporate it in the rapidly evolving landscape of CLL treatment.     

Lenalidomide in the treatment of chronic lymphocytic leukemia

INTRODUCTION: insights into the role of the tumor microenvironment and of immune dysfunction in chronic lymphocytic leukemia (CLL) have opened the way for further augmenting the therapeutic armamentarium for CLL patients. In this respect, lenalidomide represents an exciting drug since it is able to eliminate CLL cells without immunosuppression. AREAS COVERED: mechanism of action and clinical trials of lenalidomide in CLL, and suggestions for its future utilization are reviewed. The most relevant papers and the meeting abstracts published up to July 2010 were used as sources for this review. This review will help readers understand the mechanism of action of lenalidomide and will provide a comprehensive summary regarding efficacy and safety of this drug in CLL patients. EXPERT OPINION: lenalidomide shows good activity against CLL. However, the toxicity profile is significant and can result in serious and potentially life-threatening side effects. Definitive data from ongoing trials will aid better definition of its status in CLL therapy. Moreover, clarification of the exact mechanism(s) of action in CLL will allow more precise use of lenalidomide and design of more efficacious combination therapies.     

Venetoclax for the treatment of chronic lymphocytic leukemia

Introduction: Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy.

Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs.

Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features.

Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring, and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.     

Duvelisib for the treatment of chronic lymphocytic leukemia

ABSTRACT

Introduction

Duvelisib, a first in class, oral, dual PI3 k-delta/gamma inhibitor recently received FDA approval for previously treated CLL (chronic lymphocytic leukemia)/SLL (small lymphocytic lymphoma) and follicular lymphoma. Data coming from the phase III ‘DUO’ trial, in fact, showed a superior progression-free survival (PFS) in CLL patients treated with duvelisib compared to ofatumumab     

Promising therapies for the treatment of chronic lymphocytic leukemia

Introduction: The combination schedule of fludarabine, cyclophosphamide and rituximab is the gold standard of therapy for younger, physically fit chronic lymphocytic leukemia (CLL) patients; it allows achieving high and durable complete response rates. Although treatment outcome has considerably improved with chemo-immunotherapy, most patients eventually relapse and CLL is still incurable. Thus, newer and more rationally developed drugs are needed to improve CLL therapy, particularly in cases of relapsed/refractory disease.

Areas covered: The authors review preclinical and clinical data regarding newer CLL agents, currently undergoing examination, such as: signal transduction and cyclin-dependent kinase inhibitors, immunomodulatory agents, B-cell lymphoma 2 inhibitors, next generation mAbs, heat shock protein 90 and histone deacetylase inhibitors, and chimeric antigen receptor T-cell therapy.

Expert opinion: Newer compounds with different mechanisms of action, such as B-cell receptor signal transduction inhibitors, lenalidomide, next generation mAbs and several pro-apoptotic molecules, have shown efficacy in relapsed or refractory CLL patients. Several studies are under way to investigate the efficacy of combinations of these novel drugs. Hopefully, the combined use of these molecules in risk-adapted treatment strategies will change the therapeutic approach in the near future and will pave the way for a long-term control of CLL.     

氟达拉滨联合环磷酰胺治疗慢性淋巴细胞白血病疗效观察

目的观察氟达拉滨联合环磷酰胺治疗慢性淋巴细胞白血病(CLL)的疗效和安全性。方法将CLL患者24例随机分为治疗组和对照组各12例。治疗组予以氟达拉滨联合环磷酰胺方案治疗,对照组予以CHOP方案化疗。比较2组总有效率及不良反应。结果治疗组总有效率为83.3%高于对照组的66.7%(P<0.05);2组合并感染率、中性粒细胞减少发生率、血小板减少发生率及持续时间比较差异均无统计学意义(P>0.05)。结论氟达拉滨联合环磷酰胺组治疗CLL具有完全缓解率及总有效率高、不良反应轻等优点,值得临床推广应用。     

IL-17及IL-12p70与高脂血症性急性胰腺炎患者的病情及预后的关系

目的 探讨白细胞介素（IL）-17、IL-12p70与高脂血症性急性胰腺炎患者病情严重程度及预后的关系。方法 选取60例高脂血症性急性胰腺炎患者,根据病情严重程度分为轻度组（19例）、中度组（27例）和重度组（14例）,比较3组患者血清IL-17、IL-12p70水平,分析血清IL-17、IL-12p70水平与病情严重程度的关系。随访28 d,统计患者预后情况,分析高脂血症性急性胰腺炎患者死亡的影响因素。采用受试者工作特征（ROC）曲线分析血清IL-17、IL-12p70水平对高脂血症性急性胰腺炎患者死亡的预测价值。结果 轻、中、重度组患者血清IL-17、IL-12p70水平依次增高（均P<0.05）。相关性分析显示血清IL-17、IL-12p70与病情严重程度均呈正相关（rs分别为0.429、0.384,均P<0.01）。单因素分析显示,死亡患者的性别,合并糖尿病、高血压、冠心病比例及年龄、血清降钙素原（PCT）、空腹血糖（Glu）、总胆固醇（TC）、血淀粉酶（AMY）水平与生存患者比较差异均无统计学意义（P>0.05）,死亡患者的重度比例及血清C反应蛋白（CRP）...     

IL-17、IL-10在急性期和亚急性期川崎病患儿血清中浓度变化及意义

目的探讨急性期和亚急性期川崎病（kawasaki disease,KD）患儿血清IL-17及IL-10水平的变化,并进一步分析其临床意义。方法采用ELISA方法检测31例急性期及亚急性期KD患儿血清IL-17及IL-10的水平,并与同期22例健康儿童对照。结果急性期、亚急性期KD患儿组血清IL-17及IL-10水平均高于正常对照组（P〈0．01）;急性期KD患儿组血清IL-17及IL-10水平均高于亚急性期KD患儿组（P〈0．01）;急性期KD患儿血清IL-17水平与血清IL-10水平呈正相关。（r=0．630,P〈0．05）。亚急性期KD患儿血清IL-17水平与血清IL-10水平呈负相关。（r=-0．810,P〈0．05）。结论急性期KD患儿血清IL-17水平和IL-10水平均明显增高,亚急性期KD患儿血清IL-17水平显著下降,而亚急性期血清IL—10水平虽较急性期下降,但仍维持较高水平。IL-17是一种强的促炎细胞因子,而IL-10是一种抑炎细胞因子,二者血清水平的变化提示它们分别在KD发生和发展的不同阶段发挥着各自重要作用。在临床上可以通过检测血清IL-17和IL-10的水平为KD的诊断和治疗提供依据。     

氟达拉滨联合环磷酰胺对慢性淋巴细胞白血病的临床疗效研究

目的观察氟达拉滨联合环磷酰胺对慢性淋巴细胞白血病的临床疗效及对外周血Th17和Treg细胞比例的影响。方法 200例慢性淋巴细胞白血病患者随机分为对照组100例和试验组100例。对照组患者第1³天静脉滴注氟达拉滨25 mg·m^-2;试验组第1³天静脉滴注氟达拉滨25 mg·m^-2和环磷酰胺250 mg·m^-2。2组均4周为1个周期,治疗2个周期。比较2组患者的临床疗效、不良反应发生情况以及外周血Th17和Treg细胞比例。结果试验组患者总改善率为98.0%,显著高于对照组的72.0%（P<0.05）。试验组患者总不良反应发生率为8.0%,显著低于对照组的29.0%（P<0.05）。试验组患者Th17细胞和Treg细胞状况均显著优于对照组（P<0.05）。结论氟达拉滨联合环磷酰胺能够有效地治疗慢性淋巴细胞白血病,降低不良反应发生率,并能显著改善外周血Th17和Treg细胞比例。     

Phase I study of a novel pro-apoptotic drug R-etodolac in patients with B-cell chronic lymphocytic leukemia

Summary R-etodolac is a novel pro-apoptotic agent with potential antitumor activity against B-cell chronic lymphocytic leukemia (B-CLL). This phase I clinical trial was conducted to determine the tolerability, safety, and maximum tolerated dose (MTD) of R-etodolac, administered orally twice a day (BID), in patients with B-CLL. Secondary objectives included evaluating clinical response, pharmacodynamic activity (reduction of lymphocytes), and pharmacokinetic (PK) profile. Forty-three patients were enrolled in the study. The most frequently reported adverse events were diarrhea, rash, pruritus, and headache. Increases in alanine aminotransferase (ALT) were also observed. Adverse events were generally mild and self-limiting, although in an apparent dose–response relationship, grade 2 and 3 gastrointestinal toxicities and grade 3 skin toxicities were reported with the highest dose regimens (1,800 and 2,400 mg BID). Hematologic toxicity was rare. The MTD was determined to be 1,200 mg BID. PK results indicated that oral absorption of R-etodolac was rapid (time to maximum concentration ranged from 2 to 4 h), and the half-life ranged from 5 to 7 h. The increase in maximum concentration, however, was not proportional to the increase in dose. R-etodolac significantly reduced absolute lymphocyte count (ALC) in B-CLL patients in a dose-dependent manner up to 1,800 mg BID and caused partial responses in 2 patients. Further study of R-etodolac as a possible new maintenance therapy or as a part of combination therapy of B-CLL appears warranted.     

Selective cytotoxic activity of cyclosporins against tumor cells from patients with B cell chronic lymphocytic leukemia

A fluorometric microculture cytotoxicity assay was employed for the study of cyclosporin A induced cytotoxicity in tumor samples from patients with B type chronic lymphocytic leukemia (B-CLL). Tumor cells from patients with B-CLL were found to be significantly more sensitive to the cytotoxic actions of cyclosporin A than normal blood mononuclear cells and tumor cells obtained from patients with different types of acute leukemia and solid tumors. The effect of cyclosporin A on B-CLL samples could be reproduced by a non-immunosuppressive cyclosporin A analogue. One B-CLL patient treated with cyclosporin A responded with a significant decrease in tumor mass and alleviation of anemia and B symptoms. The results show that cyclosporin A and its non-immunosuppressive analogues appear selectively toxic to B-CLL cells, an observation which may have clinical implications.