Nilotinib.

With imatinib still being linked to the breakthrough in CML therapy and probably being the most prescribed drug, second-generation TKIs are increasingly gaining importance. Showing higher response rates while not leading to more adverse events, nilotinib has become an attractive option in the first-line treatment of chronic-phase chronic myeloid leukemia. By reaching deep and long-lasting molecular remissions, discontinuation of TKIs is becoming one of the central topics of future CML therapy.

Nilotinib.

Targeted therapy of Philadelphia chromosome-positive chronic myeloid leukemia (CML) using the tyrosine kinase inhibitor imatinib mesylate has been one of the most striking achievements in modern cancer medicine. However, while imatinib can establish long-term remission in many cases, resistance to or intolerance of imatinib is eventually experienced by a substantial number of patients. Subsequent advances have led to the development of novel tyrosine kinase inhibitors (TKIs).

Clinical cardiac safety profile of nilotinib.

Background: Nilotinib is a second-generation tyrosine kinase inhibitor with significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia. Despite preclinical evidence indicating a risk of prolongation of the QT interval, which was confirmed in clinical trials, detailed information on nilotinib's cardiac safety profile is lacking.

Design And Methods: Here, we retrospectively assessed cardiovascular risk factors in 81 patients who were being or had previously been treated with nilotinib therapy and evaluated cardiovascular parameters by longitudinal monitoring of the QT interval and left ventricular ejection fraction.

Tyrosine kinase inhibitors noncompetitively inhibit MCT8-mediated iodothyronine transport.

Context: Tyrosine kinase inhibitors (TKI) are used for the treatment of various cancers. Case reports and clinical trials have reported abnormal thyroid function tests (TFT) after treatment with sunitinib, imatinib, sorafenib, dasatinib, and nilotinib. An increased requirement for levothyroxine was reported in thyroidectomized patients during TKI treatment.

Omacetaxine mepesuccinate for the treatment of leukemia.

Introduction: Omacetaxine mepesuccinate, formerly known as homoharringtonine, is a first-in-class cephalotaxine that has experienced phases of increasing and waning interest since its first use in traditional Chinese medicine. With activity being reported in patients with chronic myeloid leukemia (CML) resistant to currently available tyrosine kinase inhibitors, renewed interest has recently been generated.

Areas Covered: The development of omacetaxine mepesuccinate, with emphasis on synthesis and mode of administration, is addressed.

The expanding role of nilotinib in chronic myeloid leukemia.

Importance Of The Field: Several therapeutic options, including tyrosine kinase inhibitors, exist for the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Despite impressive results, there is room for improvement for those patients who are either resistant or intolerant to imatinib.

Areas Covered In This Review: An overview is given on the clinical results with nilotinib, a rationally designed second-generation tyrosine kinase inhibitor, as first- and second-line therapy in patients with Ph-positive CML.

Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia.

Background: Thyroid dysfunction is a well-known adverse effect of first-generation tyrosine kinase inhibitors (TKIs), like sunitinib. The aim of this study was to investigate the effect of second-generation TKIs on thyroid function.

Methods: We retrospectively assessed the effect of the first-generation TKI imatinib and the second-generation TKI nilotinib and dasatinib on thyroid function tests in 73 Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia patients.

Allogeneic hematopoietic stem cell transplantation for adult acute lymphocytic leukemia.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is the single most potent treatment modality to prevent relapse in adults with acute lymphocytic leukemia, but its optimal use and timing remains a matter of intense debate and research. There is general agreement that patients with clinical features of high risk for relapse should undergo alloHCT in first complete remission. However, newer studies suggest that even patients without these risk factors may benefit.

New developments in tyrosine kinase inhibitor therapy for newly diagnosed chronic myeloid leukemia.

The biology of chronic myeloid leukemia (CML) has enabled pioneering studies with targeted therapies. BCR-ABL inhibition with imatinib results in high levels of efficacy in patients with newly diagnosed CML in chronic phase (CP), but an estimated 35% of patients could benefit from more effective treatment. Several novel treatment strategies are being investigated in newly diagnosed CML-CP.

Nilotinib.

Therapy with imatinib mesylate is a standard of care for most patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML). However, resistance or intolerance to imatinib develops in a considerable number of patients leading to relapse or discontinuation of treatment. Nilotinib is a rationally designed second-generation tyrosine kinase inhibitor (TKI) with improved affinity and specificity against the BCR-ABL kinase, when compared with imatinib.

Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia.

Background: Additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance.

Design And Methods: We assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure.

Nilotinib for the treatment of chronic myeloid leukemia.

The introduction of targeted therapy has revolutionized the treatment of chronic myeloid leukemia (CML). The pivotal role of the Philadelphia chromosome, resulting from the breakpoint cluster region-Abelson (BCR-ABL) translocation, led to the development of imatinib mesylate, a tyrosine kinase inhibitor with significant activity against the BCR-ABL oncoprotein. Unprecedented clinical activity in CML led to rapid approval and established first-line therapy with imatinib mesylate as the standard of care in most patients.

Expression profiling reveals specific gene expression signatures in gastric MALT lymphomas.

The purpose of this study is to identify genes that are involved in the etiology of Helicobacter pylori induced gastric MALT lymphoma. We compared gene expression profiles of gastric MALT lymphoma with their corresponding gastric MALT (chronic gastritis with formation of follicles and aggregates). cDNA microarrays were used to compare these two tissue types from the same patient (n = 21).

Organ-derived dendritic cells have differential effects on alloreactive T cells.

Dendritic cells (DCs) are considered critical for the induction of graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). In addition to their priming function, dendritic cells have been shown to induce organ-tropism through induction of specific homing molecules on T cells. Using adoptive transfer of CFSE-labeled cells, we first demonstrated that alloreactive T cells differentially up-regulate specific homing molecules in vivo.

IFN-gamma and Fas ligand are required for graft-versus-tumor activity against renal cell carcinoma in the absence of lethal graft-versus-host disease.

To determine the mechanisms of graft-versus-tumor (GVT) activity in the absence of graft-versus-host disease (GVHD) against a solid tumor, we established two allogeneic bone marrow transplantation models with a murine renal cell carcinoma (RENCA). The addition of 0.3 x 10(6) donor CD8(+) T cells to the allograft increased the survival of tumor-bearing mice without causing GVHD.

Absence of donor T-cell-derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity.

Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-alpha converting enzyme (TACE). To study the contribution of donor T-cell-derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNF(Delta/Delta)) as donors in murine BMT models.

Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation.

Immunoincompetence after allogeneic hematopoietic stem cell transplantation (HSCT) affects in particular the T-cell lineage and is associated with an increased risk for infections, graft failure and malignant relapse. To generate large numbers of T-cell precursors for adoptive therapy, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). We infused these cells, together with T-cell-depleted mouse bone marrow or purified HSCs, into lethally irradiated allogeneic recipients and determined their effect on T-cell reconstitution after transplantation.

Distinct gene expression profile of human mesenchymal stem cells in comparison to skin fibroblasts employing cDNA microarray analysis of 9600 genes.

Broad differentiation capacity has been described for mesenchymal stem cells (MSC) from human bone marrow. We sought to identify genes associated with the immature state and pluripotency of this cell type. To prove the pluripotent state of the MSC, differentiation into osteocytes, adipocytes, and chondrocytes was performed in vitro.

Absence of beta7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine.

The alpha4beta7 integrin plays a central role in the homing of T cells to the gut. We hypothesized that absence of the beta7 subunit would result in a reduction of intestinal graft-versus-host disease (GVHD) and an improvement in overall GVHD morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT). Analysis of alloreactive beta7-/- T cells showed intact activation, proliferation, cytokine production, and cytotoxicity.

Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication.

Purpose: Cure of infection induces remissions in most patients with early stage Helicobacter pylori- (Hp) positive gastric MALT (mucosa-associated lymphoid tissue) lymphoma (GML). We tracked the long-term stability of remissions in this prospective, multicenter trial.

Patients And Methods: In 120 patients with stage I(1E) disease, we performed sequential endoscopic-bioptic follow-up after Hp eradication and polymerase chain reaction of the rearranged immunoglobulin heavy chain gene.

CCR2 is required for CD8-induced graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8+ T cells is relevant for the control of CD8+ T-cell migration and development of GVHD.

Prognostic significance of N-RAS and K-RAS mutations in 232 patients with acute myeloid leukemia.

Reports on the prognostic impact of mutations in the RAS proto-oncogenes in patients with acute myeloid leukemia (AML) are conflicting. A peptide nucleic acid (PNA)-based technique was used on 232 AML samples to detect point mutations of the hotspots in N-RAS and K-RAS. No significant correlations between RAS mutations and clinical features, karyotype or FLT3 were found.