PI3-Kinase Inhibitors in Chronic Lymphocytic Leukemia

The phosphatidylinositol 3-kinase (PI3K) pathway is being explored as a target of inhibition for B-cell lymphoproliferative disorders, with agents specific for inhibition of the PI3K-δ subunit showing significant clinical activity in chronic lymphocytic leukemia (CLL). Idelalisib (CAL-101, GS-1101) and IPI-145 (INK-1147) are novel oral PI3K-δ inhibitors in development, with rates of objective response of 40-60 % and nodal responses exceeding 70 % in relapsed and refractory CLL. High rates of response have been seen in high-risk CLL (i.e., 17p and 11q deletions), and may allow for more effective therapy in inherently chemotherapy-resistant disease. Combination chemotherapy regimens with idelalisib have similarly demonstrated favorable tolerability and activity. Like other agents that target the B-cell receptor pathway, peripheral lymphocytosis, due to drug-induced changes in lymphocyte trafficking, is common. Noteworthy toxicities include transaminitis and pneumonia/pneumonitis. Multiple studies are evaluating PI3K-δ inhibitor combination regimens, and the rationale for these ongoing and planned studies is reviewed.     

GS-1101: A Delta-Specific PI3K Inhibitor in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) remains an incurable B-cell malignancy with many unanswered questions. While the cell of origin and etiology are still unknown, significant scientific progress has revealed numerous molecular targets for novel therapeutic interventions. Phosphatidylinositol 3-kinases (PI3K) regulate key cellular functions, including growth, survival and migration, by integrating and transmitting signals from diverse surface molecules including the B-cell receptor (BCR). In lymphocytes, the PI3Kδ isoform plays a critical role in B-cell homeostasis and function. In CLL, the PI3K pathway is constitutively active and dependent on PI3Kδ. GS-1101 is a highly selective PI3Kδ inhibitor that in CLL patients causes a rapid and sustained reduction in lymphadenopathy, accompanied by transient lymphocytosis. This article will review new insights into the pathophysiology of CLL, the preclinical rationale of a PI3Kδ inhibitor in CLL, and the clinical evidence supporting this first-in-class therapeutic target for CLL patients.     

ASH Update 2013: chronic lymphocytic leukemia and indolent lymphoma

At the annual meeting of the American Society of Hematology 2013, the focus in the field of chronic lymphocytic leukemia (CLL) and indolent lymphomas was again dominated by compelling data generated in clinical trials exploring the use of novel drugs targeting the B-cell receptor pathway. The results observed in early trials, e.g., with the Bruton’s tyrosine kinase inhibitor ibrutinib (formerly PCI-32765) and PI3Kδ inhibitor idelalisib (formerly CAL-101) have been consolidated. In view of these data, new clinical standards have been set up for the treatment of relapsed/refractory CLL. However, with the presentation of several randomized trials new standards concerning the use of immunochemotherapy are being suggested underscoring the importance of immunochemotherapeutic strategies despite the upcoming era of tyrosine kinase inhibitor treatment of CLL and indolent lymphoma.     

The PI3K pathway: clinical inhibition in chronic lymphocytic leukemia

Constitutive or mutational activation of the phosphatidylinositol 3 kinase, or PI3K, has been implicated in many cancers, including chronic lymphocytic leukemia (CLL). The δ isoform of the p110 catalytic subunit of PI3K has its primary physiologic function in B cells and appears to be the predominant mediator of most PI3K signals in CLL cells. Idelalisib is a first-in-class inhibitor of the PI3K delta isoform that shows near complete inhibition of AKT phosphorylation in CLL cells in vitro and in vivo. Idelalisib shows the classic pattern of response to BCR inhibition in CLL, with rapid nodal response and transient increase in lymphocytosis. The phase I study established the recommended dose as 150 mg twice per day. Subsequent registration trials have focused predominantly on antibody combinations, leading to the US Food and Drug Administration (FDA) approval of idelalisib with rituximab for relapsed CLL patients for whom rituximab is appropriate therapy in summer 2014. The median progression-free survival (PFS) of idelalisib–rituximab in this heavily pretreated CLL population with multiple comorbidities and frequent 17p deletion was an impressive 19.4 months. The success of idelalisib has paved the way for the development of other PI3K inhibitors in CLL, including duvelisib and TGR-1202, which are in or moving toward registration trials.     

Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma

BackgroundWhen treating indolent B-cell lymphoma, combining continuously administered oral phosphatidylinositol 3-kinase (PI3K) inhibitors with immunochemotherapy has been associated with toxicity. CHRONOS-4 (Phase III; NCT02626455) investigates the intravenous, intermittently administered pan-class I PI3K inhibitor copanlisib in combination with rituximab plus bendamustine (R-B) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed indolent B-cell lymphoma. We report safety run-in results.Patients and MethodsPatients aged ≥18 years with relapsed CD20-positive indolent B-cell lymphoma received copanlisib (45 mg, increasing to 60 mg if no dose-limiting toxicities) weekly on an intermittent schedule with R-B or R-CHOP. Primary objective was to identify a recommended Phase III dose (RP3D). We also assessed objective response, safety, and tolerability.ResultsTen patients received copanlisib plus R-B and 11 received copanlisib plus R-CHOP. No dose-limiting toxicities were reported; RP3D was 60 mg. All patients had ≥1 treatment-emergent adverse event (TEAE), most commonly (all grade/grade 3/4) for copanlisib plus R-B: decreased neutrophil count (80%/50%), nausea (70%/0%), decreased platelet count (60%/10%), hyperglycemia (60%/50%); for copanlisib plus R-CHOP: hyperglycemia (82%/64%), hypertension (73%/64%), decreased neutrophil count (64%/64%). Two and 8 patients had serious TEAEs with copanlisib plus R-B and R-CHOP, respectively. Among evaluable patients, objective response rates were 90% (5 complete, 4 partial) and 100% (3 complete, 7 partial) with copanlisib plus R-B and R-CHOP, respectively.ConclusionCopanlisib is the first PI3K inhibitor to demonstrate safe, tolerable, and effective combinability with immunochemotherapy in patients with relapsed indolent B-cell lymphoma at full dose (60 mg). Further evaluation is ongoing.     

B细胞受体通路抑制剂在慢性淋巴细胞白血病治疗中的研究进展：第57届美国血液学会年会报道

随着Bruton酪氨酸激酶（BTK）抑制剂依鲁替尼（ibrutinib）及磷脂酰肌醇-3-激酶（PI3K）抑制剂idelalisib在复发／难治非霍奇金淋巴瘤（NHL）治疗中的成功,一系列新的B细胞受体（BCR）通路抑制剂也逐步进入临床试验。第57届美国血液学会（ASH）年会继续对依鲁替尼和idelalisib单药或联合用药治疗慢性淋巴细胞白血病（CLL）的探索保持了高度热情。另外脾酪氨酸激酶（SYK）抑制剂及新的BTK和PI3K抑制剂也崭露头角,为改善依鲁替尼和idelalisib耐药患者的疗效提供了新的选择。文章就第57届ASH年会中关于BCR通路抑制剂治疗CLL的进展进行介绍。     

Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline

Rituximab is the first monoclonal antibody to be approved for use by the US Food and Drug Administration in cancer. Its role in the treatment of non-Hodgkin lymphoma, including chronic lymphocytic leukaemia (CLL), has evolved significantly. We aimed to systematically review and update the literature on rituximab in lymphoma and CLL, and provide evidence-based consensus guidelines for its rational use. Validated methodology from the Cancer Care Ontario Program in Evidence-based Care was used. A comprehensive literature search was completed by a methodologist from the Hematology Disease Site Group of Cancer Care Ontario. Data were extracted from randomised controlled trials of rituximab-containing chemotherapy regimens for patients with lymphoma or CLL. Fifty-six primary randomised controlled trials were retrievable and met all inclusion criteria. Clinically important benefits in progression-free survival or overall survival were seen in the following settings: (i) addition of rituximab to combination chemotherapy for initial treatment of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma, Burkitt lymphoma and HIV-related lymphoma with CD4 count ≥50/mm³; (ii) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; (iii) use of rituximab maintenance in patients with indolent B-cell lymphomas who have responded to chemoimmunotherapy; (iv) addition of rituximab to fludarabine-based chemotherapy or chlorambucil for initial treatment of CLL. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications.     

Molecular pathways: targeting phosphoinositide 3-kinase p110-delta in chronic lymphocytic leukemia

The advent of targeted therapy, specifically to the B-cell receptor (BCR), has changed the convention for the treatment of chronic lymphocytic leukemia (CLL). The phosphoinositide 3-kinase (PI3K) pathway, activated upstream by the BCR, receptor tyrosine kinases, and cytokine receptors, has been a potential target for a multitude of cancers, but until the recent introduction of isoform-specific inhibitors has not been widely used. In this review, we focus on describing the intricate upstream and downstream signaling, leading to cell survival mediated by PI3K in B cells with a specific focus on the impact and importance of the p110δ isoform (which is localized to hematopoietic cells and regulates distinct cellular functions in B cells). In addition, the clinical advances from targeting p110δ are described, with a focus on clinical outcome, toxicities, and rational combination therapies. The experiences with p110δ in CLL have led to a more fundamental understanding of CLL signaling defects and may be predictive of other BCR-directed therapeutics.     

Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting

Chronic lymphocytic leukemia (CLL) is a disease of marked clinical heterogeneity, and while some patients have a normal life expectancy, others develop rapidly progressive disease shortly after diagnosis. The current standard for upfront treatment of CLL is chemoimmunotherapy for younger fit patients, FCR (fludarabine, cyclophosphamide, and rituximab) being the prototype. For older patients, BR (bendamustine and rituximab) exhibits excellent activity with decreased toxicity. For the frailest patients, CD20 monoclonal antibodies with or without chlorambucil have proven to be efficacious. The novel oral kinase inhibitors ibrutinib and idelalisib are FDA-approved in the relapsed/refractory setting, and ibrutinib is approved upfront for those with del(17p). These drugs have produced long-term durable responses in the relapsed/refractory setting, and studies are underway using these as single agent upfront or in combination with both chemotherapy and monoclonal antibodies. Here, we review standard upfront therapies and new agents and combinations that are on the horizon for CLL.     

Spotlight on Rituximab in Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin’s lymphoma (NHL) and B-cell chronic lymphocytic leukemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m² intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomized comparison of eight cycles of CHOP plus rituximab 375 mg/m² intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse hematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. Conclusion: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced hematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs.     

Role of CD20 Monoclonal Antibodies in Previously Untreated Chronic Lymphocytic Leukemia

Monoclonal antibodies (MoAbs) directed against the CD20 antigen on B cells have dramatically altered the treatment landscape for patients with chronic lymphocytic leukemia (CLL). Rituximab, a chimeric mouse/human MoAb, was the first antibody to be approved for the treatment of indolent B-cell lymphomas. Although single-agent, standard-dose rituximab has limited activity as first-line therapy for patients with CLL, it has synergistic therapeutic activity when combined with chemotherapy. Indeed, chemoimmunotherapy with combined fludarabine (F), cyclophosphamide (C), and rituximab was shown to improve both progression-free and overall survival in a randomized phase III clinical trial compared with FC in previously untreated patients with CLL. In this article, we review important clinical trials that have incorporated rituximab with other agents for treatment-naive patients with CLL. We also highlight second- and third-generation CD20 MoAbs approved or in development for the treatment of CLL.     

Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma?

Although outcomes after first-line therapy for patients with indolent or aggressive non-Hodgkin lymphoma (NHL) are continually improving, relapse is still common. Current treatment options for patients with relapsed or refractory disease have limited efficacy, and various targeted therapies are under investigation to help improve outcomes in this patient population. The phosphatidylinositol 3-kinase (PI3K) pathway was identified as being involved in hematologic malignancies, leading to significant research for potential therapeutic agents. This has led to 3 PI3K inhibitors (idelalisib, copanlisib, and duvelisib) being approved for the treatment of patients with relapsed or refractory follicular lymphoma who have received at least 2 prior systemic therapies, with reported response rates of 40% to 59%. With potential class-specific and PI3K isoform–related toxicities that may limit clinical utility, the safety of the approved PI3K inhibitors has been carefully evaluated to weigh the risk/benefit ratio of therapy. Currently, there are no approved PI3K inhibitors for patients with aggressive NHL. A number of newer PI3K inhibitors are in clinical development for the treatment of relapsed or refractory NHL, aiming to improve treatment benefit for patients. We discuss a number of attributes that are important to increase the therapeutic potential of newer PI3K inhibitors. More promising results may come from combination trials with these newer PI3K inhibitors, developed to limit toxicities (including long-term adverse events), and other antitumor agents.     

Novel agents in chronic lymphocytic leukemia: efficacy and tolerability of new therapies

Alkylating agents and purine analogues have been the mainstays of therapy for chronic lymphocytic leukemia (CLL) for decades. The past decade witnessed the general clinical use of monoclonal antibodies such as rituximab and alemtuzumab, both as single agents and in combination regimens with cytotoxic drugs, for previously untreated and relapsed CLL. First-line chemoimmunotherapy regimens combining rituximab and purine analogues have greatly improved initial response rates and progression-free survival. Despite these advances in first-line therapy, patients with CLL invariably experience relapse and often acquire high-risk chromosomal abnormalities, such as del(11q22) and del(17p13), which result in resistance to current therapies. Patients who are refractory to fludarabine-based therapy have a median survival of <1 year. Therefore, new agents with novel mechanisms of action are needed for the treatment of patients with relapsed CLL, particularly for patients with high-risk genetic features. Recent clinical studies have examined the tolerability and efficacy of several novel agents in relapsed CLL: (1) the alkylator bendamustine, (2) the cyclin-dependent kinase inhibitor flavopiridol, (3) the immunomodulating drug lenalidomide, (4) the bcl-2 antisense oligonucleotide oblimersen, and (5) the Bcl-2 small-molecule inhibitor obatoclax. While these agents have demonstrated exciting clinical activity against genetically high-risk CLL, they have also induced toxicities that have not been commonly observed with previous CLL therapies. The most notable toxicities have been tumor lysis syndrome and tumor flare, which are potentially serious or even fatal complications of these new therapies. Thus, further studies are needed to define these agents' biologic mechanism(s) of action, clinical activity, and safety.     

Targeting B Cell Signaling in Chronic Lymphocytic Leukemia

In recent years, a revolution in the management of chronic lymphocytic leukemia (CLL) has centered on the targeting of the B cell receptor (BCR) signaling pathway. Our improved understanding of the biology of cell signaling in CLL and the development of oral kinase inhibitors directed at the BCR pathway has led to the approval of two new agents and has the potential to radically change the treatment of CLL in both the relapsed/refractory and upfront settings. In this review, we will describe the underlying biology of the BCR signaling pathway. We will discuss the landmark clinical trials resulting in the approval of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We will highlight ongoing trials that are evaluating the use of combinations of these agents with standard chemotherapy. We will evaluate some of the emerging data regarding toxicity, potential off-target effects, and mechanisms of resistance to BCR signaling pathway blockade. Finally, we will highlight some of the next-generation BCR pathway inhibitors currently in development.     

Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia

B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (Btk), or phosphoinositide 3′-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to “mobilization” of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.     

New developments in immunotherapy for non-Hodgkin’s lymphoma

The clinical development of immunotherapy with rituximab (chimeric anti-CD20 monoclonal antibody) has markedly affected the treatment approach for patients with B-cell non-Hodgkin’s lymphoma (NHL). Rituximab was initially evaluated in relapsed indolent lymphoma and has substantial activity in this setting both alone and in combination with chemotherapy. Ongoing efforts in indolent NHL are seeking to optimize the dose and schedule of rituximab through ‘maintenance’ strategies exploring chemotherapyrituximab combinations and the use of other biologic agents or antibodies that may enhance activity when employed together with rituximab. Other studies in indolent NHL suggest that radiolabeled anti-CD20 antibodies (such as I-131 tositumomab and Y-90 ibritumomab tiuxetan) may be useful in relapsed and refractory disease and have potential utility as part of initial treatment as well. In diffuse large B-cell lymphoma, the addition of rituximab to CHOP chemotherapy can improve survival, though benefits are more limited in mantle cell lymphoma. Further studies of unlabeled and radiolabeled immunotherapies are ongoing in order to optimize their use for maximal clinical benefit.     

Clinical use of PI3K inhibitors in B-cell lymphoid malignancies: today and tomorrow

Introduction: PI3K inhibitors are an important new therapeutic option for the treatment of relapsed and refractory B-cell lymphoid malignancies. Idelalisib is a PI3Kδ inhibitor that has been approved for the treatment of lymphoma and chronic lymphocytic leukemia in the relapsed/refractory setting, and several other PI3K inhibitors are being developed targeting other isoforms of the PI3K enzyme, which results in distinct toxicities and variable efficacy in the clinical setting.

Areas covered: We provide a general overview of PI3K inhibitors, recommended applications, and the mechanism and management of toxicities. We further review trials, ongoing and completed, leading to the approval of idelalisib as well other PI3K inhibitors currently in development. Articles were obtained from PubMed, and abstracts were searched for the past 5 years from the websites for ASCO, ASH, EHA, and ICML/Lugano.

Expert commentary: PI3K inhibitors provide an important and powerful pharmacologic tool in the armamentarium against hematologic malignancies, especially for relapsed/refractory B-cell lymphoid malignancies. Unique toxicities are associated with inhibition of different isoforms of the PI3K enzyme, as demonstrated with the infectious and autoimmune toxicities associated with the PI3Kδ inhibitor, idelalisib. Due to these unique toxicities, PI3K inhibitors should only be used in formally approved combinations and settings.     

A Canadian perspective on bendamustine for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma

Despite the success of standard treatments in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), patients are often unable to tolerate aggressive regimens, and they require effective alternatives. Bendamustine is a bifunctional alkylator with unique properties that significantly distinguish it from other agents in its class. In untreated CLL, bendamustine has demonstrated rates of response and progression-free survival (PFS) that are superior to those with chlorambucil, with an acceptable toxicity profile. In the relapsed setting, combination treatment with bendamustine-rituximab (BR) has demonstrated promising activity in high-risk patients such as those refractory to fludarabine or alkylating agents. In untreated patients with indolent NHL and mantle cell lymphoma, BR has demonstrated a PFS significantly longer than that achieved with R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone), with significantly reduced toxicity. In the relapsed setting, br has demonstrated rates of response and PFS superior to those with fludarabine-rituximab, with comparable toxicity. In the United States and Europe, bendamustine has been approved for the treatment of CLL and indolent NHL; its approval in Canada is pending and eagerly awaited. Once available, bendamustine will benefit many Canadian patients with NHL and CLL.     

Monoclonal antibodies in the treatment of chronic lymphocytic leukemia

Traditional therapy for chronic lymphocytic leukemia (CLL) has consisted of alkylating agents, purine analogs, or a combination of these drugs. These agents are effective at producing remissions but are not curative. Thus, new drugs are still needed to improve the outcome of patients with CLL. The introduction of monoclonal antibodies, such as rituximab and alemtuzumab, provides a novel therapeutic modality. Rituximab is an active agent in CLL. Standard doses of rituximab result in higher response rates in previously untreated than in relapsed patients but low complete response (CR) rates. Rituximab is most effective in combination with chemotherapy, especially fludarabine-based regimens in the first-line and salvage setting. Rituximab is also useful in the treatment of complications of CLL, such as pure red cell aplasia, autoimmune thrombocytopenia, and autoimmune hemolytic anemia. Alemtuzumab has impressive activity in patients with refractory CLL and may play an important role in the consolidation treatment of CLL. Alemtuzumab is most efficacious at clearing disease in the peripheral blood and bone marrow. Bulky lymphadenopathy is less sensitive to therapy. Because of the significant lymphopenia associated with alemtuzumab, antibacterial and antiviral prophylaxis should always be used.