ABSTRACT
PURPOSE: Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome-negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 µg/m(2)/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. RESULTS: Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 µg/m(2)/day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 µg/m(2)/day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 µg/m(2)/day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days). CONCLUSION: In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 µg/m(2)/day. Single-agent blinatumomab showed antilymphoma activity.
Subject(s)
Antibodies, Bispecific/therapeutic use , Antineoplastic Agents/therapeutic use , Immunotherapy/methods , Lymphocyte Activation/drug effects , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/immunology , Molecular Targeted Therapy/methods , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Adult , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/adverse effects , Antigens, CD19/drug effects , Antigens, CD19/immunology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , CD3 Complex/drug effects , CD3 Complex/immunology , Drug Administration Schedule , Female , Germany , Humans , Infusions, Intravenous , Lymphocyte Activation/immunology , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/immunology , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/immunology , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/immunology , Male , Maximum Tolerated Dose , Middle Aged , Nervous System Diseases/chemically induced , Recurrence , Remission Induction , Treatment OutcomeABSTRACT
The Na(+)/Ca(2+) exchanger gene family encompasses three distinct proteins, NCX1, NCX2, and NCX3, which mediate cellular Ca(2+) efflux and thus contribute to intracellular Ca(2+) homeostasis. NCX1 is expressed ubiquitously while NCX2 and NCX3 are limited to brain and skeletal muscle. NCX1 exchanges 3 extracellular Na(+) for 1 intracellular Ca(2+). In addition to transporting Na(+) and Ca(2+), NCX1 activity is also regulated by these cations. NCX1 is especially important in regulating cardiac contractility.
Subject(s)
Calcium/metabolism , Myocardium/metabolism , Sodium-Calcium Exchanger/physiology , Sodium/metabolism , Biological Transport/physiology , Humans , Multigene Family/physiology , Sodium-Calcium Exchanger/chemistryABSTRACT
An overview of the molecular physiology of the Na(+)/Ca(2+) exchanger is presented. This includes information on the variety of exchangers that have been described and their regulatory properties. Molecular insight is most detailed for the cardiac Na(+)/Ca(2+) exchanger (NCX1). Parts of the NCS1 molecule involved in regulation and ion transport have been elucidated, and initial information on the topology and structure is available.
Subject(s)
Sodium-Calcium Exchanger/physiology , Alternative Splicing , Animals , Brain/physiology , Heart/physiology , Kidney/physiology , Models, Molecular , Organ Specificity , Protein Conformation , Sodium-Calcium Exchanger/chemistry , Sodium-Calcium Exchanger/geneticsABSTRACT
The cardiac-specific sodium-calcium exchanger (NCX1) is a GATA-4 dependent gene that is upregulated during cardiac hypertrophy and heart failure. To date, lack of an appropriate inhibitor of NCX1 and embryonic lethality of NCX1 knockout mice have slowed investigation of the relation between NCX1 upregulation and cardiac hypertrophy. Recently, in vitro studies have shown that cyclosporin A (CSA), a calcineurin inhibitor, significantly downregulated expression of the hypertrophic genes atrial natriuretic factor and beta-myosin heavy chain and protected against cardiac hypertrophy and heart failure in calcineurin overexpressing mice. This suggested that CSA might play an important role in the treatment of hypertrophy and heart failure. In an in vitro model of cardiac hypertrophy, we showed that CSA is a potent inhibitor of NCX1 basal expression and NCX1 promoter activity. Female homozygous transgenic mice that overexpress NCX1 develop heart failure and die prematurely after two or more pregnancies. Others have demonstrated that pressure overloaded wild-type mice treated with CSA do not develop cardiac hypertrophy and downregulate expression of NCX1. We investigated the effect of CSA on NCX1 expression and transverse aortic constriction-induced cardiac hypertrophy in NCX1 overexpressing mice. We found that CSA blunted these responses.