Posted by rob on March 11, 2010 under Uncategorized | 
Conclusion
Treatment with IFN enables discontinuation of imatinib in most patients after prior imatinib/IFN combination therapy and may result in improved molecular response. Induction of a proteinase-3–specific CTL response by IFN may contribute to this effect. (Source: Journal of Clinical Oncology)
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Highly Phosphorylated FOXO3A Is an Adverse Prognostic Factor in Acute Myeloid Leukemia.
Clin Cancer Res. 2010 Mar 9;
Authors: Kornblau SM, Singh N, Qiu Y, Chen W, Zhang N, Coombes KR
PURPOSE: The Forkhead transcription factors (FOXO) are tumor suppressor genes regulating differentiation, metabolism, and apoptosis that functionally interact with signal transduction pathways shown to be deregulated and prognostic in acute myelogenous leukemia (AML). This study evaluated the level of expression and the prognostic relevance of total and phosphorylated FOXO3A protein in AML. EXPERIMENTAL DESIGN: We used reverse-phase protein array methods to measure the level of total and phosphoprotein expression of FOXO3A, in leukemia-enriched protein samples from 511 newly diagnosed AML patients. RESULTS: The expression range was similar to normal CD34+ cells and similar in blood and marrow. Levels of total FOXO3A were higher at relapse compared with diagnosis. Levels of pFOXO3A or the ratio of phospho to total (PT) were not associated with karyotpe but were higher in patients with FLT3 mutations. Higher levels of pFOXO3A or PT-FOXO3A were associated with increased proliferation evidenced by strong correlation with higher WBC, percent marrow, and blood blasts and by correlation with higher levels of Cyclins B1, D1 and D3, pGSK3, pMTOR, and pStat5. Patients with High levels of pFOXO3A or PT-FOXO3A had higher rates of primary resistance and shorter remission durations, which combine to cause an inferior survival experience (P = 0.0002). This effect was independent of cytogenetics. PT-FOXO3A was a statistically significant independent predictor in multivariate analysis. CONCLUSIONS: High levels of phosphorylation of FOXO3A is a therapeutically targetable, independent adverse prognostic factor in AML. Clin Cancer Res; 16(6); 1865-74.
PMID: 20215543 [PubMed - as supplied by publisher]
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Antineoplastic Mechanisms of Niclosamide in Acute Myelogenous Leukemia Stem Cells: Inactivation of the NF-{kappa}B Pathway and Generation of Reactive Oxygen Species.
Cancer Res. 2010 Mar 9;
Authors: Jin Y, Lu Z, Ding K, Li J, Du X, Chen C, Sun X, Wu Y, Zhou J, Pan J
NF-kappaB may be a potential therapeutic target for acute myelogenous leukemia (AML) because NF-kappaB activation is found in primitive human AML blast cells. In this report, we initially discovered that the potent antineoplastic effect of niclosamide, a Food and Drug Administration-approved antihelminthic agent, was through inhibition of the NF-kappaB pathway in AML cells. Niclosamide inhibited the transcription and DNA binding of NF-kappaB. It blocked tumor necrosis factor-induced IkappaBalpha phosphorylation, translocation of p65, and expression of NF-kappaB-regulated genes. Niclosamide inhibited the steps TAK1–>IkappaB kinase (IKK) and IKK–>IkappaBalpha. Niclosamide also increased the levels of reactive oxygen species (ROS) in AML cells. Quenching ROS by the glutathione precursor N-acetylcysteine attenuated niclosamide-induced apoptosis. Our results together suggest that niclosamide inhibited the NF-kappaB pathway and increased ROS levels to induce apoptosis in AML cells. On translational study of the efficacy of niclosamide against AML, niclosamide killed progenitor/stem cells from AML patients but spared those from normal bone marrow. Niclosamide was synergistic with the frontline chemotherapeutic agents cytarabine, etoposide, and daunorubicin. It potently inhibited the growth of AML cells in vitro and in nude mice. Our results support further investigation of niclosamide in clinical trials of AML patients. Cancer Res; 70(6); 2516-27.
PMID: 20215516 [PubMed - as supplied by publisher]
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A gene expression signature of primary resistance to imatinib in chronic myeloid leukemia.
Leuk Res. 2010 Feb;34(2):254-7
Authors: de Lavallade H, Finetti P, Carbuccia N, Khorashad JS, Charbonnier A, Foroni L, Apperley JF, Vey N, Bertucci F, Birnbaum D, Mozziconacci MJ
Using gene expression profiling we show that the expression of 105-probe sets in mononuclear cells collected from chronic myeloid leukemia (CML) chronic phase (CP) patients with raised leukocyte counts who subsequently achieved complete cytogenetic response after 12 months on imatinib, differed substantially from that of patients who failed to achieve any degree of cytogenetic response. In the non-responder cohort, 9 of the 50 overexpressed genes were involved in DNA repair by homologous recombination, whereas 36 genes, including PTEN, were downregulated. This pattern of altered gene expression in responders and non-responders was validated in another independent dataset. These findings may prove useful for identifying at the time of diagnosis a subset of CP-CML patients who are likely to be resistant to imatinib and require an alternative treatment.
PMID: 19880181 [PubMed - indexed for MEDLINE]
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Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia.
Leuk Res. 2010 Feb;34(2):129-34
Authors: Breccia M, Alimena G
Imatinib mesylate is currently the standard of care for chronic myeloid leukemia (CML) patients in early chronic phase. However, the emergence of resistance and intolerance has dampened the enthusiasm for this drug. To overcome this phenomenon, different strategies have been developed, including novel targeted agents. Nilotinib, formerly known as AMN107, is a second-generation tyrosine kinase inhibitor 30-fold more potent than imatinib, with high affinity and selectivity on BCR/ABL, and also active against a wide range of mutant clones, except T315I mutation. Phase II trials of nilotinib showed high activity in imatinib-resistant or intolerant CML patients, whereas front-line treatment of the disease in chronic phase demonstrated rapid and stable cytogenetic responses and increasing molecular responses. We here review the development of nilotinib and the efficacy data in phase II and front-line trials. The aim of this review is to evaluate the pharmacology, pharmacokinetic and pharmacodynamic properties of the drug and the recent results of clinical trials performed in patients with CML and Ph+ acute lymphoblastic leukemia (ALL).
PMID: 19783301 [PubMed - indexed for MEDLINE]
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Imatinib achieved complete cytogenetic response in a CML patient received 32-year indirubin and its derivative treatment.
Leuk Res. 2010 Feb;34(2):e75-7
Authors: Chen F, Li L, Ma D, Yan S, Sun J, Zhang M, Ji C, Hou M
PMID: 19773083 [PubMed - indexed for MEDLINE]
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Response to Imatinib mesylate in chronic myeloid leukemia patients with variant BCR-ABL fusion transcripts.
Ann Hematol. 2010 Mar;89(3):241-7
Authors: Sharma P, Kumar L, Mohanty S, Kochupillai V
Chronic myeloid leukemia patients with different BCR-ABL transcripts might respond differently to Imatinib mesylate. This prompted us to study BCR-ABL transcripts in chronic myeloid leukemia (CML) patients and their correlation with response to Imatinib. Eighty-seven chronic phase CML patients (median age, 35 years; range, 13-62 years; M/F, 59:28) were included in this study; 57 patients had received interferon-alpha and/or hydroxyurea, and 30 were previously untreated. All patients received Imatinib mesylate (Gleevec) 400 mg daily. Complete hematological remission rate and major cytogenetic response (CGR) rates were 99% and 72%, respectively. B3a2 transcript was present in 53% of patients, b2a2 in 39%, and both transcripts in 8% of patients. Twenty of 34(59%) patients with b2a2 type achieved complete CGR compared to 15 of 53 (28%) patients with b3a2, p = 0.04. Among 24 patients with minor or no CGR, six (25%) had b2a2 compared to 18 (75%) b3a2 type, p = 0.04. Expression of BCR-ABL/ABL% was higher in b3a2 patients compared to b2a2, p = 0.120. Pre-treatment characteristics-mean spleen size (6.6 vs. 6.4 cm, p = 0.868), mean hemoglobin (G/dl; 12.0 vs. 11.8, p = 0.690), mean WBC count (83 x 10(9) vs. 77 x 10(9)/L, p = 0.923), and mean platelets counts (360×10(9) vs. 340 x 10(9)/L, p = 0.712)-were not significantly different in the b3a2 vs. b2a2 transcripts groups. Our preliminary findings suggest that CML patients with b2a2 BCR-ABL transcript might have higher CGRs to Imatinib mesylate (Gleevec).
PMID: 19714331 [PubMed - indexed for MEDLINE]
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TKIs and transplant for chronic myeloid leukemia.
Leuk Res. 2010 Feb;34(2):137-8
Authors: Litzow MR
PMID: 19651441 [PubMed - indexed for MEDLINE]
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BCR-ABL transcripts are not detected in cord blood or the peripheral blood of the newborn child whose mother developed chronic myeloid leukemia while pregnant.
Leuk Res. 2010 Feb;34(2):e78-81
Authors: Salomon O, Tohami T, Trakhtenbrot L, Meirov R, Kneller A, Berkowitz M, Nagler A, Sivan E, Goldman JM, Rechavi G, Amariglio N
BACKGROUND AND OBJECTIVES: The treatment of choice for the pregnant woman with CML has not been defined. Exposure to imatinib while pregnant may cause serious fetal malformations and interferon-alpha is sometimes associated with side effects. Furthermore, little is known of the possibility that BCR/ABL-positive cells might be passed to the fetus and the role of the treatment given to the pregnant mother. DESIGN AND METHODS: Detection of BCR-ABL transcripts in the peripheral blood of the mother, the newborn and the cord blood was performed by quantitative real time PCR and FISH. RESULTS: A patient with CML diagnosed at the beginning of pregnancy was treated with leukapheresis at 31 weeks of gestation until delivery without any untoward effects. Since no tyrosine kinase inhibitor was administered BCR-ABL transcripts contamination of the cord blood and peripheral blood of the newborn was a reasonable concern. In practice no transcripts were detected in the cord blood or in the peripheral blood of the newborn at birth, at 1 month or 3 at months of age despite the fact that throughout her pregnancy and on the day of delivery the mother had 90% BCR/ABL positive cells in her blood. INTERPRETATION AND CONCLUSIONS: Leukapheresis does not eliminate the malignant clone; however the absence of BCR-ABL transcripts in the peripheral blood of the neonate and in the cord blood supports the view that transmission of CML to a fetus is improbable even if the mother’s treatment during pregnancy is suboptimal.
PMID: 19640586 [PubMed - indexed for MEDLINE]
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Second-generation tyrosine kinase inhibitors before allogeneic stem cell transplantation in patients with chronic myeloid leukemia resistant to imatinib.
Leuk Res. 2010 Feb;34(2):143-7
Authors: Breccia M, Palandri F, Iori AP, Colaci E, Latagliata R, Castagnetti F, Torelli GF, Usai S, Valle V, Martinelli G, Rosti G, Foà R, Baccarani M, Alimena G
Philadelphia-positive chronic myeloid leukemia (Ph+ CML) patients who are resistant to imatinib are commonly treated with second-generation tyrosine kinase inhibitors (TKIs). Limited data exist on the possible effects of these drugs on subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT).The outcome of 12 imatinib-resistant CML patients treated with dasatinib or nilotinib or both before allo-HSCT, was retrospectively analyzed. Patients were treated with second-generation TKIs for 1-17 months (median, 8). At the time of transplant, 3 patients were in complete cytogenetic response (CCgR), 3 patients in partial cytogenetic response (PCgR) and 6 patients were in less than PCgR. Donors were HLA-matched related in 4 cases and unrelated in 8 cases. Stem cell source was peripheral blood, bone marrow or cord blood in 6, 5 and 1 cases, respectively. All patients engrafted successfully and all but one achieved a full donor chimerism. Three patients experienced acute and chronic graft-versus-host disease. No cases of transplant-related mortality were recorded. Best response to allo-HSCT was complete molecular response (CMR) in 9 patients, major molecular response (MMR) in 1 patient and CCgR in 2 patients. Median follow-up was 16.5 months. At the last evaluation, 9 patients were in continuous CMR and 1 patient was in MMR; 2 patients had died of disease progression. Second-generation TKIs given before allo-HSCT do not negatively affect transplant engraftment and response rate, nor increases transplant-related toxicity.
PMID: 19481800 [PubMed - indexed for MEDLINE]
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