Role of Tyrosine Kinase Inhibitors in Indolent and Other Mature B-Cell Neoplasms.

Targeting tyrosine kinases represents a highly specific treatment approach for different malignancies. This also includes non-Hodgkin lymphoma since it is well known that these enzymes are frequently involved in the lymphomagenesis. Hereby, tyrosine kinases might either be dysregulated intrinsically or be activated within signal transduction pathways leading to tumor survival and growth. Among others, Bruton's tyrosine kinase (Btk) is of particular interest as a potential therapeutic target. Btk is stimulated by B-cell receptor signaling and activates different transcription factors such as nuclear factor κB. The Btk inhibitor ibrutinib has been approved for the treatment of chronic lymphocytic leukemia and mantle-cell lymphoma recently. Numerous clinical trials evaluating this agent in different combinations (eg, with rituximab or classical chemotherapeutic agents) as a treatment option for aggressive and indolent lymphoma are under way. Here, we summarize the role of tyrosine kinase inhibitors in the treatment of indolent and other non-Hodgkin lymphomas (eg, mantle-cell lymphoma).

Pharmacodynamic effects of haematopoietic cytokines: the view of a clinical oncologist.

The production of haematopoietic cells is under the tight control of a group of haematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating survival, proliferation, differentiation commitment, maturation and functional activation. Granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoiesis-stimulating agents are in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. G-CSF regulates neutrophil production to maintain blood neutrophil counts in the normal range. G-CSF is used to prevent febrile neutropenia or to increase dose-density in chemotherapy regimens. Despite consistently showing a shorter duration of neutropenia, multiple prospective randomized trials have documented only modest clinical benefit. A clinical advantage of dose-dense chemotherapy has been shown only in specific chemotherapy regimens. Professional recommendations tailor the use of CSFs to patients with a high risk of adverse outcome of febrile neutropenia. EPO was used to prevent anaemia requiring red blood cell transfusion. However, recent studies strongly suggest a negative overall effect on mortality, without a plausible biological explanation. It is now proposed that its use should be restricted to patients in clinical trials. Thrombopoiesis-stimulating agents have only been recently introduced into the market for splenectomized and non-splenectomized patients with immune thrombocytopenic purpura, a rare disease. Before widely used in other conditions such as chemotherapy-induced thrombocytopenia, the lessons learned from the example of G-CSF and EPO should be taken seriously.

Immunization with a Pseudomonas aeruginosa 1244 pilin provides O-antigen-specific protection.

The O antigen is both a major structural outer membrane component and the dominant epitope of most gram-negative bacteria. Pseudomonas aeruginosa 1244 produces a type IV pilus and covalently links an O-antigen repeating unit to each pilin monomer. Here we show that immunization of mice with pure pilin from strain 1244 by use of either the mouse respiratory model or the thermal injury model resulted in protection from challenge with a pilus-null O-antigen-producing 1244 mutant. These results provide evidence that the pilin glycan stimulates a protective response that targets the O antigen, suggesting that this system could be used as the basis for the development of a variety of bioconjugate vaccines protective against gram-negative bacteria.

K-antigen-specific, but not O-antigen-specific natural human serum antibodies promote phagocytosis of Klebsiella pneumoniae.

Infections due to Klebsiella pneumoniae and other Klebsiella spp. are a leading cause of hospital-associated morbidity, especially in the intensive care setting. In this study, the hypothesis that normal human sera contain sufficient concentrations of K-antigen-specific antibodies to promote phagocytic killing of encapsulated, highly virulent Klebsiella organisms was tested. K2-antigen-specific IgG and IgM antibodies were detected in each of 10 normal sera, and such antibodies were functionally active in a phagocytic killing assay. Phagocytosis depended critically on sufficient numbers of neutrophils and was impaired by the presence of soluble Klebsiella capsular polysaccharide (CPS). Thus, insufficient numbers of neutrophils and circulation of soluble CPS but not lack of K-specific antibodies may be detrimental in Klebsiella sepsis. The efficacy of hyperimmune sera might be based not on enhancement of phagocytosis but on the neutralization of these detrimental effects of circulating CPS and LPS.

Recruitment of murine neutrophils in vivo through endogenous sialidase activity.

Upon activation with various noncytokine stimuli, polymorphonuclear leukocytes (PMNs) mobilize intracellular sialidase to the plasma membrane, where the sialidase releases sialic acid from the cell surface. This desialylation enhances PMN adherence, spreading, deformability, and motility, functions critical to diapedesis. We now have examined the role of sialidase activity in PMN adhesion to and migration across the endothelium in vivo. A polyclonal antibody prepared against Clostridium perfringens neuraminidase 1) detected surface expression of sialidase on human PMNs stimulated with IL-8 in vitro and on murine PMNs stimulated in vivo, but not on that of unstimulated cells, 2) recognized proteins in human PMN lysates and granule preparations that were not detected by preimmune antibody, 3) inhibited bacterial neuraminidase and human PMN sialidase activities in vitro, and 4) inhibited both pulmonary leukostasis in mice systemically infused with cobra venom factor and intrapulmonary transendothelial migration of PMNs into the bronchoalveolar compartment of mice intranasally challenged with interleukin-8. We conclude that the chemokine interleukin-8, like other PMN agonists, induces the translocation of sialidase to the PMN surface and that surface expression of this sialidase is a prerequisite to PMN recruitment in vivo. The ability of antibodies raised against a prokaryotic neuraminidase to recognize eukaryotic sialidase extends the concept of the neuraminidase superfamily to mammalian enzymes. Inhibition of mobilized endogenous sialidase may provide a novel strategy for limiting the inflammatory response.

Kinetics of stem cell engraftment and clearance of leukaemia cells after allogeneic stem cell transplantation with reduced intensity conditioning in chronic myeloid leukaemia.

It is hypothesised that an effective graft-vs.-leukaemia reaction contributes substantially to the therapeutic effect of reduced intensity conditioning stem cell transplantation in chronic myeloid leukaemia. However, kinetic data on eradication of leukaemia cells and stem cell engraftement which could support this assumption are lacking. Thus, we investigated bcr/abl fusion transcripts and haematopoietic chimerism in 14 patients undergoing such a transplantation protocol. Ten of them obtained a complete molecular remission, and two patients achieved haematologic remissions but remained bcr/abl positive. Weekly determinations of bcr/abl transcript numbers by qualitative and quantitative polymerase chain reaction and donor chimerism revealed that 10 responders cleared bcr/abl positive cells from the peripheral blood within a median of 9 wk (range 3-22 wk). The close relation (P = 0.0075) between the first occurrence of graft-vs.-host disease and the complete clearance of bcr/abl positive blood cells argues in favour of an effective graft-vs.-leukaemia reaction.

Allogeneic transplantation after reduced conditioning in high risk patients is complicated by a high incidence of acute and chronic graft-versus-host disease.

Background and Objectives. We studied the toxicity and efficacy of reduced intensity conditioning followed by allogeneic stem cell transplantation in 50 patients over 50 years old or with relative contraindications against myeloablative regimens. Diagnoses were chronic myeloid leukemia (n=15), acute myeloid leukemia (n=9), myelodysplastic syndromes (n=9), lymphoma (n=11) and refractory solid tumors (n=6). Design and Methods. Donors were identical siblings (n=25), non-identical family members (n=6) and unrelated volunteers (n=19). Peripheral blood stem cells (n=36) or bone marrow (n=14) were transplanted. The conditioning regimen consisted of fludarabine 180 mg/m(2), busulphan 8 mg/kg and rabbit antithymocyte globulin 40 mg/kg (Fresenius). Graft-versus-host disease (GVHD) prophylaxis was carried out with cyclosporin A (CSA) alone (n=17) or in combination with methotrexate (n=18) or mycophenolate mofetil (n=15). Results. Neutrophil counts >0.5/nL and platelet counts > 20/nL were reached after 17 (range 0-66) and 19 days (range 0-111), respectively. Three graft failures occurred. Fever lasted for a median of 2 days (range 0-15). Six patients developed veno-occlusive disease of the liver. Acute GVHD grade II-IV occurred in 47% of the patients and chronic GVHD in 46%. The 1-year overall survival probability was 44% (95% CI: 30-58%). GVHD-related complications were a major cause of the probability of 1-year non-relapse mortality of 31% (95% CI: 16-46%). Interpretation and Conclusions. In conclusion, the regimen itself can be carried out safely in patients with relative contraindications against myeloablative conditioning. However, GVHD causes significant non-relapse mortality in high risk patients.