Treating chronic lymphocytic leukemia with thalidomide and lenalidomide

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is biologically, as well as clinically, highly heterogeneous. In CLL patients, immunosuppression is a consequence of the disease, which plays a key role in effecting the quality of life and overall survival. Treatment modalities should ideally not only reduce tumor burden, but also augment immune function in CLL patients. AREAS COVERED: The current review summarizes biological and clinical data on thalidomide and lenalidomide in CLL. EXPERT OPINION: Immunomodulatory drugs such as thalidomide and lenalidomide show both antitumor activity and immunostimulation. Three main mechanisms of action seem to play a role in cancer, including i) anti-angiogenic, ii) immunomodulatory and iii) tumoricidal effects. The exact contributions of these effects seem to be unique for different diseases. The two representatives of this family of drugs studied in CLL include thalidomide and its analog lenalidomide. These drugs proved to be effective as single agents and in the combination setting in CLL. Toxicities have been identified but largely controlled by a low starting dose, with gradual dose escalation.     

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.     

Lenalidomide in lymphomas and chronic lymphocytic leukemia

Neonates in the neonatal intensive care unit experience hundreds of painful procedures at a time of rapid neurological development. Although the immediate responses to pain may be protective, the potential long-term effects of early and under-treated pain are concerning. As pain assessment is the first step in the provision of appropriate and timely pain management, attention should be directed to the quantification of pain in terms of its location, severity, intensity and duration. Over the past decade, numerous pain measures have been developed for preterm and term neonates, however, most of them have been developed for research purposes and have not been tested in the clinical setting. In order to effectively implement pain measures in the clinical setting, the psychometric properties of reliability, validity, feasibility and clinical utility must be established. This review paper will highlight the importance of neonatal pain assessment and examine the psychometric properties of various measures of neonatal pain. Pharmacological and non-pharmacological interventions to manage acute pain in high-risk neonates will be addressed and future research topics will be proposed.     

Bendamustine for treatment of chronic lymphocytic leukemia

Introduction: Chronic lymphocytic leukemia (CLL) often has an extended disease course. With a median age at diagnosis of 72 years, newer treatment options with less toxicity than standard nucleoside analogue-based regimens are needed. Historically, few therapy options are available once CLL has become refractory to nucleoside analogues. Bendamustine has emerged as a feasible therapy for older and less fit CLL patients, with clinical efficacy in previously untreated and refractory CLL.

Areas covered: This paper reviews several of the pivotal clinical trials that established the clinical activity of bendamustine in previously untreated and relapsed/refractory CLL. The toxicity profile of bendamustine, primarily myelosuppression and infections, is reviewed and compared across different CLL populations. A review of the clinical data focuses on potential explanations for differences in response rates and duration of remission reported across studies and how this may impact the development of therapies for CLL.

Expert opinion: Bendamustine is a valuable new agent for the management of CLL. Ongoing clinical trials are comparing bendamustine with standard CLL regimens in untreated disease, and investigating bendamustine combinations with novel targeted therapies and monoclonal antibodies. These studies will help to define the optimal role for bendamustine in CLL management.     

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.     

Managing the teratogenic risk of thalidomide and lenalidomide: an industry perspective

Celgene has developed and operated pregnancy prevention programs since 1998 with the first approval of thalidomide in the US. With the development and marketing of lenalidomide, an analog of thalidomide, the company further advanced its risk management activities, which now cover several territories across the globe. To date, the program is a success in as much as it has minimized the risk of fetal exposure and subsequent development of fetal malformations. Nonetheless, the company understands the need to provide a mechanism for intervention and remediation when at-risk behaviors are identified, and this forms an integral part of the risk management processes. The implementation of the thalidomide and lenalidomide pregnancy prevention program partners patients, healthcare professionals, regulators and the company in a spirit of shared responsibility. This paper also presents the authors' experience and perspective on the challenges of managing a pregnancy prevention program, which at its core aims at ensuring that the product's benefits outweigh the risk of fetal exposure.     

Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

Introduction: Ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK), is approved in many countries for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) and for previously untreated disease with a 17p deletion and, most recently, as a frontline therapy for CLL. In controlled trials in CLL, ibrutinib produced high response rates and improved survival in both the frontline and relapsed settings. While ibrutinib controls CLL with impressive efficacy, it only infrequently induces complete remissions, particularly of relapsed CLL, and does not eradicate minimal residual disease. Finally, ibrutinib is extremely expensive, has off-target toxicities, and requires indefinite therapy.

Areas covered: In this article, we provide an overview of the CLL therapeutic landscape and discuss the pharmacokinetic and pharmacodynamic aspects of ibrutinib. Major clinical trials of ibrutinib in CLL are summarized, and its safety profile explored.

Expert opinion: Ibrutinib represents a transformative advance in CLL management and has validated BTK as a therapeutic target in this disease, but has some limitations, leading to the emergence of other BTK inhibitors and mechanism-based combination strategies. Given complete BTK occupancy at lower doses of ibrutinib and declining levels of BTK on ibrutinib therapy, lower doses of ibrutinib in CLL are being explored.     

Lenalidomide and thalidomide in the treatment of chronic pain

ABSTRACT

Introduction: Doxycycline is highly effective, inexpensive with a broad therapeutic spectrum and exceptional bioavailability. However these benefits have been overshadowed by its classification alongside the tetracyclines – class D drugs, contraindicated in pregnancy and in children under 8 years of age. Doxycycline-treatable diseases are emerging as leading causes of undifferentiated febrile illness in Southeast Asia. For example scrub typhus and murine typhus have an unusually severe impact on pregnancy outcomes, and current mortality rates for scrub typhus reach 12-13% in India and Thailand. The emerging evidence for these important doxycycline-treatable diseases prompted us to revisit doxycycline usage in pregnancy and childhood.

Areas Covered: A systematic review of the available literature on doxycycline use in pregnant women and children revealed a safety profile of doxycycline that differed significantly from that of tetracycline; no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found.

Expert Opinion: The change of the US FDA pregnancy classification scheme to an evidence-based approach will enable adequate evaluation of doxycycline in common tropical illnesses and in vulnerable populations in clinical treatment trials, dosage-optimization pharmacokinetic studies and for the empirical treatment of undifferentiated febrile illnesses, especially in pregnant women and children.     

Ofatumumab for treating chronic lymphocytic leukemia: a safety profile

Introduction: Ofatumumab, the first fully human IgG1κ, belongs to the second generation of the first class of anti-CD20 monoclonal antibodies. The drug used alone and in combination with drugs having different mechanisms of action has shown a favorable toxicity profile and significant benefit especially in relapsed/refractory chronic lymphocytic leukemia (CLL) patients in doses up to 2000 mg.

Areas covered: This article reviews pharmacokinetic, clinical application for CLL treatment, and safety profile of ofatumumab as well as differences and similarity between ofatumumab and rituximab. Publications in English from 2010 through October 2015 were surveyed on the MEDLINE database for articles. Proceedings of the American Society of Hematology held during the last 5 years were also included.

Expert opinion: Ofatumumab more effectively than rituximab enhanced complement-dependent cytotoxicity playing the crucial role for its therapeutic activity. The drug is highly effective in the first-line and salvage treatment of CLL, essentially as a part of immunochemotherapy, and probably also as maintenance therapy. Its safety profile is very advantageous, since adverse events are usually limited to grade 1 and 2 infusion-related reactions, which tend to decrease throughout the treatment. Its advantage over the other anti-CD20 monoclonal antibodies in the treatment of CLL remains to be determined in the direct head-to-head trials.     

New treatment options for chronic lymphocytic leukemia

Introduction: Chemoimmunotherapy is the gold standard of therapy for patients with advanced chronic lymphocytic leukemia (CLL), resulting in high and durable complete response rates. However, all patients eventually relapse and CLL remains incurable. Newer and more rationally developed compounds are needed to improve CLL therapy, particularly in cases of refractory disease.

Areas covered: Following a literature search on PubMed using ‘chronic’, ‘lymphocytic’, ‘treatment’ and ‘therapy’ as keywords, results obtained with novel agents were critically analyzed. Abstracts presented during 2013 at ASH, EHA, ICML, IWCLL and ASCO meetings were also included in the search.

Expert opinion: New monoclonal antibodies, lenalidomide, B-cell receptor-signal transduction inhibitors and pro-apoptotic molecules have shown efficacy in patients with relapsed or refractory disease. Hopefully, the combined use of these molecules in risk-adapted treatment strategies will improve the outcome of patients with CLL and pave the way for their long-term control.     

The clinical safety of ibrutinib in chronic lymphocytic leukemia

Introduction: Ibrutinib, a targeted inhibitor of B-cell receptor signaling, achieved impressive clinical results for patients with chronic lymphocytic leukemia (CLL). These results allowed the approval of ibrutinib for the treatment of patients with CLL who have received at least one prior therapy and those with a 17p deletion regardless of line of therapy.

Areas covered: Comprehensive data from either Phase I-II or randomized Phase III studies are analyzed in this article. In addition, we reviewed data on the prevalence and the clinical management of some peculiar toxicities ibrutinib related such as lymphocytosis, major bleeding and atrial fibrillation.

Expert opinion: Ibrutinib has radically changed the scenery of relapsed/refractory CLL treatment and established an important paradigm in the molecularly targeted approach of this disease. Discontinuation of ibrutinib is rarely due to adverse events related to the drug. Patients who discontinue treatment represent a challenge to the physicians because treatment options are very limited.     

Alvocidib (flavopiridol) for the treatment of chronic lymphocytic leukemia

Introduction: Alvocidib, which has orphan drug designation in chronic lymphocytic leukemia (CLL) from the FDA and the EMA, is a plant-derived semisynthetic flavone that acts as a cyclin-dependent kinase inhibitor. It induces apoptosis in CLL cells in vitro and was introduced into clinical trials in CLL as an intravenous infusion in 1997, which proved disappointing. Since the drug avidly binds to plasma proteins, higher serum concentrations were required for clinical antileukemia activity than those suggested by in vitro studies. Subsequent studies utilizing bolus plus infusional doses revealed significant activity against CLL, even in patients with unfavorable characteristics. However, significant toxicity including high rates of major tumor lysis syndrome, cytokine release syndrome and secretory diarrhea were also observed.

Areas covered: The chemistry, pharmacodynamics, pharmacokinetics and metabolism of alvocidib are briefly discussed and phase I-II studies in CLL are discussed in detail. To date, no phase III studies in CLL have been reported.

Expert opinion: A number of much less toxic drugs with similar efficacy against CLL both with and without unfavorable cytogenetics have come to market. Furthermore, enthusiasm for the development of alvocidib as a single agent for the treatment of CLL has waned, primarily due to its toxicity.     

Evolving role of monoclonal antibodies in the treatment of chronic lymphocytic leukemia

Recognition of cancer-specific antigens resulted in development of monoclonal antibodies as treatments for various neoplasms including chronic lymphocytic leukemia (CLL). Two monoclonal antibodies, alemtuzumab and rituximab, have been extensively studied, as monotherapy or in combination, in patients with various clinical stages of CLL. Alemtuzumab, particularly when combined with fludarabine-based chemotherapy, sequentially or concomitantly, represents a promising therapeutic approach that results in improved efficacy by further reducing levels of residual disease in previously untreated or relapsed/refractory CLL. On the other hand, single-agent rituximab has limited activity by itself, even at very high doses, and seldom induces complete remissions. However, rituximab is feasible to combine with conventional chemotherapies such as purine analogs, alkylating chemotherapy and/or alemtuzumab. Newer monoclonal antibodies are already showing activity in relapsed/refractory CLL and will eventually be evaluated in combinations with conventional chemotherapy, or with already established antibodies. Modern definitions for assessment of responses such as minimal residual disease negativity (MRD negativity) are emerging and, consequently, development of assays capable of measuring such responses. MRD negativity should become the primary objective of clinical trials when evaluating treatment interventions in patients with CLL. The future of monoclonal antibodies for treatment of CLL is bright.     

沙利度胺的研究及临床应用新进展

沙利度胺及其衍生物来那度胺在治疗骨髓瘤及骨髓增生异常综合征方面有着确切的疗效,已经通过了美国FDA的审批。近年来,沙利度胺在治疗实体瘤、血液恶性肿瘤以及其他炎性疾病方面的研究层出不穷。本文以近2年来国内外有关沙利度胺研究的最新文献报道为基础,对沙利度胺在临床前及临床方面研究的最新进展进行了综述。     

FC联合强的松治疗慢性淋巴细胞白血病的疗效观察

【】 目的 研究慢性淋巴细胞白血病患者采取FC结合强的松治疗的临床效果。方法 选择我院2015年5月-2016年9月纳入的100例慢性淋巴细胞白血病患者,按照入院顺序分为两组,其中50例患者采取FC方式作为对照组,另50例患者采取FC结合强的松作为研究组,比较两组患者临床效果。结果 经过观察两组患者临床效果看出,研究组患者发热、水肿、腹胀、发热、疼痛以及脾大等症状消失时间均比对照组时间少(P＜0.05);研究组患者总有效率90.00%,明显比对照组总有效率80.00%高;且不良反应发生率仅6.00%比对照组发生率16.00%低,差别均具有统计学意义(P＜0.05)。结论 慢性淋巴细胞白血病患者采取FC结合强的松治疗效果显著,明显缓解患者相关症状,提高其生存质量,安全性较高,具有推广及应用的价值。     

Anti-CD44 mAb for the treatment of B-cell chronic lymphocytic leukemia and other hematological malignancies: evaluation of WO2013063498

Introduction: The CD44 transmembrane glycoprotein family mediates cellular responses to the microenvironment through binding of hyaluronic acid (HA) and other proteins of the extracellular matrix. These interactions start intracellular signaling cascades that foster tumor growth, survival and spread.

Areas covered: The patent concerns the use of a humanized anti-CD44 mAb (RG7356) to treat patients with aggressive forms of chronic lymphocytic leukemia (CLL). The RG7356 humanized antibody was designed to bind the constant region of CD44, preventing binding with HA. The interruption of this circuit in vitro is followed by the induction of caspase-dependent apoptosis in leukemic cells. In agreement with a functional association between CD44 and zeta-associated protein of 70 kDa (ZAP-70) in activating intracellular signaling, the strongest effects were observed in ZAP-70⁺ CLL cells, generally associated to a poor prognosis. Furthermore, these effects were confirmed using in vivo models, where CLL cells were xenografted in immunocompromised mice.

Expert opinion: In summary, these studies suggest that this new humanized mAb may provide additional clinical benefit to CLL patients receiving current standard treatments, specifically to those with a more aggressive disease.     

常规R显带和FISH技术检测慢性淋巴细胞白血病染色体异常的价值

目的 研究FISH技术检测慢性淋巴细胞性白血病(CLL)染色体异常的价值.方法 用3、12、18号标记有不同荧光素的染色体着丝粒探针,用荧光原位杂交技术(FISH)检测25例CLL,并和常规细胞遗传学(Conventional cytogenetics,CC)检测方法即R显带法进行比较,以明确何种方法对CLL染色体异常检出更敏感可靠.结果 25例CLL患者中,常规细胞遗传学检出 3, 12, 18 5例,检出率为20%;其中: 12 3例, 3、 12 1例, 3、 12、 18 1例; FISH方法检出8例异常(32%), 3 4例; 12 6例; 18 1例.CC可检出不确定异常:t(5;15) 1例;3q-,18p 1例;4q 13q-1例; 19,-22 1例.结论 FISH方法是检测CLL患者染色体异常的有效技术,可提高染色体异常检出率,明显优于常规显带法.     

On the front line: first choice pharmacotherapeutics for chronic lymphocytic leukemia

ABSTRACT

Introduction: Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with a highly variable clinical course. Frontline treatments include cytotoxic chemotherapies, immunotherapies, and small molecule inhibitors. Clinical and molecular factors guide treatment initiation and selection. Over the last decade, refinement of CLL risk stratification tools and growth of the arsenal of effective therapeutics have profoundly improved outcomes. These advances have concurrently increased the complexity of managing the early phases of treatment.

Areas covered: This review describes the factors considered in the determination of first-line treatment of CLL. Areas of emphasis include assessment of patient fitness, disease classification and risk stratification, and the mechanisms, efficacy, and toxicities associated with available pharmacotherapeutics.

Expert opinion: Multiple different treatments may be appropriate for a specific clinical scenario, and selection among them requires discussion of relative risks and benefits. Advances in frontline CLL treatment will continue to shift the treatment paradigm toward prioritizing quality of life alongside survival, limiting treatment and toxicity, and the development of biologically rational synergistic drug combinations and sequences.     

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     

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。