pci-32765 and Lymphoma--Mantle-Cell

Ibrutinib is a first-generation inhibitor of Bruton tyrosine kinase (BTK) that is currently approved to treat patients with B-cell malignancies, including Waldenström macroglobulinemia (WM), relapsed/refractory (R/R) mantle cell lymphoma (MCL), R/R marginal zone lymphoma (MZL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Off-target adverse effects, such as atrial fibrillation, hypertension, and bleeding, have been observed and may limit a patient's tolerance for treatment. Currently, there is no well-established treatment regimen for patients who cannot tolerate ibrutinib. Approaches to address such patients include managing ibrutinib side effects with supportive care or dose reductions, switching to an alternative covalent BTK inhibitor, or abandoning covalent BTK inhibitors for alternative forms of treatment. Here we review the literature and provide guidance on treating ibrutinib-intolerant patients with B-cell malignancies.

Topics: Adult; B-Lymphocytes; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors

Because of lacking of head-to-head comparison among recently effective novel agents' combination regimens for newly diagnosed patients with mantle-cell lymphoma (MCL) who are ineligible for intensive therapy like autologous stem-cell transplantation, the optimal option for these patients still remains undefined. We searched relevant published reports. Three randomized controlled trials with 1459 subjects were identified. In the network meta-analysis, ibrutinib plus bendamustine and rituximab (Ibru + BR) significantly improved progression-free survival (PFS) when compared to bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP; hazard ratio [HR]: 0.55, p = .03) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; HR: 0.35, p < .001) for newly diagnosed patients with MCL ineligible for intensive therapy. Among these first-line treatment regimens (Ibru + BR, VR-CAP, R-CHOP, and BR), Ibru + BR had the highest probability of 94.9% to be the best intervention in PFS analysis. No significant difference was found in adverse events analysis. Our data indicated that Ibru + BR seemed to prolong the PFS when compared to VR-CAP and R-CHOP for newly diagnosed patients with MCL ineligible for intensive therapy. Considering our limits, prospective clinical trials directly comparing these regimens are warranted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Doxorubicin; Humans; Lymphoma, Mantle-Cell; Network Meta-Analysis; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic; Rituximab; Vincristine

The introduction of Bruton's tyrosine kinase (BTK) inhibitors transformed the management of patients with mantle cell lymphoma (MCL). Ibrutinib, the first-in-class BTK inhibitor is now approved in more than 80 countries and there are over 20 new BTK inhibitors in development. In addition, novel agents show potential clinical activity (alone and in combination) and are in the approval phase and/or being studied in ongoing clinical trials. How does the practicing clinician decide on the optimal therapeutic strategy for this highly heterogenous disease? In July 2020 a group of experts from Italy, convened a meeting to address and provide clarification on a series of outstanding issues in the treatment of MCL with the view of providing clinical guidance on its management. This expert opinion statement represents the panel's collective analysis, evaluation, and recommendations and is made up of a series of questions and answers (in the form of a review of the pertinent literature) designed to replicate those posed by practicing clinicians in Italy but which are applicable to clinical settings worldwide.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors

Since the US Food and Drug Administration (FDA) approved ibrutinib to treat patients with refractory/relapsed mantle cell lymphoma (R/R MCL), it is used in clinical trials, whether as a single agent or in combination with other chemotherapy agents. The efficacy and safety of ibrutinib administration alone or in combinations have not been studied systematically. This study systematically reviewed the efficacy and safety of ibrutinib-containing regimens for the treatment of patients with MCL.. We performed a systematic search in PubMed, Cochrane CENTRAL, Embase, Web of Science, and Scopus. Then, a team of independent reviewers selected relevant studies and extracted the data.. From a total of 1,436 studies, 12 trials were eligible. The overall response rates (ORRs) of patients with R/R MCL receiving single-agent ibrutinib ranged between 62.7% to 93.8%, and the ORRs of ibrutinib combinations ranged from 74 to 88%. In patients with newly diagnosed MCL receiving ibrutinib and rituximab, ORR ranged from 84 to 100%. The highest progression-free survival (PFS) was reported in patients receiving ibrutinib and rituximab (43 months). The meta-analysis performed on adverse events (AEs) demonstrated that single-agent ibrutinib had a high risk of bleeding, nausea, and diarrhea.. Single-agent ibrutinib showed acceptable efficacy and safety in the treatment of patients with MCL. Moreover, combining ibrutinib with other agents such as rituximab, venetoclax, and ublituximab can increase its efficacy and reduce chemotherapy-induced resistance in most cases; however, in the case of combination therapy, patients need to be monitored more strictly in terms of AEs. In our review, the ibrutinib and rituximab combination showed promising results in patients with R/R MCL. Also, this combination showed favorable efficacy and safety in patients with newly diagnosed untreated MCL, making it a great candidate to be studied more in large and well-designed trials.

Topics: Adult; Humans; Lymphoma, Mantle-Cell; Pyrazoles; Pyrimidines; Rituximab

Greater understanding of the mechanisms involved in the disease progression of haematological malignancies has led to the introduction of novel targeted therapies with reduced toxicity compared with chemotherapy-based regimens, which has expanded the treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a first-in-class Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with CLL/SLL or relapsed/refractory MCL. However, next-generation BTK inhibitors have been developed with improved specificity and the potential to reduce the off-target toxicity observed with ibrutinib. Acalabrutinib is a highly selective, next-generation BTK inhibitor, which was granted accelerated approval by the US Food and Drug Administration in 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. In November 2019, it was also granted approval for the treatment of adult patients with CLL/SLL on the basis of two phase 3 clinical trials. This review describes the current understanding of acalabrutinib according to clinical study data for the treatment of MCL and CLL/SLL and shares recommendations from our practice on how it should be used when treating patients in the clinic, including dosing, administration and management of adverse events.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Benzamides; Clinical Trials as Topic; Disease Progression; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Middle Aged; Piperidines; Practice Patterns, Physicians'; Pyrazines; Safety; Treatment Outcome; United States; United States Food and Drug Administration

Mantle cell lymphoma is a rare subtype of B-cell non-Hodgkin's lymphomas that is generally classified as an aggressive lymphoma requiring front-line chemo-immunotherapy with stem cell rescue. Despite effective treatment, many patients relapse or are refractory to front-line therapy. In addition, these patients may also develop drug resistance requiring novel modalities for subsequent lines. Bruton's tyrosine kinase inhibitors have demonstrated a well-tolerated safety and efficacy profile across several B-cell malignancies. Ibrutinib, acalabrutinib, and zanubrutinib are FDA-approved as treatment options for patients with Mantle cell lymphoma following one prior line of therapy. Various factors should be considered which include the adverse event profile of these agents and ability to adhere to therapy. In this article, we review the role of Bruton's tyrosine kinase inhibitors for the management of Mantle cell lymphoma and review the clinical pharmacology, pharmacokinetics, safety and efficacy, and future directions.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Benzamides; Humans; Immunotherapy; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that can be either aggressive or indolent. Although MCL usually responds well to initial treatment with chemotherapy-based regimens, the disease often relapses or becomes refractory within a few years. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. WIthout head-to-head clinical trial data, estimation of the comparative efficacy and safety of new therapeutic entities provides valuable information for patients, clinicians, and health care payers. The objective of this analysis was to compare the efficacy and safety of acalabrutinib versus other targeted therapies employed for the treatment of relapsed/refractory MCL by using matching-adjusted indirect comparisons.. Individual data from 124 patients treated with acalabrutinib in the Phase II ACE-LY-004 trial were adjusted to match average baseline characteristics of populations from studies using alternative targeted treatment regimens for relapsed/refractory MCL (for monotherapy: ibrutinib, bortezomib, lenalidomide, and temsirolimus; for combination therapies: ibrutinib + rituximab, bendamustine + rituximab, and lenalidomide + rituximab). Patient populations were matched on age, sex, race, Eastern Cooperative Oncology Group performance status, Simplified MCL International Prognostic Index score, tumor bulk, lactate dehydrogenase concentration, extranodal disease, bone marrow involvement, and number of previous treatment regimens. Outcomes assessed included overall response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), and adverse events.. After matching, acalabrutinib was associated with significant increases in ORR and CR rate (estimated treatment difference [95% CI]) versus ibrutinib (ORR, 9.3% [0.3-18.3]; CR, 14.9% [5.4-24.3]), bortezomib (ORR, 50.6% [40.2-61.0]; CR, 18.8% [9.1-28.5]), lenalidomide (ORR, 38.1% [27.1-49.1]; CR, 43.5% [34.8-52.3]), and temsirolimus (ORR, 40.7% [31.0-50.4]; CR, 27.1% [19.2-35.0]). PFS (hazard ratio [95% CI]) with acalabrutinib was significantly increased versus bortezomib (0.36 [0.26-0.51]), lenalidomide (0.65 [0.48-0.89]), lenalidomide + rituximab (0.57 [0.35-0.93]), and temsirolimus (0.33 [0.24-0.45]). Acalabrutinib was associated with significantly increased OS (hazard ratio) versus bortezomib (0.36 [0.22-0.61]) and temsirolimus (0.32 [0.23-0.44]). The overall safety profile of acalabrutinib was similar or better compared with the monotherapies; however, infection risk increased versus bendamustine + rituximab, and anemia increased risk versus lenalidomide + rituximab and ibrutinib + rituximab.. This comparison of targeted therapies used in the treatment of relapsed/refractory MCL showed that acalabrutinib has the potential to provide increased response rates, with trends for increased PFS and OS, and an improved safety profile.

Topics: Adenine; Antineoplastic Agents; Benzamides; Bortezomib; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrazines; Pyrazoles; Pyrimidines; Rituximab; Sirolimus; Treatment Outcome

Ibrutinib, a Bruton's tyrosine kinase inhibitor has reformed the treatment of various B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Although generally well tolerated, here we describe our institutional experience of unique adverse effects encountered with the use of ibrutinib in patients with B-cell lymphomas.. This is a retrospective observational study done at a tertiary care facility, to evaluate adverse events in patients with B-cell malignancies on treatment with ibrutinib between 2014 and 2018. Further details including type of malignancy, cytogenetics, interventions for treatment of the side effect, and outcomes were obtained through electronic health record.. We found 10 patients with unique adverse events related to ibrutinib. Among those, six had chronic lymphocytic leukemia, two had Waldenstrom's macroglobulinemia, and two had mantle cell lymphoma. The events included palindromic rheumatoid arthritis, diffuse spongiotic dermatitis, bullous pemphigoid, recurrent hemorrhagic stroke, peripheral neuropathy, recurrent paronychia, intramedullary fibrosis, recurrent joint pains, pulmonary aspergillosis, dyspnea with exacerbation of atrial fibrillation, and resolution of autoimmune hemolytic anemia.. Our case series illustrates the wide variety of unique events recognized in patients treated with ibrutinib, some of which required cessation and most had dose reduction of the treatment. Thus, stressing the importance of early identification and intervention for the events to avoid worsening of toxicity and inability to continue treatment in such patients.

Topics: Adenine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Waldenstrom Macroglobulinemia

As part of its Single Technology Appraisal process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of ibrutinib (Janssen) to submit evidence on the clinical effectiveness and cost effectiveness of ibrutinib for the treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL). The School of Health and Related Research Technology Assessment Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company's submission to NICE. The clinical effectiveness evidence for ibrutinib included one randomised controlled trial comparing ibrutinib and temsirolimus and two single-arm studies. The company's indirect comparison of ibrutinib versus rituximab plus chemotherapy (R-chemo) produced a hazard ratio (HR) for progression-free survival (PFS) of 0.28. The ERG's random effects network meta-analysis (NMA) indicated that the treatment effect on PFS was highly uncertain (HR 0.27; 95% credible interval (CrI) 0.06-1.26). The company's Markov model assessed the cost effectiveness of ibrutinib versus R-chemo for the treatment of R/R MCL from the perspective of the National Health Service (NHS) and Personal Social Services over a lifetime horizon. Based on a re-run of the company's model by the ERG, the incremental cost-effectiveness ratio (ICER) for ibrutinib versus R-chemo [including the company's original patient access scheme (PAS)] was expected to be £76,014 per quality-adjusted life-year (QALY) gained. The ERG had several concerns regarding the company's model structure and the evidence used to inform its parameters. The ERG's preferred analysis, which used the ERG's NMA and the observed Kaplan-Meier curve for time to ibrutinib discontinuation and excluded long-term disutilities for R-chemo, produced ICERs of £63,340 per QALY gained for the overall R/R MCL population and of £44,711 per QALY gained for patients with one prior treatment. Following an updated PAS and consideration of evidence from a later data-cut of the RAY trial, the appraisal committee concluded that the most plausible ICER for the one prior treatment subgroup was likely to be lower than the company's estimate of £49,848 per QALY gained. The company's ICER for the overall R/R MCL population was higher, at £62,650 per QALY gained. The committee recommended ibrutinib as an option for treating R/R MCL in adults only if they have receiv

Topics: Adenine; Adult; Antineoplastic Agents; Cost-Benefit Analysis; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Rituximab; Technology Assessment, Biomedical

Although a variety of therapeutic schemes for Mantle Cell Lymphoma (MCL) have been attempted, the clinical outcome of patients continues to be unsatisfactory especially among patients with a very high-risk profile and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel approaches, either by the use of biological agents in chemotherapy-free schedules or by integrating them with chemoimmunotherapy regimens. Areas covered: The efficacy of lenalidomide monotherapy and combination therapy established in clinical studies mainly involving relapsed/refractory MCL is reviewed. The mechanism of action of lenalidomide is also discussed. Furthermore, the current position of lenalidomide in the MCL treatment algorithm is debated. Expert opinion: Lenalidomide demonstrated high efficacy and tolerability in several clinical trials as well as in retrospective real-world reports, even in patients who relapsed or were resistant to bortezomib and ibrutinib. In 2013, lenalidomide was approved by the Food and Drug Administration (FDA) for relapsed/refractory MCL after two prior therapies including at least one prior treatment with bortezomib. However, the potential synergistic anti-neoplastic effects of lenalidomide in combination with other biological agents, i.e. ibrutinib and venetoclax, especially in the management of p53-mutated cases, still remain an open issue.

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; Treatment Outcome

Although advances in mantle cell lymphoma (MCL) therapy have improved overall survival (OS), managing relapsed/refractory (R/R) cases remains a great challenge. Bruton tyrosine kinase (BTK) inhibitors have broadened therapeutic options in MCL and became the backbone of second-line strategies. Areas covered: Ibrutinib, the first-in-class BTK inhibitor registered for MCL therapy, is efficient, with clear benefits of its use. However, ibrutinib-related adverse events due to off-target inhibition of other kinases led to the development of more selective molecules with comparable efficacy and better safety profiles. Expert commentary: Acalabrutinib, a new BTK inhibitor, currently being evaluated in numerous clinical studies is approved by FDA in relapsing/refractory MCL. Its role will evolve over the next few years. Efficacy and good tolerability of acalabrutinib gives even greater opportunity for potential upfront use and new therapeutic combinations, including monoclonal antibodies, antibody-drug conjugates, immune checkpoint inhibitors, bcl-2 (B-cell lymphoma-2) or IP3K (phosphoinositide 3-kinase) inhibitors.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Benzamides; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Survival Rate

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma that is largely chemoresistant. Ibrutinib, a drug that inhibits Bruton's tyrosine kinase (BTK), has improved the overall survival of patients with MCL; however, resistance to ibrutinib has emerged as a decisive, negative factor in the prognosis of MCL. Adopting a more patient-centric therapeutic approach that incorporates applied genomics and interrogation of B cell signaling pathways may offer an alternative route to reach durable remission in patients with MCL. Although targeting genetic variants in MCL is not yet feasible in the clinical setting, the identification and targeting of increasingly active B cell signaling pathways may be a viable therapeutic strategy that may improve patient outcomes. Genome-editing tools and sequencing platforms could play dominant roles in patient-centric approaches of treatment in the future, potentially improving clinical outcomes for patients with MCL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Apoptosis; B-Lymphocytes; Humans; Lymphoma, Mantle-Cell; Models, Biological; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction

Ibrutinib is an oral covalent inhibitor of Bruton's tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrӧm's macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction.. We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach.. There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52-5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17-7.64) with high quality evidence.. Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation.

Topics: Adenine; Atrial Fibrillation; Databases, Factual; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antigens, CD20; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cardiovascular Diseases; Clinical Trials as Topic; Forecasting; Gastrointestinal Neoplasms; Hemorrhage; Humans; Immunologic Factors; Lymphocytosis; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Neoplasm Proteins; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Salvage Therapy

Background Tumor lysis syndrome results when intracellular contents are released during cell lysis. Ibrutinib, a Bruton tyrosine kinase inhibitor, is used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Tumor lysis syndrome caused by ibrutinib therapy is potentially life threatening, but is rare and not often reported in clinical trials. Objective The purpose of this case series is to describe the occurrence of tumor lysis syndrome in two patients initiated on ibrutinib, and to highlight the importance of close monitoring during therapy. Discussion One patient with chronic lymphocytic leukemia/small lymphocytic lymphoma and one patient with mantle cell lymphoma developed laboratory and clinical tumor lysis syndrome following initiation of ibrutinib therapy. Assessment with the Naranjo Adverse Drug Reaction Probability Scale indicated one probable relationship and one possible relationship between ibrutinib therapy and tumor lysis syndrome. There were additional factors that may have confounded the laboratory and clinical factors observed, including baseline laboratory values and concurrent medications. Both patients were managed with supportive therapies. A literature review identified five additional reported cases of tumor lysis syndrome following ibrutinib therapy. Conclusion This case series identifies one patient with a probable relationship and one patient with a possible relationship between the development of tumor lysis syndrome and treatment with ibrutinib. Although uncommon, proper attention should be given to monitoring for this adverse drug reaction and appropriate follow-up should occur despite ibrutinib's ease of administration.

Topics: Adenine; Aged; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tumor Lysis Syndrome

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder comprising about 6-10% of all B cell lymphoma cases. Ibrutinib is an inhibitor of Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. Although treatment with ibrutinib has significantly improved the outcome of MCL patients, approximately one-third of the patients have primary drug resistance while others appear to develop acquired resistance. Understanding the molecular events leading to the primary and acquired resistance to ibrutinib is essential for achieving better outcomes in patients with MCL. In this review, we describe the biology of the BCR signalling pathway and summarize the landmark clinical trials that have led to the approval of ibrutinib. We review the molecular mechanisms underlying primary and acquired ibrutinib resistance as well as recent studies dealing with overcoming ibrutinib resistance.

Topics: Adenine; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; Signal Transduction

Mantle cell lymphoma is an aggressive Non-Hodgkin's lymphoma that is considered incurable with standard therapies. Most patients treated with frontline immunochemotherapy relapse within a few years and do not usually respond to salvage chemotherapy. Persistent activation of the B-cell receptor pathway is critical to the pathogenesis of mantle cell lymphoma. Inhibition of Bruton's tyrosine kinase, an essential B-cell receptor pathway component with ibrutinib has shown clinical activity and has changed how MCL is treated in the relapsed/refractory setting. However, resistance to ibrutinib is common and response is limited. Novel agents targeting the B-cell receptor pathway along with therapies outside of the pathway will be reviewed in this article. Ongoing and future studies will better define how these agents should be utilized in the ever-changing treatment landscape of mantle cell lymphoma.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Humans; Lymphoma, Mantle-Cell; Neoplasm Proteins; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Recurrence

Acalabrutinib, a selective Bruton tyrosine kinase (BTK) inhibitor, was granted accelerated approval by the FDA on 31 October 2017 for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Areas covered: This narrative review provides an overview of acalabrutinib, its use in clinical practice and potential future developments. Expert commentary: BTK inhibitors have demonstrated efficacy in patients with relapsed or refractory MCL. To prepare patients for therapy, all preexisting infections should be diagnosed and treated, and infection prophylaxis undertaken. Serious adverse reactions are rare with acalabrutinib; however, patients should be made aware of common adverse events such as headaches, which usually resolve within one month without medical treatment. Interaction with other drugs appears to be less of an issue with acalabrutinib than with ibrutinib; however, patients receiving acalabrutinib therapy must be advised not to take any additional medications without first consulting with their treating physician. A key unmet medical need is treatment options for patients in whom BTK inhibitors are discontinued, because of either intolerance or refractory disease. Patients not tolerating ibrutinib could be switched to acalabrutinib, which has improved selectivity and increased tolerability. First-line treatment with acalabrutinib is being investigated.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Humans; Infection Control; Infections; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

Novel targeted therapeutics has significantly improved the outlook of patients with relapsed/refractory mantle cell lymphoma (R/R MCL). Despite significant efficacy, one of the major limitations of these targeted agents is presence of primary or acquired resistance to these novel drugs. Patients who fail primary therapy especially with ibrutinib have poor outcomes and may respond poorly to subsequent therapies. Hence, it is important to understand resistance mechanisms a priori to identify patients who are unlikely to respond, and to explore alternative therapeutic strategies. In this review, we will discuss the currently most active two drugs: ibrutinib and venetoclax, both of which have shown high response rates in R/R MCL. We review current understanding of genomic alterations associated with resistance, and discuss possible strategies to overcome these resistance mechanisms.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Patient Selection; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Sulfonamides

Maintenance therapy has evolved as a strategy to prolong remissions in patients with diffuse large B cell lymphoma (DLBCL) or mantle cell lymphoma (MCL), typically following a more intensive therapy, such as induction therapy or stem cell transplantation. In randomized, controlled clinical trials, this approach has successfully prolonged overall survival in some MCL clinical settings, including after autologous stem cell transplantation and after R-CHOP induction, but has generally been unsuccessful in DLBCL. This most likely reflects differences in the biology and natural history of each disease. In DLBCL, a majority of patients are cured with frontline therapy, leaving fewer who can potentially benefit from maintenance. When the disease relapses, it is usually within the first 2 years and is usually clinically aggressive and difficult to control with low-intensity therapy. In contrast, nearly all patients with MCL will eventually relapse, and the disease may remain quiescent for many years. There may also be differences in sensitivity of minimal residual disease to maintenance treatments. Thus, future strategies to improve DLBCL treatments should focus on improved induction and possibly consolidation regimens rather than maintenance. In MCL, maintenance therapy will continue to play a role in the near future, although in both diseases, applying novel immunotherapies with the potential to eradicate residual disease clones persisting after induction may be the most successful strategy to improve patient outcomes.

Topics: Adenine; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Doxorubicin; Everolimus; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Prednisone; Pyrazoles; Pyrimidines; Rituximab; Vincristine; Young Adult

Bruton's tyrosine kinase (BTK) is crucial in B-cell development and survival. The role of BTK as a downstream kinase in the B-cell receptor (BCR) signaling pathway is well described. As a key player in the pathogenesis of B-cell malignancies, targeting of dysregulated BCR signaling has been explored by development of inhibitors of downstream mediators. Discovery of the biological function of BTK and the development of covalent inhibitors for clinical use, ibrutinib as the lead agent and acalabrutinib as the second clinically approved BTK inhibitor, have revolutionized the treatment options for B-cell malignancies. Currently, ibrutinib is approved for mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma and chronic graft versus host disease, while acalabrutinib is approved for mantle cell lymphoma. Potential expansion of indications in other diseases is under investigation in several clinical trials, while combination of BTK inhibitors with either chemoimmunotherapy or other targeted agents is being systematically explored in B-cell malignancies.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; B-Lymphocytes; Benzamides; Drug Therapy, Combination; Humans; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. The biological function of BTK in several B-cell lymphoid malignancies has led to the development of the oral BTK inhibitor ibrutinib. In chronic lymphocytic leukemia (CLL), ibrutinib has demonstrated durable clinical responses in relapsed/refractory (R/R) patients, including those with the high-risk del(17p) cytogenetic abnormality. These findings have paved the way for trials evaluating ibrutinib in previously untreated CLL patients, and also in combination with chemoimmunotherapy or other novel agents. Durable clinical responses have also been demonstrated in mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM) patients treated with ibrutinib. Ibrutinib is generally well tolerated, although current follow-up remains short and patients of advanced age are more likely to discontinue treatment for toxicity. Treatment-specific side effects such as bleeding and atrial fibrillation may, at least partly, be related to off-target inhibition of non-BTK kinases. Studies evaluating other potential indications for BTK inhibition are ongoing, including in post-allogeneic hematopoietic stem cell transplant patients for whom ibrutinib may be effective in modulating graft-versus-host disease. Combination trials of ibrutinib with venetoclax, a Bcl-2 inhibitor, are underway and are supported by sound preclinical rationale. Several next-generation BTK inhibitors are under development with the goal of decreasing treatment-related toxicity and resistance.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Drug Discovery; Graft vs Host Disease; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non-blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0-1, non-bulky disease and non-blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.

Topics: Adenine; Antineoplastic Agents; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Survival Analysis; 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

Ibrutinib, a Bruton's kinase inhibitor, was granted an accelerated approval by the US Food and Drug Administration in November, 2013, for the treatment of relapsed or refractory mantle cell lymphoma and subsequently for the treatment of relapsed refractory chronic lymphocytic leukemia in February, 2014. In the pivotal phase 2 study of 111 patients with relapsed or refractory mantle cell lymphoma, the overall response rate in patients who received ibrutinib 560 mg daily was 68%. The median progression-free survival was 13.9 months, and the overall survival was 58% at 18 months. In a recently published phase 3 trial (RESONATE) that compared ibrutinib and ofatumumab for the treatment of relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, ibrutinib at the daily dosage of 420 mg demonstrated a significantly higher overall response rate (43% in ibrutinib vs. 4% in ofatumumab) and a significantly improved overall survival at 12 months (90% ibrutinib vs. 81% ofatumumab). Similar clinical benefits were shown regardless of del (17 p). Ibrutinib was well tolerated, and dose-limiting toxicity was not observed. Ibrutinib has shown durable remission, improved progression-free survival and overall survival, and favorable safety profile in indolent B-cell lymphoid malignancies. Ibrutinib, as a monotherapy, is an effective treatment modality as a salvage therapy for treatment of mantle cell lymphoma and chronic lymphocytic leukemia / small lymphocytic lymphoma, particularly in older patients (age ≥70 years) who are not a candidate for intensive chemotherapy and/or those with del (17 p). In patients with chronic lymphocytic leukemia and del (17 p), the current practice guideline recommends ibrutinib as an upfront treatment option. Current on-going trials will further define its role as upfront therapy and/or as a combination therapy in indolent B-cell lymphoid malignancies.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Disease-Free Survival; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma previously considered to have a poor prognosis. Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients. In particular, greater depth of understanding of the molecular pathophysiology of MCL has resulted in an explosion of specifically targeted new efficacious agents. In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib. We review recent advances in the understanding of MCL biology and outline our recommended approach to therapy, including choice of chemoimmunotherapy, the role of stem-cell transplantation, and mechanism-based targeted therapies, on the basis of a synthesis of the data from published clinical trials.

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bortezomib; Cytarabine; Drug Administration Schedule; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Lenalidomide; Lymphoma, Mantle-Cell; Maintenance Chemotherapy; Molecular Targeted Therapy; Neoplasm Staging; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Risk Factors; Rituximab; Thalidomide; Transplantation, Autologous

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase which acts by downstream inhibition of the B-cell receptor. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile in relapsed/refractory MCL. Although the majority of disease responses are partial, efficacy data are impressive with more than two-thirds of patients demonstrating a durable response. This article focuses on all aspects of ibrutinib in the context of MCL, including a summary of the basic pharmacology and pharmacokinetics; a review of the safety and efficacy data published to date and a discussion of the future implications in MCL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Recurrence; Treatment Outcome

codynamic interactions are also likely in view of its adverse effect profile. There is no consensus on the treatment of patients with refractory or relapsed mantle cell lymphoma, or for patients with relapsed or possibly refractory chronic lymphocytic leukaemia. Ibrutinib inhibits an enzyme involved in regulating B lymphocyte activity. It has been authorised in the European Union for these conditions. Clinical evaluation of ibrutinib in mantle cell lymphoma is based on a single non-comparative trial in 111 patients, in which the median overall survival time was 22.5 months. Clinical evaluation of ibrutinib in chronic lymphocytic leukaemia is based on two randomised trials. One unblinded trial compared ibrutinib versus ofatumumab and involved 391 patients, most of whom were sufficiently fit to receive anticancer combination therapy. Ibrutinib was more effective than ofatumumab, but the choice of this comparator might not have been appropriate for most of the patients who received it. The other double-blind, placebo-controlled trial involved 578 patients with relapsed or refractory chronic lymphocytic leukaemia. Ibrutinib was added to the bendamustine + rituximab combination. No significant difference in mortality was observed between the two groups. The main adverse effects of ibrutinib were: gastrointestinal disorders such as diarrhoea; life-threatening infections and bleeding disorders; and cardiac disorders, including atrial fibrillation. Ibrutinib carries a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely in view of its adverse effect profile.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Treatment Outcome

Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle cell lymphoma in 2012. Because he was ineligible for intensive treatment (age, previous myocardial infarction [MI]), he received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy for 6 cycles (reaching complete response) and then rituximab maintenance (RM) for 2 years. One year after the end of RM, he relapsed with disseminated disease. He was started on ibrutinib 560 mg/day. Two weeks after the start of ibrutinib, he developed grade 3 diarrhea that required interruption of ibrutinib. Two weeks after the regular dose was restarted (month 3), the patient had repeated bleeding (patient was receiving aspirin for previous MI) and had to stop ibrutinib again. Because the patient was in partial response (PR) with lack of disease-associated symptoms, he was restarted on ibrutinib 280 mg/day with no further adverse events, and he had maintained PR at last follow-up (month 9 on ibrutinib).

Topics: Adenine; Aged; Aspirin; Diarrhea; Hemorrhage; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Staging; Piperidines; Pyrazoles; Pyrimidines

Ibrutinib (Imbruvica®) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation.

Topics: Adenine; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic

Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long-term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell-derived malignancies could be beneficial and result in new indications for clinical applications.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Atrial Fibrillation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoproliferative Disorders; Mice; Multiple Myeloma; Osteoclasts; Phosphorylation; Piperidines; Protein Binding; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Ibrutinib (Imbruvica®) is a first-in-class, orally administered once-daily, that inhibits B-cell antigen receptor signaling downstream of Bruton's tyrosine kinase (BTK). Ibrutinib has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. In clinical studies, ibrutinib induced an impressive overall response rate (68%) in patients with relapsed/refractory MCL (phase II study). In CLL, ibrutinib has shown to significantly improve progression-free survival, response rate and overall survival in patients with relapsed/refractory CLL, including in those with del 17p. Ibrutinib had an acceptable tolerability profile. Less than 10% of patients discontinued their treatment because of adverse events. Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma. An approval extension has already been enregistered for Waldenström disease in USA in January 2015. Given its efficacy and tolerability, ibrutinib is an emerging treatment option for patients with B-cell malignancies.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Chromosome Deletion; Genes, p53; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recurrence

Most lymphomas and lymphoid leukemias are of B cell origin. Indolent B cell lymphomas, most commonly follicular lymphoma but including Waldenstrom's macroglobulinemia and mantle cell lymphoma, as well as chronic lymphocytic leukemia, are incurable with standard therapy. New treatments are needed. Survival of normal and many abnormal B cells depends on signals through the B-cell receptor, and a key element of this pathway is Bruton's tyrosine kinase (BTK). The oral BTK inhibitor ibrutinib is already US FDA approved in four different indications based on marked treatment benefit in indolent B cell lymphoma/leukemia.. This review covers the clinical pharmacology of ibrutinib, its efficacy in clinical trials in chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia, as well as safety and toxicity. Future directions are discussed.. Ibrutinib is a well-tolerated once-daily oral BTK inhibitor with impressive activity in treating indolent B cell lymphoproliferative disorders. As a single agent, it is already altering treatment paradigms in its approved indications. Ongoing studies will determine its movement to the front-line setting in these and other B cell disorders, as well as combination approaches.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Ibrutinib is a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase that has demonstrated clinical benefit for many patients with B cell malignancies. Positive results in initial trials led the U.S. Food and Drug Administration to grant ibrutinib three breakthrough therapy designations for mantle cell lymphoma (MCL), del17p chronic lymphocytic leukemia (CLL), and Waldenström's macroglobulinemia (WM). Ibrutinib was approved for these three cancers within 14 months of the original U.S. approval. Additionally, ibrutinib is approved for patient subsets with MCL and/or CLL in >45 other countries. Via a unique mechanism of action, ibrutinib inhibits B cell signaling pathways that regulate the survival, proliferation, adhesion, and homing of cancerous cells. This marks a paradigm shift from the conventional cytotoxic chemotherapy approach to treating B cell malignancies. Ibrutinib continues to be evaluated across a range of B cell malignancies, either as single-agent therapy or in combination with other therapies, and continues to transform the lives of these patients.

Topics: Adenine; Antineoplastic Agents; B-Lymphocytes; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

In this article, we provide an accurate overview of both standard treatment option and novel promising therapeutics. Major impact is on novel agents now being tested in randomized clinical trials. While the initial data are promising, they may rapidly expand treatment options, change existing paradigms and further improve outcomes for mantle cell lymphoma (MCL) patients.. MCL is a disease with indolent histology, but aggressive clinical course. However, for now, MCL remains incurable and the search for the most effective and tumor-specific treatment still represents a great challenge for oncohematologists. However, the implementation of chemotherapy together with the anti-CD20 antibody rituximab, as well as the growing use of autologous stem cell transplantation in first remission, have improved effects of treatment in MCL, including even some improvement in overall survival. Recently, treatment modalities for MCL have been expanded by strategies based on several biologically targeted agents, including m-TOR kinase or proteasome inhibitors and immunomodulatory agents, such as lenalidomide. B-cell receptor pathway inhibitors, such as ibrutinib and idelalisib, and histone deacetylase or cyclin-dependent kinase inhibitors have also shown promising activity in resistant or relapsed disease.. Although enormous progress was made in the treatment of MCL over the last year, the disease remains incurable. One chance for the significant life prolongation is intensive treatment with consolidative auto SCT. However, real progress may be afforded by developing the novel agents described in this article. In this way, MCL may soon become another potentially curable oncological malignancy.

Topics: Adenine; Antineoplastic Agents; Drug Resistance, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Lenalidomide; Lymphoma, Mantle-Cell; Piperidines; Proteasome Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recurrence; Rituximab; Thalidomide

Recent clinical data suggest remarkable activity of ibrutinib, the first-in-class covalent inhibitor of Bruton's tyrosine kinase (BTK), in chronic lymphocytic leukemia (CLL), as well as excellent activity in other B cell malignancies, including in particular mantle cell lymphoma and Waldenstrom macroglobulinemia. This review evaluates the data from ongoing clinical and correlative studies of ibrutinib in B cell malignancies with a particular focus on CLL, and considers these data in the context of other B cell receptor pathway inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Disease-Free Survival; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; Waldenstrom Macroglobulinemia

Ibrutinib (Imbruvica™) is a small molecule, first-in-class, once-daily, orally available, Bruton's tyrosine kinase inhibitor that is under development for the treatment of B cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL), as well as multiple myeloma (MM), follicular lymphoma (FL) and Waldenstrom's macroglobulinemia (WM). It has been developed by Pharmacyclics, Inc. and Janssen Biotech, Inc. Ibrutinib acts by blocking B-cell antigen receptor signalling, thereby reducing malignant proliferation of B cells and inducing cell death. Based chiefly on findings from a phase Ib/II study, ibrutinib has been approved in the USA for the treatment of MCL in previously treated patients and is one of the first approvals through the US FDA's Breakthrough Therapy Designation Pathway. An application has been filed in the EU seeking regulatory approval in this indication. In both the USA and EU, further applications have been filed with regulatory bodies seeking approval for the use of ibrutinib in patients with previously treated CLL/small lymphocytic lymphoma (SLL). Phase III trials are underway worldwide to evaluate ibrutinib in the treatment of patients with CLL/SLL, DLBCL and MCL, and the agent is in phase II development for use in WM, FL and MM. This article summarizes the milestones in the development of ibrutinib leading to its first approval in MCL.

Topics: Adenine; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Multiple Myeloma; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

The standard frontline therapy for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) includes the use of chemoimmunotherapy and/or radiation therapy. When patients with these diseases relapse or are refractory to therapy, their diseases are considered incurable outside of the setting of an autologous or allogeneic stem cell transplant, which many patients are not candidates for due to age or comorbidities. The oral Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, targets the B-cell receptor (BCR) signaling pathway that is critical in the survival of these malignancies. It has shown promising activity in certain subtypes of DLBCL, in relapsed or refractory FL, and in relapsed or refractory MCL for which it has recently received FDA approval and should be considered for use in patients in first relapse. Ibrutinib is an oral therapy taken daily that has been well tolerated by patients. Given the high response rates, tolerability, and acceptable toxicities of ibrutinib therapy, it is now being evaluated in combination therapy both in relapsed B-cell malignancies and frontline studies in DLBCL and MCL. Several other promising agents targeting different kinases in the BCR signaling pathway also are currently under investigation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Boronic Acids; Bortezomib; Clinical Trials as Topic; Disease-Free Survival; Humans; Lenalidomide; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Piperidines; Protein-Tyrosine Kinases; Pyrazines; Pyrazoles; Pyrimidines; Signal Transduction; Thalidomide; Treatment Outcome

Ibrutinib is a novel oral tyrosine kinase inhibitor that irreversibly binds and inhibits tyrosine-protein kinase BTK (Bruton tyrosine kinase). BTK has been found to be important in the function of B-cell receptor signaling and therefore in the maintenance and expansion of various B-cell malignancies including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Targeting BTK with ibrutinib has been found to be an effective strategy in treating these malignancies. Phase I clinical testing in non-Hodgkin's lymphomas and CLL showed that the drug was extremely well tolerated with no major dose-limiting toxicities and a 54% overall response rate. Subsequently, two phase Ib/II studies were performed on patients with CLL, one in relapsed/refractory CLL and one in previously untreated elderly patients with CLL. Both of these studies continued to show good tolerability of the drug and an overall response rate of about 71% with extended duration of response. Another phase II study using ibrutinib in relapsed/refractory MCL was conducted and also showed that it was well tolerated with an overall response rate of 68% and extended duration of response. Due to these results, the U.S. Food and Drug Administration granted accelerated approval for ibrutinib in November 2013 for patients with MCL who had received at least one prior therapy and in February 2014 for patients with CLL who had received at least one prior therapy. This review will discuss the preclinical pharmacology, pharmacokinetics and clinical efficacy to date of ibrutinib in the treatment of CLL and MCL.

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

Ibrutinib (PCI-32765)--a potent, covalent inhibitor of Bruton tyrosine kinase (BTK), an important kinase in the B-cell receptor signaling pathway--was recently approved by the FDA for the treatment of relapsed or refractory mantle cell lymphoma (MCL). The drug was granted accelerated approval based on the findings of an international, multicenter, single-arm phase II study that enrolled patients with relapsed or refractory MCL. In the study, ibrutinib (560 mg daily) was well tolerated as a single agent and resulted in an overall response rate of 68% and an estimated median response duration of 17.5 months. Ibrutinib's response rate and duration of response compare favorably with those for other novel agents approved for the treatment of relapsed or refractory MCL, while being less toxic than most chemotherapy or chemoimmunotherapy regimens. Ibrutinib is currently being studied in combination with chemoimmunotherapy, monoclonal antibody therapy, and novel agents in both the initial and the relapsed/refractory treatment settings. We review the mechanism of action, preclinical and clinical development, and the role of ibrutinib in the context of other available treatments.

Topics: Adenine; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Lymphoma, Mantle-Cell; Multicenter Studies as Topic; Piperidines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic

Over the past 3 years, ibrutinib (PCI-32765) has emerged as a breakthrough in targeted therapy for patients with certain types of B cell malignancies. Early stage clinical trials found ibrutinib to be particularly active in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), providing the rationale for ongoing phase 3 trials. In contrast to conventional chemo-immunotherapy, ibrutinib is not myelosuppressive, and responses are not affected by disease features that predict failure to respond to or short remission durations after chemo-immunotherapy, such as del17p. In CLL, ibrutinib characteristically causes an early redistribution of tissue-resident CLL cells into the blood, with rapid resolution of enlarged lymph nodes, along with a surge in lymphocytosis. Later, after weeks to months of continuous ibrutinib therapy, the growth- and survival-inhibitory activities of ibrutinib result in the normalization of lymphocyte counts and remissions in a majority of patients. This review discusses the discovery, preclinical and clinical development of ibrutinib, its pathophysiological basis, and outlines perspectives for future use of ibrutinib.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Autoimmune Diseases; B-Lymphocytes; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction

Topics: Adult; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines

Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition.. We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247.. Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance.. BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.

Topics: Adenine; Adult; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Cell-Free Nucleic Acids; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Morpholines; Phosphatidylinositol 3-Kinases; Piperidines; Pyrazoles; Pyrimidines

Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton's tyrosine kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib (IBR) has shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual reassessment method of 6 combinations of IBR (280 mg, 420 mg, and 560 mg by mouth daily) and VEN (max dose of 200 mg and 400 mg by mouth daily). Eligible participants were not previously exposed to BTKi and not high risk for tumor lysis syndrome (TLS). VEN, initiated first at 100 mg, then at 20 mg by mouth daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level assigned. Combination treatment continued for six 28-day cycles. Thirty-five participants were enrolled and treated. One TLS event occurred with starting dose of 100 mg VEN; no TLS was seen with 20 mg. The optimal dosing combination was considered to be VEN 200 mg and IBR 420 mg with an overall response rate (ORR) of 93.8% (95% CI: 73.6% to 99.7%) and DLT incidence of 6.2% (95% CI: 0.3% to 26.4%). ORR for all arms was 82.3% (28/34; 95% CI: 65.5% to 93.2%) with a complete response (CR) rate of 42.4% (14/33; 95% CI: 25.5% to 60.8%). A participant was not allocated to IBR 560 mg and VEN 400 mg. ORR benefit was not seen with higher dosing combinations and toxicity was higher; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560.

Topics: Adenine; Adult; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Sulfonamides

Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years).. We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed.. The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of. IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

Topics: Adenine; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Exome Sequencing; Female; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Progression-Free Survival; Rituximab; Sequence Analysis, RNA; Time Factors

The need for an individualized management of indolent clinical forms in mantle cell lymphoma (MCL) is increasingly recognized. We hypothesized that a tailored treatment with ibrutinib in combination with rituximab (IR) could obtain significant responses in these patients.. This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 12 Spanish GELTAMO sites (ClinicalTrials.gov identifier: NCT02682641). Previously untreated MCL patients with indolent clinical forms defined by the following criteria were eligible: no disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm. Both leukemic non-nodal and nodal subtypes were recruited. Patients received ibrutinib 560 mg once daily and a total of eight doses of rituximab 375 mg/m. Fifty patients with MCL (male 66%; median age 65 years) were enrolled. After 12 cycles of treatment, 42 (84%; 95% CI, 74 to 94) patients had an overall response, including 40 (80%; 95% CI, 69 to 91) with CR. Moreover, undetectable MRD in peripheral blood was achieved in 87% (95% CI, 77 to 97) of cases. At 2 years, 24 of 35 evaluable patients (69%) could discontinue ibrutinib because of undetectable MRD. Four patients had disease progression; three were non-nodal MCL and carried high genomic complexity and. Frontline IR combination achieves a high rate of CRs and undetectable MRD in indolent clinical forms of MCL. Discontinuation seems appropriate in cases with undetectable MRD, except for

Topics: Adenine; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm, Residual; Piperidines; Rituximab

Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma.. We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m. 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related.. Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma.. Pharmacyclics, Janssen.

Topics: Adenine; Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Doxorubicin; Humans; Lymphoma, Mantle-Cell; Lymphopenia; Methotrexate; Middle Aged; Piperidines; Rituximab; Thrombocytopenia; Treatment Outcome; Vincristine

Topics: Adenine; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrimidines; Quinazolines

Topics: Adenine; Adult; Arthralgia; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Musculoskeletal Pain; Myalgia; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.. We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed.. Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group.. Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Topics: Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Disease Progression; Humans; Lymphoma, Mantle-Cell; Maintenance Chemotherapy; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Rituximab; Survival Analysis

Mantle cell lymphoma (MCL) is a rare, incurable lymphoma subtype characterized by heterogeneous outcomes. To better understand the clinical behavior and response to treatment, predictive biomarkers are needed. Using residual archived material from patients enrolled in the MCL3001 (RAY) study, we performed detailed analyses of gene expression and targeted genetic sequencing. This phase III clinical trial randomized patients with relapsed or refractory MCL to treatment with either ibrutinib or temsirolimus. We confirmed the prognostic capability of the gene expression proliferation assay MCL35 in this cohort treated with novel agents; it outperformed the simplified MCL International Prognostic Index in discriminating patients with different outcomes. Regardless of treatment arm, our data demonstrated that this assay captures the risk conferred by known biological factors, including increased MYC expression, blastoid morphology, aberrations of TP53, and truncated CCND1 3' untranslated region. We showed the negative impact of BIRC3 mutations/deletions on outcomes in this cohort and identified that deletion of chromosome 8p23.3 also negatively impacts survival. Restricted to patients with deletions/alterations in TP53, ibrutinib appeared to abrogate the deleterious impact on outcome. These data illustrate the potential to perform a molecular analysis of predictive biomarkers on routine patient samples that can meaningfully inform clinical practice.

Topics: 3' Untranslated Regions; Adenine; Adult; Biological Factors; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Sirolimus

Ibrutinib plus venetoclax, given with an ibrutinib lead-in, has shown encouraging clinical activity in early phase studies in mantle cell lymphoma (MCL). The ongoing phase 3 SYMPATICO study evaluates the safety and efficacy of concurrently administered, once-daily, all-oral ibrutinib plus venetoclax in patients with relapsed/refractory MCL. A safety run-in (SRI) cohort was conducted to inform whether an ibrutinib lead-in should be implemented for the randomized portion. Patients received concurrent ibrutinib 560 mg continuously plus venetoclax in a 5-week ramp-up to venetoclax 400 mg for up to 2 years. The primary endpoint was occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs). The SRI cohort enrolled 21 patients; six and 15 were in low- or increased-risk categories for TLS, respectively. During the 5-week venetoclax ramp-up, three patients had DLTs, and one patient at increased risk for TLS had a laboratory TLS; no additional TLS events occurred during follow-up. With a median follow-up of 31 months, the overall response rate was 81% (17/21); 62% (13/21) of patients had a complete response. SRI data informed that the randomized portion should proceed with concurrent ibrutinib plus venetoclax, with no ibrutinib lead-in. Ibrutinib plus venetoclax demonstrated promising efficacy; no new safety signals were observed.Trial registration: ClinicalTrials.gov, NCT03112174. Registered 13 April 2017, https://clinicaltrials.gov/ct2/show/NCT03112174 .

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Sulfonamides; Treatment Outcome

Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was reported, and venetoclax at 400 mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events. The complete response rate assessed by positron emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10/14 patients) and 100% of untreated MRD-evaluable patients (n = 12) at the end of 3 cycles. The median follow-up for relapsed patients was 17 months (range, 10-35 months). The 2-year progression-free survival (PFS) was 69.5% (95% confidence interval [CI], 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%) for overall survival. The median follow-up was 14 months (range, 5-19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5%-100%). The combination of obinutuzumab, ibrutinib, and venetoclax is well tolerated and provides high response rates, including at the molecular level, in relapsed and untreated MCL patients. This trial was registered at www.clinicaltrials.gov as #NCT02558816.

Topics: Adenine; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Female; Follow-Up Studies; Genes, p53; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm, Residual; Piperidines; Progression-Free Survival; Prospective Studies; Sulfonamides; Treatment Outcome

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoma, Mantle-Cell; Middle Aged; Neoplasm Recurrence, Local; Oligopeptides; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Administration, Oral; Adult; Aged; Aged, 80 and over; Area Under Curve; Bupropion; Contraceptives, Oral; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Drug Interactions; Ethinyl Estradiol; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Levonorgestrel; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Mantle-Cell; Metabolic Clearance Rate; Midazolam; Middle Aged; Piperidines; Waldenstrom Macroglobulinemia

The aim of this retrospective study was to investigate the safety and efficacy of allogeneic hematopoietic cell transplantation (alloHCT) in patients pre-treated with ibrutinib. Eligible were patients aged >18 years allotransplanted for chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) after prior exposure to ibrutinib who were registered with the EBMT registry. Seventy patients (CLL 48, MCL 22) were included. At the time of alloHCT, 73% of the patients were ibrutinib responsive. All patients except one engrafted, and acute GVHD grade 2-4 (3-4) was observed in 49% (12%) of 68 evaluable patients. The cumulative incidence of chronic GVHD was 54% 1 year after transplant. In the CLL group, 12-month non-relapse mortality, relapse incidence (RI), progression-free survival (PFS), and overall survival (OS) were 10, 30, 60, and 72%, respectively, and in the MCL group 5, 19, 76, and 86%, respectively. Pre-transplant ibrutinib failure and poor performance status predicted inferior RI, PFS and OS in the CLL group. In conclusion, ibrutinib does not affect the safety of a subsequent alloHCT. While the relatively high post-transplant relapse risk in ibrutinib-exposed patients with CLL deserves further study, in patients with MCL consolidating disease responses to ibrutinib with alloHCT seems to be a promising option.

Topics: Adenine; Adult; Aged; Allografts; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Survival Rate

Patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or mantle cell lymphoma often do not derive durable benefit from ibrutinib monotherapy. We hypothesised that dual B-cell receptor pathway blockade would be tolerable and efficacious. We investigated a next-generation phosphoinositide-3-kinase-δ inhibitor (PI3K-δi), umbralisib, plus a Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma.. We did an investigator-initiated, multicentre, phase 1-1b study of patients from five sites in the USA (academic and community sites). Patients were 18 years and older with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma, with an Eastern Cooperative Oncology Group performance status of 2 or less, and were given umbralisib orally once daily (400 mg, 600 mg, or 800 mg) and ibrutinib orally once daily (420 mg for chronic lymphocytic leukaemia or 560 mg for mantle cell lymphoma) until disease progression or unacceptable toxicity. The phase 1 dose-escalation cohorts for each histology escalated independently in a standard 3 × 3 design. The primary endpoints were intention-to-treat assessment of maximum-tolerated dose, safety, and dose-limiting toxicities. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02268851.. Between Dec 5, 2014, and March 7, 2018, we enrolled 44 patients, of which 42 were given at least one dose of study drug (chronic lymphocytic leukaemia, n=21; mantle cell lymphoma, n=21). Patients had a median age of 68 years (range 48-85) and had a median of two (IQR 1-3) previous therapies. No dose-limiting toxicities were observed and the maximum-tolerated dose of umbralisib was not reached. The recommended phase 2 dose of umbralisib when given in combination with ibrutinib was 800 mg once daily. The most frequent adverse events included diarrhoea (22 [52%] patients, 10% of whom had grade 3), infection (21 [50%], 17% grade 3-4), and transaminitis (ten [24%], 2% grade 3). Serious adverse events occurred in 12 (29%) patients and included lipase elevation, atrial fibrillation, hypophosphataemia, adrenal insufficiency, transaminitis, and infections.. Umbralisib plus ibrutinib is well tolerated and active in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma, with a recommended phase 2 dose of umbralisib 800 mg once daily. To the best of our knowledge, these are the first clinical data on a BTKi and PI3K-δi doublet in B-cell malignancies, and the results suggest that this approach is feasible and worthy of further study.. TG Therapeutics, Leukemia and Lymphoma Society Therapy Accelerator Program.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Topics: Adenine; Asian People; Female; Follow-Up Studies; Humans; Japan; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines

Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton's tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Piperazines; Piperidines; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Survival Rate

Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone.. In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m. Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17·8 months (IQR 14·7-20·9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3-4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke.. Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial.. Janssen and Celgene.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Resistance, Neoplasm; Female; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Male; Middle Aged; Mutation; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Rituximab; Survival Analysis; Thalidomide; Treatment Outcome

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Humans; International Agencies; Lymphoma, Mantle-Cell; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Salvage Therapy; Sirolimus; Survival Rate

Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination.. We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.. The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).. In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).

Topics: Adenine; Administration, Oral; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Examination; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Historically Controlled Study; Humans; Intention to Treat Analysis; Lymph Nodes; Lymphoma, Mantle-Cell; Male; Middle Aged; Mutation; Neoplasm, Residual; Piperidines; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Sulfonamides; Survival Rate

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR-MCL). We report the long-term outcome and safety profile of a single-centre, single arm, open-label, phase 2 study of RR-MCL treated with IR. Overall, the median follow-up time was 47 months (range 1-52 months), median duration on treatment was 16 months (range 1-53 months) and median number of treatment cycles was 17 (range 1-56). Twenty-nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty-eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1-2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression-free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL-related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR-MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR-MCL is under exploration.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Follow-Up Studies; Humans; Ki-67 Antigen; Lymphoma, Mantle-Cell; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Recurrence; Remission Induction; Rituximab; Salvage Therapy; Survival Analysis

Multiple studies have demonstrated the efficacy and safety of ibrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). This first-in-class inhibitor of Bruton's tyrosine kinase has become a standard treatment for patients with CLL and MCL.. We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with ibrutinib versus comparators. Data were pooled from 4 completed randomized controlled studies that had included 756 ibrutinib-treated and 749 comparator-treated patients with CLL/SLL or relapsed/refractory MCL. Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates.. The median treatment duration was 13.3 months (maximum, 28.2 months) for ibrutinib and 5.8 months (maximum, 27.3 months) for comparators. When adjusted for exposure, diarrhea, atrial fibrillation, and hypertension were the only common grade ≥ 3 AEs more often reported with ibrutinib than with the comparators. Dose reductions (7% vs. 14%) and discontinuation (12% vs. 16%) because of AEs occurred less often with ibrutinib, and deaths due to AEs occurred at similar rates (6% vs. 7%). When adjusted for exposure, the corresponding data were all lower with ibrutinib than with the comparators (0.06 vs. 0.22, 0.11 vs. 0.22, and 0.06 vs. 0.09 patient-exposure-years, respectively). The prevalence of common grade 3/4 AEs with ibrutinib generally decreased over time, with the exception of hypertension.. These results from an integrated analysis support a favorable benefit/risk profile of ibrutinib in patients with CLL/SLL and MCL.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Patient Safety; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Rituximab; Sirolimus; Survival Rate

Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Pyrazoles; Pyrimidines; Quality of Life; Retreatment; Sirolimus; Treatment Outcome

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Humans; Lymphoma, Mantle-Cell; Models, Theoretical; Molecular Targeted Therapy; Piperidines; Pyrazoles; Pyrimidines; Research Design; Sulfonamides; Treatment Outcome

Lenalidomide is an immunomodulatory agent that has demonstrated clinical benefit for patients with relapsed or refractory mantle cell lymphoma (MCL); however, despite this observed clinical activity, the mechanism of action (MOA) of lenalidomide has not been characterized in this setting. We investigated the MOA of lenalidomide in clinical samples from patients enrolled in the CC-5013-MCL-002 trial (NCT00875667) comparing single-agent lenalidomide versus investigator's choice single-agent therapy and validated our findings in pre-clinical models of MCL. Our results revealed a significant increase in natural killer (NK) cells relative to total lymphocytes in lenalidomide responders compared to non-responders that was associated with a trend towards prolonged progression-free survival and overall survival. Clinical response to lenalidomide was independent of baseline tumour microenvironment expression of its molecular target, cereblon, as well as genetic mutations reported to impact clinical response to the Bruton tyrosine kinase inhibitor ibrutinib. Preclinical experiments revealed lenalidomide enhanced NK cell-mediated cytotoxicity against MCL cells via increased lytic immunological synapse formation and secretion of granzyme B. In contrast, lenalidomide exhibited minimal direct cytotoxic effects against MCL cells. Taken together, these data provide the first insight into the clinical activity of lenalidomide against MCL, revealing a predominately immune-mediated MOA.

Topics: Adaptor Proteins, Signal Transducing; Adenine; Coculture Techniques; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Humans; Immunologic Factors; Killer Cells, Natural; Lenalidomide; Lymphocyte Count; Lymphoma, Mantle-Cell; Mutation; Peptide Hydrolases; Piperidines; Pyrazoles; Pyrimidines; Thalidomide; Treatment Outcome; Tumor Cells, Cultured; Tumor Microenvironment; Ubiquitin-Protein Ligases

Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity.. Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients.. Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16·5 months (IQR 12·09-19·28), 44 (88%, 95% CI 75·7-95·5) patients achieved an objective response, with 22 (44%, 30·0-58·7) patients achieving a complete response, and 22 (44%, 30·0-58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment.. Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data.. Pharmacyclics LLC, an AbbVie Company.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Diarrhea; Epistaxis; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Lymphoma, Mantle-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Rituximab; Treatment Outcome

Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.. This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74).. Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]).. Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.. Janssen Research & Development, LLC.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Sirolimus; Treatment Outcome

To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-κB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-κB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-κB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-κB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors.

Topics: Adenine; Amino Acid Substitution; Apoptosis; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Lymphoma, Mantle-Cell; Male; Mutation, Missense; Piperidines; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; Survival Rate; Transcription Factor RelA

In this multicenter, single-arm, phase II study, the efficacy and safety of ibrutinib were examined in Japanese patients with relapsed or refractory mantle cell lymphoma (MCL). Patients (age ≥20 years) with relapsed or refractory MCL who had progressed after receiving at least one prior treatment regimen, were enrolled. Patients were treated with oral ibrutinib (560 mg once daily; 28-day cycle) until disease progression (or relapse), unacceptable toxicity, or study end. The primary end-point was overall response rate. Secondary end-points included duration of response (DOR), time to response, progression-free survival (PFS), overall survival, and safety. Of the 16 patients who received treatment, 5 patients discontinued the study (progressive disease, 4; sepsis, 1). Median duration of ibrutinib exposure was 6.5 months (range, 2.8-8.3 months). The overall response rate was 87.5% (90% confidence interval, 65.6-97.7; complete response = 2 [12.5%]; partial response = 12 [75.0%]). Median time to response for all responders (n = 14) was 1.8 months (range, 0.7-5.3 months). The median DOR and PFS were not estimable due to censoring (range: DOR, 1.1-6.4+ months; PFS, 2.8-8.0+ months). Overall survival data were immature due to the limited observation period. A total of 8/16 patients (50%) had at least one grade 3 adverse event (AE), and 5 (31.3%) patients reported serious AEs. The most commonly reported AEs were diarrhea and stomatitis (37.5% each), platelet count decrease (31.3%), and anemia (25%). Overall, orally administered single agent ibrutinib was efficacious with an acceptable safety profile in Japanese patients with relapsed or refractory MCL. Clinical trial registration NCT02169180 (ClinicalTrials.gov).

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Treatment Outcome

Ibrutinib is an oral Bruton's tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients.. Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25-12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling.. A two-compartment PK model with sequential zero-first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively.. The proposed population PK model was able to describe the plasma concentration-time profiles of ibrutinib across various trials. The linear model indicated that the compound's PK was dose independent and time independent.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Biological Availability; Cohort Studies; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Food-Drug Interactions; Half-Life; Humans; Intestinal Absorption; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Models, Biological; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.. In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.. The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.. Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

Topics: Adenine; Administration, Oral; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Drug Resistance, Neoplasm; Female; Humans; Lymphocyte Count; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recurrence; Survival Analysis

Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.

Topics: Adenine; Antigens, CD19; Antineoplastic Agents; B-Lymphocytes; Blotting, Western; CD5 Antigens; Cell Adhesion; Chemotaxis, Leukocyte; Flow Cytometry; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Ibrutinib revolutionized therapy for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Real-world data on the outcome of unselected patients are still limited. We analyzed 77 R/R MCL patients receiving ibrutinib with at least one prior systemic anti-lymphoma therapy. After a median follow-up of 14.0 months, 56 patients relapsed/progressed, and 45 died. The overall response rate was 66%, with 31% of complete metabolic remissions on PET/CT. The median progression-free and overall survival (OS) rates were 10.3 and 23.1 months, respectively. The median OS from ibrutinib failure was 3.7 months. High proliferation rate by Ki67 (≥ 30%) and two or more previous therapy lines both negatively correlated with outcome (HR = 2.2, p = 0.04, and HR = 2.06, p = 0.08, respectively). Female gender borderline correlated with better outcome (HR = 0.53, p = 0.08). In multivariate analysis, Ki67 and response to ibrutinib both correlated with OS (p < 0.05). Importantly, ibrutinib appeared to better control nodal and extranodal lymphoma than bone marrow (BM) involvement. From 20 patients with detectable BM infiltration (before ibrutinib initiation) achieving complete (n = 13) or partial (n = 7) metabolic remission, none achieved remission in BM. We confirmed good efficacy of ibrutinib in unselected heavily pre-treated MCL patients. Our findings support the use of a combination of ibrutinib and rituximab in patients with BM involvement.

Topics: Adult; Czech Republic; Female; Humans; Ki-67 Antigen; Lymphoma, Mantle-Cell; Positron Emission Tomography Computed Tomography

Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma characterized by frequent relapses. The development of resistance to ibrutinib therapy remains a major challenge in MCL. We previously showed that glutaminolysis is associated with resistance to ibrutinib. In this study, we confirmed that glutaminase (GLS), the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant MCL cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis. Furthermore, we discovered that GLS expression correlates with MYC expression and the functioning of the glutamine transporter ASCT2. Depletion of glutamine or GLS significantly reduced cell growth, while GLS overexpression enhanced glutamine dependency and ibrutinib resistance. Consistent with this, GLS inhibition by its specific inhibitor telaglenastat suppressed MCL cell growth both in vitro and in vivo. Moreover, telaglenastat showed anti-MCL synergy when combined with ibrutinib or venetoclax in vitro, which was confirmed using an MCL patient-derived xenograft model. Our study provides the first evidence that targeting GLS with telaglenastat, alone or in combination with ibrutinib or venetoclax, is a promising strategy to overcome ibrutinib resistance in MCL.

Topics: Adult; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Inhibitors; Glutaminase; Glutamine; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local

Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase indicated for the treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). The Named Patient Program in Australia and New Zealand (ANZ NPP) provided access to ibrutinib treatment to 1126 R/R CLL/SLL and 330 R/R MCL patients, prior to Pharmaceutical Benefits Scheme listing. This study aimed to assess the duration of treatment for the ANZ NPP patients, as an indicator of efficacy and tolerability of ibrutinib in the real world. Based on the NPP data, ibrutinib provided a median of 47 months clinical benefit for participants with CLL/SLL and 14 months clinical benefit for those with MCL; outcomes that are consistent with the clinical trial results and further support the well-established efficacy and safety profile of ibrutinib in the real world.

Topics: Adult; Australia; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; New Zealand; Recurrence

Mantle cell lymphoma (MCL), a rare and aggressive B-cell non-Hodgkin lymphoma, mainly develops in the lymph node (LN) and creates a protective and immunosuppressive niche that facilitates tumor survival, proliferation and chemoresistance. To capture disease heterogeneity and tumor microenvironment (TME) cues, we have developed the first patient-derived MCL spheroids (MCL-PDLS) that recapitulate tumor oncogenic pathways and immune microenvironment in a multiplexed system that allows easy drug screening, including immunotherapies. MCL spheroids, integrated by tumor B cells, monocytes and autologous T-cells self-organize in disc-shaped structures, where B and T-cells maintain viability and proliferate, and monocytes differentiate into M2-like macrophages. RNA-seq analysis demonstrated that tumor cells recapitulate hallmarks of MCL-LN (proliferation, NF-kB and BCR), with T cells exhibiting an exhaustion profile (PD1, TIM-3 and TIGIT). MCL-PDLS reproduces in vivo responses to ibrutinib and demonstrates that combination of ibrutinib with nivolumab (anti-PD1) may be effective in ibrutinib-resistant cases by engaging an immune response with increased interferon gamma and granzyme B release. In conclusion, MCL-PDLS recapitulates specific MCL-LN features and in vivo responses to ibrutinib, representing a robust tool to study MCL interaction with the immune TME and to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.

Topics: Adenine; Adult; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Tumor Microenvironment

Topics: Adult; Cell Line, Tumor; Humans; Lymphoma, Mantle-Cell; Piperidines; Ubiquitin; Ubiquitin Thiolesterase

The use of Bruton tyrosine kinase inhibitors, such as ibrutinib, to block B-cell receptor signaling has achieved a remarkable clinical response in several B-cell malignancies, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and affects the long-term survival of these patients. Here, we demonstrate that the transcription factor early growth response gene 1 (EGR1) is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell-like subtype DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment. Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. Mechanistically, TCF4 and EGR1 self-regulation induce EGR1 overexpression that mediates metabolic reprogramming to oxidative phosphorylation (OXPHOS) through the transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation increases intracellular adenosine triphosphate production, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL.

Topics: Adult; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Early Growth Response Protein 1; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Metformin; Mice; Oxidative Phosphorylation

A patient with relapsed mantle cell lymphoma (MCL) showed stable disease after receiving ibrutinib therapy as a salvage therapy, after the failure of his first chimeric antigen receptor (CAR)-T 19 cell therapy.. The combined effects of CAR-T 19 cells from the patient and ibrutinib on JeKo-1 cell were explored in vitro and in vivo.. The expression of programmed death-1 (PD-1) receptor on CD3+ T cells in the peripheral blood decreased from 82.95% in the first CAR-T 19 cell therapy to approx. 40% after 14 months of ibrutinib therapy. When the disease progressed again during the ibrutinib therapy, the patient was enrolled into the same clinical trial of CAR-T 19 cell therapy.. The efficacy of CAR-T 19 cells increased after the ibrutinib therapy. The mRNA expression level of PD-1 in CAR-T 19 cells after ibrutinib therapy was lower than in CAR-T 19 cells before the ibrutinib therapy. Nevertheless, CAR-T 19 cell therapy combined with ibrutinib had no synergistic effect in a short term in vitro and in the JeKo-1 cell mouse model.. We expect our results to provide evidence for the combination treatment of ibrutinib for MCL or even other types of B-cell lymphomas. Moreover, the improvement in CAR-T 19 cell function was based on long-term ibrutinib therapy.

Topics: Adenine; Adult; Animals; Humans; Immunotherapy, Adoptive; Lymphoma, Mantle-Cell; Mice; Piperidines; Receptors, Chimeric Antigen

Despite significant efficacy of ibrutinib therapy in mantle cell lymphoma (MCL), about one-third of MCL patients will display primary resistance. In time, secondary resistance occurs almost universally with an unlikely response to salvage chemotherapy afterwards. While intense efforts are being directed towards the characterization of resistance mechanisms, our focus is on identifying the signalling network rewiring that characterizes this ibrutinib resistant phenotype. Importantly, intrinsic genetic, epigenetic and tumour microenvironment-initiated mechanisms have all been shown to influence the occurrence of the ibrutinib resistant phenotype. By using in vitro and in vivo models of primary and secondary ibrutinib resistance as well as post-ibrutinib treatment clinical samples, we show that dual targeting of the BCL-2 and PI3-kinase signalling pathways results in synergistic anti-tumour activity. Clinically relevant doses of venetoclax, a BCL-2 inhibitor, in combination with duvelisib, a PI3Kδ/γ dual inhibitor, resulted in significant inhibition of these compensatory pathways and apoptosis induction. Our preclinical results suggest that the combination of venetoclax and duvelisib may be a therapeutic option for MCL patients who experienced ibrutinib failure and merits careful consideration for future clinical trial evaluation.

Topics: Adenine; Adult; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Tumor Microenvironment

Ibrutinib has revolutionized the treatment of mantle cell lymphoma (MCL). Both ibrutinib monotherapy and ibrutinib-based combination therapy are important salvage options for patients with relapsed/refractory (R/R) MCL. The real-world efficacy and safety profile of the two strategies in Chinese patients with R/R MCL remain unclarified.. In the present study, data of 121 R/R MCL patients who received either ibrutinib monotherapy (N = 68) or ibrutinib combination therapy (N = 53) in 13 medical centers in China were retrospectively reviewed.. With a median follow-up of 20.5 months, the overall response rate was 60.3% versus 84.9% (p = 0.003), complete remission rate was 16.2% versus 43.4% (p < 0.001), and median progression-free survival (PFS) was 18.5 months (95% confidence interval [CI], 12.1-21.8) vs. 30.8 months (95% CI, 23.5-NR) (hazard ratio, 0.53 [95% CI, 0.30-0.93]; p = 0.025), with ibrutinib monotherapy and ibrutinib-based combination therapy, respectively. Subgroup analysis showed that patients with male gender, no refractory disease, Ki67 <30%, previous line of therapy = 1, non-blastoid subtype, and the number of extranodal sites involved <2 might benefits more from the combination therapy. Treatment-emergent adverse events were similar, except for a higher incidence of all grade neutropenia in the ibrutinib combination group (12.7% vs. 32.0%, p = 0.017).. Ibrutinib combination therapy demonstrated potentially superior efficacy and comparable tolerability to ibrutinib monotherapy. Ibrutinib-based combination therapy could be one of the prominent treatment options for R/R MCL patients.

Topics: Adult; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Recurrence, Local; Pyrazoles; Pyrimidines; Retrospective Studies

This retrospective study evaluated 66 patients diagnosed with relapsed and/or refractory mantle cell lymphoma (R/R MCL) treated with ibrutinib in Spain in routine clinical practice. At diagnosis, patients had a median age of 64.5 years, 63.6% presented with intermediate/high sMIPI (simplified prognostic index for advanced-stage mantle cell lymphoma), 24.5% had the blastoid variant, and 55.6% had a Ki67 > 30%. Patients had received a median of 2 prior lines of therapy (range 1-2; min-max 1-7). Overall response rate was 63.5%, with 38.1% of patients achieving complete response (CR). With a median duration of ibrutinib exposure of 10.7 months (range 5.2-19.6; min-max 0.3-36), the median progression-free survival (PFS) and overall survival (OS) were 20 months [95% confidence interval (CI) 8.8-31.1] and 32 months (95% CI 22.6-41.3), respectively, and were not reached in patients achieving CR. No grade ≥ 3 cardiovascular toxicity or bleeding was reported. This study supports that treatment with ibrutinib leads to high response rates and favorable survival outcomes in patients with R/R MCL.

Topics: Adenine; Adult; Humans; Lymphoma, Mantle-Cell; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies

Topics: Adenine; Humans; Lymphoma, Mantle-Cell; Piperidines

Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Topics: Adult; Aged; Aged, 80 and over; Central Nervous System; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Pyrazoles; Pyrimidines; Retrospective Studies; Treatment Outcome

Treatment options in patients with mantle cell lymphoma (MCL) failing ibrutinib are limited, with no standard therapies defined. This study aimed to investigate real-world treatment patterns and outcomes for patients with MCL following ibrutinib.. This study utilized a de-identified hospital-based claims database (Medical Data Vision) in Japan. Eligible patients were adults who were diagnosed with MCL and had received antitumor drugs between December 2010 and July 2020. Patients were followed from the first antitumor drug treatment until the end of available data up to July 2021. Time-to-event analyses utilized the Kaplan-Meier method. Factors for receiving post-ibrutinib therapy were explored with logistic regression analysis.. Of the 1386 patients who started antitumor drug therapy, 247 patients received and discontinued ibrutinib at any line of therapy. Among them, 137 patients (55.5%) received subsequent therapy. The median age at the end of ibrutinib therapy was 77 (range 42-95), and 44 patients had a dependent activity of daily living (ADL). Factors negatively associated with receiving post-ibrutinib therapy after discontinuation of ibrutinib were age ≥ 75 years (odds ratio [95% CI] 0.46 [0.26-0.80]) and emergency hospital admissions (0.37 [0.17-0.84]). Immediate post-ibrutinib therapy regimens were highly diverse, with BR (bendamustine, rituximab) only prescribed in more than 10% of patients. The median duration of post-ibrutinib therapy was 1.5 months (95% CI 1.07-2.07). The median overall survival from the end of ibrutinib therapy in patients regardless of the receipt of post-ibrutinib therapy (n = 247), in those who did not receive post-ibrutinib therapy (n = 110), and in those who received post-ibrutinib therapy (n = 137) was 5.6 months (95% CI 3.8-8.7), 2.3 months (95% CI 1.2-3.9), and 8.7 months (95% CI 5.6-13.8), respectively. The most common adverse event during post-ibrutinib therapy was infection, with the use of anti-infectives (17%).. Patients with MCL previously treated with ibrutinib have poor ability to carry out ADL and experience very poor outcomes. New safe, effective therapies are needed.

Topics: Adenine; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Japan; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies; Rituximab

Topics: Adenine; Adult; Bendamustine Hydrochloride; Humans; Lymphoma, Mantle-Cell; Piperidines; Rituximab

Topics: Adenine; Adult; Bendamustine Hydrochloride; Humans; Lymphoma, Mantle-Cell; Piperidines; Rituximab

Topics: Adenine; Adult; Bendamustine Hydrochloride; Humans; Lymphoma, Mantle-Cell; Piperidines; Rituximab

Topics: Adenine; Adult; Bendamustine Hydrochloride; Humans; Lymphoma, Mantle-Cell; Piperidines; Rituximab

Ibrutinib improves the treatment of relapsed or refractory mantle cell lymphoma, a mature B cell neoplasm. However, relapses following treatment with this Bruton tyrosine kinase inhibitor occur frequently, and the outcome of affected patients is poor.. Single-cell RNA sequencing (scRNA-seq) can track trends in gene expression of mantle cell lymphoma cells across ibrutinib treatment and new therapeutic targets can be defined based on the detected resistance mechanisms.. The ibrutinib-sensitive mantle cell lymphoma cell line REC‑1 was treated with ibrutinib for 6 h and 48 h. Droplet-based scRNA-seq was performed to examine the transcriptomic alterations of surviving cells using the 10× Genomics platform. Extracellular flux analysis and flow cytometry were applied to further study the observed adaptations to ibrutinib treatment.. REC‑1 harbored a subpopulation with potential for crosstalk with microenvironment and therefore greater risk for aggressiveness and drug resistance. Following ibrutinib treatment, NF-κB signaling was turned off. In contrast, the cells upregulated B-cell receptor genes and surface antigens such as CD52, and switched their metabolism to increased dependence on oxidative phosphorylation.. Targeting oxidative phosphorylation or CD52 in combination with or as follow-up to ibrutinib might overcome resistance and provide improved prognosis for mantle cell lymphoma patients.. HINTERGRUND: Der Einsatz von Ibrutinib verbessert die Überlebensrate von Patienten mit rezidiviertem oder refraktärem Mantelzelllymphom, einer reifen B‑Zell-Neoplasie. Jedoch sind Rückfälle nach der Behandlung mit diesem Bruton-Tyrosinkinase-Inhibitor häufig und resultieren in einer schlechten Prognose für die betroffenen Patienten.. Durch eine Einzelzell-RNA-Sequenzierung können Trends in der Genexpression von Mantelzelllymphomzellen im Verlauf einer Ibrutinib-Behandlung nachvollzogen und gezielte Therapieansätze basierend auf den entdeckten Resistenzmechanismen definiert werden.. Die Ibrutinib-sensitive Mantelzelllymphomzelllinie REC‑1 wurde für 6 h und 48 h mit Ibrutinib behandelt. Die Veränderungen im Transkriptom überlebender Zellen wurden mit der Einzelzell-RNA-Sequenzierung auf Basis der 10× Genomics-Tröpfchen-Mikrofluidik analysiert. Die beobachteten Anpassungen an die Ibrutinib-Therapie wurden mittels extrazellulärer Flux-Analyse und Durchflusszytometrie näher untersucht.. Eine Subgruppe der REC‑1 wies das Potenzial zur Interaktion mit dem Tumormikromilieu und damit ein höheres Risiko für aggressives Verhalten und Therapieresistenz auf. Durch die Ibrutinib-Behandlung wurde die NF-κB-Signalübertragung reduziert. Hingegen steigerten die Zellen die Expression von Genen des B‑Zell-Rezeptors und von Oberflächenantigenen wie CD52 und stellten ihren Metabolismus um, wodurch eine erhöhte Abhängigkeit von der oxidativen Phosphorylierung entstand.. Oxidative Phosphorylierung und CD52 könnten als neue Ansätze für Ibrutinib Kombinations- oder Konsolidierungstherapien dienen, wodurch Resistenzmechanismen umgangen und Mantelzelllymphompatienten eine bessere Prognose ermöglicht wird.

Topics: Agammaglobulinaemia Tyrosine Kinase; CD52 Antigen; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Pyrazoles; Pyrimidines; RNA, Small Cytoplasmic; Single-Cell Analysis; Tumor Microenvironment

Topics: Adult; Brain; Central Nervous System; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local

Since the use of Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in relapsed/refractory (R/R) mantle cell lymphoma (MCL), the problem of drug resistance has become increasingly prominent. Though it has been proven that the nonclassic nuclear factor κB pathway (nonclassic NF-κB pathway) correlates with ibrutinib resistance in MCL, the upstream regulator is unknown. In the present study, conserved helix-loop-helix ubiquitous kinase (CHUK) overexpression accelerated proliferation and suppressed apoptosis of MCL cells after ibrutinib treatment in vitro. The results of luciferase reporter assay, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blot revealed that CHUK was targeted and negatively regulated by miRNA-223-3p. miRNA-223-3p knockdown promoted proliferation and inhibited apoptosis of MCL cells after ibrutinib treatment in vitro and vivo, whereas CHUK knockdown reversed downregulated miRNA-223-3p-promoted cell proliferation after ibrutinib treatment in vitro. In conclusion, miRNA-223-3p modulates ibrutinib resistance through regulation of the CHUK/NF-κB signaling pathway in MCL, which is crucial in providing a marker to predict disease response.

Topics: Adenine; Animals; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; I-kappa B Kinase; Lymphoma, Mantle-Cell; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; NF-kappa B; Piperidines; Protein Kinase Inhibitors; Signal Transduction

Mantle cell lymphoma (MCL) is a rare and clinically aggressive lymphoma subtype. Current approaches have greatly improved patients outcomes, but relapse is inevitable. In phase IIIII clinical trials, ibrutinib has shown significant activity in patients with relapsed or refractory (R/R) MCL.. To assess efficacy and toxicity of ibrutinib monotherapy in patients with R/R MCL in routine practice outside of clinical trials.. The study enrolled patients with confirmed R/R MCL who had received at least one line of previous chemotherapy. ECOG 24, cytopenia, infectious complications, hemorrhagic syndrome were not exclusion criteria. Patients received daily oral ibrutinib 560 mg until progression or unacceptable toxicity.. From May 2015 to September 2020 ibrutinib therapy was started in 106 patients with R/R MCL in 16 regions of Russia. The median age was 66 years; ECOG2 18%, blastoid variant (or Ki6740% or WBC50109/l) 43%. The median number of previous treatment lines was 2 (111). The ORR was 78.4% (CRR 27.4%). The median PFS was 13.6 months and OS 23.2 months. In the blastoid group the median PFS was 4.4 months vs 36.5 months in the alternative group (p0.001), the median OS 9.0 vs 41.0 (p=0.001). The median OS of patients after progression on ibrutinib was 3.2 months. The common complications are hemorrhages (63%), diarrhea (62%), myalgia and muscle cramps (60%), infections (31%), skin and nail toxicity 15%, arrhythmia 8%. None of recipients had to completely discontinue ibrutinib therapy due to complications.. Ibrutinib is effective and well tolerated in routine practice of R/R MCL treatment and our results are consistent with international clinical trials. The favorable toxicity profile and the high response rate made it possible to prescribe ibrutinib in severe somatic status, cytopenia, and even in the presence of infectious complications.. Обоснование. Лимфома из клеток мантийной зоны (ЛКМЗ) редкая и агрессивная В-клеточная лимфома. Интенсификация химиотерапии значительно улучшила результаты лечения, но развитие рецидива неизбежно. В исследованиях IIIII фазы ибрутиниб продемонстрировал высокую эффективность у пациентов с рецидивом и резистентным (р/р) течением ЛКМЗ. Цель. Оценить эффективность и токсичность монотерапии ибрутинибом у пациентов с р/р ЛКМЗ в повседневной практике. Материалы и методы. В исследование включены пациенты с подтвержденным диагнозом р/р ЛКМЗ, получившие не менее одной линии химиотерапии. Тяжелый соматический статус, цитопения, инфекционные осложнения и геморрагический синдром не служили противопоказаниями для начала терапии. Ибрутиниб назначался в дозе 560 мг ежедневно до прогрессирования или развития неприемлемой токсичности. Результаты. С мая 2015 по сентябрь 2020 г. включены 106 пациентов в 16 регионах России. Медиана возраста 66 лет; ECOG2 18%; бластоидный вариант (или Ki6740%, или WBC50109/л) 43%. Медиана предшествующих линий терапии 2 (111). Общий ответ достигнут у 78,4% (полная ремиссия 27,4%). Медиана беспрогрессивной выживаемости (БПВ) 13,6 мес, общей выживаемости (ОВ) 23,2 мес. При бластоидном варианте медиана БПВ составила 4,4 мес против 36,5 мес в альтернативной группе (p0,001), медиана ОВ 9,0 мес против 41,0 мес (р=0,001). Медиана ОВ при развитии резистентности к ибрутинибу 3,2 мес. Наиболее частые осложнения: геморрагии (63%), диарея (62%), миалгии и мышечные судороги (60%), инфекции (31%), кожная токсичность 15%, аритмия 8%. Ни одному из пациентов полностью терапию ибрутинибом из-за токсичности не остановили. Заключение. Ибрутиниб эффективен и хорошо переносится в рутинной практике терапии р/р ЛКМЗ, а результаты согласуются с данными международных исследований. Благоприятный профиль токсичности и высокая частота ответов позволили назначать ибрутиниб при тяжелом соматическом статусе, цитопении или наличии инфекционных осложнений.

Topics: Adenine; Aged; Clinical Trials as Topic; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Russia

This is a 5-year real-world study of 65 patients treated with ibrutinib for relapsed/refractory mantle cell lymphoma across the UK and Ireland. Ibrutinib was well tolerated with no fatal adverse events. The median progression-free survival and overall survival (OS) was 12 and 18·5 months, respectively. Overall, 80% of patients discontinued treatment, predominantly for progressive disease. On discontinuation, 20% received alternative immunochemotherapy with a median OS of 24 months. Ibrutinib was used as a bridge to transplant in 8% (median OS not reached). These observations are comparable with trial outcomes with encouraging responses to immunochemotherapy at relapse.

Topics: Adenine; Aged; Aged, 80 and over; Disease-Free Survival; Female; Follow-Up Studies; Humans; Ireland; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Recurrence; Survival Rate; United Kingdom

Topics: Adenine; Aged; Antineoplastic Agents; COVID-19; COVID-19 Drug Treatment; Follow-Up Studies; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Recurrence; Retreatment; Treatment Outcome

The experience of patients with mantle cell lymphoma (MCL) in community oncology practices, including reasons for treatment discontinuation, is sparse. This retrospective study sought to elucidate treatment patterns and outcomes of patients with MCL treated with ibrutinib in the community setting. Patients were identified from the US Oncology Network electronic medical records database, iKnowMed

Topics: Adenine; Aged; Aged, 80 and over; Electronic Health Records; Female; Humans; Lymphoma, Mantle-Cell; Middle Aged; Piperidines; Protein Kinase Inhibitors; Survival Analysis; Treatment Outcome; United States

Topics: Adenine; Aged; Diabetic Nephropathies; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Renal Dialysis; Renal Elimination; Treatment Outcome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Comorbidity; COVID-19; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; SARS-CoV-2

Limited published real-world data describe adverse events (AEs) among patients treated for mantle-cell lymphoma (MCL). The aim of this retrospective study was to describe treatment patterns, AEs, and associated healthcare costs.. Patients had two or more claims coded for MCL diagnosis, the first claim date (07/01/2012-05/31/2017) was the index date. Patients with pre-index MCL diagnosis or systemic treatment, or hematopoietic stem cell transplantation were excluded. Cohorts by regimen were followed for up to three lines of therapy.. Patients (n=395; median age 72 years; 31% female) were observed over a total of 576 lines of therapy, the most common being bendamustine plus rituximab; rituximab monotherapy; R-CHOP; and ibrutinib. The most frequent AEs were hypertension (40.5%), anemia (37.7%), and infection (36.1%). However, hepatotoxicity ($19,645), stroke ($18,893), and renal failure ($9,037) were associated with the highest medical costs per patient per month.. Among patients receiving common systemic treatments for MCL, AEs occurred frequently; some imposed substantial inpatient care costs.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Chemical and Drug Induced Liver Injury; Cyclophosphamide; Doxorubicin; Female; Health Care Costs; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Prednisone; Renal Insufficiency; Retrospective Studies; Rituximab; Stroke; Vincristine

Topics: Adenine; Adult; Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrimidines; Sulfonamides

Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cytarabine; Disease Progression; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Outcome Assessment, Health Care; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Recurrence; Retrospective Studies; Rituximab; State Medicine; United Kingdom; Withholding Treatment

Topics: Adenine; Adult; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Republic of Korea; Retrospective Studies

Topics: Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Drug Resistance, Neoplasm; Fatal Outcome; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Recurrence, Local; Piperidines; Splenic Rupture; Sulfonamides; Treatment Failure; Withholding Treatment

Since the approval of ibrutinib for relapsed/refractory mantle cell lymphoma (MCL), the treatment of this rare mature B-cell neoplasm has taken a great leap forward. Despite promising efficacy of the Bruton tyrosine kinase inhibitor, resistance arises inevitably and the underlying mechanisms remain to be elucidated. Here, we aimed to decipher the response of a sensitive MCL cell line treated with ibrutinib using time-resolved single-cell RNA sequencing. The analysis uncovered five subpopulations and their individual responses to the treatment. The effects on the B cell receptor pathway, cell cycle, surface antigen expression, and metabolism were revealed by the computational analysis and were validated by molecular biological methods. The observed upregulation of B cell receptor signaling, crosstalk with the microenvironment, upregulation of

Topics: Adenine; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lymphoma, Mantle-Cell; Piperidines; Reproducibility of Results; RNA-Seq; Single-Cell Analysis; Time Factors

Topics: Adenine; Adult; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines

Ibrutinib, a bruton's tyrosine kinase (BTK) inhibitor, provokes robust clinical responses in aggressive mantle cell lymphoma (MCL), yet many patients relapse with lethal Ibrutinib-resistant (IR) disease. Here, using genomic, chemical proteomic, and drug screen profiling, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the aggressive phenotypes of IR. Accordingly, IR MCL cells are vulnerable to inhibitors of the transcriptional machinery and especially so to inhibitors of cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Further, CDK9 inhibition disables reprogrammed signaling circuits and prevents the emergence of IR in MCL. Finally, and importantly, we find that a robust and facile ex vivo image-based functional drug screening platform can predict clinical therapeutic responses of IR MCL and identify vulnerabilities that can be targeted to disable the evolution of IR.

Topics: Adenine; Animals; Cell Cycle Proteins; Cell Line, Tumor; Cyclin-Dependent Kinase 9; Drug Resistance, Neoplasm; Enhancer Elements, Genetic; Humans; Lymphoma, Mantle-Cell; Male; Mice, Inbred NOD; Mice, SCID; Piperidines; Protein Kinases; RNA Polymerase II; Signal Transduction; Transcription Factors; Transcription, Genetic; Transcriptome; Treatment Outcome

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR-S1 (a close analog of the clinical-stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model, OR-S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2-specific inhibitor GSK126, OR-S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR-S1-sensitive or insensitive MCL cell lines and showed that OR-S1 treatment modulated B-cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for the treatment of aggressive ibrutinib-resistant MCL via CDKN1C-mediated cell cycle arrest.

Topics: Adenine; Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p57; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Mantle-Cell; Mice; Piperidines; Polycomb Repressive Complex 2; Syndecan-1; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The efficacy and side effects of the second-time humanized CD19 chimeric antigen receptor (CD19-CAR) T-cell therapy after unsuccessful first-time anti-CD19-CAR T-cell therapy and subsequent ibrutinib salvage treatment were observed in patients with refractory B-cell lymphoma. In our study, 3 patients with refractory mantle cell lymphoma (MCL) and 4 patients with refractory follicular lymphoma (FL) reached stable disease (SD), partial remission (PR), or progression of disease (PD) after first-time humanized anti-CD19-CAR T-cell therapy. They received ibrutinib as a salvage treatment and kept an SD in the following 7-16 mo, but their disease progressed again during ibrutinib salvage treatment. All 7 patients received a second-time humanized anti-CD19-CAR T-cell therapy, which was the same as their first-time anti-CD19-CAR T-cell therapy. In total, 3 MCL patients and 3 FL patients reached complete response (CR) with the second-time anti-CD19-CAR T-cell therapy combined with ibrutinib, whereas 1 FL patient reached PR. There were no differences in the transduction efficiency and proliferation between the 2 instances of anti-CD19-CAR T-cell therapy. However, the second-time anti-CD19-CAR T-cell therapy led to higher peaks of anti-CD19-CAR T cells and anti-CD19-CAR gene copies, but also to higher grades of cytokine release syndrome (CRS) and more serious hematological toxicity. The successful outcome of the second-time anti-CD19-CAR T-cell therapy might suggest that the previous ibrutinib treatment improved the activities of anti-CD19-CAR T cells.

Topics: Adenine; Adult; Aged; Combined Modality Therapy; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Immunotherapy, Adoptive; Interleukin-6; Interleukin-8; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Receptors, Chimeric Antigen; Receptors, Interleukin-2; Remission Induction; Retreatment; Salvage Therapy; Treatment Outcome

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunophenotyping; Lymphoma, Mantle-Cell; Male; Middle Aged; Phenotype; Piperidines; Sulfonamides

Despite the unprecedented success of ibrutinib in lymphoma therapy, the development of ibrutinib resistance due to acquired BTK or PLCγ2 mutations has become a new clinical problem. However, not all resistance is mediated by these mutations and these mechanisms are poorly understood due to a lack of study tools that truly recapitulate this clinical scenario.. We established a novel patient-derived ibrutinib-resistant mantle cell lymphoma (MCL) line named MCIR1. Using immunological, molecular, and cytogenetic approaches, we comprehensively characterized MCIR1 and further demonstrated its utility in the study of resistance mechanisms and treatments to overcome this resistance.. We show that MCIR1 is a bona fide ibrutinib-resistant MCL cell line with normal BTK-/PLCγ2 but ibrutinib-resistant ERK1/2 and AKT1 signaling. RNA-Seq analysis revealed a robust non-canonical NF-kB signaling that drives the ibrutinib resistance. We also demonstrate the potential utility of a MCIR1-based cell and mouse model for the discovery of new treatments to overcome BTK inhibitor resistance.. We have established the first patient-derived ibrutinib-resistant MCL cell line MCIR1 that lacks BTK or PLCγ2 mutations but exhibits a hyperactive non-canonical NF-kB pathway. We further demonstrate its utility in the discovery and validation of new drugs to overcome this resistance.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; B-Lymphocytes; Cell Line, Tumor; Drug Resistance, Neoplasm; Founder Effect; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Mantle-Cell; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Biological; NF-kappa B; Phospholipase C gamma; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction

This study assessed treatment patterns in patients with mantle cell lymphoma (MCL) and compared health care resource utilization (HRU) and costs of ibrutinib with or without rituximab (I ± R) versus chemoimmunotherapy (CIT) in patients with relapsed/refractory MCL.. For this retrospective cohort study, adults with MCL observed between May 13, 2013, and June 30, 2019, were identified using Optum's de-identified Clinformatics Data Mart Database. Treatment patterns were described among patients who received ≥1 line of therapy (LOT). HRU and costs (payer's perspective) were compared between patients treated with I ± R and CIT in the second or later line (2L+) of therapy. To account for differences in baseline characteristics between the 2 cohorts, inverse probability of treatment weighting was used. Monthly HRU and costs starting from I ± R or CIT treatment initiation (index date) were compared during the first Oncology Care Model (OCM) episode (ie, first 6 months) postindex and during the observed duration of I ± R or CIT LOT (index LOT) using rate ratios (RRs) and mean monthly cost differences (MMCDs), respectively.. Among 1346 patients with ≥1 LOT (median follow-up, 15.3 months), 870 (64.6%) were treated with CIT in the first line. Only 348 (25.9%) had a 2L of therapy, of whom 110 (31.6%) were treated with CIT and 98 (28.2%) with an ibrutinib-based therapy. A total of 300 patients were included for the comparison of HRU and costs between 2L+ I ± R and 2L+ CIT. The weighted cohorts (after inverse probability of treatment weighting) included 149 patients treated with I ± R (mean age, 71.6 years; 73.7% men) and 151 treated with CIT (mean age, 71.5 years; 76.2% men). During the first OCM episode and during the index LOT, the I ± R cohort had significantly fewer monthly days with outpatient services compared to the CIT cohort (OCM, RR = 0.63 [P < 0.001]; index LOT, RR = 0.73 [P = 0.004]). Compared to the CIT cohort, the I ± R cohort incurred significantly higher monthly pharmacy costs (MMCDs: OCM, 9938 US dollars [USD] [P < 0.001]; index LOT, 8920 USD [P < 0.001]) that were fully offset by lower monthly medical costs (MMCDs: OCM, -19,373 USD [P < 0.001]; index LOT, -13,548 USD [P < 0.001]), resulting in monthly total health care cost savings (MMCDs, OCM, -9435 USD [P < 0.001]; index LOT , -4628 USD [P = 0.01]).. Over a median follow-up of 15.3 months, most patients with MCL were treated with CIT in the first line, and only one fourth had a 2L therapy. Patients with relapsed/refractory MCL treated with I ± R had significantly fewer days with outpatient services and lower monthly total health care costs versus those treated with CIT during the first OCM episode and the index LOT.

Topics: Adenine; Adult; Aged; Female; Health Care Costs; Humans; Lymphoma, Mantle-Cell; Male; Patient Acceptance of Health Care; Piperidines; Pyrimidines; Retrospective Studies

We herein report the case of a 73-year-old male patient who was diagnosed with leukemic non-nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second-line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single-agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2-4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression-free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab-intolerant patient with an ibrutinib-resistant MCL. This case suggests that obinutuzumab- and venetoclax-based combination therapy might be salvage therapy in patients with ibrutinib-resistant MCL.

Topics: Adenine; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Remission Induction; Salvage Therapy; Sulfonamides

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system, caused by reactivation of John Cunningham polyomavirus, affecting mainly patients in an immunocompromised state. Recently, drug-associated PML is gaining attention as more cases of PML in connection with the use of various immunomodulatory drugs emerge. Over the last couple of years, sporadic reports have occurred about a possible association between PML and the use of a new immunomodulatory drug, ibrutinib (Imbruvica), primarily indicated for the treatment of various B-cell malignancies.. Herein, we report a case of a 62-year-old female patient with bilateral mantle cell lymphoma of conjunctiva diagnosed at IVA clinical stage (according to the Ann Arbor staging of lymphomas) of the disease. As a first line of treatment, the patient was given 6 cycles of rituximab-based chemotherapy followed by a complete remission. Seven years later, the patient relapsed, at which point the treatment with ibrutinib was initiated. Three weeks after the initial dosage, the patient started to show signs of progressive neurological symptomatology and died 4 months thereafter due to bilateral bronchopneumonia. Due to unspecific MRI signs and negative PCR results, the diagnosis of PML was confirmed only postmortem.. This case report demonstrates a possible severe adverse effect of the immunomodulatory drug ibrutinib and the importance of a multidisciplinary approach in its diagnosis. Since PML is a rare but highly fatal disease, it is of utmost importance to be aware of the possible connection with the use of this drug to prevent missed or delayed diagnosis, considering that timely therapeutic intervention is crucial for improved prognosis.

Topics: Adenine; Fatal Outcome; Female; Humans; Leukoencephalopathy, Progressive Multifocal; Lymphoma, Mantle-Cell; Middle Aged; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Adult; Humans; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Piperidines; SOXC Transcription Factors

Therapy with irreversible Bruton's tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) is associated with bleeding.. To propose the predictive markers of such bleeding, as well as mechanisms responsible for decreased bleeding at later therapy stages.. We investigate platelet functional activity in 50 CLL and 16 MCL patients on ibrutinib using flow cytometry and light transmission aggregometry.. Prior to treatment, both patient groups had decreased platelet counts; impaired aggregation with adenosine diphosphate (ADP); and decreased binding of CD62P, PAC1, and annexin V upon stimulation. Bleeding in patients treated with ibrutinib was observed in 28 (56%) CLL patients, who had decreased aggregation with ADP and platelet count before therapy. Their platelet count on therapy did not change, platelet aggregation with ADP steadily improved, and aggregation with collagen first decreased and then increased in anticorrellation with bleeding. Bleeding in MCL was observed in 10 (62%) patients, who had decreased dense granule release before therapy. ADP and ristocetin induced platelet aggregation in ibrutinib-treated MCL patients increased on therapy, while collagen-induced aggregation evolved similarly to CLL patients.. Our results suggest that ibrutinib-dependent bleeding in CLL patients involves three mechanisms: decreased platelet count (the most important discriminator between bleeding and non-bleeding patients), impaired platelet response to ADP caused by CLL, and inhibition by ibrutinib. Initially, ibrutinib shifts the balance to bleeding, but then it is restored because of the improved response to ADP.

Topics: Adenine; Adult; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Cell Transdifferentiation; Cellular Reprogramming; Combined Modality Therapy; Epigenesis, Genetic; Epigenome; Gene Rearrangement; Genes, Immunoglobulin Heavy Chain; Humans; Immunotherapy; Lymph Nodes; Lymphoma, Mantle-Cell; Neoplasms, Second Primary; Piperidines; Receptors, Antigen, T-Cell; Rituximab; Sarcoma; Transplantation, Autologous; Tumor Cells, Cultured

Topics: Abnormal Karyotype; Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Biomarkers, Tumor; Bortezomib; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 8; Cyclin D1; Cytarabine; Drug Resistance, Neoplasm; Fatal Outcome; Gene Duplication; Genes, myc; Humans; Lymphoma, Mantle-Cell; Male; Oncogene Proteins, Fusion; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Rituximab; Translocation, Genetic

Rituximab is a well-established component of treatment regimens for B-cell non-Hodgkin lymphoma. Rituximab binds the CD20 antigen on the surface of B lymphocytes, causing an enhanced clearance of malignant and benign B cells. Thus, rituximab leads to depletion of normal B lymphocytes as well, which can cause substantial immunodeficiency. Ibrutinib inhibits the Bruton tyrosine kinase and thereby B-cell activity. It is used for the treatment of different B-lymphocyte malignancies, such as mantle cell lymphoma. Recently, the combination of both drugs has been tested in various clinical scenarios.. We present a case of disseminated enterovirus infection resulting from combined rituximab and ibrutinib maintenance treatment in a 57-year-old Caucasian patient. with mantle cell lymphoma. Initially presenting with myositis symptoms, further diagnostic investigation revealed myocarditis, enteritis, myeloencephalitis, and hepatitis. These organ manifestations led to potentially life-threatening complications such as rhabdomyolysis, delirium, and heart rhythm disturbances. After treatment with high-dose intravenous immunoglobulins, virus clearance was achieved and organ functions could be restored.. This case emphasizes the risk of combined therapy with rituximab/ibrutinib for severe immune-related side effects with the necessity of continuous patient monitoring. High-dose intravenous therapy should be considered as treatment for severe enterovirus infection. In severe enterovirus infections, we recommend subtyping for the development of efficient preventive and therapeutic strategies.

Topics: Adenine; Adult; Antigens, CD20; Enterovirus Infections; Humans; Lymphoma, Mantle-Cell; Middle Aged; Piperidines; Rituximab

Combination venetoclax plus ibrutinib for the treatment of mantle cell lymphoma (MCL) has demonstrated efficacy in the relapsed or refractory setting; however, the long-term impact on patient immunology is unknown. In this study, changes in immune subsets of MCL patients treated with combination venetoclax and ibrutinib were assessed over a 4-year period. Multiparameter flow cytometry of peripheral blood mononuclear cells showed that ≥12 months of treatment resulted in alterations in the proportions of multiple immune subsets, most notably CD4+ and CD8+ effector and central memory T cells and natural killer cells, and normalization of T-cell cytokine production in response to T-cell receptor stimulation. Gene expression analysis identified upregulation of multiple myeloid genes (including S100 and cathepsin family members) and inflammatory pathways over 12 months. Four patients with deep responses stopped study drugs, resulting in restoration of normal immune subsets for all study parameters except myeloid gene/pathway expression, suggesting long-term combination venetoclax and ibrutinib irreversibly affects this population. Our findings demonstrate that long-term combination therapy is associated with immune recovery in MCL, which may allow responses to subsequent immunotherapies and suggests that this targeted therapy results in beneficial impacts on immunological recovery. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

Topics: Adenine; Adult; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukocytes, Mononuclear; Lymphoma, Mantle-Cell; Piperidines; Pyrimidines; Sulfonamides

Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon. Here we present the case of a 70-year-old male patient who was diagnosed with classic MCL in 2015. The patient achieved complete remission (CR) in 2017 but relapsed with CNS involvement in 2019. He entered a deep coma and was treated with ibrutinib (560 mg daily) via nasogastric tube. He regained full consciousness after 15 days, and the presence of lymphoma cells in his cerebrospinal fluid disappeared 3 months later. We believe that ibrutinib administration via nasogastric tube is effective for MCL patients with CNS relapse.

Topics: Adenine; Aged; Central Nervous System; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Recurrence, Local; Piperidines

Topics: Adenine; Adult; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton's tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19'c, 21c and 21'c showed potent effect in MCL cells with IC

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Cell Proliferation; Drug Design; Half-Life; Humans; Lymphoma, Mantle-Cell; Microsomes, Liver; Pyrazoles; Structure-Activity Relationship

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Indoles; Lymphoma, Mantle-Cell; Molecular Structure; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Adenine; Aged; Antineoplastic Agents; Eye Neoplasms; Humans; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Male; Piperidines; Pyrazoles; Pyrimidines; Treatment Outcome; Visual Acuity

Inhibitors of Bruton tyrosine kinase (BTK), a kinase downstream of BCR, display remarkable activity in a subset of mantle cell lymphoma (MCL) patients, but the drug resistance remains a considerable challenge. In this study, we demonstrate that aberrant expression of ROR1 (receptor tyrosine kinase-like orphan receptor 1), seen in a large subset of MCL, results in BCR/BTK-independent signaling and growth of MCL cells. ROR1 forms a functional complex with CD19 to persistently activate the key cell signaling pathways PI3K-AKT and MEK-ERK in the BCR/BTK-independent manner. This study demonstrates that ROR1/CD19 complex effectively substitutes for BCR-BTK signaling to promote activation and growth of MCL cells. Therefore, ROR1 expression and activation may represent a novel mechanism of resistance to inhibition of BCR/BTK signaling in MCL. Our results provide a rationale to screen MCL patients for ROR1 expression and to consider new therapies targeting ROR1 and/or CD19 or their downstream signaling pathways for MCL-expressing ROR1.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor Tyrosine Kinase-like Orphan Receptors; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell; Signal Transduction; Structure-Activity Relationship

Ibrutinib is highly effective in patients with relapsed or refractory mantle cell lymphoma (MCL) in major clinical trials. Although there has been a dramatic improvement in survival outcomes in the salvage setting, nonresponders to ibrutinib have a bleak prognosis. Therefore, this retrospective study was conducted to identify the most appropriate therapeutic strategy and prognosis-related factors to predict the response of patients with relapsed or refractory MCL to ibrutinib monotherapy. Thirty-three consecutive refractory or relapsed MCL patients treated with ibrutinib were analyzed in this study. The median overall survival (OS) and progression-free survival (PFS) after initiation of ibrutinib were 35.1 months and 27.4 months, respectively. Risk factor analysis showed that high risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI) and nonresponse to ibrutinib at the first three cycles were significantly associated with inferior OS. Poor PFS was associated with high-risk biologic MIPI, prior bendamustine exposure, and nonresponse to ibrutinib during the first three cycles. After ibrutinib failure, primary nonresponders had poorer OS and PFS than inconsistent responders. The overall response rate for the first salvage therapy was only 33%, with a median TTP of 3.2 months. There was no effective therapeutic strategy except for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies, such as selecting inconsistent responders for earlier allo-HSCT.

Topics: Adenine; Adult; Aged; Antineoplastic Agents; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Salvage Therapy; Treatment Outcome

There are limited data on treatment patterns, adverse events (AEs), and economic burden in younger, commercially insured patients treated for mantle cell lymphoma (MCL).. Adults with ≥1 treatment for MCL between 1 November 2013-31 December 2017 were identified from IQVIA Real-World Data Adjudicated Claims-US; index date was first treatment. Patients carried ≥1 MCL diagnosis, were newly treated, and were enrolled continuously for ≥12 months prior to and ≥30 days following index. Patients receiving the four most common MCL regimens were included. Measures included frequency of incident AEs, resource use, and costs overall and by number of AEs. Adjusted logistic regression and generalized linear modeling evaluated risk of hospitalization and all-cause costs per patient per month (PPPM).. Two thousand five hundred and nine treated patients had a drug-specific code and were classified to a specific treatment regimen. Of those patients, 1785 patients received at least one of the four most commonly used MCL regimens (R-CHOP, rituximab monotherapy, B-R, and ibrutinib) at some point over follow-up (median 23 months). R-CHOP was the most common regimen observed in the first line (26%), followed by rituximab monotherapy (19%), B-R (15%), and ibrutinib (5%). The median age was 57 years; median Charlson Comorbidity Index was 0. Among patients receiving the four most common regimens, 63% of patients experienced ≥1 incident AE (R-CHOP 77%, B-R 58%, and ibrutinib 52%). An increasing number of incident AEs was associated with increased hospitalization risk (odds ratio = 2.4; 95% Confidence Interval [CI] 2.1-2.7) and increased mean costs PPPM (cost ratio = 1.1; 95% CI 1.1-1.2).. This is the largest study describing treatment patterns and clinical and economic impact of MCL treatment. The most common regimens were R-CHOP, rituximab monotherapy, B-R, and ibrutinib. The majority of treated patients experienced at least one incident AE, with hospitalization risk and all-cause costs increasing as the number of AEs increased.

Topics: Adenine; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cost of Illness; Cyclophosphamide; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Health Care Costs; Health Care Rationing; Hospitalization; Humans; Incidence; Insurance, Health; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Practice Patterns, Physicians'; Prednisone; Pyrazoles; Pyrimidines; Retrospective Studies; Rituximab; Treatment Outcome; United States; Vincristine; Young Adult

Topics: Adenine; Aged; Cardiomyopathies; Humans; Lymphoma, Mantle-Cell; Male; Mesentery; Piperidines; Pyrazoles; Pyrimidines

A 65-year-old man with multiple lymphadenopathy presented to our hospital and was diagnosed with StageIVA blastoid-variant mantle cell lymphoma (MCL), with a Ki-67 index of 93%. Partial response was achieved after four courses of CHASER (cyclophosphamide, cytarabine, dexamethasone, etoposide, and rituximab) chemotherapy, and complete response was achieved after autologous stem cell transplantation (ASCT). Six months after ASCT, the MCL relapsed with occurrence of tumors one on the left upper arm and one in the cerebrum, which were proved to be resistant to the conventional chemotherapy and progressed rapidly. These tumors disappeared with scarring following the local irradiation (45 Gy). However, the unirradiated regions became enlarged. The bulky abdominal lesion was treated with local irradiation (41 Gy) combined with 560 mg of ibrutinib but still resulted in progressive disease 1 month after initiating the ibrutinib treatment. Finally, the patient died 5 months post-relapse. The prognosis of patients with blastoid-variant MCL with high Ki-67 index is extremely poor. Furthermore, the risk of central nervous system (CNS) involvement is very high. Therefore, ibrutinib maintenance therapy post ASCT might be a treatment option to prevent CNS involvement. Further efforts might be needed to improve the outcomes of blastoid-variant MCL with a high Ki-67 index.

Topics: Adenine; Aged; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Transplantation, Autologous

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Humans; Lymphoma, Mantle-Cell; Male; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Survival Rate; TOR Serine-Threonine Kinases

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Dopamine D2 Receptor Antagonists; Doxorubicin; Drug Resistance, Neoplasm; Drug Substitution; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Male; Molecular Targeted Therapy; Neoplasm Proteins; Oligopeptides; Piperidines; Prednisone; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Rituximab; Stress, Physiological; Vincristine

The dysregulation of PI3K signaling has been implicated as an underlying mechanism associated with resistance to Bruton's tyrosine kinase inhibition by ibrutinib in both chronic lymphocytic leukemia and mantle cell lymphoma (MCL). Ibrutinib resistance has become a major unmet clinical need, and the development of therapeutics to overcome ibrutinib resistance will greatly improve the poor outcomes of ibrutinib-exposed MCL patients. CUDC-907 inhibits both PI3K and HDAC functionality to exert synergistic or additive effects. Therefore, the activity of CUDC-907 was examined in MCL cell lines and patient primary cells, including ibrutinib-resistant MCL cells. The efficacy of CUDC-907 was further examined in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model. The molecular mechanisms by which CUDC-907 dually inhibits PI3K and histone deacetylation were assessed using reverse protein array, immunoblotting, and chromatin immunoprecipitation (ChIP) coupled with sequencing. We showed evidence that CUDC-907 treatment increased histone acetylation in MCL cells. We found that CUDC-907 caused decreased proliferation and increased apoptosis in MCL in vitro and in vivo MCL models. In addition, CUDC-907 was effective in inducing lethality in ibrutinib-resistant MCL cells. Lastly, CUDC-907 treatment increased histone acetylation in MCL cells. Overall, these studies suggest that CUDC-907 may be a promising therapeutic option for relapsed or resistant MCL.

Topics: Adenine; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Histones; Humans; Lymphoma, Mantle-Cell; Male; Mice; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pyrazoles; Pyrimidines; Signal Transduction; Xenograft Model Antitumor Assays

Topics: Adenine; Clinical Trials as Topic; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Salvage Therapy; Survival Rate

Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.

Topics: Activating Transcription Factor 3; Adenine; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Chromatin; Chromosomal Proteins, Non-Histone; Circulating Tumor DNA; Cohort Studies; DNA Helicases; Drug Resistance, Neoplasm; Genome, Human; Humans; Lymphoma, Mantle-Cell; Models, Biological; Mutation; Nuclear Proteins; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Sulfonamides; Transcription Factors; Treatment Outcome

The covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it is not selective for BTK, and multiple mechanisms of resistance, including the C481S-BTK mutation, can compromise its efficacy. We hypothesized that small-molecule-induced BTK degradation may overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that BTK degradation results in potent suppression of signaling and proliferation in cancer cells and that BTK degraders efficiently degrade C481S-BTK. Moreover, we discovered DD-03-171, an optimized lead compound that exhibits enhanced antiproliferative effects on mantle cell lymphoma (MCL) cells in vitro by degrading BTK, IKFZ1, and IKFZ3 as well as efficacy against patient-derived xenografts in vivo. Thus, "triple degradation" may be an effective therapeutic approach for treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Cell Proliferation; Humans; Ikaros Transcription Factor; Lymphoma, Mantle-Cell; Mice; Mice, Inbred NOD; Mice, SCID; Piperidines; Proteolysis; Pyrazoles; Pyrimidines; Signal Transduction; Small Molecule Libraries; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Topics: Adenine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell

Topics: Adenine; Antineoplastic Agents, Immunological; Gene Rearrangement; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Mutation; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Tumor Suppressor Protein p53

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Synergism; Humans; Hydrazines; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Niacinamide; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Triazoles; Tumor Cells, Cultured

Topics: Adenine; Aged; Antineoplastic Agents; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Serositis; Treatment Outcome; United States

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Biomarkers, Tumor; CD79 Antigens; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Leukocytes, Mononuclear; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Receptors, Antigen, B-Cell; Recurrence; Stem Cell Transplantation; Syk Kinase; Treatment Outcome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Drug Resistance, Neoplasm; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Mutation; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzeneacetamides; Biomarkers, Tumor; Cell Line, Tumor; Glutaminase; Humans; Lymphoma, Mantle-Cell; Metabolic Networks and Pathways; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction; Thiadiazoles

The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation, and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. Here, we focused on the interplay between MCL cells and the associated monocytes/macrophages. Using circulating MCL cells (n = 58), we showed that, through the secretion of CSF1 and, to a lesser extent, IL-10, MCL polarized monocytes into specific CD163

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Interleukin-10; Lymphoma, Mantle-Cell; Macrophages; Male; Monocytes; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Cell Surface; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Tumor Microenvironment

A 37-year-old male was admitted with an atypical presentation of central nervous system (CNS) aspergillosis while on ibrutinib therapy for a CNS relapse of mantle cell lymphoma. This case highlights the importance of a high clinical suspicion of opportunistic infections in patients receiving small-molecule kinase inhibitors. This report includes a review of reported cases of Aspergillus infections in patients receiving ibrutinib and the shared features of these cases.

Topics: Adenine; Adult; Humans; Lymphoma, Mantle-Cell; Male; Neuroaspergillosis; Piperidines; Pyrazoles; Pyrimidines; Recurrence

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton's tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

Topics: Adenine; Animals; Cell Line, Tumor; DNA Copy Number Variations; Drug Resistance, Neoplasm; Exome Sequencing; Lymphoma, Mantle-Cell; Mice; Molecular Targeted Therapy; Mutation; Oxidative Phosphorylation; Piperidines; Pyrazoles; Pyrimidines; Signal Transduction; Transcriptome

Mantle cell lymphoma (MCL) is typically an aggressive and rare form of non-Hodgkin lymphoma (NHL) with a poor prognosis despite recent advances in immunochemotherapy and targeted therapeutics against NHL. New therapeutic agents are needed for MCL. In this study, we generated a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated QS1189, and confirmed its anti-cancer effects towards MCL and other lymphomas. QS1189 was highly selective for CDK7 and showed potent anticancer effects in MCL compared to other targeted therapeutic agents, such as ibrutinib and venetoclax. Consistent with a conventional CDK7 inhibitor, QS1189 treatment significantly decreased phosphorylation of the carboxyl-terminal domain of RNA polymerase II and transcription-associated genes. QS1189 induced cell cycle arrest at the G2/M phase and apoptosis. Interestingly, QS1189 overcame the acquired resistance to venetoclax, which is mediated by Bcl-xL. Similarly, QS1189 showed potent tumour cell growth inhibition of various lymphomas. Thus, CDK7 might be a suitable therapeutic target for inhibiting lymphoma, and QS1189 is a promising therapeutic option for various lymphomas and cells with acquired resistance to targeted therapy.

Topics: Adenine; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Drug Synergism; Humans; Lymphoma, Mantle-Cell; Phosphorylation; Piperidines; Pyrazoles; Pyrimidines; RNA Polymerase II; Sulfonamides; Triazoles

With the advent of proteasome inhibitors (bortezomib) and pleiotropic pathway modulators which target cereblon E3 ligase (lenalidomide), the ubiquitin-proteasome system has emerged as a tractable target in non-Hodgkin lymphoma and multiple myeloma. Here we report that TAK-243, a small molecule inhibitor of the ubiquitin-activating enzyme (UAE), induced ER stress and the unfolded protein response in primary chronic lymphocytic leukemia cells, facilitating cell death. Moreover, targeting UAE was effective in ibrutinib-resistant mantle cell lymphoma cell lines and primary cells

Topics: Adenine; Animals; Apoptosis; Biomarkers; Cell Line, Tumor; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Mice; Piperidines; Proteasome Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Ubiquitin-Activating Enzymes; Unfolded Protein Response

There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, β blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.

Topics: Adenine; Age Factors; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Aspirin; Atrial Fibrillation; Atrial Flutter; Female; Humans; Hypertension; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Multivariate Analysis; Piperidines; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Female; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Rituximab

Topics: Acute Disease; Adenine; Female; Flank Pain; Hematoma; Humans; Kidney Diseases; Lymphoma, Mantle-Cell; Middle Aged; Perinephritis; Piperidines; Pyrazoles; Pyrimidines; Thrombocytopenia

Topics: Adenine; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retreatment; Salvage Therapy; Treatment Outcome

Mantle cell lymphoma and other lymphoma subtypes often spread to the bone marrow, and stromal interactions mediated by focal adhesion kinase frequently enhance survival and drug resistance of the lymphoma cells. To study the role of focal adhesion kinase in mantle cell lymphoma, immunohistochemistry of primary cases and functional analysis of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells co-cultured with bone marrow stromal cells (BMSC) using small molecule inhibitors and RNAi-based focal adhesion kinase silencing was performed. We showed that focal adhesion kinase is highly expressed in bone marrow infiltrates of mantle cell lymphoma and in mantle cell lymphoma cell lines. Stroma-mediated activation of focal adhesion kinase led to activation of multiple kinases (AKT, p42/44 and NF-κB), that are important for prosurvival and proliferation signaling. Interestingly, RNAi-based focal adhesion kinase silencing or inhibition with small molecule inhibitors (FAKi) resulted in blockage of targeted cell invasion and induced apoptosis by inactivation of multiple signaling cascades, including the classic and alternative NF-κB pathway. In addition, the combined treatment of ibrutinib and FAKi was highly synergistic, and ibrutinib resistance of mantle cell lymphoma could be overcome. These data demonstrate that focal adhesion kinase is important for stroma-mediated survival and drug resistance in mantle cell lymphoma, providing indications for a targeted therapeutic strategy.

Topics: Adenine; Bone Marrow; Cell Line, Tumor; Cell Movement; Drug Resistance, Neoplasm; Female; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Gene Expression; Humans; Immunohistochemistry; Lymphoma, Mantle-Cell; Male; NF-kappa B; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction; Tumor Microenvironment

We researched into the effect and mechanism of AC0010, a novel BTK inhibitor, in MCL, and compared its efficacy and safety with Ibrutinib to develop a preclinical study for the future therapy of MCL.. MTS assay was used to detect the growth inhibition caused by AC0010 and Ibrutinib, respectively, in MCL cell lines (Jeko-1 and JVM-2), primary MCL cells, and normal peripheral lymphocytes. Apoptosis of Jeko-1 and JVM-2 after exposure into AC0010 and Ibrutinib was conducted by flow cytometry; the expression of apoptosis-related proteins was checked by Western blot. q-PCR and Western blot were applied to examine the expression of BTK and p-BTK at mRNA and protein level as well as the BTK-ralated signaling pathways. MCL xenograft was developed to testify the efficacy and safety of AC0010 in vivo.. In contrast with Ibrutinib, AC0010 proved to be more toxic to MCL cells in vitro (p < 0.01) with no augment in cytotoxicity to normal peripheral lymphocytes, and it can induce obvious apoptosis in MCL cell lines (p < 0.01) through caspase family and Bcl-2 family. AC0010 at 300 mg/kg can prolong the survival rate in MCL xenograft (p < 0.01). The phosphorylation of BTK is inhibited by AC0010 following simultaneously inhibition of BCR-BTK and PI3K/AKT signaling pathway in MCL cells.. AC0010 is a novel BTK inhibitor of great efficacy and safety in MCL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Female; Humans; Lymphoma, Mantle-Cell; Mice; Mice, SCID; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Xenograft Model Antitumor Assays

Topics: Adenine; Clinical Trials as Topic; Humans; Lymphoma, Mantle-Cell; Neoplasm Grading; Piperidines; Pyrazoles; Pyrimidines

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton's tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment.. To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors.. We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects.. The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib.. The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro-survival pathways (by ibrutinib) might offer a promising new therapeutic strategy for MCL patients.

Topics: Adenine; Cell Line, Tumor; Checkpoint Kinase 1; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here, we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib-mediated downregulation of PI3K/AKT signaling. Importantly, the stromal cell-mediated ibrutinib resistance was overcome

Topics: Adenine; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Drug Resistance, Neoplasm; Humans; Interleukin Receptor Common gamma Subunit; Lymphoma, Mantle-Cell; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Piperidines; Pyrazoles; Pyrimidines; Stromal Cells; Thiazoles; Tumor Burden; Xenograft Model Antitumor Assays

Ibrutinib is a Bruton tyrosine kinase inhibitor that is used for the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell lymphoma. Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment.. We reviewed the electronic medical records of patients with lymphoid cancer at Memorial Sloan Kettering Cancer Center who received ibrutinib during a 5-year period from 1 January 2012 to 31 December 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by means of univariate and multivariate analyses.. We analyzed findings in 378 patients with lymphoid cancer who received ibrutinib. The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and invasive fungal infections (IFIs) in 16 (37.2%) .The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%).. Patients with lymphoid cancer receiving ibrutinib treatment are at risk for serious infections, including IFIs.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Bacterial Infections; Electronic Health Records; Female; Humans; Invasive Fungal Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphopenia; Male; Middle Aged; New York; Opportunistic Infections; Piperidines; Pyrazoles; Pyrimidines; Risk Factors; Young Adult

The treatment landscape for mantle cell lymphoma (MCL) has changed dramatically in recent years, with findings from clinical trials reporting improvements in survival. Data on the general patient population are, however, sparse; and it is unclear whether the effects observed in clinical trials have translated into the real-world setting. To investigate this, we examined first-line and relapsed/refractory (RR) disease management in 335 MCL patients diagnosed between 2004 and 2015 in an established population-based patient cohort, along with data on demographic, diagnostic and prognostic factors. Marked treatment and survival changes were observed; first-line rituximab immunotherapy, for example, increased from 32% to 86% over the 11-year period, and median survival increased from 2·0 years among those first treated in 2004-2011 to 3·5 years among those treated in 2012-2015. Outcomes for RR disease also improved, from 8 months in 2004-2011 to 16·8 months in 2012-2015, coinciding with the introduction of agents, such as bendamustine and ibrutinib. Encouragingly, improvements were seen across all ages; 1-year overall survival among patients over 70 years treated for RR disease almost doubled. Our analyses underscore the importance of monitoring the impact of treatment changes in the real-world setting.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Bendamustine Hydrochloride; Disease-Free Survival; Female; Humans; Immunotherapy; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Survival Rate; United Kingdom

Mantle cell lymphoma (MCL) presents a therapeutic challenge. The B cell targeting agent, ibrutinib, is currently one of the most effective second-line therapies for MCL, but frequently leads to development of drug resistance, and short overall survival time upon relapse. Olaparib targets tumor cells with deficiencies in single-strand DNA break repair and thus may slow the development of genetic drug resistance. We found that the olaparib-ibrutinib combination significantly inhibits cell culture growth compared to either drug alone in two genetically distinct MCL cell lines. Moreover, these inhibitory effects are either additive or synergistic, depending on genetic background. Culture growth is inhibited due to increases in apoptosis, cell death, and cell cycle arrest, and the magnitude of each is cell line dependent. The additive and synergistic inhibition of this combination additionally supports a therapeutic strategy involving lower dosing of each drug to reduce potential side effects.

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Humans; Lymphoma, Mantle-Cell; Phthalazines; Piperazines; Piperidines; Pyrazoles; Pyrimidines; Tumor Cells, Cultured

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.

Topics: Adenine; Animals; Benzodioxoles; Cell Line, Tumor; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Lymphoma, Mantle-Cell; Male; Mice; Piperidines; Proto-Oncogene Proteins c-myc; Purines; Pyrazoles; Pyrimidines; Xenograft Model Antitumor Assays

Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Disease-Free Survival; Female; Histone-Lysine N-Methyltransferase; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Mutation; Piperidines; Pyrazoles; Pyrimidines; Repressor Proteins; Survival Rate; Tumor Suppressor Protein p53

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

Topics: Adenine; Aged; Antineoplastic Agents; Humans; Iris; Iris Neoplasms; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Treatment Outcome; Visual Acuity

Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader antitumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell-cycle arrest and XPO-1 knockdown also retarded cell growth. Furthermore, downregulation of the NFκB gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NFκB was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IκB that was accompanied by the reduction of DNA-binding activity of NFκB, suggesting that NFκB is trapped in an inhibitory complex. Coimmunoprecipitation confirmed that p65 of NFκB and IκB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IκB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NFκB pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NFκB inhibition.

Topics: Adenine; Apoptosis; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Exportin 1 Protein; Humans; Hydrazines; I-kappa B Proteins; Karyopherins; Lymphoma, Mantle-Cell; NF-kappa B; Piperidines; Protein Subunits; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Triazoles

The cellular delivery of nucleotides through various pronucleotide strategies has expanded the utility of nucleosides as a therapeutic class. Although highly successful, the highly popular ProTide system relies on a four-step enzymatic and chemical process to liberate the corresponding monophosphate. To broaden the scope and reduce the number of steps required for monophosphate release, we have developed a strategy that depends on initial chemical activation by a sulfur atom of a methylthioalkyl protecting group, followed by enzymatic hydrolysis of the resulting phosphoramidate monoester. We have employed this ProTide strategy for intracellular delivery of a nucleotide antagonist of eIF4E in mantle cell lymphoma (MCL) cells. Furthermore, we demonstrated that chemical inhibition of cap-dependent translation results in suppression of c-Myc expression, increased p27 expression, and enhanced chemosensitization to doxorubicin, dexamethasone, and ibrutinib. In addition, the new ProTide strategy was shown to enhance oral bioavailability of the corresponding monoester phosphoramidate.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase Inhibitor p27; Drug Design; Eukaryotic Initiation Factor-4E; Female; Humans; Lymphoma, Mantle-Cell; Nuclear Cap-Binding Protein Complex; Peptides; Proto-Oncogene Proteins c-myc; Rats; Rats, Sprague-Dawley

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Burkitt Lymphoma; Disease Models, Animal; Drug Discovery; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Mice; Phosphatidylinositol 3-Kinases; Piperidines; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction; Xenograft Model Antitumor Assays

The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies.

Topics: Adenine; Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Piperidines; Protein Kinases; Proteome; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; Tumor Microenvironment; Xenograft Model Antitumor Assays

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

Topics: Adenine; Aged; Cryptococcosis; Humans; Immunocompromised Host; Lung Diseases, Fungal; Lymphoma, Mantle-Cell; Maintenance Chemotherapy; Male; Neoplasm Staging; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Solitary Pulmonary Nodule; Tomography, X-Ray Computed

The observational MCL-004 study evaluated outcomes in patients with relapsed/refractory mantle cell lymphoma who received lenalidomide-based therapy after ibrutinib failure or intolerance.. The primary endpoint was investigator-assessed overall response rate based on the 2007 International Working Group criteria.. Of 58 enrolled patients (median age, 71 years; range, 50-89), 13 received lenalidomide monotherapy, 11 lenalidomide plus rituximab, and 34 lenalidomide plus other treatment. Most patients (88%) had received ≥ 3 prior therapies (median 4; range, 1-13). Median time from last dose of ibrutinib to the start of lenalidomide was 1.3 weeks (range, 0.1-21.7); 45% of patients had partial responses or better to prior ibrutinib. Primary reasons for ibrutinib discontinuation were lack of efficacy (88%) and ibrutinib toxicity (9%). After a median of two cycles (range, 0-11) of lenalidomide-based treatment, 17 patients responded (8 complete responses, 9 partial responses), for a 29% overall response rate (95% confidence interval, 18-43%) and a median duration of response of 20 weeks (95% confidence interval, 2.9 to not available). Overall response rate to lenalidomide-based therapy was similar for patients with relapsed/progressive disease after previous response to ibrutinib (i.e., ≥PR) versus ibrutinib-refractory (i.e., ≤SD) patients (30 versus 32%, respectively). The most common all-grade treatment-emergent adverse events after lenalidomide-containing therapy (n = 58) were fatigue (38%) and cough, dizziness, dyspnea, nausea, and peripheral edema (19% each). At data cutoff, 28 patients have died, primarily due to mantle cell lymphoma.. Lenalidomide-based treatment showed clinical activity, with no unexpected toxicities, in patients with relapsed/refractory mantle cell lymphoma who previously failed ibrutinib therapy.. Clinicaltrials.gov identifier NCT02341781 . Date of registration: January 14, 2015.

Topics: Adenine; Aged; Aged, 80 and over; Disease Progression; Female; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Thalidomide

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Drug Synergism; Humans; Lymphoma, Mantle-Cell; Nuclear Receptor Subfamily 4, Group A, Member 1; Oncogenes; Piperidines; Pyrazoles; Pyrimidines

Mantle cell lymphoma accounts for 5-7% of all non-Hodgkin's lymphomas. Under the current WHO classification, it is categorized as an indolent B cell lymphoma, but has an aggressive clinical course. New insights into leukemogenic molecular pathways of mantle cell lymphoma have uncovered unique therapeutic targets. Ibrutinib, a Bruton's tyrosine kinase inhibitor, is the newest drug in the arsenal that has shown promising efficacy in relapsed mantle cell lymphoma. Long-term studies have shown that grade 3 or 4 adverse events are infrequent. Asymptomatic lymphocytosis is frequently seen with ibrutinib use in mantle cell lymphoma; however, tumor lysis syndrome is an extremely rare complication. To date, only two patients with ibrutinib-associated tumor lysis syndrome in mantle cell lymphoma have been described in a long-term follow-up study. Both patients met laboratory criteria for tumor lysis syndrome, however, but did not develop clinical tumor lysis syndrome. We, here describe a patient with relapsed mantle cell lymphoma who developed clinical tumor lysis syndrome with ibrutinib monotherapy.

Topics: Adenine; Aged; Antineoplastic Agents; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tumor Lysis Syndrome

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Male; Middle Aged; Multicenter Studies as Topic; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Treatment Outcome; United Kingdom

We describe a 71-year-old-patient receiving antiplatelet therapy and being attended by emergency medical services for psychomotor retardation and gait disturbance. An emergency computed tomographic scan showed a bilateral subacute hematoma. The patient reported a fall 2 weeks earlier. We performed bilateral drills and saw a solid mass that was biopsied. The patient had a history of mantle cell lymphoma (MCL) in complete remission (results of bone marrow biopsy and whole-body positron emission tomography-computed tomography scans were normal 6 months earlier). We diagnosed an intracranial MCL by immunohistochemistry, flow cytometry, and fluorescence in situ hybridization. We performed magnetic resonance imaging. The results of a new bone marrow biopsy were positive for recurrence of MCL. MCL constitutes approximately 5%-6% of non-Hodgkin lymphoma. The incidence of central nervous system (CNS) involvement between MCLs is 4.1%. After a review of the literatures we found small series comprising 3-5 cases and a multicenter study with 57 cases. Until now, the median survival was 3.7 months. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, has demonstrated efficacy and CNS penetration in relapsed or refractory MCL with rapid and complete response even after 1 year of follow-up. Our patient received ibrutinib and had a complete response at 3 months, which was maintained to the present (6 months). After a review of the literature, we found different pathologies that can mimic subdural hematomas. However, this is the first report of a lymphoma with CNS involvement mimicking bilateral subdural hematomas. This report contributes to the knowledge of lymphomas with CNS involvement. Its strange radiographic appearance and histologic type make it unique.

Topics: Adenine; Aged; Antineoplastic Agents; Brain Neoplasms; Diagnosis, Differential; Hematoma, Subdural; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Piperidines; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed

Ibrutinib has demonstrated significant activity in relapsed/refractory mantle cell lymphoma (MCL) in clinical trials. However, the impact of hematopoietic cell transplantation on the outcomes of ibrutinib and the predictive factors for ibrutinib response has not been well studied. Hence, we conducted a multicenter retrospective study of MCL patients who received ibrutinib to (1) determine the overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of ibrutinib in routine clinical practice, (2) examine characteristics predictive of response to ibrutinib therapy, and (3) describe the outcomes of patients failing ibrutinib. Ninety-seven patients met the eligibility criteria. Overall response rate and median DOR to ibrutinib were 65% and 17 months, respectively. Only lack of primary refractory disease was predictive of ibrutinib response on multivariate analysis. Twenty-nine patients received postibrutinib therapies, with an ORR of 48% and a median DOR of 3 months. The median OS and PFS for the entire group (n = 97) was 22 and 15 months, respectively. On multivariate analysis, ibrutinib response, low MCL international prognostic index, and absence of primary refractory disease were predictors of better PFS, while ibrutinib response and Eastern Cooperative Oncology Group performance status ≤1 were predictors of better OS. The median OS postibrutinib failure was 2.5 months. Our results confirm the high ORR and DOR of ibrutinib in MCL and that prior hematopoietic cell transplantation does not negatively influence ibrutinib outcomes. Survival following ibrutinib failure is poor with no specific subsequent therapy showing superior activity in this setting. As a result, for select (transplant eligible) patients, allogeneic transplant should be strongly considered soon after ibrutinib response is documented to provide durable responses.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Recurrence; Treatment Outcome

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

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Delayed Diagnosis; Disease Susceptibility; Disseminated Intravascular Coagulation; Fatal Outcome; Humans; Immunocompromised Host; Lymphoma, Mantle-Cell; Male; Meningitis, Bacterial; Neoplasm Proteins; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Risk Factors; Shock, Septic

Topics: Adenine; Antineoplastic Agents; Female; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Sirolimus

Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval [CI], 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Disease Progression; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Mutation; Piperidines; Proportional Hazards Models; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Retrospective Studies; Treatment Outcome

Ibrutinib is a recently approved oral anticancer agent with pharmacokinetics that is very sensitive to metabolic inhibition. We report a serious side effect of ibrutinib potentially attributable to interaction with the moderate CYP3A4 inhibitor verapamil.. A patient with mantle cell lymphoma was admitted to our emergency department with severe diarrhoea. During a prescription review, the clinical pharmacist identified a potential drug interaction between ibrutinib and verapamil present in a branded combination product also containing trandolapril. Ibrutinib was discontinued for 5 days, and verapamil was stopped. Lercanidipine 10 mg daily was prescribed as an alternative antihypertensive drug. The patient was discharged after 3 days with symptomatic treatment for his diarrhoea. Three months later, the patient maintained control with ibrutinib and olmesartan, but without verapamil.. This is the first description of a serious side effect of ibrutinib likely due to an interaction with the CYP3A4 inhibitor verapamil. Prescriptions of ibrutinib must be carefully checked to identify possible interactions with CYP3A4 inhibitors and patients monitored accordingly.

Topics: Adenine; Aged; Antihypertensive Agents; Antineoplastic Agents; Cytochrome P-450 CYP3A Inhibitors; Diarrhea; Dihydropyridines; Drug Interactions; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Verapamil

Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner.. MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models.. MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P < 0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80% to 100% of mice in the CTL019 + ibrutinib arm and 0% to 20% of mice in the CTL019 arm, respectively, remained in long-term remission (P < 0.05).. Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients with MCL and other types of B-cell lymphoma. Clin Cancer Res; 22(11); 2684-96. ©2016 AACR.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Cell Line, Tumor; Combined Modality Therapy; Drug Resistance, Neoplasm; Humans; Immunotherapy, Adoptive; Lymphoma, Mantle-Cell; Mice, Inbred NOD; Mice, SCID; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, T-Cell; T-Lymphocytes; Xenograft Model Antitumor Assays

Ibrutinib is a new-targeted therapy that irreversibly and specifically inhibits the Bruton's Tyrosine Kinase (BTK), a key component of the signaling pathways of B cells. The results are very encouraging as monotherapy in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström's macroglobulinemia. Following the results of recent studies, ibrutinib is now available in France for these three diseases.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; Clinical Trials as Topic; Drug Resistance, Neoplasm; France; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction; Waldenstrom Macroglobulinemia

Although targeting the Bruton tyrosine kinase (BTK) with ibrutinib has changed lymphoma treatment, patients with mantle cell lymphoma (MCL) remain incurable. In this study, we characterized a broad range of MCL cell lines and primary MCL cells with respect to the response to the BTK inhibitor, ibrutinib, and compared it with the response to the protein kinase C (PKC) inhibitor, sotrastaurin. At clinically relevant concentrations, each drug induced potent cell death only in the REC-1 cell line, which was accompanied by robust inhibition of AKT and ERK1/ERK2 (ERK1/2, also termed MAPK3/MAPK1) phosphorylation. In sensitive REC-1 cells, the drug-mediated impaired phosphorylation was obvious on the levels of B-cell receptor-induced and basal phosphorylation. Similar results were obtained in primary MCL cells with ibrutinib and in a subset with sotrastaurin. The various drug-resistant MCL cell lines showed very distinct responses in terms of basal AKT and ERK1/2 phosphorylation. Interestingly, targeting PKC and BTK at the same time led to ibrutinib-mediated rescue of a weak sotrastaurin-induced apoptosis in MINO cells. Additional targeting of AKT sensitized MINO cells to inhibitor-mediated cytotoxicity. In summary, MCL cells are heterogeneous in their response to BTK or PKC inhibition, indicating the need for even more individualized targeted treatment approaches in subsets of MCL patients.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Cell Death; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; MAP Kinase Signaling System; Molecular Targeted Therapy; Phosphorylation; Piperidines; Protein Kinase C; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrroles; Quinazolines; Tumor Cells, Cultured

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Female; Follow-Up Studies; Humans; Incidence; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retrospective Studies; Treatment Outcome

Topics: Adenine; Antineoplastic Agents; Bendamustine Hydrochloride; Bortezomib; Chromosomes, Human, Pair 17; Cytarabine; Humans; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Mutation; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Sirolimus; Thalidomide; Tumor Suppressor Protein p53; Vidarabine

The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL.

Topics: Adenine; CARD Signaling Adaptor Proteins; Drug Resistance, Neoplasm; Genetic Heterogeneity; Guanylate Cyclase; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Mutation; NF-kappa B; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Signal Transduction; Thalidomide; Transfection

Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation, which leads to deregulated expression of the cell cycle regulatory protein cyclin D1 (CCND1). Genomic studies of MCL have also identified recurrent mutations in the coding region of CCND1. However, the functional consequence of these mutations is not known. Here, we showed that, compared to wild type (WT), single E36K, Y44D or C47S CCND1 mutations increased CCND1 protein levels in MCL cell lines. Mechanistically, these mutations stabilized CCND1 protein through attenuation of threonine-286 phosphorylation, which is important for proteolysis through the ubiquitin-proteasome pathway. In addition, the mutant proteins preferentially localized to the nucleus. Interestingly, forced expression of WT or mutant CCND1 increased resistance of MCL cell lines to ibrutinib, an FDA-approved Bruton tyrosine kinase inhibitor for MCL treatment. The Y44D mutant sustained the resistance to ibrutinib even at supraphysiologic concentrations (5-10 μM). Furthermore, primary MCL tumors with CCND1 mutations also expressed stable CCND1 protein and were resistant to ibrutinib. These findings uncover a new mechanism that is critical for the regulation of CCND1 protein levels, and is directly relevant to primary ibrutinib resistance in MCL.

Topics: Adenine; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Cyclin D1; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Mutation; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Protein Stability; Protein Transport; Proteolysis; Pyrazoles; Pyrimidines; Ubiquitination

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma (MCL). Intrinsic resistance can occur through activation of the nonclassical NF-κB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer heat shock protein 90 (HSP90) inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IκB kinase α in MCL lines and CD40-dependent B cells, with downstream loss of MAPK and nonclassical NF-κB signaling. A proteome-wide analysis in MCL lines and an MCL patient-derived xenograft identified a restricted set of targets from HSP90 inhibition that were enriched for factors involved in B-cell receptor and JAK/STAT signaling, the nonclassical NF-κB pathway, cell-cycle regulation, and DNA repair. Finally, multiple HSP90 inhibitors potently killed MCL lines in vitro, and the clinical agent AUY922 was active in vivo against both patient-derived and cell-line xenografts. Together, these findings define the HSP90-dependent proteome in MCL. Considering the disappointing clinical activity of HSP90 inhibitors in other contexts, trials in patients with MCL will be essential for defining the efficacy of and mechanisms of resistance after ibrutinib failure.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Amino Acid Substitution; Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Isoxazoles; Lymphoma, Mantle-Cell; Mice; Mutation, Missense; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Resorcinols; Xenograft Model Antitumor Assays

The BTK (Bruton's tyrosine kinase) inhibitor ibrutinib is associated with an increased risk of bleeding. A previous study reported defects in collagen- and adenosine diphosphate (ADP)-dependent platelet responses when ibrutinib was added ex vivo to patient samples. Whereas the collagen defect is expected given the central role of BTK in glycoprotein VI signaling, the ADP defect lacks a mechanistic explanation. In order to determine the real-life consequences of BTK platelet blockade, we performed light transmission aggregometry in 23 patients receiving ibrutinib treatment. All patients had reductions in collagen-mediated platelet aggregation, with a significant association between the degree of inhibition and the occurrence of clinical bleeding or bruising (P=0.044). This collagen defect was reversible on drug cessation. In contrast to the previous ex vivo report, we found no in vivo ADP defects in subjects receiving standard doses of ibrutinib. These results establish platelet light transmission aggregometry as a method for gauging, at least qualitatively, the severity of platelet impairment in patients receiving ibrutinib treatment.

Topics: Adenine; Adenosine Diphosphate; Aged; Aged, 80 and over; Antineoplastic Agents; Blood Platelets; Cells, Cultured; Collagen; Female; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Platelet Aggregation; Pyrazoles; Pyrimidines; Severity of Illness Index

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Signal Transduction

Several studies provide evidences for mantle cell lymphoma (MCL) cell survival relying on B-cell receptor (BCR)-mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR-associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukaemic patients secreted high amount of IL-1β, IL-6, IL-8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL-1β, IL-6, IL-8, CCL5, IL-10, TNFα and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR-induced autocrine cytokine secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR-induced MCL cell adhesion to human bone marrow stromal cells (HMSCs) in short- and long-term co-culture. We demonstrated that BCR-induced survival relies on autocrine secretion of IL-1β, TNFα and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Aminopyridines; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Cells, Cultured; Coculture Techniques; Cytokines; Female; Gene Expression; Humans; Intracellular Signaling Peptides and Proteins; Lymphoma, Mantle-Cell; Male; Middle Aged; Morpholines; Oxazines; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Receptors, Antigen, B-Cell; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Syk Kinase; Tumor Cells, Cultured

Topics: Adenine; Aged; Antineoplastic Agents; Fatal Outcome; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Retreatment; Skin Neoplasms

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Bone Marrow; Humans; Lymphocytosis; Lymphoma, Mantle-Cell; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown.. We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study.. We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS.. The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Disease Progression; Drug Resistance, Neoplasm; Drug Substitution; Female; Humans; Kaplan-Meier Estimate; L-Lactate Dehydrogenase; Lymphoma, Mantle-Cell; Male; Middle Aged; Molecular Targeted Therapy; Piperidines; Proportional Hazards Models; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors; Salvage Therapy; Texas; Time Factors; Treatment Failure

The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD50 < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD50 < 10 nM). Mcl-1 and Bcl-xL both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x(L) up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Apoptosis; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; CD40 Antigens; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lymph Nodes; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; NF-kappa B; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; RNA, Messenger; RNA, Neoplasm; Sulfonamides; Tumor Microenvironment

Topics: Adenine; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Bendamustine Hydrochloride; Blood Platelets; Chemical Precipitation; Cryoglobulins; Humans; Immunotherapy; Lymphoma, Mantle-Cell; Nitrogen Mustard Compounds; Piperidines; Platelet Count; Pyrazoles; Pyrimidines; Rituximab; Thrombocytopenia

Mantle cell lymphoma (MCL) is a B cell malignancy characterized by aberrant expression of cyclin D1 due to a t(11;14) translocation. MCL is refractory to conventional chemotherapy, and treatment remains challenging. We investigated the efficacy of the histone deacetylase (HDAC) inhibitor vorinostat combined with one of several B-cell receptor (BCR) signaling inhibitors on MCL cell death and the underlying mechanisms, using MCL cell lines. The Bruton's tyrosine kinase inhibitor PCI-32765 and the spleen tyrosine kinase inhibitor R406 showed synergistic effects with vorinostat on growth inhibition. Treatment with PCI-32765 or R406 alone induced 27.3 ± 2.1 or 25.1 ± 3.2% apoptosis. When combined with vorinostat, these apoptotic fractions significantly increased to 50.8 ± 4.9 and 63.1 ± 5.0%, respectively. Activation of caspase-3 and poly-(ADP-ribose) polymerase cleavage were markedly increased. We performed gene expression profiling following treatment with the combination of vorinostat and individual BCR signaling inhibitors using a microarray, and differentially expressed genes were identified. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the nuclear factor (NF)-κB signaling pathway was significantly enriched following treatment with the combination of vorinostat and R406. Protein expression analysis confirmed the down-regulation of NF-κB1/p105 and cyclin D1, suggesting inhibition of the NF-κB pathway. Taken together, the combination of an HDAC inhibitor and a BCR signaling inhibitor may be a novel therapeutic strategy for MCL.

Topics: Adenine; Apoptosis; Caspases; Cell Line, Tumor; Cyclin D1; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma, Mantle-Cell; NF-kappa B; Oxazines; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptors, Antigen, B-Cell; Vorinostat

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

Topics: Adenine; Animals; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cell Line, Tumor; Humans; Lymphoma, Mantle-Cell; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Transplantation; Neoplasms, Experimental; Piperidines; Pyrazines; Pyrazoles; Pyrimidines; Rituximab; Tumor Cells, Cultured

Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (β1, β2, β5). All established PI (bortezomib and carfilzomib), as well as experimental drugs in the field (dalanzomib, oprozomib, and ixazomib), by design target the rate-limiting β5 subunit. It is unknown whether β2-selective proteasome inhibition can also be exploited toward anticancer treatment. Combining PI with the pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears a natural option for future improved treatment of multiple myeloma (MM) and B-cell lymphomas. However, bortezomib induces phosphorylation of IκB and activation of NF-κB in MM cells, while ibrutinib inhibits the IκB/NF-κB axis, suggesting antagonistic signaling. A β2-selective proteasome inhibitor may lack such antagonistic signaling effects.. We recently introduced LU-102, the first β2-selective PI available for preclinical testing. We here compare bortezomib with carfilzomib and LU-102 in MM and MCL in vitro with regard to their effects on pIκB/NF-κB signaling and their cytotoxic activity in combination with ibrutinib.. LU-102 reduced phosphorylation of IκB, in contrast to bortezomib and carfilzomib, and was a superior inhibitor of NF-κB activation in MM cells. This translated into highly synergistic cytotoxicity between LU-102 and ibrutinib, which was able to overcome BTZ resistance and CFZ resistance. By contrast, BTZ lacked consistent synergistic cytotoxicity with ibrutinib.. Ibrutinib is highly synergistic with β2-selective proteasome inhibition against MM and MCL in vitro. Novel β2-selective proteasome inhibitors may be exploited to overcome bortezomib/carfilzomib resistance and boost the activity of BTK inhibitors against B-cell-derived malignancies.

Topics: Adenine; Antineoplastic Agents; Boronic Acids; Bortezomib; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Humans; I-kappa B Proteins; Lymphoma, Mantle-Cell; Multiple Myeloma; Oligopeptides; Phosphorylation; Piperidines; Proteasome Inhibitors; Pyrazines; Pyrazoles; Pyrimidines

The risk of central nervous system (CNS) dissemination in mantle cell lymphoma (MCL) is low and occurs late in the course of the disease. However, prognosis in such cases remains extremely poor despite high-dose antimetabolite chemotherapy. Among novel drugs used to treat relapsing MCL patients, ibrutinib, an oral inhibitor of Bruton tyrosine kinase, shows great promise. Here we report the clinical observation of 3 MCL patients with symptomatic CNS relapse treated with single-agent ibrutinib. All 3 patients had dramatic and rapid responses with almost immediate recovery from symptoms. We also confirmed that ibrutinib crosses the blood-brain barrier with parallel pharmacokinetic analyses in plasma and cerebrospinal fluid using a validated LC-MS/MS method. All responses were ongoing after 2 months to 1 year of follow-up.

Topics: Adenine; Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Recurrence

Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-κB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-κB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclin-dependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-κB target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Although lowering the levels of the antiapoptotic B-cell lymphoma (BCL)2 family proteins, BA treatment induces the proapoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Cotreatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared with each agent alone, cotreatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells, which overexpress CDK6, BCL2, Bcl-xL, XIAP, and AKT, but lack ibrutinib resistance-conferring BTK mutation. Cotreatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Lymphoma, Mantle-Cell; Mice, Inbred NOD; Mice, SCID; NF-kappa B; Nuclear Proteins; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Pyrazoles; Pyrimidines; Transcription Factor RelA; Transcription Factors; Triazoles

On November 13, 2013, the FDA granted accelerated approval to ibrutinib (IMBRUVICA capsules; Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. On February 12, 2014, the FDA granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor that received all four expedited programs of the FDA: Fast-Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval. Both approvals were based on overall response rate (ORR) and duration of response (DOR) in single-arm clinical trials in patients with prior treatment. In MCL (N = 111), the complete and partial response rates were 17.1% and 48.6%, respectively, for an ORR of 65.8% [95% confidence interval (CI), 56.2%-74.5%]. The median DOR was 17.5 months (95% CI, 15.8-not reached). In CLL (N = 48), the ORR was 58.3% (95% CI, 43.2%-72.4%), and the DOR ranged from 5.6 to 24.2 months. The most common adverse reactions (≥ 30% in either trial) were thrombocytopenia, diarrhea, neutropenia, bruising, upper respiratory tract infection, anemia, fatigue, musculoskeletal pain, peripheral edema, and nausea.

Topics: Adenine; Aged; Clinical Trials as Topic; Drug Approval; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; United States

Bendamustine is effective in B-cell malignancies, including mantle cell lymphoma (MCL), alone and in combination with other agents. This study investigated the combination effect of bendamustine and the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 on MCL cell death and the underlying mechanisms.. Cytotoxicity was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MIT) assay. Apoptosis was assessed by annexin V/propidium iodide staining and protein expression was analyzed by western blotting.. When combined with bendamustine, PCI-32765 showed a synergistic effect on growth inhibition of the MCL cell line Jeko-1. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase was increased, indicating enhanced apoptosis induction. In addition, this combination decreased the protein expression of cyclin D1. Phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT) (Ser473) was also down-regulated, suggesting a suppression of the phosphatidylinositol 3-kinase/AKT signaling pathway.. Combination treatment with bendamustine and a BTK inhibitor may be effective in MCL therapy.

Topics: Adenine; Bendamustine Hydrochloride; Cell Proliferation; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; Signal Transduction

Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-κB (NF-κB) pathway, whereas insensitive cell lines displayed activation of the alternative NF-κB pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-κB pathway signaling components in ibrutinib-insensitive cell lines, and sequencing of 165 samples from patients with MCL identified recurrent mutations in TRAF2 or BIRC3 in 15% of these individuals. Although they are associated with insensitivity to ibrutinib, lesions in the alternative NF-κB pathway conferred dependence on the protein kinase NIK (also called mitogen-activated protein 3 kinase 14 or MAP3K14) both in vitro and in vivo. Thus, NIK is a new therapeutic target for MCL treatment, particularly for lymphomas that are refractory to BCR pathway inhibitors. Our findings reveal a pattern of mutually exclusive activation of the BCR-NF-κB or NIK-NF-κB pathways in MCL and provide critical insights into patient stratification strategies for NF-κB pathway-targeted agents.

Topics: Adenine; Baculoviral IAP Repeat-Containing 3 Protein; Base Sequence; Blotting, Western; CARD Signaling Adaptor Proteins; Cell Line; Cell Survival; DNA Primers; Guanylate Cyclase; Humans; Inhibitor of Apoptosis Proteins; Luminescent Measurements; Lymphoma, Mantle-Cell; Microarray Analysis; Molecular Sequence Data; NF-kappa B; NF-kappaB-Inducing Kinase; Piperidines; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Pyrroles; Quinazolines; Real-Time Polymerase Chain Reaction; Receptors, Antigen, B-Cell; RNA Interference; Sequence Analysis, RNA; Signal Transduction; TNF Receptor-Associated Factor 2; TNF Receptor-Associated Factor 3; Trypan Blue; Ubiquitin-Protein Ligases

The U.S. Food and Drug Administration (FDA) has approved the targeted therapy ibrutinib (Imbruvica; Johnson & Johnson and Pharmacyclics) for treating patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Drug Approval; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; United States; United States Food and Drug Administration

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Drug Industry; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one-third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib-sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti-tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Cell Cycle; Cell Death; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Knockdown Techniques; Humans; Lymphoma, Mantle-Cell; MAP Kinase Signaling System; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Tumor Cells, Cultured

Despite the unprecedented clinical activity of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in mantle cell lymphoma (MCL), acquired resistance is common. By longitudinal integrative whole-exome and whole-transcriptome sequencing and targeted sequencing, we identified the first relapse-specific C481S mutation at the ibrutinib binding site of BTK in MCL cells at progression following a durable response. This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance. Through synergistic induction of PIK3IP1 and inhibition of PI3K-AKT activation, prolonged early G1 arrest induced by PD 0332991 (palbociclib) inhibition of CDK4 sensitized resistant lymphoma cells to ibrutinib killing when BTK was unmutated, and to PI3K inhibitors independent of C481S mutation. These data identify a genomic basis for acquired ibrutinib resistance in MCL and suggest a strategy to override both primary and acquired ibrutinib resistance.. We have discovered the first relapse-specific BTK mutation in patients with MCL with acquired resistance, but not primary resistance, to ibrutinib, and demonstrated a rationale for targeting the proliferative resistant MCL cells by inhibiting CDK4 and the cell cycle in combination with ibrutinib in the presence of BTK(WT) or a PI3K inhibitor independent of BTK mutation. As drug resistance remains a major challenge and CDK4 and PI3K are dysregulated at a high frequency in human cancers, targeting CDK4 in genome-based combination therapy represents a novel approach to lymphoma and cancer therapy. Cancer Discov; 4(9); 1022-35. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 973.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Amino Acid Substitution; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; DNA Mutational Analysis; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; Genomics; Humans; Lymphoma, Mantle-Cell; Mutation; Neoplasm Recurrence, Local; NF-kappa B; Nitrates; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Polyethylene Glycols; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcr; Pyrazoles; Pyrimidines; Signal Transduction; Treatment Outcome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Humans; Lymphoma, Mantle-Cell; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin's lymphoma. It can follow a heterogeneous clinical course but generally patients relapse early after standard immunochemotherapy regimens and develop resistance to subsequent therapies. For younger patients, intensive approaches followed by autologous stem cell transplantation offer excellent long-term disease control but with the possible exception of an allogenic stem cell transplant, MCL is an incurable condition. As MCL principally affects older individuals, the majority of patients are not candidates for such intensive approaches. Ibrutinib is an orally active, Bruton's tyrosine kinase inhibitor. It inhibits signaling pathways downstream of Bruton's tyrosine kinase that appear critical for the proliferation and survival of MCL. As a single agent it has shown extremely promising activity in relapsed and refractory MCL patients with an excellent side-effect profile. The exact role for ibrutinib in the treatment of MCL is yet to be established; however, it is likely to fundamentally change the way we treat this disease.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Clinical Trials as Topic; Half-Life; Hematologic Diseases; Humans; Immunotherapy; Lymphoma, Mantle-Cell; Middle Aged; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Rituximab; Signal Transduction; Treatment Outcome

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; Agammaglobulinaemia Tyrosine Kinase; Animals; Animals, Newborn; Atrial Fibrillation; Gene Expression Regulation, Enzymologic; Humans; Infant, Newborn; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Rats; Risk Factors; Signal Transduction

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Humans; Lymphoma, Mantle-Cell; Neoplasm Proteins; Piperidines; Portraits as Topic; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Female; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that characteristically shows overexpression of cyclin-D1 due to an alteration in the t(11;14)(q13;q32) chromosomal region. Although there are some promising treatment modalities, great majority of patients with this disease remain incurable. The B-cell antigen receptor (BCR) signaling plays a crucial role in B-cell biology and lymphomagenesis. Bruton tyrosine kinase (BTK) has been identified as a key component of the BCR signaling pathway. Evidence suggests that the blockade of BTK activity by potent pharmacologic inhibitors attenuates BCR signaling and induces cell death. Notably, the expression levels and the role of BTK in MCL survival are still elusive. Here, we demonstrated a moderate to strong BTK expression in all MCL cases (n=19) compared to benign lymphoid tissues. Treatment of MCL cell lines (Mino or Jeko-1) with a potent BTK pharmacologic inhibitor, Ibrutinib, decreased phospho-BTK-Tyr(223) expression. Consistent with this observation, Ibrutinib inhibited the viability of both Mino and JeKo-1 cells in concentration- and time-dependent manners. Ibrutinib also induced a concentration-dependent apoptosis in both cell lines. Consistently, Ibrutinib treatment decreased the levels of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 protein. These findings suggest that BTK signaling plays a critical role in MCL cell survival, and the targeting of BTK could represent a promising therapeutic modality for aggressive lymphoma.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Apoptosis; Cell Line; Cell Survival; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Immunophenotyping; Lymphoma, Mantle-Cell; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines

Topics: Adenine; B-Lymphocytes; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; Signal Transduction

Topics: Adenine; Drug Approval; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; United States; United States Food and Drug Administration

Interactions between the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells, including those highly resistant to bortezomib. Co-administration of PCI-32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre- or activated B-cell-like-DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor (NF)-κB (NFKB1) inactivation, down-regulation of Mcl-1 (MCL1), Bcl-xL (BCL2L1), and XIAP, and enhanced DNA damage (e.g., γH2A.X formation) and endoplasmic reticulum (ER) stress. Similar interactions were observed in highly bortezomib-resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI-32765/bortezomib regimens displayed minimal toxicity toward normal CD34(+) bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF-κB "super-repressor" (IκBαser34/36 ) increased both PCI-32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant-negative eIF2α construct were resistant to this regimen. Finally, combined exposure to PCI-32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI-32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Boronic Acids; Bortezomib; DNA Damage; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Endoplasmic Reticulum Stress; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Mitochondria; NF-kappa B; Piperidines; Proteasome Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Pyrazines; Pyrazoles; Pyrimidines; Reactive Oxygen Species; Tumor Cells, Cultured

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