Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with infections a leading cause of morbidity and mortality. Recently there has been a paradigm shift from the use of chemo-immunotherapies to agents targeting specific B-lymphocyte pathways. These agents include ibrutinib, idelalisib and venetoclax. In this review, the risks and timing of infections associated with these agents are described, taking into account disease and treatment status. Treatment with ibrutinib as monotherapy or in combination with chemo-immunotherapies is not associated with additional risk for infection. In contrast, the use of idelalisib is associated with a 2-fold risk for severe infection and opportunistic infections. Venetoclax does not appear to be associated with additional infection risk. The evolving spectrum of pathogens responsible infections in CLL patients, especially those with relapsed and refractory disease are described, and prevention strategies (prophylaxis, monitoring and vaccination) are proposed.     

Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia

The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib, or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future. However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL.     

Idelalisib for the treatment of non-Hodgkin lymphoma

Introduction

B-cell Non-Hodgkin lymphomas (B-NHLs) include a number of disease subtypes, each defined by the tempo of disease progression and the identity of the cancerous cell. Idelalisib is a potent, selective inhibitor of the delta isoform of phosphatidylinositol-3-kinase (PI3K), a lipid kinase whose over-activity in B-NHL drives disease progression. Idelalisib has demonstrated activity in indolent B-NHL (iB-NHL) and is approved for use as monotherapy in patients with follicular lymphoma and small lymphocytic lymphoma and in combination with rituximab in patients with chronic lymphocytic leukemia.

Areas Covered

Herein we review the development and pharmacology of idelalisib, its safety and efficacy in clinical studies of iB-NHL, and its potential for inclusion in future applications in iB-NHL and in combination with other therapies.

Expert Opinion

Idelalisib adds to the growing arsenal of iB-NHL pharmacotherapeutics and to the progression of the field toward precision agents with good efficacy and reduced toxicities. Nevertheless, idelalisib carries important risks that require careful patient counseling and monitoring. The appropriate sequencing of idelalisib with other proven treatment options in addition to its potential for combination with established or novel drugs will be borne out in ongoing and planned investigations.     

What Is the Role of Chemotherapy in Patients With Chronic Lymphocytic Leukemia?

The current standard treatment for patients with chronic lymphocytic leukemia who require therapy is chemoimmunotherapy. However, the availability of an increasing number of targeted agents and combination warrants a reassessment of that approach. The high rate of durable responses with ibrutinib in relapsed refractory patients has established its role in this setting; however, because of its impressive efficacy as initial treatment, it should be considered as part of the algorithm in appropriate patients. There is virtually no role for chemotherapy in the relapsed or refractory setting, but, instead, consideration of active agents including idelalisib plus rituximab, or, particularly venetoclax. For patients with 17p-deletion, ibrutinib is the treatment of choice, with venetoclax in the setting of intolerance or relapse. Challenges include developing strategies to limit the duration of these expensive therapies, and to develop combinations with the potential to cure patients with chronic lymphocytic leukemia.     

Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies.     

Front-line treatment of CLL in the era of novel agents

Although chemoimmunotherapy prolongs survival and as such, is the standard of care for treatment-naïve patients, its effectiveness may be reduced by associated toxicity and dose reductions. In addition, it has been associated with the development of myelosuppression and secondary neoplasms; treatments are hence needed which offer greater survival and lowered toxicity. A range of new targeted agents, ibrutinib, idelalisib and venetoclax, have demonstrated such a balance in a second-line setting, offering CLL patients durable remissions and a modest toxicity profile. Ibrutinib has since been given first-line approval, and with news of second-generation targeted agents on the horizon, high-level discussions have taken place concerning their use in elderly or unfit patients; with potential use in younger patients in a first-line setting. This article reviews the potential first-line therapeutic options for treating CLL and their clinical potential and examines whether first-line chemotherapy has a place in the age of targeted agents.     

New horizons in the treatment of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world, accounting for approximately 30% of all leukemias in Europe and North America. Recently, significant progress in the characterization and understanding of the biology and prognosis of CLL has provided new opportunities for the development of innovative, more effective therapies. Several new anti-CD20 monoclonal antibodies directed against lymphoid cells have been developed and are under investigation in preclinical studies and clinical trials. Currently, the most promising is obinutuzumab, a novel third generation anti-CD20 monoclonal antibody that exhibits superior caspase-independent apoptosis and antibody-dependent cellular cytotoxicity than rituximab. The antibody has shown a safety profile similar to that of rituximab and promising efficacy in patients with CLL. The CD37 antigen may be advantageous over CD20 in diseases in which the level of CD37 expression is higher than that of CD20. The results of recent preclinical and early clinical studies suggest that anti-CD37 antibodies and related agents can be useful in the treatment of CLL, and many small molecule inhibitors targeting B-cell antigen receptor (BCR) signaling pathways have recently been under investigation in patients. Promising clinical results have been observed with a Btk inhibitor, ibrutinib, and a selective inhibitor of PI3Kδ, idelalisib. Several other agents including immunomodulating agents and those targeting the antiapoptotic bcl-2 family of proteins also show promise in treating CLL. Moreover, immune-based treatment strategies intended to augment the cytotoxic potential of T cells offer exciting new treatment options for patients with CLL.     

Efficacy of high-dose corticosteroid-based treatment for chronic lymphocytic leukemia patients with p53 abnormalities in the era of B-cell receptor inhibitors

PurposeHigh-dose methylprednisolone (HDMP) with or without anti-CD20 antibody treatment in the pre B-cell receptor inhibitor (BCRi) era was used as potential salvage therapy for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) patients bearing the 17p deletion.Patients and methodsOutcomes were compared in retrospect between r/r patients treated with HDMP (n = 20), ibrutinib (n = 39) and idelalisib with rituximab (n = 14).ResultsHigher overall response rates were found in those patients undergoing BCRi therapy compared to HDMP (79.2% vs. 0%; p < 0.0001), along with longer median progression-free survival (not reached vs. 24.1 months; p < 0.01). Nevertheless, there were no differences in the overall survival (HDMP 35.87 months vs. not reached; p = 0.58).ConclusionHDMP treatment was significantly inferior in terms of response rate and progression-free survival in r/r CLL/SLL patients with the 17p deletion, and may only be used whenever novel compounds are unavailable.     

新药时代慢性淋巴细胞白血病的治疗选择

慢性淋巴细胞白血病(CLL)是欧美国家最常见的成人白血病。我国CLL发病率虽偏低,但呈上涨趋势。既往CLL治疗以免疫化学治疗为主。近年来,布鲁顿氏酪氨酸激酶(BTK)抑制剂伊布替尼和acalabrutinib、3-磷脂酰肌醇激酶(PI3K)抑制剂idelalisib和duvelisib、B淋巴细胞瘤-2(BCL2)抑制剂venetoclax的上市使得CLL治疗获得了突破性进展,同时包括嵌合性抗原受体T淋巴细胞(CART)在内的细胞免疫治疗也初显成效。在众多治疗选择中,如何为临床特征迥异的CLL患者选择合适的个体化治疗方案,是临床医生面临的挑战。