Oral Bruton's Tyrosine Kinase Research Articles

Real-world treatment patterns, adverse events and clinical outcomes in patients with chronic lymphocytic leukaemia treated with ibrutinib in the UK.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in adults in the UK. Ibrutinib, an oral Bruton tyrosine kinase inhibitor (BTKi) for CLL approved by the UK's National Institute for Health and Care Excellence in January 2017, represented a major shift in CLL management. Real‐world data on ibrutinib use in routine clinical practice will inform patients’ and physicians’ decision‐making. We conducted a retrospective medical chart review of UK patients with CLL who initiated ibrutinib between January 2017 and July 2018. Data for 259 patients were contributed by 34 haematology‐oncology specialists, with a median follow‐up duration of 16.7 months. Median age at ibrutinib initiation was 71 years. Ibrutinib first‐line monotherapy was prescribed in 20.1% of patients. Ibrutinib was permanently discontinued in 15.4% of patients, mostly owing to progressive disease. Adverse events (AEs) were reported in 151 patients (58.3%). The most common were bruising (19.3% of patients), cytopenias (17.0%) and diarrhoea (11.6%). Ibrutinib dose reduction was observed in 14.3% of patients and was temporarily discontinued in 10.4% of patients, with the main reason for both being toxicity. These results expand the real‐world evidence on ibrutinib therapy and demonstrate a high burden of AEs, highlighting the need for more tolerable BTKis.

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton's Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia.

The understanding of the B cell receptor (BCR) pathway and its contribution to chronic lymphocytic leukemia (CLL) pathogenesis have led to the development of targeted BCR inhibitors which have transformed the treatment paradigm of CLL. Ibrutinib is a first-in-class oral Bruton’s tyrosine kinase (BTK) inhibitor which has demonstrated improvements in both progression free (PFS) and overall survival (OS) in both the treatment naïve and relapsed/refractory setting as compared to traditional chemoimmunotherapy. Despite its clinical efficacy, many patients discontinue treatment due to adverse events, which are thought to be mediated through off-target kinase inhibition. Zanubrutinib is a second-generation non-covalent BTK inhibitor with higher potency, allowing for inhibition of BTK with fewer off target effects. Early phase clinical trials have demonstrated excellent efficacy and a well-tolerated safety profile. Long-term follow-up is needed, but zanubrutinib holds promise to be an effective therapy for CLL with a manageable side effect profile and will be an exciting addition to our treatment paradigm.

Ibrutinib in Combination with R-Gemox-D in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Phase II Clinical Trial of the Geltamo Group

Ibrutinib in Combination with R-Gemox-D in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Phase II Clinical Trial of the Geltamo Group

Hydroa Vacciniforme-Like Lymphoproliferative Disorder in an Adult Patient With Chronic Lymphocytic Leukemia

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a rare Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorder (LPD) which primarily affects children from Latin America and Asia. Typical features include vesicles and ulceration in sun-exposed areas which may be accompanied by systemic symptoms such as fever, lymphadenopathy and hepatosplenomegaly. We report a 73-year-old man diagnosed with HV-LPD in the context of zanubrutinib (oral Bruton tyrosine kinase (BTK)-inhibitor) treatment for chronic lymphocytic leukemia (CLL). The patient presented with slowly progressive peri-orbital edema and erythema non-responsive to topical therapies which eventually progressed to focal crusting and erosion. Prednisolone was subsequently introduced, which led to a good response in the patient’s symptoms. J Med Cases. 2020;11(11):366-369 doi: https://doi.org/10.14740/jmc3576

CXCR4 mutational status does not impact outcomes in patients with Waldenström macroglobulinemia treated with proteasome inhibitors.

CXCR4 mutational status does not impact outcomes in patients with Waldenström macroglobulinemia treated with proteasome inhibitors.

Efficacy and Safety of Ibrutinib in Elderly Patients with Chronic Lymphocytic Leukemia

Efficacy and Safety of Ibrutinib in Elderly Patients with Chronic Lymphocytic Leukemia

Early Adoption and Outcomes of Ibrutinib As Treatment for Older Patients with Chronic Lymphocytic Leukemia (CLL): A Population-Based Study

Early Adoption and Outcomes of Ibrutinib As Treatment for Older Patients with Chronic Lymphocytic Leukemia (CLL): A Population-Based Study

What is new in the treatment of 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) inhibitoribrutinib 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.

Front-Line Ibrutinib plus Rituximab for Chronic Lymphocytic Leukemia

The oral Bruton tyrosine kinase inhibitor (TKI) ibrutinib (IBR) has demonstrated high activity in previously untreated and relapsed patients with

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

PF374 IBRUTINIB PLUS FLUDARABINE, CYCLOPHOSPHAMIDE, AND RITUXIMAB (IFCR) AS INITIAL THERAPY FOR YOUNGER PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: A SINGLE‐ARM, MULTICENTER, PHASE 2 TRIAL

Background:Fludarabine, cyclophosphamide, rituximab (FCR) can provide prolonged disease free survival for young, fit chronic lymphocytic leukemia (CLL) patients with mutated IGHV; however, patients with unmutated IGHV rarely have durable response. The oral Bruton Tyrosine Kinase inhibitor, ibrutinib, is highly effective for patients irrespective of IGHV mutation status, but requires continuous therapy. We hypothesized that a time‐limited regimen of ibrutinib plus FCR (iFCR) would have curative potential for a broad population of young, fit CLL patients.Aims:The primary objective was to determine the rate of complete remission (CR) with undetectable bone marrow minimal residual disease (BM‐uMRD) two months after completing iFCR combination therapy. Secondary objectives were to assess clinical response rates, progression‐free and overall survival, rates of best response and BM‐uMRD, safety/tolerability, ibrutinib pharmacokinetics (PK), and association of established CLL prognostic factors with clinical response.Methods:We performed a multicenter, open‐label, non‐randomized, phase 2 investigator sponsored trial of iFCR, and enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL criteria for initial treatment. Ibrutinib 420 mg daily was given for 7 days, followed by combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM‐uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity was assessed by CTCAE v4.03 and iwCLL criteria. This trial is registered with ClinicalTrials.gov (NCT02251548).Results:Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites. The median age was 55 years (range 38–65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1–6). The median AUC of ibrutinib in combination with FCR was 337.2 (IQR 198.6–553.9), and the median Cmax was 97.3 (IQR 65.1–168.8). These PK parameters are similar to ibrutinib monotherapy in prior studies, and did not appear to be altered by FCR. The rate of CR‐BM‐uMRD 2 months post‐FCR was 33% (28/85 patients, 95% CI: 0.25–1.0)), with a best rate at any point on trial that increased to 41% (35/85), and a best rate of CR/CRi irrespective of MRD status of 66%. The best rate of BM‐uMRD irrespective of IW‐CLL response status was 84% (71/85), and did not differ by IGHV mutation status (Figure 1). With a median follow‐up of 16.5 months (range 3.1–48.9), one patient progressed and one died due to a presumed cardiac event. The most common treatment‐emergent grade 3/4 adverse events were hematologic, including neutropenia 35%, thrombocytopenia 32%, and anemia 11%. Eight patients (9%) experienced grade ≥3 febrile neutropenia. No cases of Richter's Syndrome have been observed.Summary/Conclusion:The rate of BM‐uMRD induced by iFCR is, to our knowledge, the highest ever reported for a regimen treating a population of CLL patients unrestricted by prognostic marker status. The safety profile of iFCR was generally favorable, with typical toxicities of ibrutinib and FCR observed, and no additional toxicities discernable with the combination. These data establish iFCR as a highly effective novel‐agent‐containing time‐limited combination for initial therapy for young, fit CLL patients.image

Ibrutinib Displays Atrial-Specific Toxicity in Human Stem Cell-Derived Cardiomyocytes.

Ibrutinib Displays Atrial-Specific Toxicity in Human Stem Cell-Derived Cardiomyocytes.

Risk of Bleeding with Ibrutinib in Patients with B-Cell Malignancies: An Updated Meta-Analysis of Phase III Randomized Controlled Trials

Risk of Bleeding with Ibrutinib in Patients with B-Cell Malignancies: An Updated Meta-Analysis of Phase III Randomized Controlled Trials

Risk of Infection with Ibrutinib in Patients with B-Cell Malignancies: A Meta-Analysis of Phase III Randomized Controlled Trials

Risk of Infection with Ibrutinib in Patients with B-Cell Malignancies: A Meta-Analysis of Phase III Randomized Controlled Trials

Economic Evaluation for the US of Ibrutinib Versus Acalabrutinib for Patients with Relapsed or Refractory Mantle Cell Lymphoma

Economic Evaluation for the US of Ibrutinib Versus Acalabrutinib for Patients with Relapsed or Refractory Mantle Cell Lymphoma

Ibrutinib Dose Reduction Does Not Affect Progression-Free Survival in Patients with Waldenstrom Macroglobulinemia

Ibrutinib Dose Reduction Does Not Affect Progression-Free Survival in Patients with Waldenstrom Macroglobulinemia

Abstract 2857: PI3K/AKT activation in de novo and acquired resistance to ibrutinib in lymphoid malignancies

Abstract B-cell lymphoid malignancies, including CLL and DLBCL, are characterized by abnormal activation of Bruton's tyrosine kinase (BTK)-mediated B-cell receptor signaling that contributes to malignant transformation. Ibrutinib (IB) is an oral covalent BTK inhibitor that has shown impressive clinical activity. However, many IB-treated patients relapse over time with fulminant progression. We sought to define the molecular pathways that mediate Ib resistance by studying changes that occurred in vitro in cell lines and primary patient samples with prolonged exposure to IB. We found IB-increased apoptosis in a dose- and time-dependent manner, with upregulated levels of PTEN, BIM, and FOXO3a in Mec-1 and RIVA cells; followed by decreased phosphorylation (p) of Ser473-AKT and Ser253-FOXO3a. mRNA expression levels of Foxo3a and its targets Bim and Pten were significantly upregulated in a dose- and time-dependent manner. Interestingly, a subset of miRNAs, including miRNA-494 were significantly downregulated with upregulation of target transcripts Pten and Bim. Similar results were observed after IB treatment of primary CLL cells of naïve patients and those on new drug targets at high risk for relapse. To examine if miRNA-494-dependent PTEN regulation and activation of PI3K/AKT/FOXO3a signaling has a role in de novo and acquired resistance to IB in B-cell malignancies, we investigated the resistance mechanism that develops to IB therapy by generating IB-resistant (Ib-R) cells. Chronic exposure of RIVA cells to IB demonstrated AKT activation and increased pSer253-FOXO3a, in turn, leading to decreased PTEN and BIM levels; attributed to its decreased transcription as assessed by qRT-PCR in Ib-R RIVA cells. Interestingly, Ib-R RIVA cells had strikingly higher miRNA-494 expression and decreased Pten mRNA levels, indicating further regulation of PTEN/AKT/FOXO3a signaling. Moreover, unlike IB-sensitive CLL samples, patients with partial remission and Ib-R, before and after in vivo IB treatment, demonstrated significant upregulation of miRNA-494 and decreased Pten mRNA expression. The Ib-R cells were sensitized to treatment with IB by PI3K (idelalisib) and AKT (MK-2206) inhibition. MK-2206 downregulated pAKT and sensitized Ib-R cells through AKT-mediated PTEN activation. siRNA-mediated downregulation of AKT and FOXO3a significantly modulated cell survival, demonstrating the importance of these cell survival factors for Ib-R. Importantly, overexpression of miRNA-494 inhibitor increased Pten mRNA levels, further indicating regulation of apoptosis by AKT/FOXO3a signaling. Collectively, these findings reveal a novel mechanism of ibrutinib resistance in B-cell malignancies that modulates the expression and activity of tumor suppressor proteins and pro-apoptotic factors to confer drug resistance that could be effectively inhibited by a rational combination of therapeutic regimens. Citation Format: Yue Li, Isha Kapoor, Huayuan Zhu, Brian T. Hill, Wei Xu, Alex Almasan. PI3K/AKT activation in de novo and acquired resistance to ibrutinib in lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2857.

Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque–triggered thrombus formation in humans

Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque–triggered thrombus formation in humans

Ibrutinib Disrupts the Metabolic Program of CLL Cells in-Vivo

Ibrutinib Disrupts the Metabolic Program of CLL Cells in-Vivo

Ibrutinib in Waldenström macroglobulinemia: latest evidence and clinical experience.

Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor, which has recently gained approval by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with symptomatic Waldenström macroglobulinemia (WM). Herein, we review the role of BTK in the pathophysiology of WM, and present the results of the preclinical and clinical studies that led to the initial investigation and later approval of ibrutinib in WM. We also discuss aspects associated with ibrutinib therapy in WM patients, especially focusing on genomic profiling and the impact on response to ibrutinib, and the management of adverse events.