J C Byrd

..To study the impact of repetitive (three to four courses) versus a single course of high-dose cytarabine (HDAC) consolidation therapy on outcome of patients with acute myeloid leukemia (AML) and inv(16)(p13q22) or t(16;16)(p13;q22)...

..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...

..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...

..We sought to study the in vitro activity of UCN-01 against human chronic lymphocytic leukemia (CLL) cells and potential mechanisms of action for inducing this cytotoxicity...

..Rituximab administered concurrently with fludarabine in previously untreated CLL patients demonstrates marked clinical efficacy and acceptable toxicity. Phase 3 studies using this combination approach for patients with CLL are warranted...

..Here we examine pretreatment biologic features that promote resistance to apoptosis and CDC in CLL patients and correlate it with clinical outcome to rituximab-based therapy...

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

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

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..These data suggest that interphase cytogenetics in CLL may be predictive of a response to rituximab therapy and provide support for additional studies validating risk-adapted therapy in this disease...

..The combination of etanercept and thrice weekly rituximab produces durable remissions in non-del(17p13.1) CLL patients and is well tolerated...

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..This study sought to decrease the initial toxicity and optimize the pharmacokinetics with an alternative treatment schedule...

..TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol...

..Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials...

..Additional studies detailing the mechanism of action of alemtuzumab as well as new strategies for prevention of opportunistic infections will aid in the future therapeutic development of this agent...

..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...

..3%; 95% CI+/-11.2). These data provide evidence that CAI can induce apoptosis in human CLL cells in vitro at drug concentrations attainable in vivo. These findings justify phase II studies of CAI in patients with B-CLL...

..To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype...

..Similar to many other therapeutic targets, MS-275-mediated apoptosis is reduced by overexpression of Bcl-2, justifying strategies to combine HDAC inhibitors with Bcl-2 antagonists...

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..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...

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..To determine if alemtuzumab consolidation improves response rate and progression-free survival (PFS) after induction chemoimmunotherapy in previously untreated symptomatic patients with chronic lymphocytic leukemia...

..In addition, this trial served as the initial platform for additional CALGB 'doublet' combination regimes of rituximab plus other novel targeted agents...

..Rituximab was recently approved for use in relapsed, low-grade non-Hodgkin's lymphoma; however, few data exist regarding the safety of this agent in patients with a high number of tumor cells in the blood...

..Furthermore, the differential direct cytotoxic effect suggests that CD52 directed antibodies could possibly be engineered to more specifically target CLL cells...

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..Cladribine has modest clinical activity and considerable toxicity in a very selected group of patients with fludarabine-refractory CLL lacking pre-treatment neutropenia and thrombocytopenia...

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

..Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs...

..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...

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

..A randomized trial comparing lumiliximab plus FCR with FCR alone is underway to define the benefit of this combination in relapsed CLL. This trial was registered at clinicaltrials.gov as NCT00103558...

..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...

..The administration of alemtuzumab as consolidation therapy following an abbreviated fludarabine induction is feasible but requires close monitoring for CMV infection and other infectious events...

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

..These data suggest that rituximab has clinical activity in heavily pre-treated patients with Waldenstrom's macroglobulinemia. Based on these data, clinical studies of Rituximab in previously untreated and treated WM appear indicated...

..03) compared to BuCy2, resulting in similar survival. Overall, our results do not support the use of the more intensive BuCyVP regimen over BuCy2 in either early or more advanced disease AML patients...

..Clofarabine exhibits evidence of single agent activity in relapsed or refractory DLBCL. However, further study with novel administration schedules that maintain this efficacy and limit toxicity is warranted...

..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...

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

..These findings are relevant to trials with new and highly effective agents for which the incidence of serious infections after treatment might otherwise appear to be prohibitively high...

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..Therefore, this schedule of administration achieved MGd uptake into primary tumor cells in vivo, but clinical activity was modest...

..We conducted a phase 1, dose escalation and schedule optimization study of the primatized anti-CD23 antibody, lumiliximab, in patients with previously treated and refractory CLL...

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

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

..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...

..We describe generation and utilization of cell lines that stably express CD52 both in vitro and in vivo...

..These concentrations are in a range that shows biological activities. We conclude that this method provides a general and valuable tool for the pharmacologic study and clinical development of synthetic miRNAs...

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..These data suggest that Hu1D10 ligation in CLL cells induces death and survival signals for which combination therapies may be designed to greatly enhance efficiency of both Hu1D10 and other class II antibodies in development...

..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...

..Confirmation of these findings will require a prospective randomized trial comparing fludarabine and rituximab to fludarabine...

..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)...

..Although subcutaneous T-cell lymphoma (SCTCL) is considered an aggressive form of lymphoma, some patients manifest a long waxing and waning phase unaccompanied by constitutional symptoms...

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..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...

..These data suggest a cross-talk mechanism between HDACs and H3K4 demethylases via Sp1-mediated transcriptional regulation, which underlies the complexity of the functional role of HDACs in the regulation of histone modifications...

..In the following review we will discuss the clinical development and potential roles of monoclonal antibodies in the treatment of both acute and chronic leukemias...

..We report a patient with small lymphocytic lymphoma (phenotypic CLL) who developed symptomatic anemia 3 weeks after her fifth cycle of fludarabine, a T cell immunosuppressant...

..Herein, we highlight life-threatening tumor flare when higher doses of lenalidomide are administered to patients with CLL and provide a potential mechanism for its occurrence...

..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...

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..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...

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

..These findings provide strong support for further clinical development of XmAb5574 as both a monotherapy and in combination with lenalidomide for the therapy of CLL and related CD19(+) B-cell malignancies...

..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...

..These results provide the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies, including CLL...

..In addition, recent efforts to combine currently applied therapeutic antibodies with other biologic and targeted therapies with efficacy in CLL offers the potential to move toward alternative non-chemotherapy-based treatment approaches...

..Therefore, the effect of 17-DMAG on NF-kappaB signaling pathways represents a novel therapy warranting further clinical pursuit in this and other B-cell lymphoproliferative disorders...

..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...

..Future efforts focusing on novel combination-based strategies will be required to fully appreciate the benefit of this therapy in CLL...

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..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)...

..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 results suggest a novel mechanism for gene silencing mediated by RUNX1/MTG8 and support the combination of HDAC and DNMT inhibitors as a novel therapeutic approach for t(8;21) AML...

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

..A report of the clinical features, treatment, and outcome of patients who developed hemolytic anemia (HA) temporally associated with fludarabine (Fludara; Berlex Laboratories, Richmond, CA) therapy for chronic lymphocytic leukemia (CLL)...

..Whether acquired karyotype abnormalities from the MA were related to the MDS and subsequent myeloid leukemia in this woman is a speculative but intriguing consideration that is discussed...

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..2;p11.2) is a novel recurrent cytogenetic abnormality in CLL associated with early age at diagnosis and accelerated disease progression. Future efforts to identify genes disrupted by this translocation are warranted and ongoing...

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..However, such infusion toxicity is minimized with appropriate premedication and a stepped up dosing schedule, allowing safe and effective use of rituximab in this disease...

..Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients...

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

..Because high response rates and few complications are observed in previously untreated patients, the use of alemtuzumab earlier in therapy may provide optimum benefit to patients...

..CONCLUSIONS: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL...

..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...

..In view of the evidence for its activity, further exploration of bortezomib in combination with other agents is warranted...

..The unprecedented response and the profound suppression of HTLV-1 viral load observed in this patient suggest that further clinical investigation of alemtuzumab in ATL is warranted...

..Little is known about lung injury caused by fludarabine therapy...

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

..This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I...

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..These laboratory studies combined with clinical data derived from this trial will form the basis for future phase II development of this agent in CLL/SLL. ..

..The clinical and laboratory results of this trial will provide pharmacokinetic and pharmacodynamic information for additional correlative efforts in both single agent phase II and combination phase I studies. ..

..Such therapy would potentially administer different types of chemoimmunotherapy based upon the presence or absence of IgVH mutational status and p53 dysfunction. ..

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