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Betty Y Chang - One of the best experts on this subject based on the ideXlab platform.
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ibrutinib is an irreversible molecular inhibitor of itk driving a th1 selective pressure in t lymphocytes
Blood, 2013Co-Authors: Jason A Dubovsky, Samantha Jaglowski, Jennifer A Woyach, Gayathri Natarajan, Kyle A Beckwith, Betty Y Chang, Ta-ming Liu, Yiming Zhong, Joshua Hessler, Karilyn LarkinAbstract:Given its critical role in T-cell signaling, interleukin-2–inducible Kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton Tyrosine Kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.
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egress of cd19 cd5 cells into peripheral blood following treatment with the Bruton Tyrosine Kinase inhibitor ibrutinib in mantle cell lymphoma patients
Blood, 2013Co-Authors: Betty Y Chang, Martin F M De Rooij, Annemieke Kuil, Michelle Francesco, Padmaja Magadala, Susanne M Steggerda, Min Mei Huang, Sarah E M Herman, Stella Chang, Steven T PalsAbstract:Ibrutinib (PCI-32765) is a highly potent oral Bruton Tyrosine Kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.
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Bruton Tyrosine Kinase inhibitor ibrutinib pci 32765 has significant activity in patients with relapsed refractory b cell malignancies
Journal of Clinical Oncology, 2013Co-Authors: Ranjana H Advani, Joseph J Buggy, Jeff P Sharman, Sonali M Smith, Thomas E Boyd, Barbara Grant, Kathryn S Kolibaba, Richard R Furman, Sara Rodriguez, Betty Y ChangAbstract:Purpose Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton Tyrosine Kinase (BTK) is a critical signaling Kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximumtolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies. J Clin Oncol 31:88-94. © 2012 by American Society of Clinical Oncology
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Bruton Tyrosine Kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma
Blood, 2012Co-Authors: Yutzu Tai, Guang Yang, Betty Y Chang, Sun Young Kong, Mariateresa Fulciniti, Yolanda Calle, Jianhong Lin, Jianjun Zhao, Antonia Cagnetta, Michele CeaAbstract:Bruton Tyrosine Kinase (Btk) has a welldefined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF‐induced phosphorylation of Btk and downstream PLC-2 in OCs, resulting in diminished TRAP5b (ED50 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 0.5nM) and MM patients. It decreased SDF-1‐induced migrationofMMcells,anddown-regulated MIP1-/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell‐induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stemlike cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM. (Blood. 2012;120(9): 1877-1887)
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the clinically active btk inhibitor pci 32765 targets b cell receptor and chemokine controlled adhesion and migration in chronic lymphocytic leukemia
Blood, 2012Co-Authors: Martin F M De Rooij, Annemieke Kuil, Steven T Pals, Betty Y Chang, Joseph J Buggy, Christian R Geest, Eric Eldering, Marcel SpaargarenAbstract:Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton Tyrosine Kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.
Joseph J Buggy - One of the best experts on this subject based on the ideXlab platform.
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Bruton Tyrosine Kinase inhibitor ibrutinib pci 32765 has significant activity in patients with relapsed refractory b cell malignancies
Journal of Clinical Oncology, 2013Co-Authors: Ranjana H Advani, Joseph J Buggy, Jeff P Sharman, Sonali M Smith, Thomas E Boyd, Barbara Grant, Kathryn S Kolibaba, Richard R Furman, Sara Rodriguez, Betty Y ChangAbstract:Purpose Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton Tyrosine Kinase (BTK) is a critical signaling Kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximumtolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies. J Clin Oncol 31:88-94. © 2012 by American Society of Clinical Oncology
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early changes in cytokines chemokines and indices of bone metabolism in a phase 2 study of the Bruton Tyrosine Kinase btk inhibitor ibrutinib pci 32765 in patients with relapsed or relapsed refractory multiple myeloma mm
Blood, 2012Co-Authors: Ravi Vij, Yutzu Tai, Betty Chang, Stella Chang, Joseph J Buggy, Jesus G Berdeja, Carol Ann Huff, Nikoletta Lendvai, Davina Moussa, Laurence EliasAbstract:Abstract 4039 Introduction: Bruton Tyrosine Kinase (Btk) is essential in the development and function of B cells through normal B cell receptor signaling, and it is down-regulated in non-malignant plasma cells. This is not the case in malignant plasma cells of patients with MM where robust Btk gene expression is usual. In addition, Btk is expressed and functional in osteoclasts and their precursors, which play a pathogenic role in MM-related bone disease, as well as growth and survival of MM in the microenvironment. Researchers in our group (Tai, Chang et al, Blood, 2012) recently demonstrated that the Btk inhibitor ibrutinib (PCI-32765) inhibited the interaction of MM cells with stromal cells, and inhibited the growth in vitro of MM colony forming cells from patient explants. Ibrutinib suppressed in vitro osteoclast differentiation and production of multiple cytokines and chemokines including CCL3, CCL4, IL-8, and TGF-β. Ibrutinib furthermore decreased MM progression and accompanying bone destruction in an in vivo SCID-Hu myeloma model. Based on these observations, we initiated a clinical trial of ibrutinib in patients with relapsed (R) and relapsed/refractory (R/R) MM. This report of early marker changes is based upon 7 patients who have completed 3 cycles of treatment. Methods: Patients with progressive disease (PD) after at least 2 prior lines of therapy received a fixed dose of oral ibrutinib 420 mg orally once daily, with a cycle defined as 28 days. Dexamethasone 40 mg weekly could be added if no response or PD was observed by cycle 2. Blood levels of cytokines, chemokines and bone markers (bone-specific alkaline phosphatase (bAP), sclerostin and RANKL) were assessed centrally at Days 1, 2, 8, and 15 of Cycle 1, Cycle 2 Day 1 and every 2 cycles thereafter, by single or multiplexed immunoassays. Serum cross-linked C-terminal peptide of collagen I (sCTx) was determined by a central lab at the start of Cycles 1 and 2 and every other cycle thereafter. Responses were assessed following the International Myeloma Working Group criteria (modified to include minimal response). Results: Thirteen patients [M/F: 8/5; median age 62, range 49–74 years] were enrolled between March 21 and June 6, 2012. All patients had received prior treatment with lenalidomide, bortezomib, alkylators and dexamethasone. 7 were refractory to their last treatment. At the time of data cut off, 7 of the 13 patients enrolled had completed 3 cycles of therapy and were the ones used for analysis. Over the course of three cycles, several markers relevant to bone metabolism exhibited gradual decreases. At Cy4D1 plasma RANKL, sclerostin, and bAP exhibited (median) decreases of 47%, 39%, and 36%, respectively. Relative changes in sCTx were more variable at Cy2D1, but there appeared to be a trend towards subject-by-subject decreases at C4D1 ([Fig. 1][1]). Factors promoting growth and angiogenesis (e.g. VEGF, EGF, and FGF) and cytokines and chemokines (CCL3, CCL4, TNFα, Groα and MDC) with roles in MM micro-environmental interactions exhibited similar reductions ([Fig. 2][1]). Among these the most dramatic and consistent changes were in CCL3 and CCL4, chemokines enhancing adhesive interactions contributing to osteolysis in MM, which showed median decreases of 43% and 77% at Cy4D1, respectively. Ibrutinib has been uniformly well tolerated and the safety experience to date has been similar to that noted in other studies of ibrutinib in lymphoma and CLL. Conclusions: Early reductions in blood levels of cytokines, chemokines, markers of bone metabolism, and pro-angiogenic and growth factors, were observed among MM patients treated with ibrutinib, which were consistent with pre-clinical studies. Among markers related to bone metabolism, it appeared that changes in regulatory molecules (sclerostin, RANKL) were more marked and perhaps preceded changes in markers of osteoclast (sCTx) or osteoblast (bAP) activity. Elucidation of these patterns and their significance will require longer follow-up of a larger number of patients. These results indicate that ibrutinib can exert significant biologic effects on the microenvironment in MM. Clinical correlations will be forthcoming based upon maturing results over the next several months. ![FIGURES][2] ![FIGURES][2] FIGURES Disclosures: Vij: Millennium: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Onyx: Honoraria, Research Funding. Chang: Pharmacyclics, Inc.: Employment, Equity Ownership. Huff: Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Chang: Pharmacyclics, Inc.: Employment, Equity Ownership. Moussa: Pharmacyclics, Inc.: Employment, Equity Ownership. Buggy: Pharmacyclics: Employment, Equity Ownership. Elias: Pharmacyclics, Inc.: Employment, Equity Ownership. Richardson: Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. [1]: #F1 [2]: pending:yes
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the clinically active btk inhibitor pci 32765 targets b cell receptor and chemokine controlled adhesion and migration in chronic lymphocytic leukemia
Blood, 2012Co-Authors: Martin F M De Rooij, Annemieke Kuil, Steven T Pals, Betty Y Chang, Joseph J Buggy, Christian R Geest, Eric Eldering, Marcel SpaargarenAbstract:Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton Tyrosine Kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.
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the Bruton Tyrosine Kinase inhibitor pci 32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo
Blood, 2012Co-Authors: Sabine Ponader, Michael J Keating, William G Wierda, Susan Obrien, Shihshih Chen, Joseph J Buggy, Kumudha Balakrishnan, Varsha Gandhi, Nicholas Chiorazzi, Jan A BurgerAbstract:B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated Kinases, such as Bruton Tyrosine Kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.
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egress of cd19 cd5 cells into peripheral blood following treatment with the Bruton Tyrosine Kinase inhibitor pci 32765 in mantle cell lymphoma patients
Blood, 2011Co-Authors: Betty Chang, Marcel Spaargaren, Michelle Francesco, Padmaja Magadala, Min Mei Huang, Joseph J Buggy, Laurence EliasAbstract:Abstract 954 PCI-32765 is an orally administered, highly potent and specific inhibitor of Bruton Tyrosine Kinase (BTK) in clinical development for the treatment of B cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often have marked but transient increases of circulating CLL lymphocytes following treatment with PCI-32765, as has been seen with other inhibitors of the B cell receptor (BCR) pathway. In the course of the Phase I study of PCI-32765, we have noted similar effects among treated patients with other types of non-Hodgkin lymphoma (NHL) including mantle cell lymphoma (MCL). We here characterize the patterns and phenotypes of cells mobilized among patients with MCL, and further investigate the mechanism of this effect. Nine patients with MCL treated in the previously reported Phase I study (Advani et al, ASCO, 2010) had baseline absolute lymphocyte counts (ALC) of 1.04 ± 0.42 (x 109/L, Mean ± SD) and had maximal increases during the first 28 day cycle of 12 to 794% (188% increase ± 250, Mean, SD). The ALCs of four patients who were treated on a dosing schedule that included a 1 week drug holiday within each cycle were noted to show intra-cyclic increases of ALC from day 1 to day 15 of each cycle, and decreases following each week off of treatment, for up to 9 cycles (Fig. 1). Patients receiving continuous dosing exhibited gradually decreasing ALCs following the first cycle. The cyclically increasing B lymphocytes were confirmed to be CD5+ (and often also CD45lo), and thus likely to represent circulating, mobilized lymphoma cells. Patient, D005, who attained a complete response, had an easily identifiable CD19+CD45lo subpopulation of 0.47 ×109 cells/L at baseline. This subpopulation increased to 15.2 × 109/L at day 8 of the first cycle, but then decreased markedly as the patient responded clinically. One patient who failed to respond had, by contrast, few if any detectable mobilized cells. Peripheral blood CD19+CD5+ cells from MCL patients treated with PCI-32765 after 8 days were found to have reduced levels of CXC chemokine receptor 4 (CXCR4) levels, whereas pretreatment malignant cells were CXCR4hi. This likely reflects the differences in MCL surface membrane phenotype in solid tissues compared to peripheral blood. Mechanistically, we found that PCI-32765 inhibited BCR- and CXCL12-mediated adhesion and chemotaxis of MCL cell lines in vitro (EC50 = 10–100 nM), and dose-dependently inhibited BCR, stromal cell and CXCL12 stimulations of pBtk, pPLCg and pErk in MCL cells. Importantly, PCI-32765 dose-dependently inhibited the pseudoemperipoleisis of MCL in the presence of stromal cells. Conclusion: Lymphocyte mobilization into the peripheral blood is notable from MCL in response to treatment with PCI-32765. The majority of these cells are marked with a phenotype (CD19+CD5+ CXCR4lo) which is consistent with malignant cells from secondary lymphoid organs. This effect is likely to be related to PCI-32765 inhibition of BTK activation which results in inhibition of MCL cell chemotaxis, adherence and pseudo-emperipoleisis. We propose that Btk is essential for the homing of MCL cells into secondary lymphoid organs, and that its inhibition results in peripheral blood compartment shift. Disclosures: Chang:Pharmacyclics Inc: Employment. Francesco:Pharmacyclics: Employment, Equity Ownership. Magadala:Pharmacyclics: Employment. Huang:Pharmacyclics: Employment. Spaargaren:Pharmacyclics: Research Funding. Buggy:Pharmacyclics, Inc.: Employment. Elias:Pharmacyclics Inc: Consultancy.
Steven T Pals - One of the best experts on this subject based on the ideXlab platform.
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ibrutinib and idelalisib target b cell receptor but not cxcl12 cxcr4 controlled integrin mediated adhesion in waldenstrom macroglobulinemia
Haematologica, 2016Co-Authors: Martin F M De Rooij, Steven P Treon, Annemieke Kuil, Willem Kraan, Marie Jose Kersten, Steven T Pals, Marcel SpaargarenAbstract:The Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib and the phosphatidylinositol 3-Kinase δ (PI3Kδ) inhibitor idelalisib show promising clinical efficacy in the treatment of Waldenstrom macroglobulinemia (WM), a lymphoplasmacytic lymphoma.[1][1]–[3][2] Very recently, ibrutinib became the first
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ibrutinib and idelalisib synergistically target bcr controlled adhesion in mcl and cll a rationale for combination therapy
Blood, 2015Co-Authors: Martin F M De Rooij, Annemieke Kuil, Marie Jose Kersten, Steven T Pals, Arnon P Kater, Marcel SpaargarenAbstract:To the editor: Most B-cell malignancies are dependent upon signaling by the B-cell receptor (BCR) and other growth and survival signals provided by the tumor microenvironment. Two recently US Food and Drug Administration–approved drugs that target the BCR signalosome, the Bruton Tyrosine Kinase (
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egress of cd19 cd5 cells into peripheral blood following treatment with the Bruton Tyrosine Kinase inhibitor ibrutinib in mantle cell lymphoma patients
Blood, 2013Co-Authors: Betty Chang, Martin F M De Rooij, Annemieke Kuil, Michelle Francesco, Padmaja Magadala, Susanne M Steggerda, Min Mei Huang, Sarah E M Herman, Stella Chang, Steven T PalsAbstract:Ibrutinib (PCI-32765) is a highly potent oral Bruton Tyrosine Kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib
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egress of cd19 cd5 cells into peripheral blood following treatment with the Bruton Tyrosine Kinase inhibitor ibrutinib in mantle cell lymphoma patients
Blood, 2013Co-Authors: Betty Y Chang, Martin F M De Rooij, Annemieke Kuil, Michelle Francesco, Padmaja Magadala, Susanne M Steggerda, Min Mei Huang, Sarah E M Herman, Stella Chang, Steven T PalsAbstract:Ibrutinib (PCI-32765) is a highly potent oral Bruton Tyrosine Kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.
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the clinically active btk inhibitor pci 32765 targets b cell receptor and chemokine controlled adhesion and migration in chronic lymphocytic leukemia
Blood, 2012Co-Authors: Martin F M De Rooij, Annemieke Kuil, Steven T Pals, Betty Y Chang, Joseph J Buggy, Christian R Geest, Eric Eldering, Marcel SpaargarenAbstract:Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton Tyrosine Kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.
Martin F M De Rooij - One of the best experts on this subject based on the ideXlab platform.
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ibrutinib and idelalisib target b cell receptor but not cxcl12 cxcr4 controlled integrin mediated adhesion in waldenstrom macroglobulinemia
Haematologica, 2016Co-Authors: Martin F M De Rooij, Steven P Treon, Annemieke Kuil, Willem Kraan, Marie Jose Kersten, Steven T Pals, Marcel SpaargarenAbstract:The Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib and the phosphatidylinositol 3-Kinase δ (PI3Kδ) inhibitor idelalisib show promising clinical efficacy in the treatment of Waldenstrom macroglobulinemia (WM), a lymphoplasmacytic lymphoma.[1][1]–[3][2] Very recently, ibrutinib became the first
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ibrutinib and idelalisib synergistically target bcr controlled adhesion in mcl and cll a rationale for combination therapy
Blood, 2015Co-Authors: Martin F M De Rooij, Annemieke Kuil, Marie Jose Kersten, Steven T Pals, Arnon P Kater, Marcel SpaargarenAbstract:To the editor: Most B-cell malignancies are dependent upon signaling by the B-cell receptor (BCR) and other growth and survival signals provided by the tumor microenvironment. Two recently US Food and Drug Administration–approved drugs that target the BCR signalosome, the Bruton Tyrosine Kinase (
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egress of cd19 cd5 cells into peripheral blood following treatment with the Bruton Tyrosine Kinase inhibitor ibrutinib in mantle cell lymphoma patients
Blood, 2013Co-Authors: Betty Chang, Martin F M De Rooij, Annemieke Kuil, Michelle Francesco, Padmaja Magadala, Susanne M Steggerda, Min Mei Huang, Sarah E M Herman, Stella Chang, Steven T PalsAbstract:Ibrutinib (PCI-32765) is a highly potent oral Bruton Tyrosine Kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib
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egress of cd19 cd5 cells into peripheral blood following treatment with the Bruton Tyrosine Kinase inhibitor ibrutinib in mantle cell lymphoma patients
Blood, 2013Co-Authors: Betty Y Chang, Martin F M De Rooij, Annemieke Kuil, Michelle Francesco, Padmaja Magadala, Susanne M Steggerda, Min Mei Huang, Sarah E M Herman, Stella Chang, Steven T PalsAbstract:Ibrutinib (PCI-32765) is a highly potent oral Bruton Tyrosine Kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR- and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This trial was registered at www.clinicaltrials.gov as #NCT00114738.
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the clinically active btk inhibitor pci 32765 targets b cell receptor and chemokine controlled adhesion and migration in chronic lymphocytic leukemia
Blood, 2012Co-Authors: Martin F M De Rooij, Annemieke Kuil, Steven T Pals, Betty Y Chang, Joseph J Buggy, Christian R Geest, Eric Eldering, Marcel SpaargarenAbstract:Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton Tyrosine Kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.
Roger G Owen - One of the best experts on this subject based on the ideXlab platform.
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aspen results of a phase iii randomized trial of zanubrutinib versus ibrutinib for patients with waldenstrom macroglobulinemia wm
Journal of Clinical Oncology, 2020Co-Authors: Constantine S Tam, Huipeng Lee, Roger G Owen, Stephen Opat, Shirley Dsa, Wojciech Jurczak, Gavin Cull, Paula Marlton, Bjorn E Wahlin, Alessandra TedeschiAbstract:8007Background: Bruton Tyrosine Kinase (BTK) inhibition is an emerging standard of care for WM. ASPEN is a randomized phase 3 study comparing zanubrutinib (ZANU), a potent and selective BTK inhibit...
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updated results of the aspen trial from a cohort of patients with myd88 wild type myd88wt waldenstrom macroglobulinemia wm
Journal of Clinical Oncology, 2020Co-Authors: Ramon Garciasanz, Meletios A Dimopoulos, Huipeng Lee, Marek Trneny, Marzia Varettoni, Roger G Owen, Jorge J Castillo, Tanya Siddiqi, Alessandra Tedeschi, Christian BuskeAbstract:e20056Background: Inhibitors of Bruton Tyrosine Kinase (BTK) have shown significant activity in patients with WM harboring a mutation in the MYD88 gene. However, lower response rates and shorter pr...
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Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study
2019Co-Authors: Roger G Owen, Simon Rule, Marie Jose Kersten, Pier Luigi Zinzani, Helen Mccarthy, Sheeba K Thomas, Olivier Tournilhac, Francesco Forconi, Sunil IyengarAbstract:Background Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton Tyrosine-Kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. Methods This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton Tyrosine-Kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. Findings Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0–29·7), 13 (93% [95% CI 66–100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86–98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3–4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3–4 atrial fibrillation occurred in one (1%) patient and grade 3–4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). Interpretation This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies.
