pci-32765 and idelalisib

Over the last decade, there have been important developments in the treatment of lymphoproliferative disorders. Apart from conventional chemotherapy, a wide array of therapies has been developed, with different indications. The aim of this review is to evaluate the risk of infection associated with these therapies, as well as establishing prevention recommendations. In all cases, the patient's underlying disease as well as concomitant or previous therapies have an impact on the risk of infection. Anti-CD20 antibodies (rituximab, ofatumumab and obinutuzumab) have been associated with a higher risk of bacterial and viral infection, as well as reactivation of latent infections and opportunistic infections. Alemtuzumab is associated with severe, protracted immunosuppression. Ibrutinib and acalabrutinib have been linked to bacterial infections (especially respiratory infections), invasive fungal infections and opportunistic infections. Idelalisib carries a higher risk of Pneumocystis jirovecii and infection and cytomegalovirus reactivation. Venetoclax is associated with respiratory infections and neutropenia. Immune checkpoint inhibitors are not directly associated with a higher risk of infection; nevertheless, the use of corticosteroids and immunosuppressants to control immune-related adverse events results in an increase of the risk of infection. Brentuximab, lenalidomide and histone deacetylase inhibitors do not seem to be associated with a higher risk of infections. Although data are scarce, a higher number of infections have been observed with cellular therapies, mostly in patients with more than 3 previous antineoplastic treatments or those receiving tocilizumab or corticosteroids for managing the cytokine release syndrome. In all patients, we recommend appropriate vaccination, screening for latent infections, and individualized prophylaxis recommendations.

Topics: Adenine; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Communicable Disease Control; Humans; Immune Checkpoint Inhibitors; Infections; Lymphoproliferative Disorders; Piperidines; Purines; Pyrazines; Quinazolinones; Risk; Rituximab; Sulfonamides; Syndrome

Two major advances were made in the treatment of chronic lymphocytic leukaemia (CLL): the addition of the antibody rituximab to chemotherapy two decades ago and the introduction of the targeted agents during the last few years. Four targeted drugs with different mechanisms of action were added to the armamentarium of CLL treatment: the anti-CD20 antibody obinutuzumab, the two kinase inhibitors ibrutinib and idelalisib, which target the Bruton tyrosine kinase (BTK) and Phosphatidylinositiol-3-Kinase (PI3K) respectively in the B-cell receptor signalling pathway, as well as the Bcl2-antagonist venetoclax.Recently, the combination of venetoclax/obinutuzumab was approved for the first-line treatment of all CLL patients based on a phase-III trial in elderly unfit patients. This combination was shown to be clearly superior to chlorambucil/obinutuzumab and should become the preferred first-line treatment for the so called "slow-go" patients. Other options for these elderly, unfit patients are continuous ibrutinib or chlorambucil/obinutuzumab. Although data from phase-III studies are not yet available, venetoclax/obintuzumab may also be offered to younger, fit patients. Established therapeutic options for these so called "go go" patients are ibrutinib, fludarabin/cyclophosphamide/rituximab or bendemustine/rituximab (if > 65 years). Patients with the high-risk parameters deletion 17p or TP53mutation are known to poorly respond to chemo(immuno)therapy and should receive either ibrutinib or venetoclax/obinutuzumab.Thus, a choice has to be made between a continuous monotherapy with ibrutinib or a time-limited combination with either venetoclax/obinutuzumab (12 months) or chemoimmunotherapy (usually 6 months). In addition to disease-related factors (e. g. presence of deletion 17p/TP53 mutation, IgHV mutational status, prior therapies), comorbidities, co-medication and the specific side effects of the CLL therapies (myelosuppression, infections and secondary malignancies for chemoimmunotherapy; cardiac toxicity, bleeding and autoimmune disease for ibrutinib; tumour-lysis syndromes and infections for venetoclax) the patient's expectations need to be considered.. Die Aktualisierung der IWCLL-Kriterien ließ die Kriterien für die Diagnosestellung der CLL unberührt: In der Regel genügt weiterhin ein Blutausstrich und eine Immunphänotypisierung.. Auch die Kriterien für die Therapieeinleitung blieben unverändert: Nur Patienten mit symptomatischer, fortgeschrittener Erkrankung sollen behandelt werden. Die Untersuchung auf Vorliegen einer Deletion 17p und/oder TP53-Mutation als wichtigster ungünstiger Prognosefaktor und prädiktiver Faktor ist essenziell vor Einleitung jeder neuen Therapie. Die Bedeutung des Mutationsstatus der variablen Region des Immunglobulin-Schwerkettengens (IgHV) hat deutlich zugenommen.. Die Kombination des Bcl2-Antagonisten Venetoclax mit dem Antikörper Obinutuzumab wurde kürzlich für die Erstlinientherapie der CLL zugelassen. Aufgrund der klaren Überlegenheit gegenüber Chlorambucil/Obinutuzumab bei den unfitten, älteren Patienten sollte Venetoclax/Obinutuzumab von nun an die bevorzugte Behandlungsoption bei dieser Patientengruppe sein. Als Chemotherapie-freie und zeitlich limitierte Behandlung wird Venetoclax/Obinutuzumab auch bei den Hochrisikopatienten mit Deletion 17p/TP53-Mutation und bei den jüngeren, fitten Patienten künftig eine wichtige Option neben der Dauertherapie mit Ibrutinib darstellen. Bei Letzteren kann bei Vorliegen eines mutierten IgHV-Status auch eine Chemoimmuntherapie mit Rituximab, kombiniert mit Fliudarabin/Cyclophosphamid oder Bendamustin, erfolgen.. Auch in der Rezidiv-Situation werden vorzugsweise die zielgerichteten Substanzen eingesetzt unter Berücksichtigung der zyto- und molekulargenetischen Risikofaktoren der CLL, der Patientencharakteristiken, der Tiefe und Dauer des Ansprechens sowie Verträglichkeit der vorangegangenen Therapie(n).

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Comorbidity; Drug Approval; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Staging; Piperidines; Prognosis; Purines; Quinazolinones; Rituximab; Smith-Magenis Syndrome; Sulfonamides

Chronic lymphocytic leukemia has a highly variable disease course across patients, thought to be driven by the vast inter- and intrapatient molecular heterogeneity described in several large-scale DNA-sequencing studies conducted over the past decade. Although the last 5 years have seen a dramatic shift in the therapeutic landscape for chronic lymphocytic leukemia, including the regulatory approval of several potent targeted agents (ie, idelalisib, ibrutinib, venetoclax), the vast majority of patients still inevitably experience disease recurrence or persistence. Recent genome-wide sequencing approaches have helped to identify subclonal populations within tumors that demonstrate a broad spectrum of somatic mutations, diverse levels of response to therapy, patterns of repopulation, and growth kinetics. Understanding the impact of genetic, epigenetic, and transcriptomic features on clonal growth dynamics and drug response will be an important step toward the selection and timing of therapy.

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Genome-Wide Association Study; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Sulfonamides; Transcriptome; Whole Genome Sequencing

Chronic lymphocytic leukaemia (CLL) has long been thought to be an immunosuppressive disease and abnormalities in T-cell subset distribution and function have been observed in many studies. However, the role of T cells (if any) in disease progression remains unclear and has not been directly studied. This has changed with the advent of new therapies, such as chimeric antigen receptor-T cells, which actively use retargeted patient-derived T cells as "living drugs" for CLL. However complete responses are relatively low (~26%) and recent studies have suggested the differentiation status of patient T cells before therapy may influence efficacy. Non-chemotherapeutic drugs, such as idelalisib and ibrutinib, also have an impact on T cell populations in CLL patients. This review will highlight what is known about T cells in CLL during disease progression and after treatment, and discuss the prospects of using T cells as predictive biomarkers for immune status and response to therapy.

Topics: Adenine; B-Lymphocytes; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; T-Lymphocyte Subsets

The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL), including the new kinase inhibitors (KIs) ibrutinib and idelalisib, has changed the therapeutic landscape of the disease. The new KIs have also changed frequency and epidemiology of infections, that represent a major cause of morbidity and mortality of the disease. Hence, the great strides in the indications and use of new KIs need parallel amelioration of prophylaxis and supportive treatment for infections. Moving from the recognition that infection control represents an unmet need, the Italian Society of Hematology (SIE) convened a panel of experts who had published and/or expressed an interest in infection complications in CLL. The goal of the project was to provide practice recommendations for the management of the infectious complications of CLL during ibrutinib or idelalisib therapy. The present publication represents the results of a series of email correspondences and meetings held during 2017 and 2018. Three domains of infectious complications during KIs therapy for CLL were explored: risk assessment, risk management and risk monitoring. We hope these recommendations will help to minimize infectious adverse events, and we believe that an optimal management of them will be rewarded by better outcomes, and better quality of life.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Hematology; Humans; Infection Control; Infections; Italy; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Practice Guidelines as Topic; Purines; Pyrazoles; Pyrimidines; Quality of Life; Quinazolinones

Important advances in understanding the pathogenesis of chronic lymphocytic leukaemia in the past two decades have led to the development of new prognostic tools and novel targeted therapies that have improved clinical outcome. Chronic lymphocytic leukaemia is the most common type of leukaemia in developed countries, and the median age at diagnosis is 72 years. The criteria for initiating treatment rely on the Rai and Binet staging systems and on the presence of disease-related symptoms. For many patients with chronic lymphocytic leukaemia, treatment with chemotherapy and anti-CD20 monoclonal antibodies is the standard of care. The impressive efficacy of kinase inhibitors ibrutinib and idelalisib and the BCL-2 antagonist venetoclax have changed the standard of care in specific subsets of patients. In this Seminar, we review the recent progress in the management of chronic lymphocytic leukaemia and highlight new questions surrounding the optimal disease management.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Diagnosis, Differential; Genetic Predisposition to Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Recurrence; Risk Factors; Sulfonamides; Survival Analysis; Treatment Outcome

B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management.. Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis. Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.

Topics: Adenine; Antineoplastic Agents; Atrial Fibrillation; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Hemorrhage; Humans; Lymphoma, Non-Hodgkin; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Sulfonamides

Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Cell Communication; Humans; Immunosuppressive Agents; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment

The B-cell receptor (BCR) pathway is a crucial aspect of mature lymphocytes and is maintained in B-cell neoplasms. Many small module inhibitors targeting kinases within the BCR pathway are approved, with others in development, offering alternative treatment options to standard chemoimmunotherapy. Areas covered: This review covers both approved inhibitors and investigational inhibitors of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), and phosphoinositide-3-kinase (PI3K) in the treatment of B-cell lymphomas. To collect relevant articles, a literature search was completed through the use of PubMed and abstracts from ASH and ASCO national meetings. Search terms including non-Hodgkin lymphoma, and BCR inhibitors, as well as the individual drug names, were utilized. The majority of included studies are dated from 2012 to March 2018. Expert opinion: BCR pathway inhibitors, such as ibrutinib and idelalisib, are novel treatments for non-Hodgkin lymphomas. While providing alternative treatment options to those with high-risk disease, poor functional status, and relapsed disease, outside of chronic lymphocytic leukemia (CLL), they have been limited to the relapsed/refractory setting. Their mechanisms of action, off/on-target effects, and resistance patterns create unique therapeutic dilemmas. It is our opinion that more specific inhibitors, as well as combination therapy, will define the future for BCR inhibitors.

Topics: Adenine; Antineoplastic Agents; Drug Design; Humans; Lymphoma, Non-Hodgkin; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell

Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax.

Topics: Adenine; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Interactions; Food-Drug Interactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Sulfonamides

The therapy for chronic lymphocytic leukemia (CLL) is undergoing a major transformation. However, the seminal progresses realized to date with the use of novel agents, leave many practical questions unanswered. Areas covered: This review focuses on the recent data of the literature of small-kinase inhibitor (KI) molecules and how results of KI clinical trials may translate into current clinical practice. Several questions such as the advantage of combining small-KI molecules with anti-CD20 monoclonal antibodies or with chemo-immunotherapy in comparison to targeted agents alone are discussed. Expert commentary: Nowadays the challenge is to apply the principles of chemotherapy to combine different targeted agents with nonoverlapping toxicities. This approach is not likely to immediately change the standard of care, however, it raises relevant questions concerning the optimal strategy for incorporating novel agents in the treatment of CLL. Given the increasing number of patients who have access to treatment with small-KI molecules, generally administered over an extended duration, more sustainable pricing for such therapies is needed.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; Sulfonamides

Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients. New options include two agents targeting B cell receptor (BCR) signaling pathways (ibrutinib and idelalisib) and a B cell lymphoma-2 (BCL-2) inhibitor (venetoclax). Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option for younger patients with a suitable donor.

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Drug Therapy; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Recurrence; Sulfonamides; Transplantation, Homologous

Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression. Compounds now approved for the treatment of TP53-deficient CLL are the two B-cell receptor inhibitors ibrutinib and idelalisib and the BH3 mimetic venetoclax. All three compounds were approved on the basis of favorable response rates that, importantly, revealed no differences between TP53-competent and TP53-deficient CLL cases. Using these compounds, longer-lasting remissions in patients with TP53-deficient CLL could be demonstrated for the first time. Whether TP53 alterations will maintain their significance as adverse prognostic factors in treatment strategies involving novel compounds needs to be assessed. This review provides an overview of current treatment options for 17p-deleted/ TP53-mutated CLL, including those compounds that are already approved by the US Food and Drug Administration or are under advanced clinical investigation. Available clinical trial data are discussed, as is the use of novel targeted treatment options in the context of transplant strategies, and an algorithm for off-study treatment of 17p-deficient CLL is suggested.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Remission Induction; Sulfonamides; Tumor Suppressor Protein p53

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Disease Management; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Severity of Illness Index

With the recent approval of several effective and well-tolerated novel agents (NAs), including ibrutinib, idelalisib, venetoclax, and obinutuzumab, patients with chronic lymphocytic leukemia (CLL) have more therapeutic options than ever before. The availability of these agents is both an important advance for patients but also a challenge for practicing hematologist/oncologists to learn how best to sequence NAs, both with respect to chemoimmunotherapy (CIT) and to other NAs. The sequencing of NAs in clinical practice should be guided both by an individual patient's prognostic markers, such as FISH and immunoglobulin heavy chain variable region (

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Smith-Magenis Syndrome; Sulfonamides

Treatment options for chronic lymphocytic leukemia, the most common leukemia in the United States, have expanded rapidly in recent years. While traditional chemoimmunotherapy still remains a mainstay for young, fit patients, a number of novel targeted therapies have emerged that have changed the therapeutic landscape. Two innovative anti-CD20 monoclonal antibodies, obinutuzumab and ofatumomamab, have demonstrated activity in chronic lymphocytic leukemia and represent well-tolerated options in upfront management of elderly patients or in those with significant comorbidities. Agents targeting the B-cell receptor pathway, ibrutinib and idelalisib, have excellent activity in chronic lymphocytic leukemia, particularly in those patients with 17p deletions, in which responses to chemoimmunotherapy are traditionally dismal. Venetoclax (ABT-199), the recently FDA-approved BCL2 inhibitor, as well as several other agents and therapy combinations in the pipeline offer great promise for patients with chronic lymphocytic leukemia, particularly in the relapsed/refractory setting. This article comprehensively reviews the data for novel agents in chronic lymphocytic leukemia, including the pharmacology of therapies, unique toxicities, and other practical management considerations for clinicians.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months' follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods.. A systematic literature review was conducted to identify clinical trials sharing a common treatment arm with the RESONATE Phase III trial such that a network meta-analysis or indirect treatment comparisons (ITCs) could be conducted. Two trials were identified, each using the same comparator (ofatumumab) as the RESONATE study. Two pairwise ITCs were conducted using the Bucher method to establish the relative treatment efficacy of ibrutinib versus (1) idelalisib plus ofatumumab in the first study and (2) physician's choice, defined as a mix of therapies commonly used in R/R CLL, in the second study. Odds ratios for these ITCs were calculated for overall response rate (ORR) and HRs for PFS and OS.. A strong and consistent trend of superiority for ibrutinib was observed via these ITC models with idelalisib plus ofatumumab and physician's choice for ORR, PFS, and OS. Ibrutinib revealed prolonged PFS and OS versus comparators (PFS HR = 0.06; 95% CI, 0.04-0.11; and OS HR = 0.25; 95% CI, 0.12-0.54), physician's choice (PFS HR = 0.41; 95% CI, 0.25-0.66; and OS HR = 0.50; 95% CI, 0.23-1.08), and idelalisib plus ofatumumab. These findings were robust and continued to favor ibrutinib when adjusting (where appropriate) for underlying differences in patient population between the trials. Some trial differences were not accounted for in the models and thus some limitations remain; however, consistency of results supports the overall findings.. In a randomized Phase III study, ibrutinib significantly improved ORR, PFS, and OS in patients with R/R CLL versus ofatumumab. In ITC models that used ofatumumab as the common comparator, ibrutinib appears to have higher ORR and longer PFS and OS versus both idelalisib plus ofatumumab and physician's choice. In the absence of head-to-head studies and taking into consideration inherent limitations of ITCs, these models provide useful estimates of comparative efficacy.

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Disease-Free Survival; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Randomized Controlled Trials as Topic; Recurrence; Treatment Outcome

Pharmacological agents that inhibit enzymes of the B-cell receptor (BCR) pathway are of increasing importance in the treatment of B-cell malignancies. These include inhibitors of Bruton tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), splenic tyrosine kinase and protein kinase Cβ. Two agents are already approved in the USA and Europe: ibrutinib, a BTK inhibitor, for the treatment of chronic lymphatic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia; and idelalisib, a PI3Kδ inhibitor, for the treatment of CLL and follicular lymphoma. In addition, the role of these drugs in diffuse large B-cell lymphoma and marginal zone lymphoma is under investigation, as single agents and in combination with chemotherapy. In CLL, both ibrutinib and idelalisib have an established role as first-line therapy in patients with del(17p), and in MCL, ibrutinib is a standard option for patients relapsing after chemoimmunotherapy. Unexpected toxicities have been encountered when combining these potent new agents with other drugs, including chemotherapy and lenalidomide, and based on this experience the risks and benefits of novel combinations must be evaluated carefully. In this review, we summarize the efficacy and safety results with these inhibitors and discuss novel combinations that are under study and the future role of BCR inhibitors in these disorders.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Waldenstrom Macroglobulinemia

With the increasing number of targeted agents for the treatment of patients with lymphoid malignancies comes the promise of safe and effective chemotherapy-free treatment strategies. A number of single agents, such as ibrutinib and idelalisib, have demonstrated impressive efficacy with a favorable toxicity profile. The observations that most responses are, however, partial and treatment duration is indefinite have stimulated interest in combinations of these agents with chemotherapy as well as with each other. Despite the promise of this approach, several recent trials of combinations of agents have been terminated as the result of life-threatening and fatal complications. Such outcomes have generated a cautionary note of the potential for unforeseen adverse effects that challenge drug development and mitigate against the empiric combination of such drugs outside of a clinical trial setting.

Topics: Adenine; Clinical Trials as Topic; Drug Design; Humans; Lymphoma; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL) therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL with favorable disease features-particularly mutated immunoglobulin heavy chain variable region (IGHV) genes-derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. The advent of oral targeted therapies, particularly ibrutinib and idelalisib, has provided generally well-tolerated and highly effective additional options that have come into widespread use in the relapsed setting. Additional agents are advancing in clinical development, with the BCL-2 inhibitor venetoclax likely to be approved by the U.S. Food and Drug Administration (FDA) in 2016. With the development of these novel therapies for patients with relapsed CLL, many unanswered questions remain, including the optimal sequence (first vs. second line), duration, discontinuation, and combination of these agents. In addition, recent publications show the emergence of a pattern of treatment resistance in certain subgroups of patients with del(17p) and complex karyotype that needs further study and improvement. Because the field of CLL management has become much more complex, we focus here on understanding the recent data and discuss many of the questions and controversies important for how we approach patients with CLL.

Topics: Adenine; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; Sulfonamides; Vidarabine

Given the current dynamics in the development of novel agents for CLL therapy, the task to find optimal, non-toxic combinations has become the primary goal. This article gives an update of the most interesting novel drugs. The strategy of the German CLL Study Group to use these agents in combinations is described in detail, highlighting the strategy and first results of a recently started series of phase II combination trials, the BXX series using agents such as bendamustine, idelalisib, ibrutinib, obinutuzumab, ofatumumab and venetoclax.

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Precision Medicine; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Risk Factors; Sulfonamides

The 21st century has seen rapid, positive changes in the management of chronic lymphocytic leukaemia from the patient's perspective. New prognostic and predictive markers have ushered in the start of more precise and individualized therapy. For the first time, combined therapy [fludarabine, cyclophosphamide and rituximab] has been shown to prolong life significantly. Clinical trials have become more adaptive, faster and more patient friendly. Perhaps the greatest change of all is the development of novel oral agents (ibrutinib and idelalisib) and powerful monoclonal antibodies that offer robust and durable disease control. Finally, access to and understanding of these changes through an empowered and educated patient population has grown through live education forums and the Internet.

Topics: Adenine; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; History, 21st Century; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Precision Medicine; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy. As a class of medications, BCR inhibitors have some unique side effects including redistribution lymphocytosis. Ibrutinib has specific toxicities including increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities consisting of transaminitis, diarrhea and pneumonitis. Ongoing clinical trials are evaluating these agents in combination with antibodies, chemotherapy and other small molecules.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Age Factors; Atrial Fibrillation; Diarrhea; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pneumonia; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell

Half of a century ago, physicians managing chronic lymphocytic leukemia (CLL) recognized some of its presenting features such as lymphocytosis, lymphadenopathy, and splenomegaly. Subsequently, an enhanced understanding of the disease mechanisms involved in CLL led to new, more targeted treatments. There is now a plethora of treatments available for CLL. In this review article we discuss in detail several of the novel agents that are being studied or approved for the treatment of CLL including: phosphatidylinositol 3-kinase inhibitors (idelalisib and IPI-145), Bruton tyrosine kinase inhibitors (ibrutinib), B cell lymphoma 2 inhibitors (ABT-263 and ABT-199), new anti-CD20 monoclonal antibodies (obinutuzumab), cyclin-dependent kinase inhibitors (flavopiridol and dinaciclib), immunomodulators (lenalidomide) and chimeric antigen receptor T-cell therapy.

Topics: Adenine; Aniline Compounds; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cyclic N-Oxides; Flavonoids; Humans; Immunologic Factors; Indolizines; Isoquinolines; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyridinium Compounds; Pyrimidines; Quinazolinones; Receptors, Antigen, T-Cell; Sulfonamides; Thalidomide

Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Inhibitors of B-cell receptor (BCR) and pre-BCR signaling were successfully introduced into patient care for various subtypes of mature B-cell lymphoma (e.g., ibrutinib, idelalisib). Acute lymphoblastic leukemia (ALL) typically originates from pre-B cells that critically depend on survival signals emanating from a functional pre-BCR. However, whether patients with ALL benefit from treatment with (pre-) BCR inhibitors has not been explored. Recent data suggest that the pre-BCR functions as tumor suppressor in the majority of cases of human ALL. However, a distinct subset of human ALL is selectively sensitive to pre-BCR antagonists.

Topics: Adenine; DNA-Binding Proteins; Humans; Molecular Targeted Therapy; Piperidines; Pre-B Cell Receptors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; Proto-Oncogene Proteins c-bcl-6; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; STAT5 Transcription Factor

Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110δ isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL. These agents directly affect the neoplastic clone, disrupting the supportive platform provided by BCR signaling cascade and by other microenvironmental mutualistic interactions, and also interfering with chemokine gradients and adhesive properties of neoplastic B cells. In the present review, we describe the clinical efficacy of ibrutinib and idelalisib in CLL and B cell non-Hodgkin lymphoma (B-NHL), then focusing on the mode of action (MOA) of these TKIs towards the neoplastic B cell compartment. At last, the review would further expand the view on potential additional targets of ibrutinib and idelalisib belonging to other microenvironmental cellular elements.

Topics: Adenine; Antineoplastic Agents; Humans; Killer Cells, Natural; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Signal Transduction; Tumor Microenvironment

Over the last 20 years there have been sustained and dramatic improvements in the therapy of chronic lymphocytic leukemia (CLL). Until 1990, therapy for CLL was based on alkylating agents, chlorambucil and cyclophosphamide, which did not impact meaningfully on overall survival. The more recent therapeutic regimens, built on combination chemoimmunotherapy, achieve complete responses in 40-50% of cases. However, these regimens are limited in their applicability mostly to the treatment of younger and physically fit patients due to their associated toxicity. Furthermore, since disease progression and drug resistance are considered inevitable, CLL remains incurable. Fortunately, significant progress in the understanding of CLL biology has enabled the development of new molecular drugs targeting the B-cell receptor signaling pathway, such as ibrutinib and idelalisib, which have shown impressive results in patients with relapsed/refractory disease or with TP53 mutation/deletion. Furthermore, obinutuzumab, a type II anti-CD20 antibody, which results in direct cell death and antibody-dependent cell-mediated cytotoxicity, also has proven efficacy when used in combination with chlorambucil in previously untreated and unfit patients. All these three new drugs have recently received FDA approval for the treatment of CLL. This review focuses on the role of ibrutinib, idelalisib and obinutuzumab in therapy of CLL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Class Ia Phosphatidylinositol 3-Kinase; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Treatment Outcome

Chronic lymphocytic leukemia (CLL) is frequently diagnosed after 71 years, though median age in published clinical trials with standard chemoimmunotherapy regimens in frontline or relapse setting is mostly below 70 years (58-71 years). Development of oral, less toxic and thus more affordable targeted therapies offers new therapeutic options in those patients deemed unfit for chemotherapy.. This review will discuss results of these new agents in the therapy of elderly patients. Apart from discussing the impact of chronological age, creatinine clearance and cumulative illness rating scale scores in the clinical outcomes, we will also discuss how individualized treatment decision-making should include more precise geriatric assessment tools to thoroughly assess life expectancy, anticipate tolerability, to avoid deleterious stress precipitating prefrail patients into definitive loss of capacity, with dramatic social and economic costs.. In the era of new targeted agents to fight cancers, we propose concepts to help us understand how elderly dedicated trial designs and geriatric assessment tools (apart from the evaluation of CLL biological risk factors) will undoubtedly revolutionize therapeutic approaches in everyday practice CLL patients.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Comorbidity; Cost-Benefit Analysis; Creatinine; Decision Making; Geriatric Assessment; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Life Expectancy; Molecular Targeted Therapy; Patient Selection; Piperidines; Precision Medicine; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Chronic lymphocytic leukaemia (CLL) is mostly considered a disease of the elderly. As such, many patients present with comorbidities. Several scores allow for a qualitative and quantitative assessment of comorbidity in patients with CLL. Although our knowledge about the impact of comorbidity on outcomes in patients with CLL is still incomplete, it is becoming increasingly apparent that comorbidities could negatively interfere with CLL treatment. Recently, a number of new agents have been approved for use in patients with previously untreated CLL and comorbidities (i.e. obinutuzumab, ofatumumab), as well as in patients with previously treated or high-risk CLL (i.e. idelalisib, ibrutinib). This review discusses the role of comorbidity in patients with CLL, together with the changing treatment landscape for CLL in this patient population.

Topics: Adenine; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Comorbidity; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Hairy cell leukemia (HCL) cells engage in complex cellular and molecular interactions with accessory cells, matrix proteins, and various cytokines in the bone marrow and spleen, collectively referred to as the tissue microenvironment. Chemokine receptors and adhesion molecules are critical players for homing and retention within these microenvironments. Engagement of B cell antigen receptors and CD40 on HCL cells promote survival and proliferation. In this chapter, we summarize the current knowledge about the cellular and molecular interactions between HCL cells and their supportive tissue microenvironment, and provide insight into new therapeutic approaches targeting B cell receptor signaling in HCL.

Topics: Adenine; Antineoplastic Agents; B-Lymphocytes; Bone Marrow; CD40 Antigens; Gene Expression Regulation, Leukemic; Humans; Intercellular Adhesion Molecule-1; Leukemia, Hairy Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Receptors, CXCR4; Signal Transduction; Spleen; Tumor Microenvironment; Vascular Cell Adhesion Molecule-1

Small-molecule kinase inhibitors, especially the two Food and Drug Administration-approved agents idelalisib and ibrutinib, have changed the treatment landscape for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). However, with these positive changes comes the new challenge of managing patients who relapse after these agents. The number of patients who have relapsed after taking idelalisib and ibrutinib is low, but as the drugs gain wider use and patients are treated for longer, this number is likely to grow. Because these patients can be challenging to manage effectively, coordinated efforts now to determine how and why patients relapse along with optimal treatment strategies are required to better serve our patients in the future. As well, identification of mechanisms of resistance is crucial to develop rational strategies for management. Current work has identified mechanisms of resistance to ibrutinib, and resistance to idelalisib is also under active investigation. In this review, we will discuss these mechanisms of resistance, as well as current and potential strategies for the management of kinase inhibitor-resistant CLL.

Topics: Adenine; Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Remission Induction; Risk Factors; Signal Transduction

The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specifically the B-cell receptor (BCR) pathway (especially Bruton's tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development in rewiring the patient's own immune system to treat CLL. This has been done through modifying autologous T cells to express a chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplification of the transduced T cells relies on signaling and co-signaling domains and provides significant killing of CLL cells. As exciting as these novel agents and approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identified a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is how to incorporate novel agents without eliminating the long term benefits possible with chemoimmunotherapy in a subset of patients with CLL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal, Humanized; Antigens, CD19; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Humans; Immunotherapy; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; Small Molecule Libraries; Sulfonamides; Vidarabine

Chemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as ibrutinib has the potential to eliminate the role of chemotherapy in the treatment of CLL. How to best incorporate old and new therapies for CLL in this landscape is increasingly complex.. This article reviews current data available to clinicians and integrates these data to provide a strategy that can be used to approach the treatment of CLL in the era of BCR signaling inhibitors.. Current strategies separate patients based on age or functional status as well as genetics [presence or absence of del(17)(p13.1)]. In the era of targeted therapy, this will likely continue based on current available data. Phase III studies support chemoimmunotherapy as the initial standard therapy for patients without del(17)(p13.1). Choice of chemotherapy (fludarabine plus cyclophosphamide, bendamustine, or chlorambucil) and anti-CD20 antibody (rituximab, ofatumumab, or obinutuzumab) varies based on regimen and patient status. For patients with del(17)(p13.1), no standard initial therapy exists, although several options supported by phase II clinical trials (methylprednisolone plus alemtuzumab or ibrutinib) seem better than chemoimmunotherapy. Treatment of relapsed CLL seems to be best supported by ibrutinib-based therapy. Completion of trials with ibrutinib and other new agents in the near future will offer opportunity for chemotherapy-free treatment across all groups of CLL.. Therapy for CLL has evolved significantly over the past decade with introduction of targeted therapy for CLL. This has the potential to completely transform how CLL is treated in the future.

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Chlorambucil; Cyclophosphamide; Drug Resistance, Neoplasm; Gene Deletion; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Nitrogen Mustard Compounds; Piperidines; Practice Patterns, Physicians'; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Vidarabine

The development of targeted treatment of chronic lymphocytic leukaemia (CLL) is changing the prognostic outlook for CLL patients. The B-cell antigen receptor pathway is identified as pivotal for CLL pathogenesis and CLL cell proliferation. Inhibition of this pathway by ibrutinib (Bruton's tyrosin kinase inhibition) and idelalisib (phosphatidylinositol 3-kinase inhibition) has recently shown impressive clinical results, also for CLL patients with relapsed/refractory disease and unfavourable prognostic markers. Apoptosis induction by inhibition of BCL2 with ABT-199 is reported with likewise promising clinical results.

Topics: Adenine; Aminopyridines; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Morpholines; Oxazines; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; Sulfonamides

Chronic lymphocytic leukemia (CLL) is a neoplasm resulting from the progressive accumulation of functionally incompetent monoclonal B lymphocytes in the blood, bone marrow, lymph nodes, and spleen. It is the most common leukemia in Western countries and typically occurs in elderly patients. Initial treatment of CLL often includes a first-generation anti-CD20 antibody (rituximab) with chemotherapy and is the current standard of treatment for "younger" old adults (< 70 yrs of age) or older, clinically fit patients. However, because disease progression and drug resistance are inevitable, patients typically die from their disease or treatment-related complications. Improved understanding of the B-cell receptor signaling pathway, which is essential for normal B-cell growth and tumorigenesis, has led to the development of targeted therapies, with improved short-term clinical outcomes. Ibrutinib, obinutuzumab, and idelalisib, three novel agents recently approved by the U.S. Food and Administration for CLL, all have the potential to change the treatment paradigm. In this article, we describe the pathogenesis of CLL and some of its prognostic factors. Emphasis is on the pharmacology, dosing, clinical efficacy, safety, and place of therapy of ibrutinib, obinutuzumab, and idelalisib. Investigational agents that target different parts of the CLL pathogenic pathway are also described.

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world. Recent advances in understanding the biology of B-cell malignancies have resulted in the development of novel agents targeting key prosurvival pathways in the neoplastic B cell.. The goal of this article was to summarize current literature on the emerging therapeutic approaches in CLL and B-cell malignancies.. A literature review was performed, identifying pathways and key clinical trials involving novel therapies in CLL, with special emphasis on B-cell receptor (BCR)-targeting agents.. Understanding the biology of the BCR-signaling pathway has led to identification of novel molecular targets. Most notably, inhibitors of Bruton tyrosine kinase and phosphatidylinositide 3-kinase-δ have entered clinical trials and demonstrated high response rates in CLL, including high-risk disease. Cyclin-dependent kinase inhibitors may evolve into an alternative therapeutic approach in CLL. New drugs that target molecules within and outside of the BCR-signaling pathway have shown promise in preclinical studies.. Both preclinical and early clinical trial results involving novel targeted therapies suggest that the standard treatment paradigm in CLL and B-cell malignancies will soon change. Particular attention should be paid to the BCR-targeting agents, whose favorable adverse effect profile may improve the lives of elderly patients with CLL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; B-Lymphocytes; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction

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.

Topics: Adenine; Aminopyridines; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Morpholines; Oxazines; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Risk Factors; Signal Transduction

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors are provided that support their survival. Signaling pathways activated in the microenvironment in vivo include the B-cell receptor (BCR) and NF-κB pathways. Thus, CLL is a disease "addicted to the host" and is dependent on pathways that promote normal B-cell development, expansion, and survival; this is particularly true in the case of the BCR signaling cascade. Small-molecule inhibitors of kinases that are essential for BCR signal transduction abrogate the stimulating effects of the microenvironment on CLL cells. The orally administered tyrosine kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and refractory CLL patients, mostly with moderate side effects. Reductions in lymphadenopathy and splenomegaly are seen within weeks and are frequently accompanied by a transient rise in absolute lymphocyte count that is asymptomatic and probably the result of changes in CLL cell trafficking. This review discusses the biologic basis for kinase inhibitors as targeted therapy of CLL and summarizes the exciting early clinical experience with these agents.

Topics: Adenine; Aminopyridines; Antineoplastic Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Medical Oncology; Morpholines; Mutation; NF-kappa B; Oxazines; Phosphatidylinositol 3-Kinases; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; src-Family Kinases

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs-ibrutinib, idelalisib, and venetoclax-have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Autoimmune Diseases; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Purines; Quinazolinones; Sulfonamides

Topics: Adenine; Autoimmune Diseases; Disease-Free Survival; Female; Hematologic Diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Survival Rate

Topics: Adenine; Adolescent; Adult; Child; Female; Follow-Up Studies; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prevalence; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Retrospective Studies; Risk Factors

The infection risk in patients receiving ibrutinib, idelalisib or venetoclax for chronic lymphocytic leukaemia (CLL) or B-cell lymphoma treated outside of clinical trials is incompletely defined. We sought to identify the severe infection rate and associated risk factors in a 'real-world' cohort.. We conducted a retrospective cohort study of adult patients with CLL or lymphoma treated with ibrutinib, idelalisib or venetoclax.. Of 67 patients identified (ibrutinib n = 53, idelalisib n = 8 and venetoclax n = 6), 32 (48%) experienced severe infection. Severe infection occurred at a rate of 65 infections per 100 person-years, with a median of 17.8 months of therapy. Median time to first infection (IQR) was 5.4 months (1.4-15.9). Poor baseline Eastern Cooperative Oncology Group (ECOG) performance status and high Charlson Comorbidity Index (CCI) score associated with increased risk of severe infection [hazard ratios (95% CI) 1.57 (1.07-2.31, p = .018) and 1.3 (1.05-1.62, p = .016) respectively].. The severe infection rate for patients receiving ibrutinib, idelalisib or venetoclax for lymphoma and CLL exceeded those reported in clinical trials. Patients with poor ECOG or high CCI should be closely monitored for early signs of infection and prevention strategies actively pursued. Further prospective research is required to define optimal antimicrobial prophylaxis recommendations.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Retrospective Studies

Idelalisib (idela), a phosphatidylinositol 3-kinase inhibitor, and ibrutinib, a Bruton tyrosine kinase inhibitor, were the first oral targeted agents approved for relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). However, no randomised trials of idelalisib plus rituximab (R-idela) versus ibrutinib have been conducted. Therefore, we performed a real-world retrospective analysis of patients with R/R CLL treated with R-idela (n = 171) or ibrutinib (n = 244). The median age was 70 versus 69 years, with a median of two previous lines. There was a trend towards higher tumour protein p53 (TP53) aberrations and complex karyotype in the R-idela group (53% vs. 44%, p = 0.093; 57% vs. 46%, p = 0.083). The median progression-free survival (PFS) was significantly longer with ibrutinib (40.5 vs. 22.0 months; p < 0.001); similarly to overall survival (OS; median 54.4 vs. 37.7 months, p = 0.04). In multivariate analysis, only PFS but not OS remained significantly different between the two agents. The most common reasons for treatment discontinuation included toxicity (R-idela, 39.8%; ibrutinib, 22.5%) and CLL progression (27.5% vs. 11.1%). In conclusion, our data show significantly better efficacy and tolerability of ibrutinib over R-idela in patients with R/R CLL treated in routine practice. The R-idela regimen may still be considered a reasonable option in highly selected patients without a suitable treatment alternative.

Topics: Aged; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Registries; Retrospective Studies; Rituximab

Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax).. Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real-life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020.. Severe infections incidence was 23% during 17-month median follow-up; cumulative incidence was higher in the first 3-6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3-1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1-4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05-3.3). Infection-related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed.. A high proportion of patients presented severe infections during follow-up, with non-negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered.

Topics: Adenine; Adolescent; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunocompromised Host; Infections; Lymphopenia; Lymphoproliferative Disorders; Male; Middle Aged; Piperidines; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazines; Quinazolinones; Retrospective Studies; Risk Factors; Sulfonamides; Young Adult

We describe the opportunistic infections occurring in 362 patients with lymphoproliferative disorders treated with ibrutinib and idelalisib in clinical practice. Overall, 108 of 362 patients (29·8%) developed infections, for a total of 152 events. Clinically defined infections (CDI) were 49·3% (75/152) and microbiologically defined infections (MDI) were 50·7% (77/152). Among 250 patients treated with ibrutinib, 28·8% (72/250) experienced one or more infections, for a total of 104 episodes. MDI were 49% (51/104). Bacterial infections were 66·7% (34/51), viral 19·6% (10/51) and invasive fungal diseases (IFD) 13·7% (7/51). Among the 112 patients treated with idelalisib, 32·1% (36/112) experienced one or more infections, for a total of 48 episodes. MDI were 54·2% (26/48). Bacterial infections were 34·6% (9/26), viral 61·5% (16/26) and IFD 3·8% (1/26). With ibrutinib, the rate of bacterial infections was significantly higher compared to idelalisib (66·7% vs. 34·6%; P = 0·007), while viral infections were most frequent in idelalisib (61·5% vs. 19·6%; P < 0·001). Although a higher rate of IFD was observed in patients treated with ibrutinib, the difference was not statistically significant (13·7% vs. 3·8% respectively; P = 0·18). Bacteria are the most frequent infections with ibrutinib, while viruses are most frequently involved with idelalisib.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Bacterial Infections; Case-Control Studies; Enzyme Inhibitors; Female; Humans; Invasive Fungal Infections; Italy; Lymphoproliferative Disorders; Male; Middle Aged; Molecular Targeted Therapy; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Purines; Quinazolinones; Retrospective Studies; Risk Factors; Virus Diseases

Recently, clinical trial results have established inhibitors of B-cell receptor (BCR)-associated kinase (BAKi), with or without CD20 moniclonal antibodies (mAbs), as the preferred first-line treatment for most chronic lymphocytic leukaemia (CLL) patients. Using phosphospecific flow cytometry, we showed that in leukaemic cells from CLL patients the CD20 therapeutic antibodies - rituximab, ofatumumab, and obinutuzumab - inhibited BCR signalling pathways targeting preferentially pBTK

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Purines; Quinazolinones; Receptors, Antigen, B-Cell; Rituximab; Signal Transduction

Treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) has significantly improved more recently with the approval of several new agents, including ibrutinib, idelalisib, and venetoclax. Despite the outstanding efficacies observed with these agents, these treatments are sometimes discontinued due to toxicity, unresponsiveness, transformation of the disease and/or resistance. Constitutive NF-κB activation that protects CLL cells from apoptotic stimuli represents one of molecular mechanisms that underlie the emergence of drug resistance. As prostaglandin E (EP)4 receptor agonists have been shown to successfully inhibit the NF-κB pathway in B-cell lymphoma cells, we investigated the potential of the highly specific EP4 receptor agonist L-902688 for the potential treatment of patients with CLL. We show here that low micromolar concentrations of L-902688 can indeed induce selective cytotoxicity towards several B-cell malignancies, including CLL. Moreover, L-902688-mediated activation of the EP4 receptor in patient derived CLL cells resulted in inhibition of the NF-κB pathway, cell proliferation, and induction of apoptosis. Most importantly, we show for the first time that in combination with ibrutinib, idelalisib, or venetoclax, L-902688 induces synergistic cytotoxic activity against patient derived CLL cells. To conclude, the modulation of NF-κB activity by EP4 receptor agonists represents an innovative approach to improve the treatment of patients with CLL. In particular, EP4 receptor agonists appear to represent promising adjuncts to the already existing therapies for patients with CLL due to these promising synergistic activities.

Topics: Adenine; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Drug Synergism; Humans; Jurkat Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Piperidines; Purines; Pyrrolidinones; Quinazolinones; Receptors, Prostaglandin E, EP4 Subtype; Sulfonamides; Tetrazoles; U937 Cells

To compare the capacity of ibrutinib (IB) and idelalisib-rituximab (IDELA-R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only.. A real-life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study.. At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA-R vs IB HR = 0.5, 95% CI = 0.36-0.71) although with some limitations due to the non-randomized and retrospective nature of the study and to the lower number of patients in the IDELA-R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA-R (HR = 0.67, 95% CI = 0.45-0.98, P = .04) independent of potential confounders.. Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Resistance, Neoplasm; Female; Humans; Immunoglobulins; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Piperidines; Proportional Hazards Models; Purines; Quinazolinones; Recurrence; Retreatment; Rituximab; Treatment Outcome

High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents.. Functional enzymatic assays and patients' plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels.. High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub.. Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Biomarkers, Pharmacological; Female; Gene Expression Regulation, Neoplastic; Glucuronosyltransferase; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mass Spectrometry; Middle Aged; Minor Histocompatibility Antigens; NF-kappa B; Piperidines; Purines; Quinazolinones; Vidarabine

Using next-generation sequencing (NGS), we recently documented T-cell oligoclonality in treatment-naïve chronic lymphocytic leukemia (CLL), with evidence indicating T-cell selection by restricted antigens.. Here, we sought to comprehensively assess T-cell repertoire changes during treatment in relation to (i) treatment type [fludarabine-cyclophosphamide-rituximab (FCR) versus ibrutinib (IB) versus rituximab-idelalisib (R-ID)], and (ii) clinical response, by combining NGS immunoprofiling, flow cytometry, and functional bioassays.. T-cell clonality significantly increased at (i) 3 months in the FCR and R-ID treatment groups, and (ii) over deepening clinical response in the R-ID group, with a similar trend detected in the IB group. Notably, in constrast to FCR that induced T-cell repertoire reconstitution, B-cell receptor signaling inhibitors (BcRi) preserved pretreatment clones. Extensive comparisons both within CLL as well as against T-cell receptor sequence databases showed little similarity with other entities, but instead revealed major clonotypes shared exclusively by patients with CLL, alluding to selection by conserved CLL-associated antigens. We then evaluated the functional effect of treatments on T cells and found that (i) R-ID upregulated the expression of activation markers in effector memory T cells, and (ii) both BcRi improved antitumor T-cell immune synapse formation, in marked contrast to FCR.. Taken together, our NGS immunoprofiling data suggest that BcRi retain T-cell clones that may have developed against CLL-associated antigens. Phenotypic and immune synapse bioassays support a concurrent restoration of functionality, mostly evident for R-ID, arguably contributing to clinical response.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clonal Evolution; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Female; Humans; Immunological Synapses; Immunophenotyping; Leukemia, Prolymphocytic, T-Cell; Male; Middle Aged; Piperidines; Purines; Quinazolinones; Rituximab; T-Lymphocytes; Vidarabine

High-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.. Outcomes were compared in retrospect between r/r patients treated with HDMP (n = 20), ibrutinib (n = 39) and idelalisib with rituximab (n = 14).. Higher 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).. HDMP 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.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Methylprednisolone; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Prognosis; Proto-Oncogene Proteins c-bcr; Purines; Quinazolinones; Retrospective Studies; Salvage Therapy; Survival Rate; Tumor Suppressor Protein p53

Despite the emergence of small molecule inhibitors, current treatment strategies for chronic lymphocytic leukemia (CLL) are not curative, and the search for new therapeutic modalities continues. Prosurvival signaling derived from the microenvironment is often mediated via JAK signaling. However, whether JAK inhibitors are useful in CLL therapy has not been studied extensively. JAK inhibitors are valuable therapeutic agents in myelofibrosis and show promising results in graft-versus-host-disease. However, JAK inhibition is associated with an increased infection risk, presumably because of the effect on other immune cells, a feature shared with other kinase inhibitors used for CLL treatment, such as the BTK inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We compared functional effects of the JAK1/2 inhibitors momelotinib and ruxolitinib, the BTK inhibitors ibrutinib and tirabrutinib, and PI3Kδ inhibitor idelalisib on malignant CLL cells but also on healthy human T, B, and NK lymphocytes. We found several interesting differences among the inhibitors, apart from expected and well-known effects. Momelotinib but not ruxolitinib blocked cytokine-induced proliferation of CLL cells. Momelotinib also reduced BCR signaling, in contrast to ruxolitinib, indicating that these JAK inhibitors in fact have a distinct target spectrum. In contrast to tirabrutinib, ibrutinib had inhibitory effects on T cell activation, probably because of ITK inhibition. Remarkably, both BTK inhibitors stimulated IFN-γ production in a mixed lymphocyte reaction. Collectively, our results demonstrate that kinase inhibitors directed at identical targets may have differential effects on lymphocyte function. Their unique profile could be strategically employed to balance desired versus unwanted lymphocyte inhibition.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Benzamides; Cell Proliferation; Cell Survival; Humans; Imidazoles; Janus Kinases; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Mice; NIH 3T3 Cells; Nitriles; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Treatment Outcome

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Humans; Isoquinolines; Lymphoma; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Topics: Adenine; Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Substitution; Humans; Leukemia, Prolymphocytic, B-Cell; Male; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Retreatment; Rituximab; Signal Transduction; Sulfonamides; Treatment Outcome

Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies.. In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0-1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination.. We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need.. Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.

Topics: Adenine; Antineoplastic Agents; beta 2-Microglobulin; Bridged Bicyclo Compounds, Heterocyclic; Databases, Factual; Female; Hemoglobins; Humans; Immunotherapy; L-Lactate Dehydrogenase; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prognosis; Proportional Hazards Models; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Sulfonamides; Survival Rate

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Down-Regulation; Drug Synergism; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Histones; Humans; Indazoles; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyridones; Pyrimidines; Quinazolinones; Signal Transduction; Sulfonamides; Tumor Microenvironment

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Retrospective Studies; Sulfonamides

Topics: Adenine; Drug Substitution; France; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Retrospective Studies; Treatment Outcome

The lymph node and bone marrow microenvironments promote the survival and proliferation of CLL cells. Defining the immunophenotype of CLL cells from the tumor microenvironment may help to better understand the mechanisms of action of current therapies and identify novel drug targets. Significant changes in the levels of 25 CD antigens were identified using the DotScan™ antibody microarray following CLL-cell culture with CD40L-expressing fibroblasts. Ibrutinib or idelalisib countered the change in expression of 11 of these antigens (CD23, CD27, CD53, CD58, CD71, CD80, CD84, CD97, CD126, CD150, and FMC7), which have known roles in cell activation and adhesion. The immunophenotypic changes identified may provide further insight into the mechanisms by which CLL cells interact with the tumor microenvironment and better define how ibrutinib and idelalisib release CLL cells from the lymph nodes and bone marrow.

Topics: Adenine; Animals; Antigens, CD; Cell Adhesion; Coculture Techniques; Fibroblasts; Humans; Immunophenotyping; L Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; Mice; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Tumor Cells, Cultured; Tumor Microenvironment

Novel therapies including kinase inhibitors (KI) have led to high and durable response in patients with chronic lymphocytic leukemia (CLL), however, some patients stop therapy. This study evaluates reasons for treatment changes among CLL patients who stopped KI in real-world practice. Sixty-nine US oncologists/hematologists provided patient-level data abstracted from charts of CLL adult patients who initiated a KI and later (1) switched to another anti-neoplastic regimen (Switched cohort), (2) discontinued the KI and remained untreated (Discontinued cohort), or (3) restarted the same KI after an interruption of ≥60 days (Restarted cohort). Demographics, clinical/treatment characteristics, and reasons for stopping, restarting, and switching the KI therapy were described. In the Switched cohort, reasons for stopping included disease progression (72.5%), low/no disease activity (3.9%), adverse event [AE]/ intolerance/comorbidity (15.7%), and planned cellular therapies (7.9%). In the Discontinued cohort, approximately half (46.0%) of patients stopped KI therapy because they were terminally ill/died, or were moved to best supportive care - these patients were older, had more severe disease, and high comorbidity burden. The other half (54.0% of patients) stopped due to low/no disease activity (24.0%), AEs/toxicity (12.0%), or patient-requested drug holiday (18.0%). In the Restarted cohort, the most common reasons for stopping KIs were patient request (37.3%), AEs/intolerance (31.4%), and economic reasons (10%). Patients restarted when disease progressed (60.8%) or when they recovered from the AE (33%). Reasons for KI stop and subsequent treatment patterns were varied and multifactorial, suggesting heterogeneous disease management and a need for more evidence around supporting strategies and physician education.

Topics: Adenine; Age Factors; Aged; Aged, 80 and over; Disease Progression; Disease-Free Survival; Drug Substitution; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Medication Adherence; Middle Aged; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Treatment Outcome

There is limited amount of data available on the comparative efficacy of ibrutinib and idelalisib, the B-cell receptor inhibitors (BCRi) newly approved for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) treatment. The aim of our study was to analyze and compare the outcomes of real-world r/r CLL/SLL patients treated with these two BCRi in outside clinical trials.. A comparative case matched 1:2 analysis was performed on idelalisib combined with rituximab and ibrutinib efficacy in 102 patients with r/r CLL/SLL from two observational studies of the Polish Adult Leukemia Group (PALG).. Both therapies produced similar overall response rates (idelalisib plus rituximab 76.4% and ibrutinib 72.1%). Median progression-free survival (PFS) and overall survival (OS) in both groups were not reached. Furthermore, no significant difference was observed between both BCRi regimens in regard to PFS (HR=0.75, 95% CI=0.30-1.86, p=0.55) and OS (HR=0.65, 95%CI=0.26-1.68, p=0.39).. In summary, the results of this retrospective analysis suggest that idelalisib combined with rituximab and ibrutinib therapies have comparable activity in r/r CLL/SLL in daily clinical practice.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Case-Control Studies; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Poland; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Retrospective Studies; Rituximab

The antibody-dependent cell-mediated cytotoxicity (ADCC) of the anti-CD20 monoclonal antibodies (mAbs) rituximab and obinutuzumab against the cell line Raji and isolated CLL cells and its potential impairment by kinase inhibitors (KI) was determined via lactate dehydrogenase release or calcein retention, respectively, using genetically modified NK92 cells expressing CD16-176V as effector cells. Compared to peripheral blood mononuclear cells, recombinant effector cell lines showed substantial alloreactivity-related cytotoxicity without addition of mAbs but afforded determination of ADCC with reduced interassay variability. The cytotoxicity owing to alloreactivity was less susceptible to interference by KI than the ADCC of anti-CD20 mAbs, which was markedly diminished by ibrutinib, but not by idelalisib. Compared to rituximab, the ADCC of obinutuzumab against primary CLL cells showed approximately 30% higher efficacy and less interference with KI. Irreversible BTK inhibitors at a clinically relevant concentration of 1 

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Antigens, CD20; B-Lymphocytes; Benzamides; Cell Line, Tumor; Cytotoxins; Humans; Killer Cells, Natural; Leukocytes, Mononuclear; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Rituximab

Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.. We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).. A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06).. In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Piperidines; Proportional Hazards Models; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Retrospective Studies; Sulfonamides; Treatment Outcome; Young Adult

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Genes, p53; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Medical Oncology; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; Sequence Deletion; Sulfonamides; Tumor Suppressor Protein p53

Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3Kδ or Bruton's tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; B-Lymphocytes; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Cytidine Deaminase; Enzyme Inhibitors; Female; Genomic Instability; Humans; Immunoglobulin Class Switching; Immunoglobulin Heavy Chains; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Mice; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Recombination, Genetic; Somatic Hypermutation, Immunoglobulin; Translocation, Genetic

The broad therapeutic arsenal and the biological heterogeneity of patients with chronic lymphocytic leukemia (CLL) makes it difficult to standardize treatment for CLL patients with specific clinical settings in routine clinical practice. These considerations prompted us to elaborate the present consensus document, which constitutes an update of the previous version published in 2013, mainly focusing on novel treatment strategies that have been developed over last 5 years, namely B-cell receptor inhibitors (ibrutinib and idelalisib), anti-CD20 monoclonal antibodies (ofatumumab and obinutuzumab), and Bcl-2 inhibitors (venetoclax).. A group of experts from the Spanish Chronic Lymphocytic Leukemia Group reviewed all published literature from January 2010 to January 2016, in order to provide recommendations based on clinical evidence. For those areas without strong scientific evidence, the panel of experts established consensus criteria based on their clinical experience.. The project has resulted in several practical recommendations that will facilitate the diagnosis, treatment, and follow-up of patients with CLL.. There are many controversial issues in the management of CLL with no appropriate studies for making consensus recommendations.

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Sulfonamides

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; B-Lymphocytes; Cell Death; Cell Line; Humans; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemokine CXCL12; Gene Expression Regulation, Neoplastic; Humans; Integrin alpha4beta1; Molecular Targeted Therapy; Myeloid Differentiation Factor 88; Piperidines; Plasma Cells; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Receptors, CXCR4; Signal Transduction; Vascular Cell Adhesion Molecule-1; Waldenstrom Macroglobulinemia

Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Apoptosis; Bendamustine Hydrochloride; Cell Proliferation; Female; Follow-Up Studies; Humans; Lectins, C-Type; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcriptome; Tumor Cells, Cultured

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Alleles; Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Class I Phosphatidylinositol 3-Kinases; Gene Expression; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Prognosis; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Sulfonamides; Tumor Suppressor Protein p53

Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models.. Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed.. Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib.. The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, B-Cell; MAP Kinase Kinase Kinases; Mice; Molecular Targeted Therapy; Niacinamide; Piperidines; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Signal Transduction; Xenograft Model Antitumor Assays

The Bcl-2 antagonist ABT-199 (venetoclax) has demonstrated promising clinical activity in patients with chronic lymphocytic leukemia (CLL). ABT-199 is strongly cytotoxic against unstimulated peripheral blood CLL cells in vitro but is much less effective against CLL cells that have received survival signals from the microenvironment. In particular, stimulation of CLL cells with CD40L results in substantial resistance mediated by induction of the antiapoptotic Bcl-2 family proteins Bcl-xL and Bfl-1. In this study, we investigated whether resistance to ABT-199 can be conferred by B-cell receptor (BCR) stimulation, which is another important survival signal from the leukemic microenvironment. We show that sustained BCR stimulation results in significant ABT-199 resistance, which correlates with induction of the antiapoptotic protein Mcl-1 and less consistently with downregulation of proapoptotic Bmf, Hrk, and BimEL A major role for Mcl-1 in conferring ABT-199 resistance is additionally supported by knockdown and enforced expression experiments with primary CLL cells. We further show that SYK, BTK, and phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitors significantly downregulate Mcl-1, but with different efficacy. Complete Mcl-1 downregulation was consistently achieved only with SYK inhibitors R406 and GS-9973 (entospletinib), whereas the BTK inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib in more than half of the cases had only a partial effect. The greater ability of SYK inhibitors to downregulate Mcl-1 correlated with their greater capacity to block BCR-mediated inactivation of GSK-3, a major negative regulator of Mcl-1. The finding that BCR signaling inhibitors differ in their ability to target Mcl-1 is relevant for the design of clinical trials combining these agents with ABT-199.

Topics: Adenine; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Oxazines; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Sulfonamides

Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax.

Topics: Adenine; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cellular Microenvironment; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Imaging, Three-Dimensional; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Quinazolinones; Reproducibility of Results; Signal Transduction; Stromal Cells; Sulfonamides; Sunitinib; Up-Regulation

B-cell receptor kinase inhibitor (KI) therapy represents a paradigm shift in chronic lymphocytic leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 patients with CLL (ibrutinib = 143; idelalisib = 35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter transformation (RT) (8%). Median progression-free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS; however, RT portended significantly inferior OS (P = .0007). One hundred fourteen patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI-intolerant patients treated with an alternate KI was not reached vs 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, that patients who discontinue KI due to toxicity can respond to an alternate KI, and that these responses may be durable. This trial was registered at www.clinicaltrials.gov as #NCT02717611 and #NCT02742090.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cohort Studies; Disease Progression; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Proportional Hazards Models; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Retrospective Studies; Salvage Therapy; Treatment Outcome

The novel Bruton tyrosine kinase inhibitor ibrutinib and phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib are promising drugs for the treatment of chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma, either alone or in combination with anti-CD20 antibodies. We investigated the possible positive or negative impact of these drugs on all known mechanisms of action of both type I and type II anti-CD20 antibodies. Pretreatment with ibrutinib for 1 hour did not increase direct cell death of cell lines or chronic lymphocytic leukemia samples mediated by anti-CD20 antibodies. Pre-treatment with ibrutinib did not inhibit complement activation or complement-mediated lysis. In contrast, ibrutinib strongly inhibited all cell-mediated mechanisms induced by anti-CD20 antibodies rituximab, ofatumumab or obinutuzumab, either in purified systems or whole blood assays. Activation of natural killer cells, and antibody-dependent cellular cytotoxicity by these cells, as well as phagocytosis by macrophages or neutrophils were inhibited by ibrutinib with a half maximal effective concentration of 0.3-3 μM. Analysis of anti-CD20 mediated activation of natural killer cells isolated from patients on continued oral ibrutinib treatment suggested that repeated drug dosing inhibits these cells in vivo. Finally we show that the phosphatidyl-4-5-biphosphate 3-kinase-δ inhibitor idelalisib similarly inhibited the immune cell-mediated mechanisms induced by anti-CD20 antibodies, although the effects of this drug at 10 μM were weaker than those observed with ibrutinib at the same concentration. We conclude that the design of combined treatment schedules of anti-CD20 antibodies with these kinase inhibitors should consider the multiple negative interactions between these two classes of drugs.

Topics: Adenine; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Case-Control Studies; Cell Proliferation; Cells, Cultured; Complement Activation; Flow Cytometry; Fluorescent Antibody Technique; Humans; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Macrophages; Neutrophils; Phagocytosis; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzylamines; Chemokine CXCL12; Class I Phosphatidylinositol 3-Kinases; Cyclams; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Heterocyclic Compounds; Humans; Immunoglobulin Heavy Chains; Integrin alpha4; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Natalizumab; Piperidines; Prognosis; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, CXCR4; Signal Transduction; Survival Analysis

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Humans; Membrane Proteins; Piperidines; Proto-Oncogene Proteins; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, CXCR4; Sulfonamides; Waldenstrom Macroglobulinemia

BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton's tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechanisms underlying this phenomenon are incompletely understood. In this study, we showed that the egress receptor, sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), was expressed at low levels in normal germinal centers and CLL lymph nodes in vivo but became upregulated on normal B cells and, to a variable and lesser extent, CLL cells following in vitro incubation in S1P-free medium. Spontaneous recovery of S1PR1 expression on normal B and CLL cells was prevented by BCR cross-linking, whereas treatment of CLL cells with idelalisib increased S1PR1 expression and migration toward S1P, the greatest increase occurring in cases with unmutated IgH V region genes. Intriguingly, ibrutinib and fostamatinib had no effect on S1PR1 expression or function. Conversely, chemokine-induced migration, which requires integrin activation and is essential for the entry of lymphocytes into lymph nodes as well as their retention, was blocked by ibrutinib and fostamatinib, but not idelalisib. In summary, our results suggest that different BCR signaling inhibitors redistribute CLL cells from lymph nodes into the blood through distinct mechanisms: idelalisib actively promotes egress by upregulating S1PR1, whereas fostamatinib and ibrutinib may reduce CLL cell entry and retention by suppressing chemokine-induced integrin activation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aminopyridines; Antineoplastic Agents; B-Lymphocytes; Case-Control Studies; Cell Movement; Class I Phosphatidylinositol 3-Kinases; Gene Expression Regulation, Leukemic; Germinal Center; Human Umbilical Vein Endothelial Cells; Humans; Integrins; Intracellular Signaling Peptides and Proteins; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lysophospholipids; Morpholines; Oxazines; Piperidines; Primary Cell Culture; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Syk Kinase

The latest Annual Meeting of the American Society of Hematology, held in San Francisco, included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL). MABTENANCE and PROLONG study suggest that either rituximab or ofatumumab improves progression-free survival in CLL. According to final analysis of CLL-10 trial, rituximab and bendamustine may have a role in the upfront treatment of fit elderly patients. Further insight into the use of ibrutinib, a first-in-class covalent Bruton’s tyrosine kinase-inhibitor that is currently approved for patients with relapsed/refractory CLL and with del(17p), was also presented. Idelalisib, a selective inhibitor of PI3K delta, demonstrated its activity with manageable toxicity in previously untreated patients ≥65 years with CLL or small lymphocytic lymphoma. Finally, a series Phase I/II studies of BCL-2 inhibitor (i.e., venetoclax, GDC-0199) used alone or in combination provide promising results in patients with relapsed/refractory CLL.

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bendamustine Hydrochloride; Disease-Free Survival; Drug Discovery; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; San Francisco; Societies, Medical

To evaluate the impact of approval of ibrutinib and idelalisib on pharmaceutical costs in the treatment of chronic lymphocytic leukemia (CLL) at the societal level and assess individual out-of-pocket costs under Medicare Part D.. Average wholesale price of commonly used CLL treatment regimens was ascertained from national registries. Using the population of Olmsted County, Minnesota, we identified the proportion of patients with newly diagnosed CLL who experience progression to the point of requiring treatment. Using these data, total pharmaceutical cost over a 10-year period after diagnosis was estimated for a hypothetic cohort of 100 newly diagnosed patients under three scenarios: before approval of ibrutinib and idelalisib (historical scenario), after approval of ibrutinib and idelalisib as salvage therapy (current scenarios A and B), and assuming use of ibrutinib as first-line treatment (potential future scenario).. Estimated 10-year pharmaceutical costs for 100 newly diagnosed patients were as follows: $4,565,929 (approximately $45,659 per newly diagnosed patient and $157,446 per treated patient) for the historical scenario, $7,794,843 (approximately $77,948 per newly diagnosed patient and $268,788 per treated patient) for current scenario A, $6,309,162 (approximately $63,092 per newly diagnosed patient and $217,557 per treated patient) for current scenario B, and $16,414,055 (approximately $164,141 per newly diagnosed patient and $566,002 per treated patient) for the potential future scenario. Total out-of-pocket cost for 100 patients with newly diagnosed CLL under Medicare Part D increased from $9,426 under the historical scenario (approximately $325 per treated patient) to $363,830 and $255,051 under current scenarios A and B (approximately $8,800 to $12,500 per treated patient) and to $1,031,367 (approximately $35,564 per treated patient) under the future scenario.. Although ibrutinib and idelalisib are profound treatment advances, they will dramatically increase individual out-of-pocket and societal costs of caring for patients with CLL. These cost considerations may undermine the potential promise of these agents by limiting access and reducing adherence.

Topics: Adenine; Antineoplastic Agents; Cost-Benefit Analysis; Drug Costs; Health Expenditures; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Medicare Part D; Minnesota; Models, Economic; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Time Factors; Treatment Outcome; United States

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Median age at diagnosis is around 70 years. To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, CD20 and CD23 has to be confirmed by flow cytometry. A bone marrow biopsy is not mandatory for the diagnosis. Before start of treatment the assessment of 17 p deletion and/or TP53-mutational status is recommended. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts (Lymphocyte doubling time less than 6 months). The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit patients. An alternative regimen is the combination of bendamustine and rituximab (BR) or ofatumumab. Physically compromised patients can be treated with the oral drug chlorambucil in combination with an anti-CD20 antibody. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17 p deletion and/or TP53-mutation, lack of response to standard therapy or early relapse. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab, obinutuzumab, in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Novel agents have been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton's tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL is the BH3-mimetic inhibitor of the Bcl-2 family of pro-survival proteins, ABT-199. Given all these novel agents and targets, chemo-free or at least chemo-reduced concepts may become reality in the near future for our patients suf

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Remission Induction; Rituximab; Vidarabine

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Adhesion; Cell Proliferation; Drug Synergism; Flow Cytometry; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Proto-Oncogene Proteins c-bcr; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Tumor Cells, Cultured

The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110δ with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110δ and p110γ in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110δ and p110γ isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT(Ser473) is observed with an IC50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 μM IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKT(Ser473), BAD(Ser112), ERK(Thr202/Tyr204) and S6(Ser235/236) are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B- and T-lymphocytes.

Topics: Adenine; Aged; Aged, 80 and over; Apoptosis; Bone Marrow Cells; Case-Control Studies; Cell Proliferation; Cell Survival; Chemokine CCL3; Chemokine CCL4; Chemotaxis; Female; Humans; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Male; Middle Aged; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Piperidines; Prognosis; Proto-Oncogene Proteins c-akt; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Ribosomal Protein S6 Kinases; Signal Transduction; Stromal Cells

Topics: Adenine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones

Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB=30-66%, ABC=45-57%). Combination treatment with the PI3K-δ inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB=16-38%, ABC=25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus+bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction.

Topics: Adenine; Antineoplastic Agents; Bortezomib; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Antagonism; Drug Synergism; Humans; Lymphoma, Large B-Cell, Diffuse; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; Sirolimus

B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor-prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B-PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches.

Topics: Adenine; Alemtuzumab; Antibodies, Monoclonal, Humanized; B-Lymphocytes; Disease Progression; Humans; Immunophenotyping; Immunotherapy; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Mutation; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Recurrence; Stem Cell Transplantation; T-Lymphocytes; Treatment Outcome; Tumor Suppressor Protein p53

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones

To investigate the proliferation inhibitory role and mechanism of PI3Kδ inhibitor CAL-101 on multiple myeloma (MM) cells, and to provide new therapeutic options for MM treatment.. MM cell lines U266 and RPMI8226 cells were treated with various concentrations of CAL-101. MTT assay and CalcuSyn software were performed to determine the inhibitory effect of CAL-101 and the synergistic effect with PCI- 32765, SAHA (suberoylanilide hydroxamic acid), BTZ (Bortezomib) on MM cells. The protein expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ processed by CAL-101 were analyzed by Western blot.. CAL-101 at concentration of 15, 20, 25, 30 and 40 μmol/L could induce significant dose-dependent proliferation inhibition on U266 cells after treatment for 48 hours. The cell proliferation inhibition rates were (33.54 ± 1.23)%, (41.72 ± 1.78)%, (53.67 ± 2.01)%, (68.97 ± 2.11)% and (79.25 ± 1.92)%, respectively. Similar results were found in RPMI8226 cell line. Western blots showed high expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ in cell lines and MM primary cells. p-AKT and p-ERK protein expression levels were down-regulated significantly by CAL-101 treatment. Synergistic effect has been verified between CAL-101 and PCI-32765, SAHA and Bortezomib in U266 cell line, and PCI-32765, Bortezomib in RPMI8226 cell line with CI values less than 1.. CAL-101 could inhibit proliferation of MM cell lines. High levels of p-AKT, p-ERK, AKT, ERK and PI3Kδ protein expression were observed in both cell lines and primary cells. Down-regulation of p-AKT and p-ERK probably related with the mechanism of CAL-101 in MM cell proliferation inhibition. CAL-101 has significant synergistic effect with PCI-32765, SAHA and BTZ.

Topics: Adenine; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Humans; Multiple Myeloma; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazines; Pyrazoles; Pyrimidines; Quinazolinones

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclin-Dependent Kinases; Cysteine; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Mutation; Piperazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Serine

Topics: Adenine; Antineoplastic Agents; Casein Kinase II; Drug Synergism; Hematologic Neoplasms; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Naphthyridines; Phenazines; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; Vidarabine

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by short median survival despite intensive therapies. The clinical behavior of MCL may be due to the complex pathophysiology of the disease which includes its genetic hallmark, the chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1, alteration in the DNA damage response, and constitutive activation of key anti-apoptotic pathways such as phosphatidyl-inositol 3-kinase (PI3K)/Akt and nuclear factor-kB (NF-kB). Collectively, these changes result in cell cycle dysregulation and give rise to profound genetic instability. Given this complex pathophysiology, the limited number of options for patients with relapsed/refractory MCL, and the difficulty in achieving long-lasting remissions with conventional approaches, it is essential to explore new treatment options targeting the numerous dysregulated pathways that are operable in MCL. We have recently reported that milatuzumab, a fully humanized anti-CD74 monoclonal antibody (mAb), in combination with anti-CD20 mAbs has significant preclinical and clinical activity in MCL. Here we discuss these results, provide additional insights into milatuzumab-mediated MCL cell death, and report preliminary data on the activity of other targeted biologic agents including PCI-32765 and CAL-101 currently undergoing evaluation at our institution and others.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antigens, Differentiation, B-Lymphocyte; B-Lymphocytes; Cell Cycle; Clinical Trials as Topic; Cyclin D1; DNA Repair; Female; Histocompatibility Antigens Class II; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Molecular Targeted Therapy; NF-kappa B; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-akt; Purines; Pyrazoles; Pyrimidines; Quinazolinones; TOR Serine-Threonine Kinases; Translocation, Genetic

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; B-Lymphocytes; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; Standard of Care