piperidines and Waldenstrom-Macroglobulinemia

Bruton tyrosine kinase (BTK) inhibitors have taken a central role in the management of patients with Waldenström macroglobulinemia and are the only agents approved by the Food and Drug Administration (FDA) to treat these patients. Although associated with high rates of durable responses, unmet needs with BTK inhibitor therapy include indefinite duration therapy, high cost, scarcity of complete responses, and lower rates and shorter duration of response in patients with CXCR4 mutations. Herein, we review the data supporting the use of covalent BTK inhibitors, selected management issues, clinical trials with covalent BTK inhibitor combination regimens, and up-and-coming non-covalent BTK inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Lymphoma, B-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tyrosine Kinase Inhibitors; Waldenstrom Macroglobulinemia

The development of Bruton tyrosine kinase (BTK) inhibitors has significantly changed the treatment landscape for patients with Waldenström macroglobulinemia (WM). Ibrutinib was the first BTK inhibitor to receive FDA approval for this disease, but in recent years additional more selective BTK inhibitors have become available. Zanubrutinib, the most recently FDA-approved therapy for WM, has demonstrated comparable efficacy regarding hematologic response, but with an improved side effect profile compared to other BTK inhibitors.. In this review, we highlight the pivotal studies that have formed the foundation for the use of zanubrutinib in WM, including safety and efficacy data from prospective clinical trials of the currently available BTK inhibitors.. BTK inhibitors are very effective in WM and have an overall response rate higher than 90%. The side effect profile of these medications is manageable but does include a risk of atrial fibrillation, infection, and bleeding. The newer BTK inhibitors, such as acalabrutinib and zanubrutinib, are known to have less off-target effects and are potential treatment options. BTK inhibitors should be considered as a treatment option in treatment-naïve and previously treated disease depending on the individual patient preferences, comorbidities, and molecular profile.

Topics: Adult; Agammaglobulinaemia Tyrosine Kinase; Humans; Lymphoma, B-Cell; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Waldenström macroglobulinemia (WM) is a hematological malignancy; it is a monoclonal gammopathy, a disease characterized by presence of a monoclonal immunoglobulin in serum and/or urine. The median age at dia-gnosis is 71 years. WM is not an aggres-sive disease and patients with this dia-gnosis can live for several years. Infiltration of the bone marrow with lymphoplasmacytoid cells causes anemia, leading to various problems, mainly fatigue. Hepatomegaly, splenomegaly and lymphadenopathy can also occur. Hyperviscosity syndrome can appear and is caused by excessive production of immunoglobulin M. A mutation in MYD88 gene is detected in almost every WM patient, and in almost one third of them, a mutation in CXCR4 gene is detected. The detection of MYD88 mutation is important for a correct therapeutic strategy, since a Brutons tyrosine kinase inhibitor, ibrutinib, is most effective in patients with mutated MYD88 and wt CXCR4. The therapy is started when first symptoms occur.. The aim of this study is to summarize current knowledge about this disease, its dia-g-nostics, molecular basis and treatment.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Myeloid Differentiation Factor 88; Piperidines; Protein Kinase Inhibitors; Waldenstrom Macroglobulinemia

There are multiple treatment options in patients with Waldenström macroglobulinemia, including chemotherapy, monoclonal antibodies, proteasome inhibitors, and covalent Bruton tyrosine kinase (BTK) inhibitors. The choice of therapy should take into account the patient's clinical presentation, comorbidities, and preferences. A thorough discussion should take place to outline the administration, safety, and efficacy of the regimens under consideration. The patient's genomic profile can provide insightful information for the treatment selection. In the frontline and relapsed settings, we favor ibrutinib monotherapy over chemoimmunotherapy or proteasome inhibitor-based regimens in patients with MYD88 and without CXCR4 mutations. For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome inhibitor-based regimens are favored, but efficacy data with ibrutinib in combination with rituximab and with novel covalent BTK inhibitors are emerging. Autologous stem cell transplant should be considered in special cases in the relapsed setting. Participation in clinical trials is positively encouraged in WM patients in frontline and relapsed settings. Agents of interest include the BCL2 antagonist venetoclax, the CXCR4 inhibitor mavorixafor, and the non-covalent BTK inhibitors pirtobrutinib and ARQ-531.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Benzamides; Humans; Mutation; Myeloid Differentiation Factor 88; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Rituximab; Waldenstrom Macroglobulinemia

Waldenstrom Macroglobulinaemia (WM) is a heterogenous condition which poses a challenge to manage. Novel therapies such as Ibrutinib have been shown to be efficacious in treating WM. The landscape of Ibrutinib's role in treating WM is everchanging with new discoveries in disease genomics and evolution together as well as through new findings in clinical trials.. A systematic literature review was carried out using two databases 'Medline' and 'Embase' from 2009 to July 2019. Keywords used included 'Ibrutinib,' 'Waldenstrom Macroglobulinaemia,' and 'lymphoma.' There were four major clinical trials identified primarily describing outcomes of Ibrutinib in managing WM which this paper evaluates in detail. The authors present evidence of the role of Ibrutinib in the management of specific complications associated with WM. They also explore the recently discovered genomics of the disease affecting response to therapy.. The evidence for the use of Ibrutinib as a treatment option for relapsed/refractory WM is compelling in MYD88 mutated WM with the response and survival rates potentially better than conventional salvage chemoimmunotherapy. There is also a case for it to be used in the frontline setting in patients unfit for conventional frontline chemoimmunotherapy.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Clinical Trials as Topic; Humans; Piperidines; Pyrazoles; Pyrimidines; Salvage Therapy; Survival Rate; Treatment Outcome; Waldenstrom Macroglobulinemia

Waldenstrom's Macroglobulinemia (WM) is a rare, indolent lymphoplasmacytic lymphoma characterized by heterogeneous clinical and genomic profile. Bruton's tyrosine kinase (BTK) is central to the signaling pathways required for clonal WM cell survival, and BTK inhibitors currently have an imperative role in the treatment of WM.. The central role of BTK in WM will be described, and the rationale behind the development of BTKi. Clinical trial data that led to the approval of ibrutinib (the first-in-class BTKi) will be reviewed. Despite its potency and safe toxicity profile, ibrutinib does not induce deep remissions, and responses are mutational-status dependent. The mechanisms that lead to resistance to this agent are being investigated. Ibrutinib treatment has to be continuous; consequently, patients face the effects of long-term toxicity. In that context, second-generation inhibitors are in clinical development with fewer off-target effects and an efficacy profile, which will be determined based on long-term follow-up data.. The optimal therapeutic approach for WM patients remains to be established. The question of whether a combinatory (or synergistic) regimen to overcome resistance and allow for a fixed treatment duration will allow for deep and durable response is being addressed in ongoing clinical trials.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Drug Development; Drug Resistance, Neoplasm; Humans; Piperidines; Protein Kinase Inhibitors; Signal Transduction; Waldenstrom Macroglobulinemia

Waldenström's Macroglobulinemia (WM) is an indolent lymphoma with uniquely distinct and heterogenous clinical and genomic profiles. Clonal lymphoplasmacytic cells secrete monoclonal IgM. More than 90% of patients harbor a mutation in MYD88 gene, leading to the constitutive activation of downstream pathways, involving BTK-mediated signaling. The use of BTK inhibitors has changed the treatment landscape of WM and has paved the way for new approaches to therapy.. WM is an orphan disease and ibrutinib is the only FDA/EMA approved agent. Currently established agent combinations will be reviewed with a focus on emerging therapeutic options. These include second generation inhibitors, agents that target other molecules in the BCR signaling pathway, CXCR4 inhibitors, proteasome inhibitors and anti-CD38 antibodies. The current research goal is to establish a combination that can induce deep and durable responses with minimal associated toxicity. In addition, agents that can overcome ibrutinib resistance or act in a synergistic manner with BTKi are under investigation.. The optimal therapeutic approach for WM patients is not currently established. The question of whether a combinatory (or synergistic) regimen to overcome resistance and allow for fixed- duration treatment will allow for deep/durable responses is being addressed in ongoing clinical trials.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Drug Design; Drug Resistance; Humans; Mutation; Myeloid Differentiation Factor 88; Orphan Drug Production; Piperidines; Protein Kinase Inhibitors; Rare Diseases; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Lymphoma, Large B-Cell, Diffuse; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Atrial Fibrillation; Benzamides; Central Nervous System Diseases; Clinical Trials as Topic; Febrile Neutropenia; Gastrointestinal Diseases; Gene Expression Regulation, Neoplastic; Humans; Multicenter Studies as Topic; Myeloid Differentiation Factor 88; Neoplasm Proteins; NF-kappa B; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Quality of Life; Receptors, CXCR4; Recurrence; Salvage Therapy; Signal Transduction; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphohistiocytosis, Hemophagocytic; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Salvage Therapy; Waldenstrom Macroglobulinemia

Bing-Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS-penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS.

Topics: Adenine; Amino Acid Substitution; Brain Neoplasms; Humans; Magnetic Resonance Imaging; Mutation, Missense; Myeloid Differentiation Factor 88; Neoplasm Proteins; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma. The diagnosis of WM is established by the presence of lymphoplasmacytic lymphoma in the bone marrow or other organs, a monoclonal IgM paraproteinemia and the recurrent MYD88 L265P somatic mutation. Some patients with WM can be asymptomatic, in which case treatment is not indicated. However, most patients with WM will become symptomatic during the course of the disease, due to anemia, hyperviscosity, neuropathy, or other processes, necessitating therapy. Current treatment options for symptomatic WM patients include alkylating agents, proteasome inhibitors and anti-CD20 monoclonal antibodies. The approval of the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib alone and in combination with rituximab has expanded the treatment options for WM patients. The present Perspective would focus on exciting treatment strategies under development for WM patients, such as proteasome inhibitors (e.g., ixazomib), BTK inhibitors (e.g., acalabrutinib, zanubrutinib, vecabrutinib), BCL2 inhibitors (e.g., venetoclax), and anti-CXCR4 antibodies (e.g., ulocuplumab), among others. It is certainly an exciting time for WM therapy development with novel and promising treatment options in the horizon.

Topics: Adenine; Antibodies, Monoclonal; Antigens, CD20; Benzamides; Bone Marrow; Disease-Free Survival; Hematology; Humans; Immunoglobulin M; Mutation; Piperidines; Proteasome Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Pyrazoles; Pyrimidines; Quality of Life; Waldenstrom Macroglobulinemia

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of ibrutinib (Janssen) to submit evidence on the clinical and cost effectiveness of ibrutinib for treating Waldenström's macroglobulinaemia (WM). 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 for the clinical and cost effectiveness of ibrutinib based on the company's submission to NICE. The clinical evidence was derived from one phase II, single-arm, open-label study of ibrutinib in adult patients with WM who had received at least one prior therapy (Study 1118E) and an indirect comparison using a matched cohort from a retrospective European chart review of patients receiving various treatments for WM. The indirect comparison suggested a hazard ratio for progression-free survival (PFS) of 0.25 (95% confidence interval 0.11-0.57). The ERG had concerns regarding the high risk of bias in Study 1118E, the limited generalisability of the study, and the absence of randomised controlled trial evidence. The company's Markov model assessed the cost effectiveness of ibrutinib versus rituximab/chemotherapy for patients with relapsed/refractory (R/R) WM from the perspective of the National Health Service (NHS) and Personal Social Services (PSS) over a lifetime horizon. Based on the company's original Patient Access Scheme (PAS), the company's probabilistic model generated an incremental cost-effectiveness ratio (ICER) for ibrutinib versus rituximab/chemotherapy of £58,905 per quality-adjusted life-year (QALY) gained. Following a critique of the model, the ERG's preferred analysis, which corrected cost errors and used the observed mortality rate from Study 1118E, generated a probabilistic ICER of £61,219 per QALY gained. Based on this amended model, additional exploratory analyses produced ICERs for ibrutinib that were > £60,000 per QALY gained. Subsequently, the company offered to provide ibrutinib at a price that resulted in ibrutinib being cost effective within the Cancer Drugs Fund (CDF). The Committee recommended ibrutinib for use in the CDF as an option for treating WM in adults who have had at least one prior therapy, only if the conditions in the managed access agreement for ibrutinib are followed.

Topics: Adenine; Adult; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Cost-Benefit Analysis; Humans; Models, Economic; Piperidines; Progression-Free Survival; Pyrazoles; Pyrimidines; Technology Assessment, Biomedical; United Kingdom; Waldenstrom Macroglobulinemia

Bruton tyrosine kinase plays a critical role in hastening cell proliferation. Bruton tyrosine kinase inhibitors are a class of immunotheraputic agents that disrupt this signaling pathway. Ibrutinib, a novel Bruton tyrosine kinase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of Waldenstrom macroglobulinemia in patients who have failed treatment with other agents, has emerged as an important therapeutic agent in the management of Waldenstrom macroglobulinemia and other plasma cell dyscrasias. Ibrutinib has shown to increase progression free survival and improve overall mortality. We present a review of ibrutinib, beginning with an overview of the Bruton tyrosine kinase pathway and clinically relevant gene mutations impacting treatment and prognosis for patients with Waldenstrom macroglobulinemia, followed by evidence supporting therapeutic indications for ibrutinib, and detailing its safety and efficacy evidence, current clinical guidelines, adverse effects and their management, and finally challenges of drug resistance. We also present findings on newly developed Bruton tyrosine kinase inhibitors in the therapeutic pipeline to provide readers insight into this rapidly evolving corner of oncology pharmacy practice.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

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

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

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

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Blood Viscosity; Gene Expression; Humans; Immunoglobulin M; Mutation; Myeloid Differentiation Factor 88; Piperidines; Progression-Free Survival; Proteasome Inhibitors; Pyrazoles; Pyrimidines; Receptors, CXCR4; Rituximab; Treatment Outcome; Waldenstrom Macroglobulinemia

Waldenström macroglobulinemia is a rare indolent B-cell lymphoma. Whole-exome sequencing studies have improved our knowledge of the Waldenström macroglobulinemia mutational landscape. The MYD88 L265P mutation is present in nearly 90% of patients with Waldenström macroglobulinemia. CXCR4 mutations are identified in approximately 30% of MYD88L265P cases and have been associated with ibrutinib resistance in clinical trials. Mutations in CD79B, ARID1a, or TP53 were described at lower frequency. Deciphering the earliest initiating lesions and identifying the molecular alterations leading to disease progression currently represent important goals in the future to identify the most relevant targets for precision therapy in Waldenström macroglobulinemia.

Topics: Adenine; Drug Resistance, Neoplasm; Humans; Mutation; Neoplasm Proteins; Piperidines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Signal Transduction; Waldenstrom Macroglobulinemia

Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma that is heavily dependent on Bruton tyrosine kinase (BTK) hyperactivation. Ibrutinib is a first-generation BTK inhibitor that has shown high activity and durable responses in patients with relapsed/refractory WM. Newer and more selective BTK inhibitors are currently being tested in several clinical trials and are expected to address the toxicity and the acquired resistance observed in patients receiving ibrutinib. Updates on ibrutinib and second-generation BTK inhibitors are summarized in this review.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Drug Resistance, Neoplasm; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Waldenström macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, has witnessed several practice-altering advances in recent years. With availability of a wider array of therapies, the management strategies have become increasingly complex. Our multidisciplinary team appraised studies published or presented up to December 2015 to provide consensus recommendations for a risk-adapted approach to WM, using a grading system.. Waldenström macroglobulinemia remains a rare, incurable cancer, with a heterogeneous disease course. The major classes of effective agents in WM include monoclonal antibodies, alkylating agents, purine analogs, proteasome inhibitors, immunomodulatory drugs, and mammalian target of rapamycin inhibitors. However, the highest-quality evidence from rigorously conducted randomized clinical trials remains scant.. Recognizing the paucity of data, we advocate participation in clinical trials, if available, at every stage of WM. Specific indications exist for initiation of therapy. Outside clinical trials, based on the synthesis of available evidence, we recommend bendamustine-rituximab as primary therapy for bulky disease, profound hematologic compromise, or constitutional symptoms attributable to WM. Dexamethasone-rituximab-cyclophosphamide is an alternative, particularly for nonbulky WM. Routine rituximab maintenance should be avoided. Plasma exchange should be promptly initiated before cytoreduction for hyperviscosity-related symptoms. Stem cell harvest for future use may be considered in first remission for patients 70 years or younger who are potential candidates for autologous stem cell transplantation. At relapse, retreatment with the original therapy is reasonable in patients with prior durable responses (time to next therapy ≥3 years) and good tolerability to previous regimen. Ibrutinib is efficacious in patients with relapsed or refractory disease harboring MYD88 L265P mutation. In the absence of neuropathy, a bortezomib-rituximab-based option is reasonable for relapsed or refractory disease. In select patients with chemosensitive disease, autologous stem cell transplantation should be considered at first or second relapse. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM. Our recommendations are periodically updated as new, clinically relevant information emerges.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bortezomib; Cyclophosphamide; Dexamethasone; Everolimus; Humans; Myeloid Differentiation Factor 88; Piperidines; Plasma Exchange; Pyrazoles; Pyrimidines; Retreatment; Risk Assessment; Rituximab; Waldenstrom Macroglobulinemia

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Commonly recurring mutations include MYD88 (95% to 97%), CXCR4 (30% to 40%), ARID1A (17%), and CD79B (8% to 15%). Diagnostic discrimination of WM from overlapping B-cell malignancies is aided by MYD88 mutation status. Transcription is affected by MYD88 and CXCR4 mutations and includes overexpression of genes involved in VDJ recombination, CXCR4 pathway signaling, and BCL2 family members. Among patients with MYD88 mutations, those with CXCR4 mutations show transcriptional silencing of tumor suppressors associated with acquisition of mutated MYD88. Deletions involving chromosome 6q are common and include genes that modulate nuclear factor-κB, BCL2, BTK, apoptosis, differentiation, and ARID1B. Non-chromosome 6q genes are also frequently deleted and include LYN, a regulator of B-cell receptor signaling. MYD88 and CXCR4 mutations affect WM disease presentation and treatment outcome. Patients with wild-type MYD88 show lower bone marrow disease burden and serum immunoglobulin M levels but show an increased risk of death. Patients with CXCR4 mutations have higher bone marrow disease burden, and those with nonsense CXCR4 mutations have higher serum immunoglobulin M levels and incidence of symptomatic hyperviscosity. Mutated MYD88 triggers BTK, IRAK1/IRAK4, and HCK growth and survival signaling, whereas CXCR4 mutations promote AKT and extracellular regulated kinase-1/2 signaling and drug resistance in the presence of its ligand CXCL12. Ibrutinib is active in patients with WM and is affected by MYD88 and CXCR4 mutation status. Patients with mutated MYD88 and wild-type CXCR4 mutation status exhibit best responses to ibrutinib. Lower response rates and delayed responses to ibrutinib are associated with mutated CXCR4 in patients with WM. MYD88 and CXCR4 mutation status may be helpful in treatment selection for symptomatic patients. Novel therapeutic approaches under investigation include therapeutics targeting MYD88, CXCR4, and BCL2 signaling.

Topics: Adenine; Genomics; Humans; Mutation; Myeloid Differentiation Factor 88; Piperidines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Signal Transduction; Waldenstrom Macroglobulinemia

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

Waldenström macroglobulinemia is defined by the presence of monoclonal immunoglobulin IgM type (M-IgM) and evidence of lymphoplasmacytic bone marrow infiltration. The disease has an indolent course, the treatment is only initiated when the disease has begun to damage its carrier. The following symptoms are regarded as proven indications for initiating therapy: B symptoms, symptomatic lymphadenopathy, splenomegaly, anemia with hemoglobin below 100 g / l or thrombocytopenia < 100 × 10(9)/l, caused by lymphoplasmacytic bone marrow infiltration. Frequent indications for initiating treatment include clinical evidence of hyperviscosity or cryoglobulinemia. M-IgM tends to have a character of autoantibody reaching up to 50 %, which may harm the organism, and therefore any proven damage to the organism by an autoimmune activity of M-IgM is also an indication for treatment. The text includes an overview of rare and very rare types of damage to the organism by M-IgM autoimmune activity. A combination of rituximab, cyclophosphamide and dexamethasone (RCD) is recommended for the initial treatment, possibly extended to R-CHOP regimen (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In our cohort of 43 patients the therapy involving a combination of R-CHOP achieved 3 (8.1 %) complete remissions and 31 (83.8 %) partial remissions. The remission in 75 % of the patients lasted more than 3 years. In case of recurrence after > 2 years, the same therapy can be used, in case of a relapse within a shorter period of time different treatment schedules are recommended. High-dose chemotherapy with an autologous transplant of stem cells obtained from peripheral blood is only recommended after the first recurrence for people under 65 years of age without contraindications. The text analyses the benefits of the new drugs for the treatment of Waldenström macroglobulinemia (bendamustine, thalidomide, lenalidomide, ibrutinib and high-dose chemotherapy).

Topics: Adenine; Anemia; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Dexamethasone; Doxorubicin; Humans; Immunoglobulin M; Lenalidomide; Lymphatic Diseases; Neoplasm Recurrence, Local; Piperidines; Prednisone; Prognosis; Pyrazoles; Pyrimidines; Remission Induction; Rituximab; Splenomegaly; Thalidomide; Thrombocytopenia; Vincristine; Waldenstrom Macroglobulinemia

Newer therapeutic strategies are emerging in Waldenström's Macroglobulinemia (WM), which has traditionally been an orphan disease diagnosis. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor was FDA-approved in 2015 as the first ever drug for the treatment of WM. This being a targeted therapy, has given rise to increased research into novel agents and pathways that can be exploited for clinical benefit in WM. In order to understand the underlying mechanisms of disease behavior as well as to test the benefit of various drugs, appropriate preclinical models are required. Historically there had been a lack of representative preclinical models in WM, but in recent years this has dramatically changed. This review highlights the currently available preclinical models and data regarding drug resistance pathways in WM. Knowledge from these will certainly help in paving the future course of treatment in this rare disorder which is indolent and yet, so far incurable.

Topics: Adenine; Animals; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Neoplasms, Experimental; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Waldenstrom's macroglobulinaemia (WM) is a B-cell neoplasm in which bone marrow is infiltrated by lymphoplasmacytic cells that secrete monoclonal immunoglobulin M (IgM). More than a decade ago, specific criteria were agreed to define diagnosis and symptomatic disease requiring therapy; however, treatment recommendations change as new options emerge. Treatment decisions consider specific disease characteristics (burden of disease, IgM levels, presence of cytopenias) and patient characteristics (age, comorbidities, toxicity). Recently, the impact of specific mutations (in MYD88 and CXCR4) in response to specific therapies has been reported, and this may affect treatment decisions in the future. Chemo-immunotherapy combinations based on rituximab with cyclophosphamide/dexamethasone, bendamustine or bortezomib/dexamethasone are indicated for most patients. The BTK inhibitor ibrutinib was recently approved for patients with WM, and is a new option for selected newly diagnosed or relapsing patients. New B-cell receptor inhibitors, second-generation proteasome inhibitors and mammalian target of rapamycin inhibitors are promising; however, more data are needed from high-quality clinical trials.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bortezomib; Clinical Trials as Topic; Cyclophosphamide; Dexamethasone; Humans; Immunotherapy; Mutation; Myeloid Differentiation Factor 88; Piperidines; Practice Guidelines as Topic; Pyrazoles; Pyrimidines; Receptors, CXCR4; Rituximab; Waldenstrom Macroglobulinemia

Waldenström macroglobulinemia (WM) is a rare lymphoma characterized by the accumulation of IgM-producing lymphoplasmacytic cells. Although WM patients can experience prolonged remissions, the disease invariably recurs. Therefore, novel treatments associated with higher success rates and lower toxicity profiles are needed. The discovery of recurrent mutations in the MYD88 and CXCR4 genes has unraveled potential therapeutic targets in WM patients. As a result of these findings and based on the design and execution of a prospective clinical trial, the FDA granted approval to ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, to treat patients with symptomatic WM. The present review focuses on potential therapies that could change the landscape of treatment of patients with WM, specifically focusing on inhibitors or antagonists or the proteasome, BTK, CD38, BCL2 and the CXCR4 and MYD88 genes themselves. Novel agents with novel mechanisms of action should be evaluated in the context of carefully designed clinical trials.

Topics: Adenine; ADP-ribosyl Cyclase 1; Agammaglobulinaemia Tyrosine Kinase; Clinical Trials as Topic; Humans; Membrane Glycoproteins; Myeloid Differentiation Factor 88; Piperidines; Prospective Studies; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Receptors, CXCR4; Waldenstrom Macroglobulinemia

Waldenström Macroglobulinemia (WM) is a rare B-cell lymphoma characterized by the uncontrolled accumulation of malignant lymphoplasmacytic cells, mainly in the bone marrow, and monoclonal IgM production. Despite its rarity, our understanding of the biology of this disease has improved significantly in recent years with the identification of recurrent mutations in the MYD88 and CXCR4 genes. Based on the diversity of clinical features observed in WM patients, therapy should be highly personalized having into account several factors such as age, co-morbidities, IgM levels, and presence of hyperviscosity, coagulopathy, cryoglobulinemia, or cold agglutinin disease. In this chapter, we review the recent advances in the biology of WM and the current therapeutic options for untreated and relapsed WM patients. Finally, we discuss the role of prognostic factors and current evidence supporting an improvement in the survival of WM patients in the last decade.

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boronic Acids; Bortezomib; Everolimus; Humans; Piperidines; Prognosis; Proteasome Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Salvage Therapy; Sirolimus; Stem Cell Transplantation; Waldenstrom Macroglobulinemia

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

Waldenström macroglobulinemia (WM) is a B-cell non-Hodgkin lymphoma (NHL) characterized by IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Until recently, there was no drug specifically approved for WM by the US FDA, leading to wide variations in therapeutic strategies across the globe. Ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, is the first drug approved specifically for WM by the FDA after a clinical trial showed impressive response in previously treated WM. Ibrutinib is a non-stem cell toxic and non-neurotoxic option and suitable for long-term oral maintenance therapy, with the potential of improving survival in WM. With identification of novel genetic mutations impacting response to ibrutinib, it would be possible to individualize therapy based on MYD88 and CXCR4 genotypes. However, long-term safety and efficacy data are required, and cost-effectiveness needs to be addressed before ibrutinib can gain widespread acceptance for front-line therapy of WM.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Drug Approval; Drug Costs; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

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

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 double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE.. Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety.. With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250;. In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Double-Blind Method; Female; Humans; Male; Middle Aged; Mutation; Myeloid Differentiation Factor 88; Piperidines; Progression-Free Survival; Receptors, CXCR4; Rituximab; Time Factors; Waldenstrom Macroglobulinemia

Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

Topics: Adenine; Female; Humans; Male; Middle Aged; Piperidines; Prognosis; Progression-Free Survival; Prospective Studies; Protein Kinase Inhibitors; Treatment Outcome; Waldenstrom Macroglobulinemia

MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.

Topics: Adenine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Humans; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Receptors, CXCR4; Waldenstrom Macroglobulinemia

Ibrutinib is highly active in Waldenström macroglobulinaemia (WM) patients, but disease progression can occur due to acquired mutations in BTK, the target of ibrutinib, or PLCG2, the protein downstream of BTK. However, not all resistant patients harbour these alterations. We have performed a whole-exome sequencing study to identify alternative molecular mechanisms that can drive ibrutinib resistance. Our findings include deletions on chromosomes 6q, including homozygous deletions, and 8p, which encompass key regulators of BTK, MYD88/NF-κB, and apoptotic signalling. Moreover, we have identified recurring mutations in ubiquitin ligases, innate immune signalling, and TLR/MYD88 pathway regulators in ibrutinib-resistant WM patients.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Apoptosis; Chromosome Deletion; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 8; Drug Resistance, Neoplasm; Exome Sequencing; Humans; Male; Middle Aged; Myeloid Differentiation Factor 88; NF-kappa B; Phospholipase C gamma; Piperidines; Signal Transduction; Waldenstrom Macroglobulinemia

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cohort Studies; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Salvage Therapy; Survival Rate; Waldenstrom Macroglobulinemia

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Survival Rate; Waldenstrom Macroglobulinemia

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous stem cell transplantation. Overall, 19% of patients received ibrutinib during the course of the disease. According to IPSSWM, 63% were classified as low risk, 27% as intermediate risk and 10% as high risk. Five-year OS was shorter in high-risk as compared with low or intermediate risk patients (92.9% vs 100% P = .002). According to revised IPSSWM, 92% were classified as very low or low risk and 8% as intermediate risk, with a shorter 5-year OS in the latter group (87.5% vs 100%, P = .028). The OS of young WM patients was not significantly reduced as compared with age-matched, sex-matched and calendar year-matched general population. Early diagnosis, absence of high-risk features in symptomatic patients and high efficacy of modern treatments are the main determinants of the excellent outcome of young WM patients.

Topics: Adenine; Adult; Age Factors; Autografts; Disease-Free Survival; Female; Humans; Immunotherapy; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Risk Factors; Stem Cell Transplantation; Survival Rate; Waldenstrom Macroglobulinemia

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

Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

Topics: Humans; Myeloid Differentiation Factor 88; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Disease-Free Survival; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Survival Rate; Waldenstrom Macroglobulinemia

Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.. We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.. At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%).. Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Disease-Free Survival; Female; Hemoglobins; Humans; Immunoglobulin M; Infusions, Intravenous; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Survival Analysis; Waldenstrom Macroglobulinemia

Waldenström macroglobulinemia (WM), an incurable B-cell malignancy, is sensitive to Bruton tyrosine kinase (BTK) inhibition with ibrutinib, a first-generation BTK inhibitor. Off-target effects of ibrutinib against TEC- and EGFR-family kinases are implicated in some adverse events. Patients with CXCR4

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Mutation; Myeloid Differentiation Factor 88; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease.. This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete.. Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5-18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3-11·7) increased to 11·4 g/dL (10·9-12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8-13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report.. The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia.. Pharmacyclics LLC, an AbbVie Company.

Topics: Adenine; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Staging; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Rituximab; Salvage Therapy; Survival Rate; Waldenstrom Macroglobulinemia

Ibrutinib produces high response rates and durable remissions in Waldenström macroglobulinemia (WM) that are impacted by MYD88 and CXCR4

Topics: Adenine; Aged; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Proteins; Piperidines; Pyrazoles; Pyrimidines; Signal Transduction; Waldenstrom Macroglobulinemia

Topics: Adenine; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Risk Factors; Time Factors; Waldenstrom Macroglobulinemia

MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib.. We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects.. After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%).. Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Disease-Free Survival; Female; Hemoglobins; Humans; Immunoglobulin M; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Myeloid Differentiation Factor 88; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, CXCR4; Survival Rate; Waldenstrom Macroglobulinemia

Ibrutinib represents the first approved treatment for patients with Waldenström macroglobulinemia (WM). There are very few published experiences outside of a clinical trial. In this study, we investigated treatment response, survival, and safety in a real life setting. We retrospectively analyzed 49 consecutive R/R WM patients, managed in 8 Tuscan onco-hematological centers, that received ibrutinib after its approval, at a maximum dose of 420 mg once per day, until disease progression or unacceptable toxicity. Median age was 65 years (range 32-86), and the median number of previous regimens was 2 (range 1-5). Overall and major response rate were 91.8% and 87.7%, respectively. At best response, median IgM level declined from 3,094 to 831 mg/dl, and Hb level increased from 10.4 to 12.7 g/dl. In an intention-to-treat analysis, 36/49 patients (73.5%) were still receiving treatment, while 13/49 (26.5%) had discontinued therapy. Six out of 49 cases (12.2%) relapsed after an initial response, and 13/49 (26.5%) had a dose reduction. Estimated 2-year PFS, DOR, and OS were 76.7%, 88.7%, and 84.1%, respectively. After a median follow-up of 18.3 months, 43/49 patients (87.8%) were alive. The most frequent AE included atrial fibrillation or flutter (6/49 cases, 12.2%), bleeding (6/49 cases, 12.2%), arthralgia/myalgia (5/49 cases, 10.2%). Ibrutinib is a suitable treatment option for R/R WM patients and also suggested by ESMO, NCCN, and other societies. PFS and OS were durable, and DOR was sustained for responsive patients. Treatment toxicity is not negligible, but manageable in most cases without treatment discontinuation.

Topics: Adult; Aged; Aged, 80 and over; Humans; Lymphoma; Middle Aged; Piperidines; Retrospective Studies; Waldenstrom Macroglobulinemia

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Piperidines; Waldenstrom Macroglobulinemia

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Prognosis; Prospective Studies; Survival Rate; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Myeloid Differentiation Factor 88; Piperidines; Receptors, CXCR4; Waldenstrom Macroglobulinemia

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; P < .001) and deep response (OR, 0.3; 95% CI, 0.2-0.6; P = .001). CXCR4 mutations (hazard ratio [HR], 2.0; 95% CI, 1.2-3.4; P = .01) and platelet count 100 K/uL or less (HR, 2.5; 95% CI, 1.3-4.9; P = .007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these 2 factors. The median PFS for patients with 0, 1, and 2 risk factors were not reached, 5 years and 3 years (P < .001). Patients with 2 risk factors had HR 2.2 (95% CI, 1.3-3.8; P = .004) compared with 1 factor, and patients with 1 factor had HR 2.3 (95% CI, 1.1-5.1; P = .03) compared with 0 factors. Age ≥65 years was the only factor associated with overall survival (HR, 3.2; 95% CI, 1.4-7.0; P = .005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy.

Topics: Adenine; Aged; Humans; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

The pivotal role that ibrutinib plays in the management of Waldenström macroglobulinemia (WM) is undisputed but there are ongoing questions regarding its positioning in the therapeutic algorithm of WM as well as in some peculiar clinical situations. A panel of experts from Italy was convened to provide real world recommendations on the use of BTK inhibitors in lymphoproliferative diseases in general, and in patients with WM in particular. This position paper represents the panel's collective analysis, evaluation, and opinions and is made up of a series of questions frequently asked by practicing clinicians and answers based on currently available evidence.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Recently, the non-covalent Bruton tyrosine kinase (BTK) inhibitor fenebrutinib was presented as a therapeutic option with strong inhibitory efficacy against a single (C481S) and double (T474S/C481S) BTK variant in the treatment of Waldenström macroglobulinemia (WM). However, the molecular events surrounding its inhibition mechanism towards this variant remain unresolved. Herein, we employed in silico methods such as molecular dynamic simulation coupled with binding free energy estimations to explore the mechanistic activity of the fenebrutinib on (C481S) and (T474S/C481S) BTK variant, at a molecular level. Our investigations reveal that amino acid arginine contributed immensely to the total binding energy, this establishing the cruciality of amino acid residues, Arg132 and Arg156 in (C481S) and Arg99, Arg137, and Arg132 in (T474S/C481S) in the binding of fenebrutinib towards both BTK variants. The structural orientations of fenebrutinib within the respective hydrophobic pockets allowed favorable interactions with binding site residues, accounting for its superior binding affinity by 24.5% and relative high hydrogen bond formation towards (T474S/C481S) when compared with (C481S) BTK variants. Structurally, fenebrutinib impacted the stability, flexibility, and solvent accessible surface area of both BTK variants, characterized by various alterations observed in the bound and unbound structures, which proved enough to disrupt their biological function. Findings from this study, therefore, provide insights into the inhibitory mechanism of fenebrutinib at the atomistic level and reveal its high selectivity towards BTK variants. These insights could be key in designing and developing BTK mutants' inhibitors to treat Waldenström macroglobulinemia (WM).

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Amino Acids; Arginine; Drug Resistance, Neoplasm; Humans; Mutation; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Pyrimidines; Solvents; Waldenstrom Macroglobulinemia

Ibrutinib, a first-class Bruton tyrosine kinase inhibitor, is known to be associated with adverse bleeding events and has been recently approved for the treatment of relapse Waldenström macroglobulinemia (WM). Here, we report the exhaustive clinical and biological follow-up of 2 patients treated by ibrutinib alone in the context of relapsed WM with an acquired von Willebrand syndrome (AVWS) complication. In two cases, ibrutinib has been shown to be quickly efficient and safe for treating both AVWS and its underlying condition the WM, without bleeding complications. Interestingly, ibrutinib treatment brings a rapid and extended over time normalization of von Willebrand factor clearance. These observations show that ibrutinib is a valuable therapeutic option in relapsed WM patients associated with AVWS and highlighting the need for further cohort studies with long-term follow-up of patients to confirm the efficacy and safety of a treatment by ibrutinib for WM patients with AVWS complication.

Topics: Humans; Neoplasm Recurrence, Local; Piperidines; von Willebrand Diseases; Waldenstrom Macroglobulinemia

Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% confidence interval [CI]: 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI: 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 days after discontinuing ibrutinib (OR 4.12, 95% CI: 1.07- 18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI: 26-75). Response to salvage therapy was associated with better OS after ibrutinib (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.

Topics: Adenine; Humans; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM).. Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity.. The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL (. Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by

Topics: Adenine; Adult; Aged; Aged, 80 and over; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Survival Rate; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Piperidines; Prognosis; Progression-Free Survival; Pyrimidines; Waldenstrom Macroglobulinemia

Zanubrutinib is a potent, second-generation Bruton's tyrosine kinase inhibitor that is currently being investigated in patients with B-cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B-cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed-effects modeling. Zanubrutinib PKs were adequately described by a two-compartment model with sequential zero-order then first-order absorption, and first-order elimination. A time-dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B-cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft-Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid-reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.

Topics: Adult; Aged; Aged, 80 and over; Biological Variation, Population; Case-Control Studies; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Humans; Leukemia, B-Cell; Lymphoma, B-Cell; Male; Middle Aged; Models, Biological; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia; Young Adult

Topics: Adenine; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lymphoma, B-Cell; Molecular Targeted Therapy; Nerve Tissue Proteins; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Receptors, Cell Surface; Sulfonamides; Waldenstrom Macroglobulinemia

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bortezomib; Chlorambucil; Cyclophosphamide; Dexamethasone; Doxorubicin; Humans; Kaplan-Meier Estimate; Piperidines; Prednisone; Progression-Free Survival; Proportional Hazards Models; Retrospective Studies; Rituximab; Treatment Outcome; Veterans; Vidarabine; Vincristine; Waldenstrom Macroglobulinemia

Immune modulation in COVID-19 is emerging as an important therapeutic strategy as increasing evidence suggests that inflammatory pathways are implicated in lung damage. Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, are commonly used to treat indolent B-cell neoplasms and chronic graft-versus-host disease (GvHD). Given their potential to suppress pulmonary inflammatory cytokines and lessen acute lung injury, this could be applicable in the context of hospitalised COVID-19 patients. We describe an 81 year-old male receiving ibrutinib for Waldenstrom macroglobulinaemia (WM) who was hospitalised with COVID-19. On stopping the BTKi due to concerns of additional immunosuppression, he required non-invasive ventilation (NIV) in the intensive care unit (ICU) and demonstrated prompt clinical recovery when ibrutinib was reinstated. Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKis and other immunomodulatory agents on the clinical course of COVID-19 as is currently being carried out in a number of clinical trials.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged, 80 and over; COVID-19; COVID-19 Drug Treatment; Humans; Immunomodulation; Male; Piperidines; Protein Kinase Inhibitors; SARS-CoV-2; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Blood Cell Count; Central Nervous System Neoplasms; Cerebrospinal Fluid; Diagnosis, Differential; Eye Diseases; Eye Pain; Humans; Magnetic Resonance Imaging; Male; Optic Disk; Optic Nerve; Pain; Piperidines; Tomography, X-Ray Computed; Vision Disorders; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bortezomib; Clonal Evolution; Cyclophosphamide; Disease Progression; Doxorubicin; Fatal Outcome; Female; Humans; Immunoglobulin kappa-Chains; Immunoglobulin M; Lymph Nodes; Myeloid Differentiation Factor 88; Neoplasm Proteins; Piperidines; Plasmablastic Lymphoma; Prednisone; Protein Kinase Inhibitors; Vincristine; Waldenstrom Macroglobulinemia

To report a case of serous macular detachment in a patient with Waldenstrom macroglobulinemia treated with ibrutinib.. The patient underwent a complete ophthalmic examination and imaging at presentation and at follow-up visits up to 13 months.. At presentation, there were serous macular detachments bilaterally with no dye leakage on fluorescein angiography or vasculature abnormalities on optical coherence tomography angiography. After treatment with ibrutinib, there was near resolution of the patient's retinopathy with an improvement in vision at 13 months' follow-up.. Serous macular detachments in Waldenstrom macroglobulinemia-associated retinopathy may be due to the disruption of the retinal pigment epithelium pump mechanism by hyperglobulinemia. The favorable course of this patient, treated with the novel tyrosine kinase inhibitor ibrutinib, suggests this may be the preferred treatment for Waldenstrom macroglobulinemia patients with associated retinopathy.

Topics: Adenine; Humans; Piperidines; Retinal Detachment; Treatment Outcome; Waldenstrom Macroglobulinemia

Ibrutinib-related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment-naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off-study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major-response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2-4] and 5·7 (95% CI: 4-12) months, respectively. The median follow-up was 19 (95% CI: 14-21) months; 18-month progression-free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3-16·7) months, and the median duration-of-response was 32 (range: 23-32) months. Twenty-five patients (31%) had discontinued therapy at last follow-up (68% due to treatment-related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial-fibrillation (11%) were common non-haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunoglobulin M; Kaplan-Meier Estimate; Male; Middle Aged; Piperidines; Practice Patterns, Physicians'; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Salvage Therapy; Treatment Outcome; Waldenstrom Macroglobulinemia

To assess whether neuropathy with anti-myelin-associated glycoprotein (MAG) antibody may improve after treatment with ibrutinib, an oral inhibitor of Bruton tyrosine kinase, we prospectively treated with ibrutinib a cohort of 3 patients with anti-MAG neuropathy and Waldenström macroglobulinemia (WM).. All the patients reported an early and subjective benefit, consistent with the objective improvement, especially of the sensory symptoms as shown by clinical scales. Treatment was well tolerated.. These preliminary data point to a possible efficacy of ibrutinib in anti-MAG antibody neuropathy, which is the most common disabling paraproteinemic neuropathy, where active treatment is eagerly needed.. This study provides Class IV evidence that for patients with anti-MAG antibody neuropathy, ibrutinib improves neuropathy symptoms.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Autoimmune Diseases of the Nervous System; Female; Humans; Male; Myelin-Associated Glycoprotein; Piperidines; Polyneuropathies; Protein Kinase Inhibitors; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Betacoronavirus; Coronavirus Infections; COVID-19; Female; Humans; Lung Injury; Male; Middle Aged; Pandemics; Piperidines; Pneumonia, Viral; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; SARS-CoV-2; Waldenstrom Macroglobulinemia

Topics: Humans; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Our case of a patient with untreated lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia with extramedullary pleural effusion is the first documented case of pleural fluid MYD88 L265P mutation status in a community hospital setting. Our patient was intolerant to 420 mg ibrutinib, but still achieved a lasting complete remission, as defined by National Comprehensive Cancer Network guidelines, with a dose reduction to 240 mg of ibrutinib.. A 72-year-old Caucasian (white) man diagnosed with monoclonal immunoglobin M kappa lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia monitored without treatment for 2 years, presented with dyspnea and a left pleural effusion. At presentation, computed tomography scans of his chest, abdomen, and pelvis showed layering left pleural effusion and para-aortic lymphadenopathy. Pleural fluid cytology demonstrated B-cell lymphoma of the lymphoplasmacytic subtype, with monoclonal kappa B-cell population on flow and a positive MYD88 L265P mutation. The pleural effusion recurred post-thoracentesis and he achieved a lasting complete remission as defined by National Comprehensive Cancer Network guideline with 240 mg ibrutinib.. Our discussion details a comprehensive literature review of extramedullary pulmonary involvement in Waldenstrom's macroglobulinemia. Establishing a malignant etiology for pleural effusion in Waldenstrom's macroglobulinemia can be challenging, as standard techniques may be insensitive. Allele-specific polymerase chain reaction for detecting MYD88 L265P mutations is more sensitive for confirming lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia in pleural fluid. Extramedullary pulmonary involvement usually presents post-diagnosis of Waldenstrom's macroglobulinemia and responds well to Waldenstrom's macroglobulinemia-directed treatment regimens. Allele-specific polymerase chain reaction is a sensitive assay for detecting MYD88 L265P mutations in pleural fluid to support the diagnosis of malignant pleural effusion in the setting of Waldenstrom's macroglobulinemia and helps guide the treatment decision to use ibrutinib. Although intolerant of ibrutinib 420 mg, our patient achieved complete and sustained remission of pleural effusion with a dose of 240 mg with progression free survival of over 30 months.

Topics: Adenine; Aged; Dose-Response Relationship, Drug; Humans; Male; Mutation; Myeloid Differentiation Factor 88; Piperidines; Pleural Effusion, Malignant; Remission Induction; Tomography, X-Ray Computed; Waldenstrom Macroglobulinemia

Topics: Adenine; Adolescent; Agammaglobulinaemia Tyrosine Kinase; Female; Humans; Myeloid Differentiation Factor 88; Piperidines; Syndrome; Waldenstrom Macroglobulinemia

Topics: Follow-Up Studies; Humans; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Topics: Adenine; Antineoplastic Agents; Central Nervous System Neoplasms; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Drug Resistance; Humans; Mutation; Myeloid Differentiation Factor 88; Piperidines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Treatment Outcome; Waldenstrom Macroglobulinemia

Little is known about TP53 mutations in Waldenström Macroglobulinaemia (WM). We evaluated 265 WM patients for TP53 mutations by next-generation sequencing, and validated the findings by Sanger sequencing. TP53 mutations were identified and validated in 6 (2·6%) patients that impacted the DNA-binding domain. All six were MYD88- and CXCR4-mutated. Ibrutinib showed activity in patients carrying all three mutations. With a median follow-up of 18 months, 2 (33%) with biallelic TP53 inactivation died of progressive disease. TP53 mutations are rare in WM, and associate with MYD88 and CXCR4 mutations. WM patients with TP53 mutations show response to ibrutinib.

Topics: Adenine; Adult; Aged; Disease-Free Survival; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mutation; Myeloid Differentiation Factor 88; Piperidines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Survival Rate; Tumor Suppressor Protein p53; Waldenstrom Macroglobulinemia

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Invasive Fungal Infections; Male; Middle Aged; Piperidines; Pneumocystis carinii; Pneumonia, Pneumocystis; Pyrazoles; Pyrimidines; Risk Factors; Waldenstrom Macroglobulinemia

The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.

Topics: Adenine; Adult; Aged; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Bing-Neel syndrome is a rare complication of Waldenström macroglobulinemia, characterized by infiltration of lymphoplasmacytic cells to the central nervous system. Multiple treatment modalities exist including purine analogs, bendamustine, high-dose methotrexate, or high-dose cytarabine. Of interest, ibrutinib, a Bruton tyrosine kinase inhibitor has also displayed efficacy in Bing-Neel syndrome. Current literature is limited for the treatment of Bing-Neel syndrome considering its rarity, and while ibrutinib is indicated for the treatment of Waldenström macroglobulinemia, it is utilized off-label for treatment of Bing-Neel syndrome. Additionally, debate exists regarding the recommended dosing strategy for ibrutinib for this indication with disease remission demonstrated at 560 mg and 420 mg. We present a case report that provides additional evidence for this debate with a patient who received 560 mg of ibrutinib initially and maintained disease control despite a dose reduction to 420 mg for tolerability. Ultimately, more data are needed to develop standardized Bing-Neel syndrome treatment strategies with specific consideration to the use of ibrutinib in this condition.

Topics: Adenine; Brain Diseases; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

The Bruton's tyrosine kinase inhibitor ibrutinib represents a highly effective single substance in the treatment of Waldenström's macroglobulinemia. Ibrutinib monotherapy is a valid therapeutic option either in the relapsed or refractory setting or in patients first line, particulary when they are ineligible for chemotherapy. However, the treatment success depends on the genotype. Recent data suggest that ibrutinib in combination with rituximab may partially overcome this genotype dependency.

Topics: Adenine; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Chemokine CXCL12; Enzyme Inhibitors; Humans; Myeloid Differentiation Factor 88; Piperidines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Rituximab; Waldenstrom Macroglobulinemia

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

Waldenstrom's macroglobulinaemia (WM) is a lymphoproliferative disorder of the B cell origin. It is characterised by the presence of IgM paraprotein in the serum and lymphoplasmacytic lymphoma cells in the bone marrow with extranodal involvement relatively uncommon. Bing-Neel syndrome (BNS) is a neurological complication of WM that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. We present an interesting case of BNS that responded remarkably to ibrutinib monotherapy.

Topics: Adenine; Brain; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Mutation; Myeloid Differentiation Factor 88; Neurodegenerative Diseases; Piperidines; Pyrazoles; Pyrimidines; Syndrome; Waldenstrom Macroglobulinemia

Ibrutinib is associated with response rate of 90% and median progression-free survival (PFS) in excess of 5 years in Waldenström macroglobulinaemia (WM) patients. CXCR4 mutations are detected in 30-40% of patients with WM and associate with lower rates of response and shorter PFS to ibrutinib therapy. Both frameshift (CXCR4

Topics: Adenine; Adult; Aged; Aged, 80 and over; Disease-Free Survival; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Proteins; Piperidines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Survival Rate; Waldenstrom Macroglobulinemia

Ibrutinib is an oral inhibitor of Bruton tyrosine kinase approved for the treatment of chronic lymphocytic leukaemia, mantle cell lymphoma and refractory Waldenstrom's disease. It increases progression-free survival, overall survival, response rate. The most frequent adverse reactions, are increased risk in of bleeding and atrial fibrillation, but several reports of more dangerous rhythm disturbances have been recently reported in literature. A case of a patient with refractory Waldenstrom's disease, who developed ventricular fibrillation while taking ibrutinib, is reported, along with a concise literature review.

Topics: Adenine; Death, Sudden, Cardiac; Electrocardiography; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Ventricular Fibrillation; Waldenstrom Macroglobulinemia

Topics: Adenine; Biomarkers; Combined Modality Therapy; Female; Humans; Liver Failure, Acute; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Cell Transformation, Neoplastic; Central Nervous System Diseases; Female; Humans; Middle Aged; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4-fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.

Topics: Adenine; Aged; Disease Progression; Female; Humans; Immunoglobulin M; Kaplan-Meier Estimate; Male; Middle Aged; Myeloid Differentiation Factor 88; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, CXCR4; Retrospective Studies; Salvage Therapy; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Blood Transfusion; Female; Hemolysis; Humans; Middle Aged; Piperidines; Prognosis; Programmed Cell Death 1 Receptor; Pyrazoles; Pyrimidines; Transfusion Reaction; Waldenstrom Macroglobulinemia

Topics: Adenine; Antineoplastic Agents; Biomarkers; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Substance Withdrawal Syndrome; Waldenstrom Macroglobulinemia; Withholding Treatment

Topics: Adenine; Aged; Brain; Brain Diseases; Humans; Magnetic Resonance Imaging; Male; Piperidines; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti-CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib-resistant lines) elicited antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI-WM1-xenografted mice. CD38 is reported to augment B-cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib-resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single-agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti-WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co-targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.

Topics: Adenine; ADP-ribosyl Cyclase 1; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cytotoxicity, Immunologic; Humans; Mice, Inbred NOD; Phagocytosis; Piperidines; Pyrazoles; Pyrimidines; Tumor Cells, Cultured; Waldenstrom Macroglobulinemia; Xenograft Model Antitumor Assays

The authors present a case of an elderly man with a history of Waldenstrom macroglobulinaemia in remission who presented with progressively worsening gait abnormalities and falls for several months. His examination was notable for bilateral lower extremity weakness and an unsteady gait. Brain and spinal MRI showed focal leptomeningeal enhancement in the brain and spinal column. Lumbar puncture was performed and cerebrospinal fluid flow cytometry demonstrated a monoclonal CD5/CD10-negative, CD20-positive B-cell lymphocyte population consistent with a diagnosis of Bing-Neel syndrome. He was started on ibrutinib, an oral Bruton's tyrosine kinase inhibitor, and had marked improvement in his weakness and gait. Repeat imaging 2 months after starting ibrutinib showed improvement in his leptomeningeal enhancement. During subsequent follow-up, he continued to tolerate ibrutinib and had a sustained clinical response.

Topics: Adenine; Aged; Brain; Humans; Magnetic Resonance Imaging; Male; Piperidines; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Waldenstrom Macroglobulinemia

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; Humans; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Waldenstrom Macroglobulinemia

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Immunoglobulin M; Kidney Failure, Chronic; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Proteins; Paraproteins; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Salvage Therapy; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Cryptococcosis; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Magnetic Resonance Imaging; Meningoencephalitis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a novel drug that has shown significant efficacy and survival benefit for treatment of various B-cell malignancies. The primary objective of the present study was to investigate the efficacy of ibrutinib therapy in various B-cell malignancies in the general community. The secondary objectives included studying the adverse effects, ibrutinib-induced peripheral lymphocytosis, and effect on immunoglobulin levels.. The present study was a retrospective observational cohort analysis conducted at Abington Jefferson Health. The clinical response was determined from the hematologist's assessment and evaluated independently using the response criteria for each B-cell malignancy. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The Wilcoxon signed-rank test was used to compare immunoglobulin levels before and after ibrutinib. Forty five patients with B-cell malignancies and receiving ibrutinib therapy were eligible.. Ibrutinib is a highly effective and tolerable drug for B-cell malignancies in the general community. In contrast to the previously reported rate of 5% to 7%, we observed a higher rate (11%) of atrial fibrillation, which might have resulted from the smaller sample size in the present study and the multiple comorbidities. Nonetheless, this treatment-limiting side effect requires further elucidation. Paradoxical lymphocytosis at the outset of therapy was a common and benign finding. In conjunction with the reported trials, the IgG levels decreased in the first year of continued therapy. However, the IgA levels did not increase, even after 2 years of therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Atrial Fibrillation; B-Lymphocytes; Disease-Free Survival; Female; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Retrospective Studies; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Biomarkers; Chemokine CXCL13; Cytokines; Humans; Immunoglobulin M; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

Chylothorax is an unusual cause of pleural effusion, typically caused by trauma or malignancy. Waldenstrom's macroglobulinaemia (WM) is a clinicopathological entity demonstrating lymphoplasmacytic lymphoma in the bone marrow with an IgM monoclonal gammopathy in the blood. Recurrent chylous effusions are often resistant to conservative treatment and may require surgical intervention. We present a unique case of a 50-year-old woman with recurrent chylothorax secondary to WM that completely resolved with ibrutinib therapy. To our knowledge, this is the eighth such case reported in literature and the first case of successful resolution of chylothorax with monoclonal antibody therapy.

Topics: Adenine; Chylothorax; Female; Humans; Middle Aged; Piperidines; Pleural Effusion, Malignant; Pyrazoles; Pyrimidines; Recurrence; Waldenstrom Macroglobulinemia

Topics: Adenine; Antineoplastic Agents; Biomarkers; Blood-Brain Barrier; Central Nervous System Neoplasms; Humans; Immunophenotyping; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Oral tyrosine kinase inhibitors (TKIs) are becoming increasingly common in oncology practice due to ease of administration and patient preference. This class of medications is relatively unknown to emergency physicians.. Here we present a case of electrical storm (ES) thought to be associated with ibrutinib, a TKI. The ES was unabated despite antidysrhythmic therapy and electrical cardioversion, and was treated with supportive care, which eventually included the use of extracorporeal membrane oxygenation. This patient had no risk factors or apparent causes of recurrent ventricular tachycardia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ES has not previously been described with ibrutinib, but may be associated with off-target effects of the drug.

Topics: Adenine; Amiodarone; Anti-Arrhythmia Agents; Antineoplastic Agents; Cardiotonic Agents; Electric Countershock; Electrocardiography; Electrophysiology; Emergency Service, Hospital; Extracorporeal Membrane Oxygenation; Humans; Intensive Care Units; Intra-Aortic Balloon Pumping; Isoproterenol; Lidocaine; Magnesium; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Respiration, Artificial; Syncope; Tachycardia, Ventricular; Torsades de Pointes; Waldenstrom Macroglobulinemia; Workforce

Waldenström macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab-induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib- and bortezomib-based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work-up and therapy of WM to assist Australian clinicians in the management of this disease.

Topics: Adenine; Advisory Committees; Antineoplastic Agents; Australia; Bendamustine Hydrochloride; Bone Marrow; Bortezomib; Humans; Immunoglobulin M; Mutation; Myeloid Differentiation Factor 88; Piperidines; Plasma Cells; Practice Guidelines as Topic; Pyrazoles; Pyrimidines; Rituximab; Societies, Medical; Waldenstrom Macroglobulinemia

The only available trial, a non-comparative study with 63 patients, failed to determine the efficacy of ibrutinib. In contrast, adverse effects are numerous and sometimes severe, including haematological disorders. Further evaluation of ibrutinib in this setting is necessary.

Topics: Adenine; Clinical Trials as Topic; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

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

Topics: Adenine; Aged; Central Nervous System Diseases; Female; Humans; Immunoglobulin M; Leukocyte Count; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Syndrome; Treatment Outcome; Waldenstrom Macroglobulinemia

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

Topics: Adenine; Amino Acid Substitution; Female; Humans; Immunoglobulin G; Leucine; Mutation, Missense; Myeloid Differentiation Factor 88; Piperidines; Proline; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

Activating mutations in MYD88 are present in ∼95% of patients with Waldenström macroglobulinemia (WM), as well as other B-cell malignancies including activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). In WM, mutated MYD88 triggers activation of Bruton tyrosine kinase (BTK). Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced hematopoietic cell kinase (HCK) transcription and activation, and that HCK is activated by interleukin 6 (IL-6). Over-expression of mutated MYD88 triggers HCK and IL-6 transcription, whereas knockdown of HCK reduced survival and attenuated BTK, phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259, blocked HCK activation and induced apoptosis in mutated MYD88 WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCK was a target of ibrutinib. Ibrutinib and A419259 also blocked adenosine triphosphate binding to HCK, whereas transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the half maximal effective concentration for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88-mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88.

Topics: Adenine; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Leukemic; Humans; Interleukin-6; Lymphoma, Large B-Cell, Diffuse; Molecular Targeted Therapy; Mutant Proteins; Myeloid Differentiation Factor 88; Piperidines; Proto-Oncogene Proteins c-hck; Pyrazoles; Pyrimidines; Transcriptional Activation; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Anemia, Hemolytic, Autoimmune; Humans; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Treatment Outcome; Waldenstrom Macroglobulinemia

Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD. We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo RESULTS: We found that Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenström macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenström macroglobulinemia cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: (i) activation of caspase-3, PARP and downregulation of Mcl-1, (ii) enhanced intracellular ATP and NAD. Our results show intracellular NAD

Topics: Acrylamides; Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; B-Lymphocytes; Caspase 3; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytokines; Humans; Mice; Mice, SCID; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Myeloid Differentiation Factor 88; NF-kappa B; Nicotinamide Phosphoribosyltransferase; Piperidines; Poly(ADP-ribose) Polymerases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, CXCR4; Signal Transduction; Waldenstrom Macroglobulinemia

The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.

Topics: Adenine; Apoptosis; Azepines; Benzylidene Compounds; Bortezomib; Cell Line, Tumor; Cell Survival; Deubiquitinating Enzymes; Drug Resistance, Neoplasm; Humans; Piperidines; Pyrazoles; Pyrimidines; Signal Transduction; Ubiquitin Thiolesterase; Waldenstrom Macroglobulinemia

Topics: Adenine; Antineoplastic Agents; Cell Proliferation; Clinical Trials, Phase II as Topic; Humans; Piperidines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Waldenstrom Macroglobulinemia

CXCR4(WHIM) somatic mutations are common Waldenstrom's Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis), CXCR(S338X) mutation in WM. Following SDF-1a stimulation, CXCR4(S338X) WM cells exhibited decreased receptor internalization, enhanced and sustained AKT kinase (AKT) and extracellular regulated kinase (ERK) signaling, decreased poly (ADP-ribose) polymerase and caspase 3 cleavage, and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4(S338X)-related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a-treated CXCR4(S338X) WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4(WT) cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a-treated CXCR4(S338X) WM cells demonstrating their role in SDF-1a-mediated ibrutinib resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4(WHIM) versus CXCR4(WT) WM patients, and remained active despite ibrutinib therapy in CXCR4(WHIM) patients. Last, CXCR4(S338X) WM cells showed varying levels of resistance to other WM relevant therapeutics, including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4(WHIM) mutations, and provide a framework for investigation of CXCR4 inhibitors in WM.

Topics: Adenine; Antineoplastic Agents; Drug Resistance, Neoplasm; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Humans; Mutation; Piperidines; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Receptors, CXCR4; Waldenstrom Macroglobulinemia

CXCR4(WHIM) frameshift and nonsense mutations follow MYD88(L265P) as the most common somatic variants in Waldenström Macroglobulinaemia (WM), and impact clinical presentation and ibrutinib response. While the nonsense (CXCR4(S338X) ) mutation has been investigated, little is known about CXCR4 frameshift (CXCR4(FS) ) mutations. We engineered WM cells to express CXCR4(FS) mutations present in patients, and compared their CXCL12 (SDF-1a) induced signalling and ibrutinib sensitivity to CXCR4(wild-type (WT)) and CXCR4(S338X) cells. Following CXCL12 stimulation, CXCR4(FS) and CXCR4(S338X) WM cells showed impaired CXCR4 receptor internalization, and enhanced AKT1 (also termed AKT) and MAPK1 (also termed ERK) activation versus CXCR(WT) cells (P < 0·05), though MAPK1 activation was more prolonged in CXCR4(S338X) cells (P < 0·05). CXCR4(FS) and CXCR4(S338X) cells, but not CXCR4(WT) cells, were rescued from ibrutinib-triggered apoptosis by CXCL12 that was reversed by AKT1, MAPK1 or CXCR4 antagonists. Treatment with an inhibitor that blocks MYD88(L265P) signalling triggered similar levels of apoptosis that was not abrogated by CXCL12 treatment in CXCR4(WT) and CXCR4(WHIM) cells. These studies show a functional role for CXCR4(FS) mutations in WM, and provide a framework for the investigation of CXCR4 antagonists with ibrutinib in CXCR4(WHIM) -mutated WM patients. Direct inhibition of MYD88(L265P) signalling overcomes CXCL12 triggered survival effects in CXCR4(WHIM) -mutated cells supporting a primary role for this survival pathway in WM.

Topics: Adenine; Amino Acid Substitution; Apoptosis; Cell Survival; Chemokine CXCL12; Codon, Nonsense; Drug Resistance, Neoplasm; Frameshift Mutation; Humans; Myeloid Differentiation Factor 88; Neoplasm Proteins; Piperidines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Signal Transduction; Tumor Cells, Cultured; Waldenstrom Macroglobulinemia

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

Topics: Adenine; Humans; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Waldenström macroglobulinemia (WM) is a B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig)M-secreting lymphoplasmacytic cells. MYD88 and CXCR4 warts, hypogammaglobulinemia, infections, myelokathexis syndrome-like somatic mutations are present in >90% and 30% to 35% of WM patients, respectively, and impact disease presentation, treatment outcome, and overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin <10 g/L, platelets <100 × 10(9)/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before rituximab for those with high serum IgM levels to preempt a symptomatic IgM flare. Treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Frontline treatments include rituximab alone or rituximab combined with alkylators (bendamustine and cyclophosphamide), proteasome inhibitors (bortezomib and carfilzomib), nucleoside analogs (fludarabine and cladribine), and ibrutinib. In the salvage setting, an alternative frontline regimen, ibrutinib, everolimus, or stem cell transplantation can be considered. Investigational therapies under development for WM include agents that target MYD88, CXCR4, BCL2, and CD27/CD70 signaling, novel proteasome inhibitors, and chimeric antigen receptor-modified T-cell therapy.

Topics: Adenine; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Cladribine; Cyclophosphamide; Everolimus; Gene Expression; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin M; Male; Middle Aged; Molecular Targeted Therapy; Myeloid Differentiation Factor 88; Nitrogen Mustard Compounds; Oligopeptides; Piperidines; Plasmapheresis; Pyrazines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Rituximab; Sirolimus; Transplantation, Autologous; Vidarabine; Waldenstrom Macroglobulinemia

Topics: Adenine; Humans; Mutation; Myeloid Differentiation Factor 88; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Our findings therefore provide a strong rationale for investigating Btk inhibitors in MM and WM to target both tumor cells and their supporting BM microenvironment and thereby both suppress tumor cell growth and abrogate MM-induced bone disease.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Cell Growth Processes; Disease Models, Animal; Humans; Mice; Molecular Targeted Therapy; Multiple Myeloma; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia