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      Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL

      Author(s): 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1
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      Journal: New England Journal of Medicine
      Publisher: New England Journal of Medicine (NEJM/MMS)

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          Abstract

          Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy.

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          Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.

          John C. Byrd, Bonnie Harrington, Susan O’Brien … (2016)
          Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors.
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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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                Author and article information

                Journal
                Title: New England Journal of Medicine
                Abbreviated Title: N Engl J Med
                Publisher: New England Journal of Medicine (NEJM/MMS)
                ISSN (Print): 0028-4793
                ISSN (Electronic): 1533-4406
                Publication date Created: December 2018
                Publication date (Electronic): December 2018
                Affiliations
                [1 ]From Ohio State University Comprehensive Cancer Center, Columbus (J.A.W., A.S.R., N.A.H., W.Z., K.A.R., G.L., J.S.B., H.G.O., J.C.B.); the Alliance Statistics and Data Center (A.S.R., A.M.B., B.M.-E., B.F., S.J.M.), Mayo Clinic (W.D., S.A.P., M.L.), Rochester, MN; Washington University School of Medicine, St. Louis (N.L.B.); Duke Cancer Institute, Duke University Medical Center, Durham (D.M.B., H.E.), and First Health of the Carolinas Cancer Center, Pinehurst (C.K.) — both in North Carolina; the...
                Article
                DOI: 10.1056/NEJMoa1812836
                PMC ID: 6325637
                PubMed ID: 30501481
                SO-VID: 61f8e0ff-370e-4ce2-93d3-e1455e9bf28d
                Copyright © © 2018
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                http://www.nejmgroup.org/legal/terms-of-use.htm

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