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Biomedical subjects

Michael W N Deininger

Publications and source records attributed to Michael W N Deininger.

At least 19 recordsLinked to original sources
PubMed2006

Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.

BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy. METHODS: We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events. RESULTS: The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events. CONCLUSIONS: After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)

Antineoplastic Agents↗
PubMed2006

Characterization of murine JAK2V617F-positive myeloproliferative disease.

The JAK2(V617F) mutation is present in almost all patients with polycythemia vera (PV), large proportions of patients with essential thrombocythemia and idiopathic myelofibrosis, and less frequently in atypical myeloproliferative disorders (MPD). We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis. Fluorescence-activated cell sorting of bone marrow and spleen showed proportional expansion of common myeloid progenitors, granulocyte-monocyte and megakaryocyte-erythrocyte progenitors. Megakaryocyte and late erythroid progenitors were dramatically increased, with only modest expansion of early erythroid progenitors. Erythropoietin (Epo) receptor expression was reduced on early, but normal on late erythroblasts. Serum levels of Epo and granulocyte colony-stimulating factor, but not granulocyte macrophage colony-stimulating factor, were reduced, whereas tumor necrosis factor-alpha was increased, possibly exerting a negative effect on JAK2(V617F)-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors. There were no thromboembolic events and no animals succumbed to their disease, implicating additional factors in the manifestation of human disease. The disease was not transplantable and prolonged observation showed normalization of blood counts in most JAK2(V617F) mice, suggesting that the mutation may not confer self-renewal capacity.

Animals↗
PubMed2006

Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies.

Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC50 > 5-10 micromol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y >> D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations.

Amino Acid Substitution↗
PubMed2005

BCR-ABL kinase domain mutations in chronic myeloid leukemia: not quite enough to cause resistance to imatinib therapy?

Patients with chronic myeloid leukemia (CML) treated with imatinib in early chronic phase tend to have durable remissions, but there is a high rate of relapse in patients with advanced disease. Mutations in the kinase domain of BCR-ABL that impair drug binding have been identified as the major mechanism of resistance. It is not known when exactly these mutations arise, but in some patients retrospective analysis of pretherapeutic samples demonstrated identical mutations, suggesting selection in the presence of drug. In the present study we have used a highly sensitive PCR assay to screen for kinase domain mutations in pretherapeutic samples from CML patients, irrespective of their subsequent response to imatinib. We find that kinase domain mutations are demonstrable in approximately 1/3 of patients with accelerated phase or blast crisis and that the presence of two copies of the Philadelphia chromosome is strongly correlated with mutation detection. Unexpectedly, kinase domain mutant clones were not invariably selected in the presence of drug, suggesting that additional mechanisms must contribute to a fully drug resistant leukemia.

Adult↗
PubMed2005

Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib.

PURPOSE: Chronic myeloid leukemia (CML) is effectively treated with imatinib. However, reactivation of Bcr-Abl via kinase domain mutations that reduce sensitivity to imatinib can cause relapse. As combination therapy is frequently used to prevent emergence of resistance, the combination of imatinib with an inhibitor of imatinib-resistant Bcr-Abl mutants (e.g., Src/Abl inhibitors AP23848 and BMS-354825) was investigated. EXPERIMENTAL DESIGN: To test this approach, cellular proliferation and Bcr-Abl tyrosine phosphorylation assays were done on Ba/F3 cells expressing wild-type (WT) Bcr-Abl and four common imatinib-resistant mutants (Y253F, E255K, T315I, and M351T). Colony-forming assays with primary CML cells were also done. RESULTS: Both Src/Abl inhibitors retained full inhibitory capacity when coadministered with imatinib at concentrations above typical clinical levels. For cells expressing WT Bcr-Abl or the marginally imatinib-resistant mutant M351T, inclusion of imatinib at therapeutic levels enhanced the effects of the Src/Abl inhibitors. By comparison, for the highly imatinib-resistant mutants Y253F and E255K, inclusion of imatinib at clinical levels resulted in only a slight enhancement beyond the effects of the Src/Abl inhibitors. None of the inhibitors affected Bcr-Abl T315I cells. Colony-forming assays with primary CML cells yielded analogous results. CONCLUSIONS: Our results indicate that Src/Abl inhibitors are compatible with imatinib and suggest that combined Abl inhibitor therapy is a feasible treatment strategy for patients with CML.

Adenosine Triphosphate↗
PubMed2005

The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia.

Activating mutations in tyrosine kinases have been identified in hematopoietic and nonhematopoietic malignancies. Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML)/atypical chronic myelogenous leukemia (aCML), myelodysplastic syndrome (MDS), B-lineage acute lymphoblastic leukemia (ALL), T-cell ALL, and chronic lymphocytic leukemia (CLL). Analysis of 222 patients with AML identified JAK2V617F mutations in 4 patients with AML, 3 of whom had a preceding MPD. JAK2V617F mutations were identified in 9 (7.8%) of 116 CMML/a CML samples, and in 2 (4.2%) of 48 MDS samples. We did not identify the JAK2V617F disease allele in B-lineage ALL (n = 83), T-cell ALL (n = 93), or CLL (n = 45). These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in lymphoid malignancies.

Aged↗
PubMed2005

In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.

Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Abl kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Abl kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Abl inhibitors are currently being evaluated in clinical trials: the improved potency, selective Abl inhibitor AMN107 and the highly potent dual Src/Abl inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS-354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing >90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.

Animals↗
PubMed2005

In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation-loop mutants of Kit.

Oncogenic mutations of the Kit receptor tyrosine kinase occur in several types of malignancy. Juxtamembrane domain mutations are common in gastrointestinal stromal tumors, whereas mutations in the kinase activation loop, most commonly D816V, are seen in systemic mastocytosis and acute myelogenous leukemia. Kit activation-loop mutants are insensitive to imatinib mesylate and have been largely resistant to targeted inhibition. We determined the sensitivities of both Kit mutant classes to the adenosine triphosphate (ATP)-based inhibitors AP23464 and AP23848. In cell lines expressing activation-loop mutants, low-nM concentrations of AP23464 inhibited phosphorylation of Kit and its downstream targets Akt and signal transducer and activator of transcription 3 (STAT3). This was associated with cell-cycle arrest and apoptosis. Wild-type Kit-and juxtamembrane-mutant-expressing cell lines required considerably higher concentrations for equivalent inhibition, suggesting a therapeutic window in which cells harboring D816V Kit could be eliminated without interfering with normal cellular function. Additionally, AP23464 did not disrupt normal hematopoietic progenitor-cell growth at concentrations that inhibited activation-loop mutants of Kit. In a murine model, AP23848 inhibited activation-loop mutant Kit phosphorylation and tumor growth. Thus, AP23464 and AP23848 potently and selectively target activation-loop mutants of Kit in vitro and in vivo and could have therapeutic potential against D816V-expressing malignancies.

Adenosine Triphosphate↗
PubMed2005

Can we afford to let sleeping dogs lie?

In patients with chronic myelogenous leukemia (CML) mutations of the BCR-ABL kinase domain (KD) have been identified as the leading cause of acquired resistance to imatinib, while the mechanisms underlying the persistence of minimal residual disease (MRD) are unknown. In this issue of Blood, Chu and colleagues report several patients with KD mutations at the time of complete cytogenetic response (CCR), implicating mutations as a cause of disease persistence.

Benzamides↗
PubMed2005

AMN107: tightening the grip of imatinib.

The Abl inhibitor imatinib is a highly effective therapy for patients with chronic myeloid leukemia. Relapses are relatively uncommon in newly diagnosed patients, but are the rule in patients with more advanced disease. Mutations in the BCR-ABL gene are the most common cause of relapse. Working from the imatinib chemical structure, a higher-affinity family member, AMN107, was designed. AMN107 is approximately 20-fold more potent than imatinib, and this translates into improved inhibitory activity against most of the common BCR-ABL mutations. The implications of these results, and the potential role this and other novel ABL inhibitors may have in treating patients with CML, are discussed.

Animals↗
PubMed2005

Management of early stage disease.

More than 80% of newly diagnosed patients with chronic myeloid leukemia in chronic phase will achieve a complete cytogenetic response (CCR) with the standard dose of 400 mg imatinib daily. The probability of progression free survival is tightly correlated with the level of response, approaching 100% in those patients who achieve a reduction of BCR-ABL mRNA by at least 3-log at 12 months. High Sokal risk predicts poorer outcome, but on-treatment response parameters generally override pretherapeutic prognostic variables. Standard disease monitoring includes full blood counts, cytogenetics and quantitative RT-PCR for BCR-ABL mRNA but must be tailored to the level of response attained by a given patient. Conservative therapeutic milestones include a complete hematologic response at 3 months, a minor cytogenetic response at 6, a major cytogenetic response at 12 and CCR at 18, but a more aggressive approach may be justified in specific circumstances. Failure to achieve any of these milestones should trigger a re-assessment of the therapeutic strategy. Most patients with CCR remain positive by RT-PCR, and discontinuation of drug is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells. The mechanisms underlying disease persistence are not well understood. Evidence is accumulating that early therapy intensification using high doses of imatinib (800 mg daily) or imatinib in combination with cytarabine or interferon-alpha may induce higher rates of RT-PCR negativity. Large studies will be required to determine whether this translates into improved progression free and overall survival.

Antineoplastic Agents↗
PubMed2005

In chronic myeloid leukemia white cells from cytogenetic responders and non-responders to imatinib have very similar gene expression signatures.

BACKGROUND AND OBJECTIVES: Imatinib induces complete cytogenetic responses (CCR) in the majority of patients with chronic myeloid leukemia (CML) in chronic phase (CP). However, a subgroup of patients is refractory at the cytogenetic level. Clinically, it would be advantageous to identify such patients a priori, since they may benefit from more aggressive therapy. DESIGN AND METHODS: To elucidate mechanisms underlying cytogenetic refractoriness, we used Affymetrix oligonucleotide arrays to determine the transcriptional signature associated with cytogenetic refractoriness in unselected white blood or bone marrow cells from 29 patients with CML in first CP prior to treatment with imatinib. Patients with CCR within 9 months were defined as responders (n = 16) and patients lacking a major cytogenetic response (> 35% Philadelphia-positive metaphases) after 1 year were defined as non-responders (n = 13). RESULTS: Differences in gene expression between responders and non-responders were subtle. Stringent statistical analysis with multiple comparison adjustments revealed very few differentially expressed genes. Differentially expressed genes could not be confirmed in an independent test set. INTERPRETATION AND CONCLUSIONS: We conclude that transcriptional profiling of unselected white cells is of limited value for identifying genes consistently associated with cytogenetic refractoriness to imatinib.

Adult↗
PubMed2004

Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970.

Oncogenic mutations of the receptor tyrosine kinase KIT occur in gastrointestinal stromal tumors (GISTs), some cases of acute myelogenous leukemia (AML), and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analyzed the inhibitory potential of 2 small molecule inhibitors, MLN518 and PD180970, against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT, and signal transducer and activator of transcription-3 (Stat3) phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase 1 clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations.

Animals↗
PubMed2004

Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis.

Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.

Animals↗
PubMed2004

SRCircumventing imatinib resistance.

The ABL inhibitor imatinib is a highly effective therapy for patients with chronic myeloid leukemia. Relapses after an initial response have been observed in some patients, and mutations of the BCR-ABL gene are the most common mechanism driving these relapses. Alternative ABL inhibitors have been identified that inhibit most of the common BCR-ABL mutations, and one has entered clinical trials. The structural basis for these results has yielded significant insights into the mechanism of action of these compounds, mechanisms of resistance, and their ability to inhibit the BCR-ABL mutants. These studies demonstrate the importance and impact of conducting scientific studies as part of clinical trials.

Antineoplastic Agents↗
PubMed2004

Biology of chronic myelogenous leukemia--signaling pathways of initiation and transformation.

Chronic myeloid leukemia (CML) is caused by the Bcr-Abl oncoprotein,the product of the t(9;22) chromosomal translocation that generates the Philadelphia chromosome. Different disease phenotypes are associated with each of the three Bcr-Abl isoforms: p190Bcr-Abl, p210Bcr-Abl, and p230Bcr-Abl all of which have a constitutively activated tyrosine kinase. Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signaling pathways, inhibition of apoptosis, and proteasomal degradation of physiologically important cellular proteins.CML is subject to an inexorable progression from an "indolent" chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.

Cell Transformation, Neoplastic↗