Michael R Grever

..1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome...

..We examined here the preclinical activity of silvestrol in FLT3-ITD and FLT3 wild-type (wt) AML...

..g. importance of minimal residual disease) and will require international collaboration to fully address these unanswered questions. The Hairy Cell Leukemia Consortium was established to address these unanswered questions...

..Future studies should be directed to optimizing the therapy for minimal residual disease as well as clearer definition of supportive care...

..Consideration of the median age of patients at diagnosis combined with a substantial relapse rate mandates continued pursuit of improved therapy. The ultimate goal will be to achieve cure rather than simple control of the disease...

..Patients with this disease now can live a near normal life expectancy, but the disease has not yet been cured. Clinical trials must continue to address the remaining unanswered questions...

..Continued clinical research is essential to optimize therapy for this disease...

..1) is a major focus of several investigators. Selection of therapy based on high-risk genomic features represents an appropriate treatment approach supported by currently available published data...

..These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity...

..Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated...

..199) were noted with lower TCL-1 expression. These data suggest TCL-1 expression may help predict treatment outcome in CLL patients following chemoimmunotherapy, and examination in larger studies is warranted...

..These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias...

..We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphomas (B-NHL), and CLL to determine the activity of FFR...

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..1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy...

..Mcl-1 has also been reported to mediate resistance to rituximab in CLL. We therefore investigated whether direct reduction of Mcl-1 was sufficient to induce apoptosis and increase sensitivity to rituximab...

..The combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) achieved an overall response (OR) rate >90%, with >40% complete responses (CRs) in patients with untreated chronic lymphocytic leukemia (CLL)...

..Development of treatment approaches including flavopiridol should be considered for these older patients...

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..Furthermore, our data indicates that AKT and Hsp70 protein levels are relevant pharmacodynamic endpoints to monitor the in vivo effect of 17-AAG therapy...

..To simultaneously quantify intracellular nucleoside triphosphate (NTP) and deoxynucleoside triphosphate (dNTP) pools and to assess their changes produced by interfering with ribonucleotide reductase (RNR) expression in leukemia cells...

..Because the trials described were conducted before the requirement to register them was implemented, they are not registered in a clinical trial database.)...

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..In conclusion, dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL...

..To determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML)...

..IL-12 in combination with trastuzumab and paclitaxel therefore exhibits an acceptable toxicity profile and has activity in patients with HER2-overexpressing cancers...

..Given the toxicity and lack of efficacy in this and other trials in lymphoma and solid tumors, further development of apolizumab was discontinued...

..The pretreatment VEGF:TSP ratio also correlated with overall survival (P = 0.008). A pro-angiogenic profile appears associated with diminished response and inferior survival in CLL patients receiving CIT...

..The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM...

..We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies...

..This sensitivity will enable late terminal phase concentration measurements and accurate pharmacokinetic parameter estimation in a planned clinical trial with lenalidomide and flavopiridol in patients with chronic lymphocytic leukemia...

..This study demonstrates the feasibility and preliminary clinical activity of decitabine plus bortezomib in AML and identifies FLT3 as a novel pharmacodynamic end point for future trials...

..These observations suggest that in CLL and 697 cells, flavopiridol mediates its cytotoxic effects via induction of the mitochondrial permeability transition and changes in intracellular calcium...

..Herein, we investigated the feasibility of this approach in untreated elderly AML patients by administering oblimersen sodium (G3139), an 18-mer phosphorothioate antisense to Bcl-2, during induction and consolidation treatments...

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..We hypothesized that this dual activity of silvestrol would make it especially effective in malignancies driven by aberrant cyclin D1 expression...

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..Further preclinical studies are warranted to define the toxicity and therapeutic efficacy of this novel formulation...

..It is the first analytical method reported to date for the quantitation of both 17AAG and its metabolite 17AG and can reliably quantitate concentrations of both compounds as low as 0.5 ng/mL...

..Depsipeptide as a treatment for Lat-III EBV-associated lymphoproliferative disorders should be explored further in clinical trials...

..A phase I study to determine the maximum tolerated dose (MTD) of bortezomib (B) when combined with weekly paclitaxel in patients with advanced solid tumors...

..Several other investigational CDKi in preclinical and early clinical development are briefly discussed in this review...

..Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes with deletion 5q. We report results of a phase I dose-escalation trial of lenalidomide in relapsed or refractory acute leukemia...

..Although chemoimmunotherapy (CIT) has dramatically improved response rates in patients with CLL, some CIT regimens are not well tolerated by many patients >or=70 years of age...

..The median response duration for this subset of patients was 8 months (range, 3-17 months). These data suggest that alemtuzumab may be an effective therapy for patients with CLL with p53 mutations or deletions...

..In patients with high-risk interphase cytogenetics, CK remained predictive of worse OS (P = 0·02) and EFS (P = 0·009). These findings support further evaluation of metaphase karyotype in transplant risk assessment...

..Levels of miR-29b should be validated as a predictive factor for stratification of older AML patients to decitabine treatment...

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..Future studies with depsipeptide should examine alternative administration schedules...

..Together, these data suggest an overall favorable pharmacokinetic profile of silvestrol in mice and provide crucial information for its continued development toward potential clinical testing...

..We sought to determine if flavopiridol has activity in previously treated CLL using two schedules of administration...

..The authors hypothesized that hyperglycemia may be associated with adverse outcomes in patients with acute myeloid leukemia (AML) and sought to determine whether this association exists in this population...

..This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy...

..This review focuses on a novel dosing regimen that has achieved significant clinical activity in relapsed, poor-risk chronic lymphocytic leukemia...

..Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases...

..Thus, reduced expression of DAPK1 can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CLL phenotype...

..The widespread use of computed tomography (CT) scans has prompted many to advocate for the incorporation of this test into CLL response criteria...

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..Protein identities were determined using high mass accuracy MS and shotgun proteomics...

..The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS...

..Higher levels are seemingly associated with clinical response. Monitoring the DAC-TP intracellular level may serve as a novel pharmacological endpoint for designing more effective DAC-based regimens...

..This phase I study determined the maximal-tolerated dose, dose-limiting toxicities, pharmacokinetics, and recommended dose of erlotinib with docetaxel...

..Together, these data indicate that silvestrol is a substrate of Pgp, a potential obstacle that must be considered in the development of silvestrol for oral delivery or targeting to tumors protected by Pgp overexpression...

..These data suggest use of histone H3 and H4 acetylation, inhibition of histone deacetylase, and down-regulation of FLIP as pharmacodynamic end points for further evaluation of this drug in patients...

..Future efforts in developing combination strategies with rituximab, alemtuzumab, and potentially other new antibodies offer great promise for the future treatment of CLL...

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..We discuss selection of therapy for the relapsed patient using risk stratification and the role of clinical research in continuing to pursue therapeutic advances against CLL...

..New studies should explore the combination of pentostatin and rituxan in treating the typical form of hairy-cell leukemia, and the incorporation of new agents for those with the rare variant form of this disease...

..Herein we report selective epigenetic silencing of the transcription factor TWIST2 (DERMO1) in Ig V(H) mutated CLL and describe a semiquantitative assay to study promoter methylation of this gene in primary tumor cells...

..Thus, our studies indicate that aberrant expression of PRMT5 leads to altered epigenetic modification of chromatin, which in turn impacts transcriptional performance of anti-cancer genes and growth of transformed lymphoid cells...

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..The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years)...

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..This method has been applied to the analysis of plasma samples obtained from patients treated with this drug...

..In the phase I trial, a sequential combination of rituximab and IL-2 was well tolerated and achieved biological end points. Responses were observed...

..These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL...

..5%) and were associated with no serious adverse events, autoimmune disease, or cardiotoxicity. There was preliminary evidence of clinical activity in several patients...

..The Task Force provides these guidelines in the hopes that improvements in biomarker studies will enhance the efficiency of investigational drug development...

..5% donor CD3 lymphocytes. PT demonstrated lymphodepleting effects and promising safety, supporting alloNST as early as 7 days after initiation of PT...

..In steroid-refractory aGVHD, mortality is very high. Pentostatin, a potent inhibitor of adenosine deaminase, induces lymphocyte apoptosis and may be useful in the treatment of this condition...

..Toxicity was manageable in most patients and included anemia, thrombocytopenia, infections, diarrhea, and fatigue. CONCLUSIONS:: Flavopiridol as a 24-h continuous infusion has no clinical activity in relapsed, fludarabine-refractory CLL...

..5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL...

..Two patients on the 21/28 schedule developed hematological improvement. Prolonged infusions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition...

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..E2997 is a phase III randomized Intergroup trial comparing fludarabine and cyclophosphamide (FC arm) versus fludarabine (F arm) alone in patients receiving their first chemotherapy regimen for CLL...