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Articles by Maher Albitar in JoVE
Other articles by Maher Albitar on PubMed
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Prognostic Factors and Scoring Systems in Chronic Myelomonocytic Leukemia: a Retrospective Analysis of 213 Patients
Blood.
Feb, 2002 |
Pubmed ID: 11806985 Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by wide heterogeneity of clinical presentation and course. CMML shares myelodysplastic characteristics with features of myeloproliferative disorders. No treatment has proven effective in modifying the natural course of the disease. To improve the prognostic assessment of clinical outcome, the associations of patient and disease characteristics with survival times of 213 patients with CMML was investigated retrospectively. Median survival was 12 months. Univariate analysis identified low hemoglobin level; low platelet count; high white blood cell, monocyte, and lymphocyte counts; presence of circulating immature myeloid cells, high percentage of marrow blasts, low percentage of marrow erythroid cells, abnormal cytogenetics, and high levels of serum lactate dehydrogenase and beta(2)-microglobulin as characteristics associated with shorter survival. Hemoglobin level below 120 g/L (12 g/dL), presence of circulating immature myeloid cells, absolute lymphocyte count above 2.5 x 10(9)/L, and marrow blasts 10% or more were independently associated with shorter survival by multivariate analysis and were used to generate a prognostic score. The model identified 4 subgroups of patients with median survival of 24, 15, 8, and 5 months for low, intermediate-1, intermediate-2, and high risk, respectively. Researchers could not confer objective evidence suggesting that arbitrary divisions of CMML by white blood cell counts into "dysplastic" and "proliferative" categories reflect clinical entities differing in the risk of acute leukemia development, although a trend of shorter survival in patients with leukocytosis was observed. The prognostic model was compared with 6 previously published scoring systems for myelodysplastic syndrome/CMML. The reported results should provide an improved assessment of prognosis in CMML.
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Emerging Information on the Use of Rituximab in Chronic Lymphocytic Leukemia
Seminars in Oncology.
Feb, 2002 |
Pubmed ID: 11842391 Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) is a chimeric monoclonal antibody that targets mature B cells in most lymphoid B-cell malignancies. While rituximab was approved by the US Food and Drug Administration for the treatment of recurrent B-cell lymphoma, initial studies suggested that it had less activity in small lymphocytic lymphoma, the nodal counterpart of chronic lymphocytic leukemia (CLL). Two studies have now investigated the activity of higher-dose and more intensive therapy with rituximab in CLL. They have shown a dose-response relationship and a higher response rate than previously seen in the lower-dose studies. This is presumably caused by the overcoming of lower antigen density on CLL cells compared with lymphoma cells, and the shorter half-life of rituximab in small lymphocytic lymphoma. There is now evidence that CD20 is shed into the plasma in patients with CLL, which may explain the shorter half-life of the antibody in small lymphocytic lymphoma/CLL. The higher dose may then be effective in overcoming this so-called "antigen sink." Toxicity was uncommon except in previously untreated patients and those with atypical forms of CLL such as mantle cell lymphoma and prolymphocytic leukemia. There is now evidence in vitro of additive or synergistic activity of rituximab with a variety of chemotherapeutic agents including fludarabine and cyclophosphamide. Combinations of fludarabine with rituximab or these two drugs combined with cyclophosphamide have given very high complete response rates in series of patients with both previously untreated and treated CLL. It is apparent that rituximab is playing a significant role in the management of patients with CLL as salvage therapy and is a potential potentiating agent for combined chemoimmunotherapy strategies for front-line or relapsed patients with CLL.
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Imatinib Mesylate (STI571) Therapy for Philadelphia Chromosome-positive Chronic Myelogenous Leukemia in Blast Phase
Blood.
May, 2002 |
Pubmed ID: 11986206 Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph(+) below 35%], and 4 minor [Ph(+), 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P =.001), longer median survival (7 versus 4 months, P =.04), and lower 4-week induction mortality (4% versus 15%, P =.07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.
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Therapeutic Role of Alemtuzumab (Campath-1H) in Patients Who Have Failed Fludarabine: Results of a Large International Study
Blood.
May, 2002 |
Pubmed ID: 11986207 This study investigated the efficacy, safety, and clinical benefit of alemtuzumab (Campath-1H) for patients with relapsed or refractory B-cell chronic lymphocytic leukemia exposed to alkylating agents and having failed fludarabine therapy. Ninety-three patients received alemtuzumab in 21 centers worldwide, with the aim to obtain an overall response rate of at least 20%. Dosage was increased gradually (target 30 mg, 3 times weekly, for a maximum of 12 weeks). Infection prophylaxis was mandatory, beginning on day 8, and continuing for a minimum of 2 months after treatment. Responses were assessed at weeks 4, 8, and 12, and patients were followed for 34 months. Overall objective response in the intent-to-treat population (n = 93) was 33% (CR 2%, PR 31%). Median time to response was 1.5 months (range, 0.4-3.7 months). Median time to progression was 4.7 months overall, 9.5 months for responders. At data cut-off, 27 patients (29%) were alive; overall median survival was 16 months (95% CI: 11.8-21.9) and 32 months for responders. Nineteen responders survived more than 21 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to infusion, generally grade 1 or 2 in severity, occurring mainly in the first week. Grade 3 or 4 infections were reported in 25 patients (26.9%). However, only 3 (9.7%) of 31 patients who responded to alemtuzumab treatment developed grade 3 or 4 infections on the study. Alemtuzumab induced significant responses in these patients with clinical benefit in the majority and with acceptable toxicity in a high-risk group.
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Myelodysplastic Syndrome is Not Merely "preleukemia"
Blood.
Aug, 2002 |
Pubmed ID: 12130488 Myelodysplastic syndrome (MDS) is a disease characterized by ineffective hematopoiesis. There are significant biologic and clinical differences between MDS and acute myeloid leukemia (AML). We studied a cohort of 802 patients, 279 (35%) with newly diagnosed MDS and 523 (65%) with newly diagnosed AML, and compared clinical and biologic characteristics of the 2 groups. Complete clinical and cytogenetic data were available on all patients, and a subgroup of patients was studied for apoptosis, angiogenesis, proliferation, and growth factors. Our results demonstrate that MDS is a discrete entity that is different from AML and is characterized primarily by increased apoptosis in early and mature hematopoietic cells. Using cell sorting and loss of heterozygosity, we demonstrate that the leukemic cells from MDS patients are capable of differentiation into mature myeloid cells and monocytes. We also demonstrate that there is a significant overlap between AML and MDS when MDS is defined on the basis of an arbitrary percentage of blasts of 20% or 30%. These data suggest that despite similarities between AML and MDS in their responses to treatment and outcomes, MDS is biologically and clinically different from AML and should not be considered an early phase of AML. The data indicate that MDS must be better defined on the basis of its biology rather than the percentage of blasts; further, the data suggest that there is a need to develop therapeutic approaches that specifically address the biologic abnormalities of MDS.
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Emerging Information on the Use of Rituximab in Chronic Lymphocytic Leukemia
Seminars in Oncology.
Feb, 2002 |
Pubmed ID: 28140094 Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) is a chimeric monoclonal antibody that targets mature B cells in most lymphoid B-cell malignancies. While rituximab was approved by the US Food and Drug Administration for the treatment of recurrent B-cell lymphoma, initial studies suggested that it had less activity in small lymphocytic lymphoma, the nodal counterpart of chronic lymphocytic leukemia (CLL). Two studies have now investigated the activity of higher-dose and more intensive therapy with rituximab in CLL. They have shown a dose-response relationship and a higher response rate than previously seen in the lower-dose studies. This is presumably caused by the overcoming of lower antigen density on CLL cells compared with lymphoma cells, and the shorter half-life of rituximab in small lymphocytic lymphoma. There is now evidence that CD20 is shed into the plasma in patients with CLL, which may explain the shorter half-life of the antibody in small lymphocytic lymphoma/CLL. The higher dose may then be effective in overcoming this so-called "antigen sink." Toxicity was uncommon except in previously untreated patients and those with atypical forms of CLL such as mantle cell lymphoma and prolymphocytic leukemia. There is now evidence in vitro of additive or synergistic activity of rituximab with a variety of chemotherapeutic agents including fludarabine and cyclophosphamide. Combinations of fludarabine with rituximab or these two drugs combined with cyclophosphamide have given very high complete response rates in series of patients with both previously untreated and treated CLL. It is apparent that rituximab is playing a significant role in the management of patients with CLL as salvage therapy and is a potential potentiating agent for combined chemoimmunotherapy strategies for front-line or relapsed patients with CLL. Semin Oncol 29 (suppl 2):70-74. Copyright © 2002 by W.B. Saunders Company.
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Efficacy of the Farnesyl Transferase Inhibitor R115777 in Chronic Myeloid Leukemia and Other Hematologic Malignancies
Blood.
Mar, 2003 |
Pubmed ID: 12411300 We investigated the clinical activity of the farnesyl transferase inhibitor R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic, accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10 patients with multiple myeloma (MM). R115777 was administered at 600 mg orally twice daily for 4 weeks every 6 weeks. Seven patients with CML (6 in chronic phase, 1 in advanced phase) achieved complete or partial hematologic response. Four of them had a minor cytogenetic response. Responses were transient, with a median duration of 9 weeks (range, 3-23 weeks). Two patients discontinued therapy because of toxicity while in complete hematologic response. Two MF patients had a significant decrease in splenomegaly, one had normalization of white blood cell count and differential, and one became transfusion independent. One patient with MM had a reduction in monoclonal protein of 34%. Adverse events included nausea in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%), peripheral neuropathy (2 patients, 5%), and liver toxicity (2 patients, 5%). Patients who responded to therapy had significantly higher plasma vascular endothelial growth factor (VEGF) concentrations prior to treatment than nonresponders. Plasma concentrations decreased significantly during therapy among responders. R115777 showed clinical activity in patients with CML and MF. The effect on VEGF needs to be further investigated to determine whether this might be a possible mechanism of action of R115777.
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Plasma Interleukin 8 Level Predicts for Survival in Chronic Lymphocytic Leukaemia
British Journal of Haematology.
Feb, 2003 |
Pubmed ID: 12580959 The malignant B cells of patients with chronic lymphocytic leukaemia (CLL) constitutively express interleukin 8 (IL-8) and IL-8 receptors. Ex vivo culture with exogenous IL-8 enhances IL-8 expression and prolongs leukaemia cell survival, partly through increased bcl-2 expression. IL-8 may function as an autocrine growth and apoptosis resistance factor in CLL. Therefore, we evaluated the prognostic relevance of plasma IL-8 levels in 151 CLL patients [median age 61 years (range, 32-84 years), median plasma IL-8 level 18.9 pg/ml (9.1-89.1 pg/ml)]. All Rai stages were represented; advanced stage was associated with significantly higher plasma IL-8 levels (P < 0.0001, Kruskal-Wallis). Also, plasma IL-8 level was correlated with serum beta2-microglobulin (beta2-M) (R = 0.24, P = 0.0081), haemoglobin (R = -0.39, P < 0.0001) and platelet count (R = -0.23, P = 0.0049) by Spearman's rank correlation. Univariate analysis using Cox proportional hazards models identified elevated IL-8 and beta2-M as significant prognostic factors with relative risks of 7.43 (P = 9.1 x 10(-9)) and 16.40 (P = 5.9 x 10(-10)) respectively. High levels of IL-8 were associated with shorter survival independent of beta2-M level. Using recursive-partitioning procedures, an IL-8 cut-off point of 26.2 pg/ml segregated a group of CLL patients with significantly shorter survival (median 9.3 months) (P < 0.0001). In conclusion, plasma IL-8 level in CLL patients correlates with other prognostic factors, such as Rai stage and beta2-M, and is associated with increased risk of death in CLL patients. The role of IL-8 inhibitors in the treatment of patients with CLL should be explored.
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SU5416, a Small Molecule Tyrosine Kinase Receptor Inhibitor, Has Biologic Activity in Patients with Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes
Blood.
Aug, 2003 |
Pubmed ID: 12649163 Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.
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Phase II Study of SU5416--a Small-molecule, Vascular Endothelial Growth Factor Tyrosine-kinase Receptor Inhibitor--in Patients with Refractory Myeloproliferative Diseases
Cancer.
Apr, 2003 |
Pubmed ID: 12673719 Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with myeloproliferative disorders (MPD), including agnogenic myeloid metaplasia (AMM), chronic myeloid leukemia in blastic phase (CML-BP), and chronic myelomonocytic leukemia (CMML). VEGF is a soluble, circulating, angiogenic molecule that acts through receptor tyrosine kinases (RTK), including VEGF receptor 2 (VEGFR-2). SU5416 is a small-molecule RTK inhibitor (RTKI) that targets VEGFR-2, c-kit, and fms-related tyrosine kinase Flk2.
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A Prognostic Model for Survival in Chronic Lymphocytic Leukaemia Based on P53 Expression
British Journal of Haematology.
May, 2003 |
Pubmed ID: 12752098 As the abnormal expression of p53 protein is prognostically significant in some human cancers, its significance in patients with B-cell chronic lymphocytic leukaemia (CLL) was assessed. Two investigators evaluated the percentage of bone marrow mononuclear cells that stained for p53, using biopsies stained with anti-p53 monoclonal antibody (DO-7), and graded the degree of staining (0, +, ++, +++). Samples from a cohort of 90 patients with CLL were studied (median age 60 years, range 30-89 years; 57 patients were (63%) previously untreated, 22 patients (24%) had received one or two prior regimens, 11 patients had received (12%) three to seven regimens. The overall percentage of cells positive for p53 staining was a median of 43 (range 1-88). No investigator effect was detected either in overall percentage cells rated p53 positive or on the degree of staining (Pearson's correlation coefficient 0.980, P-value < 0.001). A Cox proportional hazards model showed that the percentage of ++ and +++ p53-positive cells correlated with various prognostic factors in CLL (P < 0.0001). A multivariate model incorporating prior therapy, Rai stage, beta2 microglobulin (beta2M) and p53 expression showed that only the percentage of p53-positive cells and beta2M were predictive of survival, and enabled the development of a highly predictive model of survival based on these two parameters.
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Gemtuzumab Ozogamicin, Fludarabine, Cytarabine and Cyclosporine Combination Regimen in Patients with CD33+ Primary Resistant or Relapsed Acute Myeloid Leukemia
Leukemia Research.
Oct, 2003 |
Pubmed ID: 12860008 Clinical resistance to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia (AML) is associated with blast multidrug resistance (MDR) phenotype. A Phase II study of Mylotarg, fludarabine, ara-C and the MDR-modifier, cyclosporine (CSA) (MFAC) was conducted in 32 patients with primary resistant (11, 34%) or relapsed (21, 66%) AML. Nine (28%) patients obtained complete remission (CR), two (6%) CR with incomplete platelet recovery. Overall median survival was 5.3 months, 12-month survival rate 19%. Fourteen patients (44%) developed grade 3/4 hyperbilirubinemia; six (18%) grade 3/4 hepatic transaminitis; three (9%) hepatic veno-occlusive disease (VOD). CSA inclusion in gemtuzumab ozogamicin-based regimens is feasible. MFAC is an effective regimen for refractory AML.
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Phase II Study of Troxacitabine, a Novel Dioxolane Nucleoside Analog, in Patients with Untreated or Imatinib Mesylate-resistant Chronic Myelogenous Leukemia in Blastic Phase
Leukemia Research.
Dec, 2003 |
Pubmed ID: 12921945 A phase II study of troxacitabine, a non-natural dioxolane nucleoside L-enantiomer, was conducted in patients with chronic myelogenous leukemia in blastic phase (CML-BP). Patients were untreated for BP, or treated with imatinib mesylate (IM) as sole prior therapy for BP. Troxacitabine was given as an intravenous infusion over 30 min daily for 5 days at a dose of 8.0 mg/m(2) per day. Thirty-one patients, 29 (93%) of whom had failed prior IM therapy, received 51 courses of therapy. Grade 3 or 4 toxicities included stomatitis (4%), hand-foot syndrome (18%), and skin rash (12%). Four patients (13%) responded. Troxacitabine-based combinations merit study in IM-resistant CML.
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Clinical Relevance of Circulating Angiogenic Factors in Patients with Non-Hodgkin's Lymphoma or Hodgkin's Lymphoma
Leukemia Research.
Jun, 2004 |
Pubmed ID: 15120936 Vascular endothelial growth factor (VEGF), basic-fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and angiogenin are important angiogenic factors. In 65 patients with non-Hodgkin's lymphoma (NHL), pre-treatment VEGF, bFGF, and HGF levels were significantly elevated compared to normal individuals, while angiogenin levels were significantly subnormal. In 37 patients with Hodgkin's disease, pre-treatment levels of VEGF and HGF were significantly elevated, bFGF levels were normal, and angiogenin levels were significantly subnormal. In patients with NHL, post-therapy levels of angiogenin were independently predictive of survival. Both pre-therapy and post-therapy VEGF levels were independently predictive of survival in patients with HD.
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Effects of SU5416, a Small Molecule Tyrosine Kinase Receptor Inhibitor, on FLT3 Expression and Phosphorylation in Patients with Refractory Acute Myeloid Leukemia
Leukemia Research.
Jul, 2004 |
Pubmed ID: 15158089 Acute myeloid leukemia (AML) is associated with dysregulated hematopoietic cell proliferation and increased bone marrow angiogenesis, each regulated by signaling through receptor tyrosine kinases (RTKs). SU5416 is a small molecule inhibitor of VEGF receptors, c-kit and FLT3 and therefore provides a novel opportunity to target both angiogenesis and proliferation in AML. SU5416 was assessed in a phase II hematological malignancy trial in the US, where partial responses were observed in two of 33 patients. Since AML provides a unique platform to evaluate mechanism of action of small molecule inhibitors, investigation of the effect of SU5416 on FLT3 expression and phosphorylation in blood and bone marrow was an additional focus of this trial. Phosphorylated FLT3 was detected by immunoprecipitation/Western analysis in peripheral blood samples from 17 of 22 patients, and seven exhibited strong inhibition of phosphorylation immediately following a 1h SU5416 infusion, demonstrating that SU5416 can modulate RTK phosphorylation in humans. Although no clear correlation with clinical response was observed, analysis of patient plasma drug levels suggested that a threshold SU5416 concentration of 15 microM was associated with FLT3 inhibition. This observation was supported by data from an ex vivo model where AML cells were spiked into human blood, established to mimic the clinical setting and enable more rigorous analysis of effect of SU5416. In addition, FLT3 protein levels were downregulated in patient bone marrow samples, analyzed by an RIA assay. To identify putative predictors of response, patient plasma was analyzed for levels of secreted ligands of SU5416 targets; SCF and FLT3 ligand. Baseline levels of SCF in patients with stable or progressive disease were significantly higher than those in normal donors, whereas FLT3 ligand levels in patients who exhibited progressive disease were significantly lower than those in normal donors. The translational and clinical analyses described in this report provide some insights into the mechanism and duration of action of SU5416.
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Adaptive Randomized Study of Idarubicin and Cytarabine Alone or with Interleukin-11 As Induction Therapy in Patients Aged 50 or Above with Acute Myeloid Leukemia or High-risk Myelodysplastic Syndromes
Leukemia Research.
Jun, 2005 |
Pubmed ID: 15863204 A higher complete remission (CR) rate was observed in patients with acute myeloid leukemia (AML) who, on a prior randomized study of induction therapy, received gemtuzumab ozogamicin (GO) plus interleukin-11 (IL-11) rather than GO alone. An adaptive randomized phase III study of the addition of IL-11 to idarubicin and cytarabine (IA) induction in 100 patients >/=50 years of age with AML or high-risk myelodysplastic syndrome (MDS) was conducted. Median patient age was 67 years (range 50-82). Twenty-four of the 45 (53%) patients randomized to IA plus IL-11 achieved CR. Eight (33%) subsequently relapsed, 4 (17%) died in CR; median time to treatment failure (TTF) was 37 weeks. Twenty-nine of the 55 (53%) patients treated without IL-11 achieved CR. Eight (28%) subsequently relapsed, 2 (7%) died in CR; median TTF was 46 weeks. Median overall survivals were 21 and 59 weeks for the IA plus IL-11 and IA cohorts, respectively (p=0.271, log rank test; 0.435, Gehan-Breslow test). Ten episodes of the following grade 3 or 4 cardiopulmonary toxicities were observed in patients receiving IA plus IL-11, 12 such episodes in those receiving IA alone: atrial fibrillation, pleural effusions, myocardial infarction, bradycardia or hypotension. Two patients in each arm experienced grade 3 peripheral edema. There was no significant difference in incidence of any grade 3 or 4 adverse event, including thrombocytopenia, between treatment arms. There was no significant impact on CR rates, TTF, survival, or toxicity of adding an IL-11 regimen to IA induction in patients >/=50 years of age with AML.
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Angiogenic Factors May Have a Different Prognostic Role in Adult Acute Lymphoblastic Leukemia
Blood.
Dec, 2005 |
Pubmed ID: 16123221 Angiogenesis plays an important role in solid tumors and hematologic malignancies. The prognostic significance of angiogenic factors in adult acute lymphoblastic leukemia (ALL) remains ambiguous. We therefore analyzed the impact of angiogenic factor levels on overall survival of newly diagnosed adult ALL patients. Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-1 receptor alpha (IL-1Ralpha), IL-6, IL-8, VEGF receptors VEGFR1 and VEGFR2, and thrombopoietin (TPO) were measured in plasma samples of 95 patients by enzyme-linked immunosorbent assay (ELISA). In a univariate Cox proportional hazards model, higher levels of IL-1Ralpha, IL-8, VEGFR1, and VEGFR2 were predictive of poor survival. In contrast, higher levels of VEGF were predictive of longer survival, and higher levels of bFGF suggested a similar trend (P = .09). The multivariate model simultaneously included VEGF (relative risk [RR] for death, 8.01; P = .001 for levels less than or equal to 19.5 pg/mL), IL-1Ralpha (RR, 5.12; P = .007 for levels greater than 373 pg/mL), and VEGFR2 (RR, 4.01; P = .04 for levels greater than 8222 pg/mL) as independent factors for survival. Of interest is the association of high levels of VEGF with good prognosis and higher levels of VEGF receptors with poor outcome. These data reflect the complexity by which angiogenic factors may affect the clinical behavior of patients with ALL, and this complexity should be considered in any therapeutic strategy incorporating antiangiogenic agents.
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Mammalian Target of Rapamycin As a Therapeutic Target in Leukemia
Current Molecular Medicine.
Nov, 2005 |
Pubmed ID: 16305491 Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.
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Clinical Relevance of Soluble HLA-I and Beta2-microglobulin Levels in Non-Hodgkin's Lymphoma and Hodgkin's Disease
Leukemia Research.
Feb, 2007 |
Pubmed ID: 16545870 Plasma levels of beta-2 microglobulin (beta2M), a subunit of the human leukocyte antigen-class I (HLA-I) molecule, correlate negatively with outcome in non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). We examined the clinical relevance of soluble HLA-I (sHLA-I) levels in NHL and HD. Sera from consecutive NHL (n=65) and HD (n=37) patients were analyzed in a blinded manner. NHL and HD patients had significantly higher levels of sHLA-1 and beta2M than control subjects. In NHL patients, sHLA-I levels correlated with clinical behavior in a fashion similar to that of beta2M. However, multivariate analysis incorporating beta2M, sHLA-I, and international prognostic index (IPI) indicated that NHL patients with elevated (>312.6mug/100mL) sHLA-I levels had significantly shorter survival, independent of IPI score as well as beta2M. In HD patients, beta2M but not sHLA-I levels were associated with clinical behavior. These findings not only establish the role of sHLA-I as an independent tumor marker in NHL that can be used to stratify patients, but also suggest that beta2M and sHLA-I may reflect different biological processes in HD and NHL. Further studies are needed to assess whether the immunomodulatory properties of sHLA-I may be responsible for its divergence from beta2M as an indicator of clinical behavior in HD.
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PTK787/ZK 222584, a Small Molecule Tyrosine Kinase Receptor Inhibitor of Vascular Endothelial Growth Factor (VEGF), Has Modest Activity in Myelofibrosis with Myeloid Metaplasia
Leukemia Research.
Jul, 2007 |
Pubmed ID: 17560285 Angiogenesis is part of the pathophysiology of myelofibrosis with myeloid metaplasia (MMM). PTK787/ZK 222584 (PTK/ZK) is a novel inhibitor of vascular endothelial growth factor receptors. Twenty-nine patients with MMM received a continuous dosing schedule of PTK/ZK doses of 500 or 750 mg twice daily (BID). Transient potentially PTK/ZK related mild nausea, vomiting, dizziness, fatigue, thrombocytopenia, or anorexia occurred in 15% of patients. Dose limiting toxicities of dyspepsia, proteinurea, and/or mucositis were observed in patients treated with 750 mg BID. One (3%) and five (17%) patients achieved complete remission and clinical improvement, respectively. PTK/ZK has modest activity in patients with MMM.
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Plasma-based Testing As a New Paradigm for Clinical Testing in Hematologic Diseases
Expert Review of Molecular Diagnostics.
Sep, 2007 |
Pubmed ID: 17892367 Recent advances in molecular biology have paved the way for the detection of minute quantities of cellular components with robust assays that are amenable for use in clinical laboratories. This review discusses the recently developed series of plasma-based assays that are changing the testing paradigm for hematologic diseases. These tests are based on the concept that a high turnover of neoplastic hematologic cells, relative to normal cells, enriches plasma with tumor-specific DNA, RNA and protein. Plasma-based testing promises to reduce the need for bone marrow biopsy, allow for more frequent and accurate monitoring of changes in bone marrow, allow the detection of more aggressive subclones of the malignant cells and provide a more quantitative means to measure the load of the malignant clone. We present data demonstrating that plasma, in some situations, allows even more sensitive detection than bone marrow cells. Moreover, the lessened impact of dilution by normal cells in plasma permits a distinction between homozygous and hemizygous abnormalities. Unlike solid tumors, currently available data suggest that in hematologic diseases, plasma is superior to cells in detecting molecular abnormalities.
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A Potential Role for HSP90 Inhibitors in the Treatment of JAK2 Mutant-positive Diseases As Demonstrated Using Quantitative Flow Cytometry
Leukemia & Lymphoma.
Nov, 2007 |
Pubmed ID: 17926180 The V617F mutation of the JAK2 tyrosine kinase is found in a majority of patients with myeloproliferative disorders. Flow cytometry assays for quantitation of phosphorylated and total protein for JAK2, STAT5, and heat shock proteins (HSPs) were developed to facilitate the study of the JAK/STAT pathway. A cell line homozygous for V617F (HEL) was treated with inhibitors of JAK2 tyrosine kinase activity and the HSP90 inhibitor 17-AAG. 17-AAG reduced HSP90 levels, but increased HSP70 levels. Phospho-STAT5, total STAT5, and total AKT levels were also reduced by 17-AAG treatment. Further, phospho-JAK2, total JAK2, and cell viability were reduced to a greater extent by 17-AAG than by the pan-JAK kinase family inhibitor JKII or the JAK2-specific inhibitor AG490, and these inhibitors failed to synergize with 17-AAG. Flow-cytometry-based assays for JAK/STAT signaling pathway and HSPs are likely to have broad clinical utility for monitoring patients with abnormalities in the JAK2 pathway.
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Cell-free Bead-based Detection of Total and Phosphorylated Proteins in Plasma and Cell Lysates: Detection of FLT3
Methods in Molecular Biology (Clifton, N.J.).
2007 |
Pubmed ID: 18605083 Frequently direct measurement of proteins or their phosphorylation in intact cells is not possible, for instance, when cells are too few, frozen, or subject to degradation. We have demonstrated that tumor cells pour their DNA, RNA, and protein content into circulation because of turnover and breakdown of cell structures. Proteins in solution most likely circulate as complexes, which protects them from degradation. We describe a cell-free, bead-based method that takes advantage of this phenomenon. Our approach is based on immunoprecipitation of the protein of interest on the surface of beads, followed by detection of the protein or its modification (phosphorylation) using a secondary antibody labeled with phycoerythrin at a 1:1 ratio. Fms-like tyrosine kinase-3, which is mutated in majority of cases of acute myeloid leukemia, is used as an example. This method could be applied to the quantitation of several other proteins without the need for intact cells.
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Kit Inhibitor APcK110 Induces Apoptosis and Inhibits Proliferation of Acute Myeloid Leukemia Cells
Cancer Research.
May, 2009 |
Pubmed ID: 19383925 Kit is a membrane-bound tyrosine kinase and receptor for stem cell factor (SCF) with a crucial role in hematopoiesis. Mutations of KIT occur in almost half of patients with core-binding factor leukemias, in which they have been associated with worse outcome. Development of new compounds targeting Kit may therefore hold promise for therapy. We investigated the activity and mechanism of action of APcK110, a novel Kit inhibitor, in the mastocytosis cell line HMC1.2 (KITV560G and KITD816V), acute myeloid leukemia (AML) lines OCIM2 and OCI/AML3 (both wild-type), and primary samples from patients with AML. We show that (a) APcK110 inhibits proliferation of the mastocytosis cell line HMC1.2 and the SCF-responsive cell line OCI/AML3 in a dose-dependent manner; (b) APcK110 is a more potent inhibitor of OCI/AML3 proliferation than the clinically used Kit inhibitors imatinib and dasatinib and at least as potent as cytarabine; (c) APcK110 inhibits the phosphorylation of Kit, Stat3, Stat5, and Akt in a dose-dependent fashion, showing activity of APcK110 on Kit and its downstream signaling pathways; (d) APcK110 induces apoptosis by cleavage of caspase-3 and poly(ADP-ribose) polymerase; and (e) APcK110 inhibits proliferation of primary AML blasts in a clonogenic assay but does not affect proliferation of normal colony-forming cells. Although APcK110 activity may partly depend on cytokine responsiveness (e.g., SCF) and not exclusively KIT mutation status, it remains a potent inhibitor of AML and mastocytosis cell lines and primary AML samples. APcK110 and similar compounds should be evaluated in clinical trials of patients with AML.
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Phase 3 Randomized, Placebo-controlled, Double-blind Study of High-dose Continuous Infusion Cytarabine Alone or with Laromustine (VNP40101M) in Patients with Acute Myeloid Leukemia in First Relapse
Blood.
Nov, 2009 |
Pubmed ID: 19710500 Laromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m(2) per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m(2) (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.
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Structural Effects of Clinically Observed Mutations in JAK2 Exons 13-15: Comparison with V617F and Exon 12 Mutations
BMC Structural Biology.
Sep, 2009 |
Pubmed ID: 19744331 The functional relevance of many of the recently detected JAK2 mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked. To explore atomic-level explanations of the possible mutational effects from those overlooked mutants, we performed a set of molecular dynamics simulations on clinically observed mutants, including newly discovered mutations (K539L, R564L, L579F, H587N, S591L, H606Q, V617I, V617F, C618R, L624P, whole exon 14-deletion) and control mutants (V617C, V617Y, K603Q/N667K).
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Evidence of Serum Immunoglobulin Abnormalities Up to 9.8 Years Before Diagnosis of Chronic Lymphocytic Leukemia: a Prospective Study
Blood.
Dec, 2009 |
Pubmed ID: 19828698 Immune-related deficiencies are well-known complications of chronic lymphocytic leukemia (CLL). Although recent data indicate that almost all CLL patients are preceded by a monoclonal B-cell lymphocytosis precursor state, patterns of immune defects preceding CLL diagnosis are unclear. We identified 109 persons who developed CLL from the prospective and nationwide Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial with 77 469 participants, with serially collected prediagnostic serum samples. We assayed monoclonal (M)-proteins, kappa/lambda free light chains (FLCs) in prediagnostic obtained up to 9.8 years before CLL diagnosis. The prevalence of an abnormal FLC ratio, M-protein, and hypogamma-globulinemia before CLL diagnosis was 38% (95% confidence interval, 29%-47%), 13% (7%-21%), and 3% (1%-8%), respectively. M-proteins and abnormal FLC ratios were detected up to 9.8 years before CLL diagnosis in a total of 48 persons (44%). Hypogammaglobulinemia was not present until 3 years before the diagnosis of CLL. Among 37 patients with information on tumor cell immunophenotype, an association between immunophenotype and involved FLC (P = .024, Fisher exact test) was observed. Among 61 persons with a normal FLC ratio and without an M-protein, 17 had elevated kappa and/or lambda FLC levels, indicating polyclonal B-cell activation in 17 of 109 (16%) patients. These findings support a role for chronic immune stimulation in CLL genesis.
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Clinical Correlation of Circulating Heat Shock Protein 70 in Acute Leukemia
Leukemia Research.
May, 2010 |
Pubmed ID: 19800118 The heat shock protein 70 (HSP70) is one of the molecular chaperone family involved in the protection of cells upon exposure to various types of stresses. Plasma circulating HSP70 (cHSP70) is believed to play a role in the anti-tumor immune responses and its levels may reflect the levels of severity or the disease condition. Using electrochemiluminescence protein detection immunoassay, we measured the cHSP70 levels in the plasma of patients with acute myeloid leukemia (AML) (n=96), myelodysplastic syndrome (MDS) (n=28), and acute lymphoblastic leukemia (ALL) (n=40) and compared with those in normal individuals (n=99). cHSP70 levels were significantly higher in AML (median: 10.71 ng/mL, range: 1.93-79.0 ng/mL) and ALL (median: 27.59 ng/mL, range: 5.09-129.6 ng/mL) as compared to those in MDS (median: 4.54 ng/mL, range: 1.35-58.3 ng/mL) or healthy controls (median: 4.13 ng/mL, range: 1.75-13.6 ng/mL). Levels of cHSP70 showed significant positive correlation with lactate dehydrogenase (LDH) and white blood cells (WBC) in AML and ALL patients, which may reflect overall tumor load. Furthermore, patients with higher levels of cHSP70 had significantly shorter survival in AML (P=0.04) and ALL (P=0.05), suggesting that in these two acute diseases, cHSP70 is an indicator for poor prognosis. Our data support the potential of using free cHSP70 as a biomarker in leukemias and potentially other types of cancers.
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Circulating CD52 and CD20 Levels at End of Treatment Predict for Progression and Survival in Patients with Chronic Lymphocytic Leukaemia Treated with Fludarabine, Cyclophosphamide and Rituximab (FCR)
British Journal of Haematology.
Feb, 2010 |
Pubmed ID: 19895616 CD52 and CD20 antigens are important therapeutic targets for the monoclonal antibodies (mAbs) alemtuzumab and rituximab respectively. Circulating CD52 (cCD52) and CD20 (cCD20) have prognostic utility in lymphoid malignancies. The efficacy of mAb therapy in patients with chronic lymphocytic leukaemia (CLL) may be adversely affected by cCD52 or cCD20. In this report, blood and bone marrow (BM) cCD52 and cCD20 were measured at response assessment in previously treated (N = 235) patients with CLL who received fludarabine, cyclophosphamide, and rituximab (FCR). Univariate and multivariate statistical models evaluated correlations of pre- and response variables with progression-free (PFS) and overall survival (OS). Response variables included 1996 National Cancer Institute-Working Group (NCI-WG) response, polymerase chain reaction (PCR) for immunoglobulin heavy chain (IGHV) in BM, and cCD52 and cCD20 levels (blood and BM) at response assessment. Using multivariate analysis, response blood and BM cCD52, blood cCD20, and NCI-WG response were significant independent predictors of PFS. At the time of response assessment, BM cCD52 correlated with OS in univariate analysis. cCD52 and cCD20, therefore appear useful in predicting survival and may be important for monitoring patients following salvage FCR (fludarabine, cyclophosphamide, rituximab) therapy. These data further indicate that plasma may be a good target to evaluate for minimal residual disease using cCD52/cCD20 levels.
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Single-agent Laromustine, a Novel Alkylating Agent, Has Significant Activity in Older Patients with Previously Untreated Poor-risk Acute Myeloid Leukemia
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology.
Feb, 2010 |
Pubmed ID: 20026800 PURPOSE An international phase II study of laromustine (VNP40101M), a sulfonylhydrazine alkylating agent, was conducted in patients age 60 years or older with previously untreated poor-risk acute myeloid leukemia (AML). PATIENTS AND METHODS Laromustine 600 mg/m(2) was administered as a single 60-minute intravenous infusion. Patients were age 70 years or older or 60 years or older with at least one additional risk factor-unfavorable AML karyotype, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, and/or cardiac, pulmonary, or hepatic comorbidities. Results Eighty-five patients (median age, 72 years; range, 60 to 87 years) were treated. Poor-risk features included age 70 years or older, 78%; adverse karyotype, 47%; PS of 2, 41%; pulmonary disease, 77%; cardiac disease, 73%; and hepatic disease, 3%. Ninety-six percent of patients had at least two risk factors, and 39% had at least four risk factors. The overall response rate (ORR) was 32%, with 20 patients (23%) achieving complete response (CR) and seven (8%) achieving CR with incomplete platelet recovery (CRp). ORR was 20% in patients with adverse cytogenetics; 32% in those age 70 years or older; 32% in those with PS of 2; 32% in patients with baseline pulmonary dysfunction; 34% in patients with baseline cardiac dysfunction; and 27% in 33 patients with at least four risk factors. Twelve (14%) patients died within 30 days of receiving laromustine therapy. Median overall survival was 3.2 months, with a 1-year survival of 21%; the median duration of survival for those who achieved CR/CRp was 12.4 months, with a 1-year survival of 52%. CONCLUSION Laromustine has significant single-agent activity in elderly patients with poor-risk AML. Adverse events are predominantly myelosuppressive or respiratory. Response rates are consistent across a spectrum of poor-risk features.
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Tanespimycin Monotherapy in Relapsed Multiple Myeloma: Results of a Phase 1 Dose-escalation Study
British Journal of Haematology.
Aug, 2010 |
Pubmed ID: 20618337 Tanespimycin, a heat shock protein 90 (HSP90) inhibitor, induces apoptosis in drug-sensitive and -resistant MM cell lines and in tumour cells from patients with relapsed MM. In this phase 1 dose-escalation study, the safety, plasma pharmacokinetics, and biological/antitumour activity of tanespimycin were evaluated in heavily pretreated patients with relapsed/refractory MM. Tanespimycin (150-525 mg/m(2)) was given on days 1, 4, 8, and 11 of each 3-week cycle for up to 8 cycles. Non-haematological AEs included diarrhoea (59%), back pain (35%), fatigue (38%), and nausea (35%); haematological AEs included anaemia (24%) and thrombocytopenia (21%). One patient (3%) achieved minimal response (MR), with a progression-free survival (PFS) of 3 months, a 41% decrease from baseline in urine M protein, and a 33% decrease from baseline in serum M protein. Fifteen patients (52%) achieved SD with a median PFS of 2.1 months; 5/15 had reductions in serum M protein ranging from 7% to 38% and in urine M protein ranging from 6% to 91%. Mean HSP70 levels increased from day 1 h 0 to day 1 h 4 with further increases on day 11 h 0 and day 11 h 4, consistent with a therapeutic treatment effect. Tanespimycin monotherapy was well tolerated and demonstrated activity across all doses tested.
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Tanespimycin with Bortezomib: Activity in Relapsed/refractory Patients with Multiple Myeloma
British Journal of Haematology.
Aug, 2010 |
Pubmed ID: 20618338 Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open-label multicentre study, we compared 1.3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource-based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.
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MPL Mutation Profile in JAK2 Mutation-negative Patients with Myeloproliferative Disorders
Diagnostic Molecular Pathology : the American Journal of Surgical Pathology, Part B.
Mar, 2011 |
Pubmed ID: 21326037 Mutations in the thrombopoietin receptor gene (myeloproliferative leukemia, MPL) have been reported in patients with JAK2 V617F-negative chronic myeloproliferative disorders (MPDs). We evaluated the prevalence of MPL mutations relative to JAK2 mutations in patients with suspected MPDs. A total of 2790 patient samples submitted for JAK2 mutation analysis were tested using real-time polymerase chain reaction and bidirectional sequencing of plasma RNA. JAK2 V617F-negative samples were tested for JAK2 exons 12 to 14 mutations, and those with negative results were then tested for mutations in MPL exons 10 and 11. Of the 2790 patients, 529 (18.96%) had V617F, 12 (0.43%) had small insertions or deletions in exon 12, and 7 (0.25%) had other JAK2 mutations in exons 12 to 14. Of the 2242 JAK2 mutation-negative patients, 68 (3.03%) had MPL mutations. W515L was the predominant MPL mutation (n=46; 68%), and 10 (15%) patients had other W515 variants. The remaining MPL mutations (n=12, 17%) were detected at other locations in exons 10 and 11 and included 3 insertion/deletion mutations. The S505N mutation, associated with familial MPD, was detected in 3 patients. Overall, for every 100 V617F mutations in patients with suspected MPDs, there were 12.9 MPL mutations, 2.3 JAK2 exon 12 mutations, and 1.3 JAK2 exons 13 to 14 mutations. These findings suggest that MPL mutation screening should be performed before JAK2 exons 12 to 14 testing in JAK2 V617F-negative patients with suspected MPDs.
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Exon Scanning by Reverse Transcriptase-polymerase Chain Reaction for Detection of Known and Novel EML4-ALK Fusion Variants in Non-small Cell Lung Cancer
Cancer Genetics.
Jan, 2011 |
Pubmed ID: 21356191 Chromosomal inversions within chromosome 2p, resulting in fusions between the echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes, are a recent focus of treatment options for non-small cell lung cancer. Thirteen EML4-ALK fusion variants have been identified, affecting eight EML4 exons. We have developed an exon scanning approach using multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) to amplify known and potential variants involving the first 22 EML4 exons. A total of 55 formalin-fixed, paraffin-embedded lung cancer tumors were screened, of which 5 (9%) were positive for EML4-ALK fusions. Four positive cases harbored known fusion variants: variant 3a, 3b, or both in three cases and variant 1 in one case. The fifth positive specimen harbored two novel variants, designated 8a and 8b, involving exon 17 of EML4. Fluorescence in situ hybridization confirmed the presence of EML4-ALK fusions in three of the four RT-PCR-positive specimens with sufficient tissue for examination, and also confirmed absence of fusions in all 19 RT-PCR-negative specimens tested. Immunohistochemistry analysis confirmed ALK protein expression in the sample containing the novel 8a and 8b variants. This RT-PCR-based exon scanning approach avoids the limitations of screening only for previously identified EML4-ALK fusions and provides a simple molecular assay for fusion detection in a clinical diagnostics setting.
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Diagnostic and Prognostic Scoring System for Prostate Cancer Using Urine and Plasma Biomarkers
Genetic Testing and Molecular Biomarkers.
Mar, 2014 |
Pubmed ID: 24512523 To avoid relying solely on serum prostate-specific antigen (sPSA) in screening for prostate cancer (PCa), we developed a scoring system for detecting PCa and the prediction of aggressiveness. We analyzed urine and plasma specimens from 121 patients with PCa or benign prostatic hyperplasia (BPH) for the levels of UAP1, PDLIM5, IMPDH2, HSPD1, PCA3, PSA, TMPRSS2, ERG, GAPDH, and B2M genes. Patient age, sPSA level, and polymerase chain reaction data were entered through multiple algorithms to determine models most useful for the detection of cancer and predicting aggressiveness.
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Clonal Evolution Leading to Ibrutinib Resistance in Chronic Lymphocytic Leukemia
Blood.
Mar, 2017 |
Pubmed ID: 28049639 Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in BTK and PLCG2. The rate of resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry, TP53 aberration, advanced Rai stage, and high β-2 microglobulin were independently associated with inferior progression-free survival (P < .05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations in BTK (Cys481) and/or PLCG2 (within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying high-sensitivity testing (detection limit ∼1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
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