Posted by rob on February 7, 2010 under Uncategorized | 
Acquired resistance through genetic mutations is a common phenomenon in several cancer therapies using molecularly targeted drugs, best exemplified by the BCR-ABL inhibitor imatinib in treating chronic myelogenous leukemia (CML). Overcoming acquired resistance is a daunting therapeutic challenge, and little is known about how these mutations evolve. To facilitate understanding the resistance mechanisms, we developed a novel culture model for CML acquired resistance in which the CML cell line KCL-22, following initial response to imatinib, develops resistant T315I BCR-ABL mutation. We demonstrate that the emergence of BCR-ABL mutations do not require pre-existing BCR-ABL mutations derived from the original patient as the subclones of KCL-22 cells can form various BCR-ABL mutations upon imat…
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Drug costs and utilization after implementation of a posaconazole prophylaxis protocol in adults with acute myelogenous leukemia.
Am J Health Syst Pharm. 2010 Feb 15;67(4):295-9
Authors: Nemerovski CW, Mackler ER, Depestel DD, Collins CD, Welch KS, Stevenson JG
Purpose Drug costs and utilization after implementation of a posaconazole prophylaxis protocol in adults with acute myelogenous leukemia (AML) were studied. Methods Adult patients who initiated induction or reinduction chemotherapy for the treatment of AML between December 1, 2006, and March 31, 2008, at a tertiary care hospital were included in this retrospective cohort study. Patients were divided into two groups: preprotocol (treated before June 1, 2007) and postprotocol (treated on or after June 1, 2007). Medical charts, including pharmacy and laboratory data, were reviewed for all patients. Outcomes measured included antifungal and antibacterial drug costs and utilization and total pharmacy costs. Results A total of 66 patients were evaluated (33 in each group). Baseline characteristics, except patient age, were similar between groups. Each group incurred similar costs and utilized resources for similar periods of time as evidenced by similar lengths of stay, duration of neutropenia, and mortality. Antibacterial costs, total pharmacy costs, and other utilization outcomes were also similar between the two groups. Alterations to antifungal management strategy occurred more often in the postprotocol group (33% versus 58%, p = 0.048). Conclusion Implementation of a posaconazole protocol did not significantly alter antifungal or antibacterial drug costs or utilization or total pharmacy costs. Prophylactic posaconazole was frequently changed to alternative antifungal therapy due to an adverse drug event, perceived lack of efficacy, avoidance of a drug interaction, or inability to tolerate oral intake.
PMID: 20133535 [PubMed - in process]
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Whither the bone marrow transplant?
Hematology. 2010 Feb;15(1):1-3
Authors: Ruiz-Argüelles GJ
Bone marrow transplantation (BMT) has become an accepted and important medical intervention which has become a routine part of medical practice. Its utility has, however, been questioned recently in a number of diseases in which its role has been clearly established on the basis that there are better non-transplant therapeutic options. The suspicion that these moves to eradicate BMT as an option may not stem from purely scientific reasons has prompted the preparation of these personal reflections. I will focus this discussion only on two diseases in which BMT has been shown to be useful: chronic myelogenous leukemia (CML) and multiple myeloma (MM).
PMID: 20132655 [PubMed - in process]
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Effect of magnetic nanoparticles of Fe3O4 and 5-bromotetrandrine on reversal of multidrug resistance in K562/A02 leukemic cells.
Int J Nanomedicine. 2009;4:209-16
Authors: Cheng J, Wu W, Chen BA, Gao F, Xu W, Gao C, Ding J, Sun Y, Song H, Bao W, Sun X, Xu C, Chen W, Chen N, Liu L, Xia G, Li X, Wang X
This study aims to evaluate the multidrug resistance (MDR) reversal activity by magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) and 5-bromotetrandrine (BrTet) MDR cell line K562/A02 solitarily or symphysially. The proliferation of K562 and K562/A02 cells and the cytotoxicity on peripheral blood mononuclear cells (PMBCs) were evaluated by MTT assay. Cellular accumulation of daunorubicin (DNR) was analyzed by flow cytometry. Real-time polymerase chain reaction and Western blotting analyses were performed to examine the mRNA and protein levels of mdr1, respectively. The results showed that the combination of MNPs-Fe3O4 and BrTet with effective concentrations significantly increased cytotoxicity against MDR cell line K562/A02. Both BrTet and MNPs-Fe3O4 increased the intracellular DNR accumulation in the K562/A02 cell line, and downregulated the level of mdr1 gene and expression of P-glycoprotein. Furthermore, the combination did not have significant cytotoxicity in PMBCs. We propose that MNPs-Fe3O4 conjugated with DNR and BrTet probably have synergetic effects on MDR reversal.
PMID: 19918367 [PubMed - indexed for MEDLINE]
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Posted by rob on February 5, 2010 under Uncategorized |
We will start auto publishing new medical articles on our new Facebook page
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Posted by rob on under Uncategorized |
We have started a new CMLHope Facebook page which will provide an alternate location for messages and interaction in addition to our Google Group which has over 2,000 members. Facebook now has over 400 million members and we felt it is important that we establish a presence there to reach even more people. Please join our Facebook page by clicking on this link.
Posted by rob on under Uncategorized |
Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study.
Am J Hematol. 2009 Dec 15;
Authors: Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G
Dasatinib 70 mg twice daily is indicated for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) intolerant or resistant to imatinib. In patients with chronic-phase chronic myelogenous leukemia, once-daily dosing has similar efficacy with improved safety, compared with twice-daily dosing. A phase 3 study (n = 611) assessed the efficacy and safety of dasatinib 140 mg once daily versus 70 mg twice-daily in patients with advanced phase chronic myelogenous leukemia or Ph+ ALL resistant or intolerant to imatinib. Here, results from the Ph+ ALL subset (n = 84) with a 2-year follow-up are reported. Patients were randomly assigned to receive dasatinib either 140 mg once daily (n = 40) or 70 mg twice daily (n = 44). The rate of confirmed major hematologic response with once-daily dosing (38%) was similar to that with twice-daily dosing (32%). The rate of major cytogenetic response with once-daily dosing (70%) was higher than that with twice-daily dosing (52%). Compared with the twice-daily schedule, the once-daily schedule had longer progression-free survival (median, 3.0 months versus 4.0 months, respectively) and shorter overall survival (median, 9.1 months versus 6.5 months, respectively). Overall safety profiles were similar between two groups, with nonhematologic adverse events being mostly grade 1 or 2. Pleural effusion was less frequent with once-daily dosing than with twice-daily dosing (all grades, 18% versus 32%). Notably, none of the differences between the two schedules was statistically significant. Compared with the 70 mg twice daily, dasatinib 140 mg once daily had similar overall efficacy and safety in patients with imatinib-resistant or intolerant Ph+ ALL. (clinicaltrials.gov identifier: NCT00123487). Am. J. Hematol. 2010. (c) 2009 Wiley-Liss, Inc.
PMID: 20131302 [PubMed - as supplied by publisher]
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Chronic myeloid leukemia: reversing the chronic phase.
J Clin Oncol. 2010 Jan 20;28(3):363-5
Authors: Goldman JM
PMID: 20008612 [PubMed - indexed for MEDLINE]
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Hematology: dasatinib regimens for patients with chronic myeloid leukemia.
Nat Rev Clin Oncol. 2009 Dec;6(12):680-2
Authors: Guilhot F, Roy L
Although imatinib mesylate therapy has dramatically improved the prognosis of patients in the advanced phases of chronic myeloid leukemia, room for improvement remains. Tyrosine kinase inhibitors are undergoing evaluation as second-line therapy for patients with imatinib-resistant disease. Kantarjian et al. recently demonstrated that once-daily dasatinib 140 mg is well tolerated and achieves a high response rate.
PMID: 19942922 [PubMed - indexed for MEDLINE]
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Glutathione S-transferase M1 and T1 genes and susceptibility to chronic myeloid leukemia: a meta-analysis.
Genet Test Mol Biomarkers. 2009 Dec;13(6):791-7
Authors: Zintzaras E
Variants of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genes have been implicated as risk factors for chronic myeloid leukemia (CML). However, the genetic association studies that examined the relation between the null genotypes of GSTM1 and GSTT1 genes and risk of developing CML gave conflicting or inconclusive results. In an attempt to interpret these results, a meta-analysis of all available studies (nine studies, with 757 cases and 1959 controls) was performed. In the meta-analysis the pooled odds ratios (OR) were estimated using random effects models. The heterogeneity between studies, the sources of potential bias, and the consistency of genetic effects across ethnicities were explored. Cumulative meta-analysis was also performed. Overall, the meta-analysis showed nonsignificant association between GSTM1 null genotype and CML (OR = 1.00 [0.83-1.20]) and lack of heterogeneity between the studies (p(Q) = 0.87). The association was also nonsignificant in Whites, East Asians, and Indians: OR = 1.38 (0.43-4.46), 0.94 (0.65-1.35), and 1.16 (0.74-1.82), respectively. However, GSTT1 null genotype was associated with increased risk of CML (OR = 1.57 [1.13-2.17]) and the heterogeneity between studies was significant (p(Q) = 0.04). In Indians, the association was significant (OR = 2.89 [1.56-5.35]) whereas in East Asians it was not significant (OR = 1.07 [0.74-1.54]). The combined GSTM1 normal/GSTT1 null genotypes produced significant association (OR = 1.95 [1.17-3.24]). Cumulative meta-analysis for GSTT1 gene showed an upward trend in risk effect, whereas the trend was downward in GSTM1. There was a differential magnitude of effect in large versus small studies. In conclusion, the accumulated evidence indicated an association between GSTT1 null genotype and CML.
PMID: 19860557 [PubMed - indexed for MEDLINE]
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Posted by rob on February 4, 2010 under Uncategorized |
Deep vein thrombosis in acute myelogenous leukemia.
Acta Med Indones. 2009 Oct;41(4):200-4
Authors: Oehadian A, Iqbal M, Sumantri R
Thrombotic complications in acute leukemia are often underestimated because bleeding complications generally dominate the clinical picture. While there are many thrombogenic factors shared by both solid tumors and leukemia, many additional prothrombotic features are present in leukemia. The prothrombotic factors include hyperleukocytosis, increased expression of tissue factor and its activation in leukemic cells, and the prothrombotic adverse effects of therapeutic agents and vascular access cathethers. A 18-year old woman came with swelling on her right leg 10 days before hospital admission. Since 2 months before she had had weakness, pallor and fever without bleeding manifestation. Hematologic examinations showed anemia, leukocytosis with monoblast and thrombocytopenia. Deep vein thrombosis in right femoral and right popliteal vein was confirmed using compression ultrasonography. The treatment of such complications is challenging because of the high risk of hemorrhage in this group of patients, especially due to their severe thrombocytopenia.
PMID: 20124617 [PubMed - in process]
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Studies on biomarkers for oxidative stress in patients with chronic myeloid leukemia.
Hematol Oncol Stem Cell Ther. 2009;2(1):285-8
Authors: Singh RK, Tripathi AK, Tripathi P, Singh S, Singh R, Ahmad R
BACKGROUND: Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a unique genetic rearrangement, the Philadelphia chromosome. High reactive oxygen species (ROS) levels favor oxidative stress, which could play a vital role in normal processes and various pathophysiologies including neoplasm. Biomarkers of oxidative stress are measured as products of oxidized proteins and lipids. Plasma levels of protein carbonyl (PC), thiobarbituric acid reactive substances (TBARS) and total lipid hydroperoxide (LOOH) were used as biomarkers of oxidative stress in the past. The aim of this study was to evaluate the products of protein oxidation and lipid peroxidation in plasma as biomarkers of oxidative stress in CML patients. PATIENTS AND METHODS: The study included 40 CML patients and 20 age- and sex-matched healthy volunteers. Of 40 CML patients, 28 were in chronic phase (CML-CP) and 12 in accelerated phase (CML-AP). Plasma levels of PC, TBARS and LOOH as biomarkers of oxidative stress were evaluated by spectrophotometric methods. RESULTS: There were significant differences (P < .05) in plasma levels of PC, TBARS and LOOH in CML, CML-CP and CML-AP patients as compared to controls. CONCLUSION: PC, TBARS and LOOH might reflect oxidative stress in CML patients and might be used as biomarkers in such patients.
PMID: 20063559 [PubMed - indexed for MEDLINE]
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Additional chromosomal abnormalities in Philadelphia-positive chronic myeloid leukemia.
Hematol Oncol Stem Cell Ther. 2008 Jul-Sep;1(3):166-70
Authors: Syed NN, Usman M, Adil S, Khurshid M
BACKGROUND AND OBJECTIVE: The emergence of non-random chromosomal abnormalities is a well-recognized occurrence in chronic myeloid leukemia (CML) and detection of these abnormalities is important in prognostic stratification. The frequency and types of additional chromosomal abnormalities in CML patients has not been determined in our region. PATIENTS AND METHODS: We conducted a descriptive, prospective study of additional chromosomal abnormalities in patients with an established diagnosis of Philadelphia-positive CML from May 2001 to June 2007. Cytogenetic studies were repeated every three months with the conventional G-banding technique and described according to the international system for Human Cytogenetic Nomenclature. All patients received imatinib mesylate. RESULTS: In 219 patients with Philadelphia-positive CML, 34 (15.5%) (median age, 38 years) developed 51 additional chromosomal abnormalities. Five cases had variant translocations prior to starting imatinib; the remaining 29 cases acquired chromosomal abnormalities after starting imatinib, including 8 cases that received prior interferon-alfa. Twenty-one patients were in chronic phase, 10 in accelerated phase and 3 were in blast crisis. Trisomy 8 was the most frequent abnormality followed by random chromosomal abnormalities and variants of the Philadelphia chromosome. CONCLUSIONS: The overall frequency of additional chromosomal abnormalities was similar to that in previous reports. Early identification of these abnormalities may help in adapting to a more appropriate therapeutic approach.
PMID: 20063547 [PubMed - indexed for MEDLINE]
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Posted by rob on February 3, 2010 under Uncategorized |
The effect of homoharringtonine in patients with chronic myeloid leukemia who have failed or responded suboptimally to imatinib therapy.
Leuk Lymphoma. 2009 Nov;50(11):1889-91
Authors: Li YF, Liu X, Liu DS, Din BH, Zhu JB
PMID: 19860613 [PubMed - indexed for MEDLINE]
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Posted by rob on February 2, 2010 under Uncategorized |
Tactics to stimulate immune eradication of stem cell populations in tumors may lead to more durable remissions. (Source: Cancer Research)
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Therapeutic strategies to augment autophagy, a transient survival tactic that can be turned against cancer cells, may offer novel approaches to degrade cancer cell survival. (Source: Cancer Research)
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Acquired eosinophilia is operationally categorized into secondary, clonal, and idiopathic types. Causes of secondary eosinophilia include parasite infections, allergic or vasculitis conditions, drugs, and lymphoma. Clonal eosinophilia is distinguished from idiopathic eosinophilia by the presence of histologic, cytogenetic, or molecular evidence of an underlying myeloid malignancy. The World Health Organization classification system for hematologic malignancies recognizes 2 distinct subcategories of clonal eosinophilia: chronic eosinophilic leukemia, not otherwise specified and myeloid/lymphoid neoplasms with eosinophilia and mutations involving platelet-derived growth factor receptor /β or fibroblast growth factor receptor 1. Clonal eosinophilia might also accompany other World Health…
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Identification of BCR-ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR-ABL inhibitor, is the standard of care for the first-line treatment of patients with chronic-phase CML because of its high long-term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard-dose imatinib (400 mg daily), imatinib dose escalation (600-800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR-A…
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Conclusion A single-dose regimen for all pharmacogenetically eligible patients is not the optimum strategy for prescribing imatinib to
patients with chronic myelogenous leukaemia. We suggest that therapeutic drug monitoring aimed at ensuring a trough target
level of 1 µM would reduce the incidence of pseudo-resistance and hence personalize treatment and optimise response to imatinib.
Persistent resistance can then be probed further for other causes.
Content Type Journal ArticleCategory PharmacogeneticsDOI 10.1007/s00228-009-0779-4Authors
Alain Li-Wan-Po, Morris House, c/o Birmingham Women’s Hospital National Genetics Education and Development Centre Edgbaston Birmingham B15 2TG UKPeter Farndon, Morris House, c/o Birmingham Women’s Hospital National Genetics…
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