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      Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia.

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          Abstract

          Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.

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          Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.

          Sarah Herman, Amber Gordon, Erin Hertlein … (2011)
          B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.
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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.

            Sabine Ponader, Shih-Shih Chen, Joseph Buggy … (2012)
            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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              The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia.

              Martin de Rooij, Annemieke Kuil, Christian Geest … (2012)
              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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                Author and article information

                Journal
                Journal ID (iso-abbrev): N. Engl. J. Med.
                Title: The New England journal of medicine
                ISSN (Electronic): 1533-4406
                ISSN (Print): 0028-4793
                Publication date (Electronic): Dec 17 2015
                Volume: 373
                Issue: 25
                Affiliations
                [1 ] From the University of Texas MD Anderson Cancer Center, Houston (J.A.B.); Azienda Ospedaliera Niguarda Cà Granda (A.T.) and Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele (P.G.), Milan, and the Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara (G.G.) - all in Italy; Wilmot Cancer Institute, University of Rochester, Rochester, NY (P.M.B.); Medical University of Lodz and Copernicus Memorial Hospital, Lodz (T.R.), the Department of Cancer Prevention, School of Public Health, Medical University of Silesia, Katowice (S.G.), and the Department of Hematology, University Clinical Center of Medical University of Gdansk, Gdansk (A.H.) - all in Poland; Tom Baker Cancer Centre, Calgary, AB, Canada (C.O.); Rabin Medical Center, Beilinson Hospital and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (O.B.), and Hadassah University Hospital, Hebrew University Medical School, Jerusalem (A.P.) - both in Israel; Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds (P.H.), Kings College Hospital, London (S.D.), Royal Bournemouth Hospital, Bournemouth (H.M.), and University of Oxford, Oxford (A.S.) - all in the United Kingdom; Washington University School of Medicine, St. Louis (N.L.B.); Jiangsu Province Hospital, Nanjing, China (J.L.); North Shore Hospital, Auckland, New Zealand (D. Simpson); Stanford University School of Medicine, Stanford (S.C.), City of Hope National Medical Center, Duarte (T.S.), Pharmacyclics, Sunnyvale (D. Suri, M.C., F.C., L.S., D.F.J.), and Moores Cancer Center, University of California, San Diego, San Diego (T.J.K.) - all in California; St. Vincent's Hospital, University of Melbourne (H.Q.), and Peter MacCallum Cancer Centre and St. Vincent's Hospital (C.S.T.), Melbourne, VIC, Australia; Institute of Blood Pathology and Transfusion Medicine, National Academy of Medical Sciences of Ukraine, Lviv, Ukraine (Z.M.); Norton Cancer Institute, Louisville, KY (D.A.S.);
                Article
                Mid ID: NIHMS748304
                DOI: 10.1056/NEJMoa1509388
                PubMed ID: 26639149
                SO-VID: 6c286883-4e21-4cf8-83dd-54d04542158f
                History

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