How much and how long: tyrosine kinase inhibitor therapy in chronic myeloid leukemia.

As the first clinically successful tyrosine kinase inhibitor (TKI), imatinib pioneered a new approach to treating patients with cancer. Dramatic results from chronic myeloid leukemia (CML) clinical trials spurred the development of TKIs for other malignancies such as acute myeloid leukemia as well as kidney and lung cancer. In CML, imatinib resistance led to the rapid development of dasatinib and nilotinib, more potent second-generation ABL kinase inhibitors that can often overcome imatinib resistance.

BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib.

Point mutations in the kinase domain of BCR-ABL are the most common mechanism of drug resistance in chronic myeloid leukemia (CML) patients treated with ABL kinase inhibitors, including imatinib. It has also been shown in vitro that mutations outside the kinase domain in the neighboring linker, SH2, SH3, and Cap domains can confer imatinib resistance. In the context of ABL, these domains have an autoinhibitory effect on kinase activity, and mutations in this region can activate the enzyme.

Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo.

Background: Imatinib is a direct and potent inhibitor of the constitutively active tyrosine kinase, breakpoint cluster region-Abelson (Bcr-Abl), which is central to the pathogenesis of chronic myeloid leukaemia (CML) patients. As such, imatinib has become the front-line treatment for CML patients. However, the recent emergence of imatinib resistance, commonly associated with point mutations within the kinase domain, has led to the search for alternative drug treatments and combination therapies for CML.

Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5-benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment.

The Bcr-Abl kinase inhibitor, imatinib mesylate, is the front line treatment for chronic myeloid leukaemia (CML), but the emergence of imatinib resistance has led to the search for alternative drug treatments and the examination of combination therapies to overcome imatinib resistance. The pro-apoptotic PBOX compounds are a recently developed novel series of microtubule targeting agents (MTAs) that depolymerise tubulin. Recent data demonstrating enhanced MTA-induced tumour cell apoptosis upon combination with the cyclin dependent kinase (CDK)-1 inhibitor flavopiridol prompted us to examine whether this compound could similarly enhance the effect of the PBOX compounds.

Molecular diagnostics in chronic myeloid leukemia.

With the progress of chronic myeloid leukemia (CML) therapy, the molecular tools used to diagnose and monitor patients have become sophisticated. Despite this, a complete physical examination, complete blood count and bone marrow biopsy with metaphase karyotyping remain standard at diagnosis. Fluorescence in situ hybridization or qualitative reverse transcription polymerase chain reaction are indicated to exclude BCR-ABL1 in Philadelphia chromosome-negative patients with clinically typical CML.

Management of drug toxicities in chronic myeloid leukaemia.

Therapy for patients with chronic myeloid leukaemia has grown in complexity, first with the advent of the prototype ABL kinase inhibitor, imatinib, and subsequently with the availability of alternate (currently second-line) inhibitors. Imatinib, dasatinib and nilotinib each have specific considerations regarding safety and toxicity, in addition to a limited number common to the class of ABL kinase inhibitors. Optimal management of patients on therapy requires intimate knowledge not only of response criteria and of timing but also of potential toxicities and their basis, best approaches to avoid them, strategies to manage them when identified and how they may affect response to therapy and patient outcome.

Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.

Purpose: To review and update the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia with imatinib and second-generation tyrosine kinase inhibitors (TKIs), including monitoring, response definition, and first- and second-line therapy.

Methods: These recommendations are based on a critical and comprehensive review of the relevant papers up to February 2009 and the results of four consensus conferences held by the panel of experts appointed by ELN in 2008.

Results: Cytogenetic monitoring was required at 3, 6, 12, and 18 months.

AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.

Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL(T315I) mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants.

A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib.

In chronic-phase chronic myeloid leukemia (CML) patients, the lack of a major cytogenetic response (< 36% Ph(+) metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure, we performed gene expression array profiling of CD34(+) cells from 2 independent cohorts of imatinib-naive chronic-phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response or more than 65% Ph(+) metaphases within 12 months of imatinib therapy.

A BCR-ABL mutant lacking direct binding sites for the GRB2, CBL and CRKL adapter proteins fails to induce leukemia in mice.

The BCR-ABL tyrosine kinase is the defining feature of chronic myeloid leukemia (CML) and its kinase activity is required for induction of this disease. Current thinking holds that BCR-ABL forms a multi-protein complex that incorporates several substrates and adaptor proteins and is stabilized by multiple direct and indirect interactions. Signaling output from this highly redundant network leads to cellular transformation.

Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis.

Pioneering work with the Bcr-Abl inhibitor, imatinib, demonstrated a requirement for constant Bcr-Abl inhibition to achieve maximal therapeutic benefit in treating chronic myeloid leukemia (CML), establishing a paradigm that has guided further drug development for this disease. Surprisingly, the second-generation Bcr-Abl inhibitor, dasatinib, was reported to be clinically effective with once-daily dosing, despite a short (3- to 5-hour) plasma half-life. Consistent with this observation, dasatinib treatment of progenitor cells from chronic-phase CML patients for 4 hours, followed by washout, or continuously for 72 hours both resulted in an induction of apoptosis and a reduction in the number of clonogenic cells.

Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib.

In imatinib-treated chronic myeloid leukemia (CML), secondary drug resistance is often caused by mutations in the BCR-ABL kinase domain (KD). As alternative therapies are available for imatinib resistance, early identification of mutations may prevent disease progression. Because most patients are routinely monitored by BCR-ABL quantitative polymerase chain reaction (PCR), it is important to define the optimal increase in BCR-ABL that should trigger mutation testing.

ERK2, but not ERK1, mediates acquired and "de novo" resistance to imatinib mesylate: implication for CML therapy.

Resistance to Imatinib Mesylate (IM) is a major problem in Chronic Myelogenous Leukaemia management. Most of the studies about resistance have focused on point mutations on BCR/ABL. However, other types of resistance that do not imply mutations in BCR/ABL have been also described.

Minimally invasive dorsal percutaneous spondylodesis for the treatment of adult pyogenic spondylodiscitis.

Background: Most adult patients with pyogenic lumbar or thoracic spondylodiscitis are treated with an external orthosis and antimicrobial therapy for several weeks to months. If surgical intervention is required, a combined anterior and posterior approach for debridement and fusion with autologous bone graft or titanium mesh cage is usually performed.

Method: We here report on our experience with the use of a minimally invasive percutaneous dorsal pedicle screw-rod spondylodesis in adult patients with pyogenic lumbar or thoracic spondylodiscitis.

RNAi screen for rapid therapeutic target identification in leukemia patients.

Targeted therapy has vastly improved outcomes in certain types of cancer. Extension of this paradigm across a broad spectrum of malignancies will require an efficient method to determine the molecular vulnerabilities of cancerous cells. Improvements in sequencing technology will soon enable high-throughput sequencing of entire genomes of cancer patients; however, determining the relevance of identified sequence variants will require complementary functional analyses.

Gravitational valves in supine patients with ventriculo-peritoneal shunts.

Background: In the subgroup of bedridden hydrocephalic patients with ventriculo-peritoneal shunts and gravitational valves, we occasionally observed persisting hydrocephalic complaints even when mechanical or infection-related obstruction was excluded.

Methods: To investigate the cause of these hydrocephalic symptoms, in vitro and in vivo analyses were used to determine valve opening, intra-abdominal and hydrostatic pressure of an Aesculap-Miethke 10/40 cm H2O gravitational valve at different angles of upper body and head inclination.

Findings: Since hydrostatic pressure is lacking, the resulting intra-ventricular pressures are shown to peak up to 27 cm H2O in supine patients with head, but not upper body inclined.

New strategies for the first-line treatment of chronic myeloid leukemia: can resistance be avoided?

Imatinib is well established as a safe, effective therapy for patients with chronic myeloid leukemia (CML). However, point mutations in the kinase domain of Bcr-Abl can lead to imatinib resistance and reactivation of kinase activity. The second-generation Abl kinase inhibitors nilotinib and dasatinib were developed to reestablish disease control.

High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients.

Transforming mutations in NRAS and KRAS are thought to play a causative role in the development of numerous cancers, including myeloid malignancies. Although mutations at amino acids 12, 13, or 61 account for the majority of oncogenic Ras variants, we hypothesized that less frequent mutations at alternate residues may account for disease in some patients with cancer of unexplained genetic etiology. To search for additional, novel RAS mutations, we sequenced all coding exons in NRAS, KRAS, and HRAS in 329 acute myeloid leukemia (AML) patients, 32 chronic myelomonocytic leukemia (CMML) patients, and 96 healthy individuals.