pci-32765 and Lymphoma--Non-Hodgkin

Rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone immunochemotherapy remains standard of care for first-line treatment of diffuse large B-cell lymphoma (DLBCL). High-dose chemotherapy and stem cell transplantation is offered to most relapsing/refractory patients who respond to salvage therapy. This Q&A review evaluates recommended management strategies for second and subsequent lines of therapy in patients with DLBCL, outlining the relative efficacies of currently available options including novel agents such as ibrutinib and CAR-T cells. The combination of pixantrone and rituximab is currently under investigation as a second-line treatment for patients ineligible for stem cell transplantation, while pixantrone monotherapy is the only therapeutic option approved for multiply relapsed and refractory DLBCL beyond the second line at this time.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Immunotherapy, Adoptive; Isoquinolines; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Salvage Therapy; Stem Cell Transplantation

Waldenström's macroglobulinemia (WM) is a rare, incurable hematologic disorder with a relatively indolent course in a majority of the patients. Despite this, a significant proportion of patients require treatment because of hypersecretion of immunoglobulin M and the invasion of bone marrow and peripheral organs by neoplastic lymphoplasmacytic lymphoma cells. Historically, there has been a dearth of research and therapeutic advancements in the field of WM, with most understanding based on other, related B-cell lymphoid malignancies, including multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Recently, there has been an increase in dedicated work to better explain the pathobiology of WM, which has identified several clinical and genetic markers that serve to prognosticate disease course and patient outcomes. Furthermore, this has led to dedicated clinical trials and the development of novel drugs/regimens including the first Food and Drug Administration-approved agent for this diagnosis, ibrutinib. This review aims to document some of the recent advancements with respect to prognostic markers and therapeutic options for patients with WM, as well as certain selected novel treatments with unique mechanisms of action, that are currently under development.

Topics: Adenine; Bone Marrow; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

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

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

Primary central nervous system lymphoma (PCNSL) is a rare aggressive extranodal non- Hodgkin lymphoma. Although high remission rates can be achieved with high-dose methotrexate-based immunochemotherapy, risk of relapse and associated death is still substantial in at least a third of patients. Novel agents for treating lymphoid malignancies have substantially enriched treatment options for PCNSL. We herein systematically review the existing clinical evidence of novel agents in treatment of PCNSL, summarize ongoing studies, and discuss perspectives. The body of evidence for novel agents is still limited to noncomparative studies, but the most promising approaches include Bruton kinase inhibition with ibrutinib and immunomodulatory treatment (eg, with lenalidomide). Targeting the mammalian target of rapamycin pathway does not seem to have a meaningful clinical benefit, and evidence of checkpoint inhibition with nivolumab is limited to anecdotal evidence. Future studies should embrace the concept of induction and maintenance therapy as well as the combination of drugs with different mechanisms of action. Selection of patients based on molecular profiling and relapse patterns should be another aspect informing future comparative trials, which are urgently needed to improve prognosis for patients with PCNSL.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Humans; Lenalidomide; Lymphoma, Non-Hodgkin; Nivolumab; Piperidines; Pyrazoles; Pyrimidines; Recurrence

Bruton tyrosine kinase (BTK), a mediator of B-cell receptor (BCR) signalling, has been implicated in the pathogenesis of chronic lymphocytic leukaemia (CLL) and other B-cell malignancies. Ibrutinib is an orally bioavailable and highly specific BTK inhibitor that was recently approved for treatment of patients with recurrent CLL and mantle cell lymphoma (MCL). In addition, ibrutinib has shown efficacy in subsets of patients with diffuse large B cell lymphoma (DLBCL) and Waldenstrom macroglobulinaemia (WM). However, despite ibrutinib's activity in multiple B-cell malignancies, cases of primary and secondary resistance have emerged. The overall reported frequency of resistance is low, but follow-up in many trials was short, and we predict that the incidence of observed resistance will increase as clinical use outside clinical trials expands over time. Mutations within BTK have been described and clearly interfere with drug binding; however, there are also emerging alternative mechanisms that bypass BTK entirely and offer new opportunities for other targeted agents. Improved understanding of mechanisms of primary and secondary resistance is essential to developing appropriate therapeutic strategies to both prevent and address resistance. This review provides a comprehensive analysis of ibrutinib resistance in CLL, MCL, DLBCL and WM and considers potential strategies for further study.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Mutation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Lymphoid malignancies comprise a heterogeneous group of disorders originating from clonal proliferation of B or T lymphocytes. Treatment of lymphoid neoplasms has traditionally been pursued with cytotoxic chemotherapy. To improve efficacy and ameliorate the adverse effects associated with classic chemotherapy, molecularly targeted therapy has been developed. At the forefront of clinical development is ibrutinib, an inhibitor of Bruton's tyrosine kinase (Btk). Btk is a protein tyrosine kinase that plays an important role in regulating B-cell signaling. Dysregulated Btk results in uncontrolled B-lymphocyte proliferation, differentiation, and survival. Ibrutinib is currently being studied in numerous malignancies of lymphoid origin including chronic lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin lymphoma, follicular lymphoma, and multiple myeloma. Thus far, ibrutinib has demonstrated very promising results in treatment-naive patients as well as those with relapsed or refractory disease with an acceptable safety profile. In this article, we describe the pharmacology, efficacy, and toxicity profile of ibrutinib and depict the potential role that ibrutinib will play in the treatment paradigm of lymphoid neoplasms.

Topics: Adenine; Animals; Disease Management; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Survival and progression of patients with mature B-cell malignancies, including chronic lymphocytic leukemia and non-Hodgkin's lymphoma, depend on signals from the B -cell receptor, and Bruton's tyrosine kinase(BTK) is a critical signaling kinase in this pathway. Ibrutinib is a novel and selective inhibitor of BTK, inactivating the kinase irreversibly. It has shown exciting results in early clinical trials. In this review, the application and molecular mechanism of Ibrutinib in the treatment of B-cell malignancies are discussed.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

There has been a significant paradigm shift in the manner in which lymphoid malignancies are treated and managed. Treatment has been moving away from conventional chemotherapy and towards targeted therapy. The success of new classes of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further searches for novel pathways to inhibit. The Bruton's tyrosine kinase (Btk) pathway is a downstream mediator of the B-cell receptor (BCR) pathway, which is crucial in B-cell production and maintenance, and a potential therapeutic target.. This review will summarize the current knowledge of the Btk pathway and its role in lymphoid malignancies. It will also discuss the present data about PCI-32765 in both the preclinical and clinical setting.. PCI-32765 is an oral irreversible Btk inhibitor with high potency and both preclinical and clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). Phase I studies have demonstrated that it is well tolerated and has an excellent safety profile. Further studies are ongoing as a single agent and in combination with other targeted and conventional therapies. PCI-32765 is a very promising targeted therapy, and the data from these trials will ultimately decide its future role and success.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; B-Lymphocytes; Drug Delivery Systems; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).. In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD.. Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1-14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9-16.1] and 2.7 (95% CI, 0.7-5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1-89.2) and 27.8% (95% CI, 10.1-48.9) for patients with CLL and NHL, respectively.. The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.

Topics: Adenine; Adult; Humans; Hydrazines; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Piperidines; Pyrazoles; Pyrimidines; Triazoles

Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases.. We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing.. Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]).. The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment.. Janssen R&D.

Topics: Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Nivolumab; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Safety

Therapeutic approaches for B-cell malignancies continue to evolve, especially with regard to combination approaches. We assessed the safety and efficacy of the triplet ublituximab, umbralisib, and ibrutinib in patients with advanced B-cell malignancies.. We did an open-label, phase 1 study with dose-escalation and dose-expansion phases, at five centres in the USA. Eligible patients were aged 18 years or older with histologically confirmed lymphocytic leukaemia or relapsed or refractory B-cell non-Hodgkin lymphoma, had measurable disease, adequate organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Patients with known CNS lymphoma, active hepatitis B or C infection, or HIV were excluded. In the dose-escalation cohort, patients were treated in cycles of 28 days with escalating doses of oral umbralisib (400, 600, or 800 mg) and fixed doses of intravenous ublituximab (900 mg) and oral ibrutinib (420 mg for patients with chronic lymphocytic leukaemia; 560 mg for patients with B-cell non-Hodgkin lymphoma) in a standard 3 × 3 design until disease progression or intolerance. In the dose-expansion phase, patients were given the recommended dose of the drug combination as determined from the dose-escalation phase. The primary endpoints were safety, dose-limiting toxicities, and the maximum tolerated dose of umbralisib, when given in combination with ublituximab and ibrutinib. Safety was assessed in patients who received at least one dose of study drug; activity was assessed in all patients who had at least one post-treatment efficacy measurement. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02006485.. Between Sept 2, 2014, and Nov 6, 2017, we enrolled 46 patients: 24 in the dose-escalation cohort (n=14 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=10 B-cell non-Hodgkin lymphoma) and 22 in the dose-expansion cohort (n=9 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=13 B-cell non-Hodgkin lymphoma). 46 patients received at least one dose of study drug. The maximum tolerated dose of umbralisib was not reached. The recommended dose for the dose-expansion phase was umbralisib 800 mg orally once daily plus ibrutinib orally once daily and intravenous ublituximab 900 mg administered on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and on day 1 of cycles 9 and 12. 37 (84%) of 44 patients achieved an overall response (complete or partial response). The most common any-grade adverse events were diarrhoea (n=27 [59%]), fatigue (n=23 [50%]), infusion-related reaction (n=20 [43%]), dizziness (n=17 [37%]), nausea (n=17 [37%]), and cough (n=16 [35%]). Grade 3-4 adverse events were manageable with the most common being neutropenia (n=10 [22%]) and cellulitis (n=6 [13%]). Serious adverse events occurred in 11 (24%) of 46 patients and included rash (n=2 [4%]), pneumonia (n=2 [4%]), atrial fibrillation (n=2 [4%]), sepsis (n=2 [4%]), abdominal pain (n=1 [2%]), syncope (n=1 [2%]), cellulitis (n=1 [2%]), pneumonitis (n=1 [2%]), headache (n=1 [2%]), lung infection (n=1 [2%]), skin infection (n=1 [2%]), pleural effusion (n=1 [2%]), pericardial infusion (n=1 [2%]), upper gastrointestinal bleeding (n=1 [2%]), diarrhoea (n=1 [2%]), and weakness (n=1 [2%]). No deaths related to adverse events occurred.. The combination of ublituximab, umbralisib, and ibrutinib seems to be tolerable and is associated with encouraging activity in advanced chronic lymphocytic leukaemia and B-cell non-Hodgkin lymphoma. This triplet combination will require further investigation in future studies to improve understanding of this novel, chemotherapy-free triplet combination in the management of these cancers.. TG Therapeutics.

Topics: Adenine; Aged; Antibodies, Monoclonal; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Safety

Ibrutinib has single agent activity of 22% to 68% in relapsed B-cell non-Hodgkin lymphoma(NHL). This study evaluated the safety and efficacy of ibrutinib combined with rituximab (R) and bendamustine. Patients received R (375 mg/m(2)) on day 1, bendamustine (90 mg/m(2)) on days 1 and 2, and ibrutinib (280 or 560 mg) on days 1 to 28 every 28 days for 6 cycles followed by ibrutinib alone until progression. Forty-eight patients enrolled, including 12 patients with follicular lymphoma (FL), 16 with diffuse large B-cell lymphoma (DLCL), and 17 with mantle cell lymphoma (MCL). No dose-limiting toxicities were observed. Patients received a median of 8 cycles, with 26 completing 6 cycles and continuing ibrutinib alone in cycles 7 to 34. The overall response (OR) rate was 72%, with 52% complete responses (CRs). By histology, the OR rate was 94% (76% CR) in MCL, 37% (31% CR) in DLCL, and 90% (50% CR) in FL. Grade 3 to 4 toxicities included lymphopenia (77%), neutropenia (33%), thrombocytopenia (19%), and rash (25%). Median progression-free survival has not been reached (95% CI, 8.7 months to not reached). The recommended phase 2 dose of ibrutinib in combination with R-bendamustine in patients with NHL is 560 mg. The combination has promising efficacy, particularly in MCL and FL. This trial was registered at www.clinicaltrials.gov as #NCT01479842.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Female; Humans; Kaplan-Meier Estimate; Lymphoma, Non-Hodgkin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Nitrogen Mustard Compounds; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Young Adult

Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma.. In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750.. From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose.. Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial.. Janssen.

Topics: Adenine; Administration, Oral; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Maximum Tolerated Dose; Middle Aged; Non-Randomized Controlled Trials as Topic; Piperidines; Prednisone; Prognosis; Pyrazoles; Pyrimidines; Rituximab; Severity of Illness Index; Survival Rate; Treatment Outcome; Vincristine; Young Adult

Relapsed/refractory (r/r) central nervous system lymphoma (CNSL) exhibits aggressive behavior and poor outcomes. As an effective bruton tyrosine kinase (BTK) inhibitor, ibrutinib yields benefits in B-cell malignancies.. We aimed to explore the efficacy of ibrutinib in treating r/r CNSL patients, and whether genomic variants impact treatment outcomes.. The ibrutinib-based regimens in 12 r/r primary CNSL (PCNSL) and 2 secondary CNSL (SCNSL) patients were analyzed retrospectively. The impact of genetic variants on the effects of treatments was examined using whole-exome sequencing (WES) technology.. In PCNSL, the overall response rate was 75%, with median overall survival (OS) not reached (NR) and progression-free survival (PFS) of 4 months. Both SCNSL patients responded to ibrutinib, with median OS NR and PFS of 0.5-1.5 months. Infections were common during ibrutinib therapy (42.86%). The PCNSL patients harboring gene mutations in PIM1, MYD88 and CD79B, and the proximal BCR and nuclear factor kappa B (NF-κB) pathways responded to ibrutinib. Patients who harbored simple genetic variants and those with a low tumor mutation burden (TMB; 2.39-5.56/Mb) responded swiftly and maintained remission for more than 10 months. A patient with a TMB of 11/Mb responded to ibrutinib but continued to experience disease progression. In contrast, patients with complex genomic features, especially extremely high TMB (58.39/Mb), responded poorly to ibrutinib.. Our study demonstrates that ibrutinib-based therapy is effective and relatively safe for the treatment of r/r CNSL. Patients with less genomic complexity, especially with regard to TMB, might benefit more from ibrutinib regimens.

Topics: Central Nervous System; Central Nervous System Neoplasms; Genomics; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Retrospective Studies

Ibrutinib is reported effective in the management of refractory/relapsed primary central nervous system lymphoma but it has adverse effects. Orelabrutinib has received its first approval for the treatment of refractory/relapsed lymphoma either alone or with chemotherapy in China. The objectives of the retrospective study were to evaluate the efficacy and safety of treatment a combination of orelabrutinib (150 mg/day) and rituximab (250 mg/m 2 per week), versus orelabrutinib alone (100 mg twice a day) and ibrutinib alone (560 mg/day) among patients with refractory/relapsed primary central nervous system lymphoma. Patients received 150 mg/day orelabrutinib with 250 mg/m 2 rituximab/week (RO cohort, n = 105) or 100 mg twice in a day orelabrutinib (OB cohort, n = 107) or 560 mg/day ibrutinib (IB cohort, n = 117) until intolerable toxicity. Patients of the OB cohort continue treatment(s) for longer time than those patients of the RO and the IB cohorts ( P < .05 for both). Overall response rate (complete response + partial response) and disease control rates (complete response + partial response + no signs of progressive response) were higher for patients of the RO cohort than those of the IB cohort ( P < .0001 for both). The disease control rate was higher for patients of the OB cohort than those of the IB cohort ( P = .0062). The overall response rate was higher for patients of the RO cohort than those of the OB cohort ( P = .0188). Progression-free survival (from the initiation of disease treatment(s) to disease progression) of patients of the RO and OB cohorts were higher than those of the IB cohort ( P < .0001 for both). Overall survival (from the initiation of disease treatment(s) to death) of the patients of the IB cohort was fewer than those of the RO ( P = .0444) and the OB ( P = .0163) cohorts. Ibrutinib cause bleeding events, and orelabrutinib caused leukopenia, purpura diarrhea, fatigue, and drowsiness. Rituximab and ibrutinib cause fungal infections, atrial fibrillation, bacterial and viral infection(s), hypertension, and tumor lysis syndrome. A total of 150 mg/day oral orelabrutinib plus 250 mg/m 2 intravenous rituximab/week is efficacious and safe for patients with refractory/relapsed primary central nervous system lymphoma (Level of Evidence: IV; Technical Efficacy Stage: 5).

Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Humans; Lymphoma, Non-Hodgkin; Neoplasm Recurrence, Local; Retrospective Studies; Rituximab

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).

Topics: Adenine; Central Nervous System; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Piperidines; T-Lymphocytes

Current clinical and imaging tools remain suboptimal for predicting treatment response and prognosis in CNS lymphomas. We investigated the prognostic value of baseline [. Fifty-three patients enrolled in a prospective clinical trial and underwent brain PET before receiving single-agent ibrutinib or ibrutinib in combination with methotrexate with or without rituximab. [. Thirty-eight patients underwent single-agent therapy and 15 received combination therapy. On PET, 15/53 patients had no measurable disease. In the other 38 patients, a total of 71 lesions were identified on PET. High-intensity [. Higher lesional metabolic parameters are inversely related to outcome in patients undergoing ibrutinib-based therapies, and sumSUV. NCT02315326; https://clinicaltrials.gov/ct2/show/NCT02315326?term=NCT02315326&draw=2&rank=1.

Topics: Adenine; Fluorodeoxyglucose F18; Glycolysis; Humans; Lymphoma, Non-Hodgkin; Piperidines; Positron Emission Tomography Computed Tomography; Prognosis; Prospective Studies; Retrospective Studies; Tumor Burden

Topics: Adenine; Aged; Aged, 80 and over; Hepatitis B virus; Humans; Liver Failure; Lymphoma, Non-Hodgkin; Male; Middle Aged; Piperidines

Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL.. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry.. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages.. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Central Nervous System Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Exportin 1 Protein; Female; Humans; Hydrazines; Karyopherins; Lymphoma, Non-Hodgkin; Macrophages; Mice; Mice, Nude; Piperidines; Receptors, Cytoplasmic and Nuclear; Survival Rate; Triazoles; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

Invasive fungal diseases (IFD) are life-threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases.. Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment.. Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non-Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software.. Thirty-five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1-540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD.. The prevalence of IFD among chronic lymphocytic leukaemia/non-Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib-associated IFD.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Female; Humans; Immunocompromised Host; Invasive Fungal Infections; Israel; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies

As oral targeted agents, such as ibrutinib, become more widely used, understanding the impact of suboptimal dosing on overall survival (OS) and progression-free survival (PFS) outside of clinical trials is imperative.. Data on ibrutinib discontinuation, dose reductions, and treatment interruptions were collected on 170 non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL; n = 115, 64%) patients treated with ibrutinib at a single institution. Ibrutinib dose adherence was calculated as the proportion of days in which ibrutinib was administered out of the total number of days ibrutinib was prescribed in the first 8 weeks. Kaplan-Meier curves and log-rank tests were used to compare conditional survival outcomes beyond 8 weeks in patients with ≥ 80% dose adherence and patients with < 80% dose adherence.. Median OS among those who discontinued therapy for progression was poor (n = 51, 1.7 months; 95% confidence interval, 0.3-3.7). Lower dose adherence (< 80%) was associated with significantly worse PFS (P = .002) and OS (P = .021). However, among CLL patients, lower dose adherence was only associated with worse PFS (P = .043). Patients with early dose reductions had significantly worse PFS (P = .004) and OS (P = .014). Patients with dose interruptions lasting > 1 week had worse PFS (P = .047) but not OS (P = .577).. In this observational study, non-Hodgkin lymphoma and CLL patients experienced poor outcomes after discontinuing ibrutinib for disease progression. The inferior survival related to suboptimal dose adherence of ibrutinib was predominantly due to early dose reduction. These data confirm poor survival in CLL and lymphoma patients alike after ibrutinib discontinuation, and support recommendations for full dose at treatment initiation.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Female; Humans; Lymphoma, Non-Hodgkin; Male; Medication Adherence; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Survival Analysis; Treatment Outcome

Matrix high-throughput screening (HTS) methods are increasingly employed to rapidly define potential therapeutic drug combinations. We used combination HTS to identify compounds showing synergistic anti-proliferative activity with ibrutinib, an irreversible, small-molecule inhibitor of Bruton's tyrosine kinase. The goal was to identify ibrutinib combinations with maximum synergistic effects in heme malignancy lines, particularly in non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). Growth inhibition (GI) was used to measure cell viability; synergy scores characterized strength of synergistic interaction. Single-agent ibrutinib demonstrated varying degrees of activity across 30 cell lines evaluated. In DLBCL lines, TMD8 was the most sensitive to ibrutinib (GI

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Hematologic Neoplasms; High-Throughput Screening Assays; Humans; Lymphoma, Non-Hodgkin; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction

In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients.

Topics: Adenine; Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Expression; Genes, myc; Humans; Lymphoma, Non-Hodgkin; Mice; Mice, Knockout; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; src-Family Kinases; Xenograft Model Antitumor Assays

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Disease Models, Animal; Dogs; Drug Approval; Drug Industry; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Molecular Targeted Therapy; Piperidines; Precision Medicine; Pyrazoles; Pyrimidines; United States; United States Food and Drug Administration; Waldenstrom Macroglobulinemia

Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells. Utilizing the Eμ-myc mouse model, where Myc is overexpressed specifically in B cells, both basal and stimulated BCR signaling were increased in precancerous B lymphocytes from Eμ-myc mice compared with wild-type littermates. B cells overexpressing Myc displayed constitutively higher levels of activated CD79α, Btk, Plcγ2 and Erk1/2. Notably, Myc-overexpressing B cells maintained elevated BCR signaling despite treatment with ibrutinib, a Bruton's tyrosine kinase inhibitor. Furthermore, PI3K/Akt pathway signaling was also increased in Eμ-myc B cells, and this increase was partially suppressed with ibrutinib. In addition, experiments with Btk-null B cells revealed off-target effects of ibrutinib on BCR signaling. Our data show that in pre-malignant B cells, Myc overexpression is sufficient to activate BCR and PI3K/Akt signaling pathways and further enhances signaling following BCR ligation. Therefore, our results indicate that precancerous B cells have already acquired enhanced survival and growth capabilities before transformation, and that elevated MYC levels confer resistance to pharmacologic inhibitors of BCR signaling, which has significant implications for B-NHL treatment.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; B-Lymphocytes; CD79 Antigens; Cell Proliferation; Flow Cytometry; Humans; Lymphoma, Non-Hodgkin; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 3; Phosphatidylinositol 3-Kinases; Phospholipase C gamma; Phosphorylation; Piperidines; Precancerous Conditions; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-myc; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Splenic Neoplasms; Syk Kinase

Single-agent ibrutinib is an effective therapy for three types of non-Hodgkin lymphoma: chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma, both in relapsed and refractory cases and as a frontline treatment; relapsed and refractory mantle cell lymphoma; and Waldenstrom's macroglobulinaemia in patients who have been treated previously with a different medication. This novel agent has changed the landscape for the aforementioned three subtypes of lymphoma therapies as an oral alternative to traditional chemoimmunotherapy. You&i™ is a no-cost support programme, funded by Janssen, that connects patients taking Imbruvica with a nurse who can answer their questions and help address treatment challenges. This programme offers patients information about their disease, their treatment regimen and side effects management by telephone. The You&i programme was tested at an NHS hospital. Case studies of patients and feedback from health professionals who have used this service show its potential benefits to the patient experience and service delivery.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Drug Industry; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Nurses; Patient Education as Topic; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; State Medicine; Telephone; United Kingdom

The epigenome is often deregulated in cancer and treatment with inhibitors of bromodomain and extra-terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti-tumour activity of the novel bromodomain and extra-terminal (BET) inhibitor BAY 1238097 in preclinical lymphoma models. BAY 1238097 showed anti-proliferative activity in a large panel of lymphoma-derived cell lines, with a median 50% inhibitory concentration between 70 and 208 nmol/l. The compound showed strong anti-tumour efficacy in vivo as a single agent in two diffuse large B cell lymphoma models. Gene expression profiling showed BAY 1238097 targeted the NFKB/TLR/JAK/STAT signalling pathways, MYC and E2F1-regulated genes, cell cycle regulation and chromatin structure. The gene expression profiling signatures also highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-inhibitors, mTOR inhibitors and demethylating agents. Notably, BAY 1238097 presented in vitro synergism with EZH2, mTOR and BTK inhibitors. In conclusion, the BET inhibitor BAY 1238097 presented promising anti-lymphoma preclinical activity in vitro and in vivo, mediated by the interference with biological processes driving the lymphoma cells. Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK alongside BET bromodomains.

Topics: Adenine; Animals; Antineoplastic Agents; Benzodiazepines; Cell Death; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; Enhancer of Zeste Homolog 2 Protein; Everolimus; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Non-Hodgkin; Mice, SCID; Piperidines; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Topics: Adenine; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; GATA3 Transcription Factor; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; NF-kappa B; Piperidines; Primary Cell Culture; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes

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

A new family of 4-aminopyrido[2,3-d]pyrimidines active against non-Hodgkin's lymphomas (NHLs) is described. Among these compounds, 19 inhibits the most upstream tyrosine kinases in the B cell receptor (BCR) signaling pathway which are involved in the mature B cell neoplasms. Thus, 19 showed antiproliferative activity at 24 h and 48 h against a panel of 20 NHLs cell lines with GI50 ranging from 1.3 to 6.9 μM at 24 h, and 1.4-7.2 μM at 48 h, being this effect related to a significant (20-90%) inhibition of the phosphorylation of the BCR-related kinases Btk, Syk, and Lyn. Most importantly, 19 was able to induce a 63% reduction in Rec-1 cell proliferation, which was significantly greater than the 31% and 3% blockade of proliferation observed after cell treatment with R406, a Syk inhibitor, and ibrutinib, a Btk inhibitor, respectively. The computational blind docking and ligand binding within the pockets of Btk, Syk and Lyn kinases showed that compound 19 presents the same kind of interactions of described cocrystallized inhibitors.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Humans; Lymphoma, Non-Hodgkin; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pyridines; Pyrimidinones; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship

Topics: Adenine; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Piperidines; Prednisone; Pyrazoles; Pyrimidines; Rituximab; Vincristine

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; Chronic Disease; Disease Management; Drug Administration Schedule; Humans; Lymphoma, Non-Hodgkin; Oligonucleotides; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Rituximab; Standard of Care