Posted by rob on June 13, 2010 under Uncategorized | 
Generation of iPSCs from cultured human malignant cells.
Blood. 2010 May 20;115(20):4039-42
Authors: Carette JE, Pruszak J, Varadarajan M, Blomen VA, Gokhale S, Camargo FD, Wernig M, Jaenisch R, Brummelkamp TR
Induced pluripotent stem cells (iPSCs) can be generated from various differentiated cell types by the expression of a set of defined transcription factors. So far, iPSCs have been generated from primary cells, but it is unclear whether human cancer cell lines can be reprogrammed. Here we describe the generation and characterization of iPSCs derived from human chronic myeloid leukemia cells. We show that, despite the presence of oncogenic mutations, these cells acquired pluripotency by the expression of 4 transcription factors and underwent differentiation into cell types derived of all 3 germ layers during teratoma formation. Interestingly, although the parental cell line was strictly dependent on continuous signaling of the BCR-ABL oncogene, also termed oncogene addiction, reprogrammed cells lost this dependency and became resistant to the BCR-ABL inhibitor imatinib. This finding indicates that the therapeutic agent imatinib targets cells in a specific epigenetic differentiated cell state, and this may contribute to its inability to fully eradicate disease in chronic myeloid leukemia patients.
PMID: 20233975 [PubMed - indexed for MEDLINE]
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Why doesn’t imatinib cure chronic myeloid leukemia?
Oncologist. 2010;15(2):182-6
Authors: Redner RL
Imatinib mesylate has transformed the treatment for chronic myeloid leukemia (CML). The vast majority of patients obtain hematologic remission, with a low probability of progression of disease. Yet imatinib rarely cures CML, and current recommendations dictate lifelong treatment with imatinib. In this review we analyze the biology behind the failure of imatinib to fully eradicate CML. We review evidence that indicates that the leukemic stem cell for CML is inherently resistant to imatinib, and that imatinib treatment itself may enhance this resistance.
PMID: 20124443 [PubMed - indexed for MEDLINE]
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Abstract: To characterize the molecular mechanisms involved in the transition from the chronic phase to blast crisis in chronic myelogenous leukemia (CML), gene expression profiles of leukemic cells from patients in the chronic and blast crisis phases were analyzed using an 8.7K cDNA chip and real-time PCR. A transient transfection analysis was conducted to evaluate the role of FLT3, which was significantly upregulated in the blast crisis patients. Abl and c-Kit induction was detected in K562 cells transfected with FLT3 cDNA (K562/FLT3), and Abl and c-Kit levels were reduced in K562/FLT3 cells transfected with FLT3-siRNA (K562/FLT3-siRNA). The induction of FLT3 in CML cells attenuated imatinib-induced apoptosis. The opposite effect was observed in K562/FLT3-siRNA cells. An increased level …
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Despite the development of intensive combination chemotherapy, many leukemia patients still succumb to drug-resistant leukemia. In contrast to the success of ‘targeted’ tyrosine kinase inhibitor (TKI) therapy in BCR-ABL-driven chronic myelogenous leukemia (CML) [particularly in chronic phase (CP)], BCR-ABL-driven acute lymphoblastic leukemias (including ‘de novo’ Ph+ ALLs, and CML patients in lymphoid blast-crisis [LBC]) invariably relapse while on single-agent tyrosine kinase inhibitor therapy . In these TKI-resistant leukemias, a number of well-characterized drug-resistant BCR-ABL Kinase Domain (KD) mutations frequently emerge in the dominant drug-resistant leukemic clone(s) . While tyrosine kinase inhibitors can be safely added to intensive combination chemotherapy regimens and …
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We present the results of numerous simulated treatment programs in which imatinib treatment is temporarily stopped to stimulate and leverage the anti-leukemia immune response to combat CML. The simulations presented in this paper imply that treatment programs that involve strategic treatment interruptions may prevent leukemia from relapsing and may prevent remission for significantly longer than continuous imatinib treatment. Moreover, in many cases, strategic treatment interruptions may completely eliminate leukemic cells from the body. Thus, strategic treatment interruptions may be a feasible clinical approach to enhancing the effects of imatinib treatment for CML. We study the effects of both the timing and the duration of the treatment interruption on the results of the treatment. We a…
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Authors: Etienne G, Milpied B, Réa D, Rigal-Huguet F, Tulliez M, Nicolini FE
Nilotinib (Tasigna(R)) is a second-generation BCR-ABL kinase inhibitor, recently introduced and used for the treatment of chronic or accelerated phase CML patients, intolerant or resistant to imatinib. This treatment represents and important step forward for the disease control of such patients but can lead to side effects, sometimes serious, which can limit its optimal use. We propose here some guidelines that might be of help in daily practice, in order to manage properly these side effects.
PMID: 20529767 [PubMed - as supplied by publisher] (Source: Bulletin du Cancer)
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Posted by rob on June 10, 2010 under Uncategorized |
Strategic Treatment Interruptions During Imatinib Treatment of Chronic Myelogenous Leukemia.
Bull Math Biol. 2010 Jun 9;
Authors: Paquin D, Kim PS, Lee PP, Levy D
Although imatinib is an effective treatment for chronic myelogenous leukemia (CML), and nearly all patients treated with imatinib attain some form of remission, imatinib does not completely eliminate leukemia. Moreover, if the imatinib treatment is stopped, most patients eventually relapse (Cortes et al. in Clin. Cancer Res. 11:3425-3432, 2005). In Kim et al. (PLoS Comput. Biol. 4(6):e1000095, 2008), the authors presented a mathematical model for the dynamics of CML under imatinib treatment that incorporates the anti-leukemia immune response. We use the mathematical model in Kim et al. (PLoS Comput. Biol. 4(6):e1000095, 2008) to study and numerically simulate strategic treatment interruptions as a potential therapeutic strategy for CML patients. We present the results of numerous simulated treatment programs in which imatinib treatment is temporarily stopped to stimulate and leverage the anti-leukemia immune response to combat CML. The simulations presented in this paper imply that treatment programs that involve strategic treatment interruptions may prevent leukemia from relapsing and may prevent remission for significantly longer than continuous imatinib treatment. Moreover, in many cases, strategic treatment interruptions may completely eliminate leukemic cells from the body. Thus, strategic treatment interruptions may be a feasible clinical approach to enhancing the effects of imatinib treatment for CML. We study the effects of both the timing and the duration of the treatment interruption on the results of the treatment. We also present a sensitivity analysis of the results to the parameters in the mathematical model.
PMID: 20532990 [PubMed - as supplied by publisher]
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[Guidelines for the management of nilotinib (Tasigna (R))-induced side effects in chronic myelogenous leukemia: recommendations of French Intergroup of CML (Fi-LMC group).]
Bull Cancer. 2010 Jun 8;
Authors: Etienne G, Milpied B, Réa D, Rigal-Huguet F, Tulliez M, Nicolini FE
Nilotinib (Tasigna(R)) is a second-generation BCR-ABL kinase inhibitor, recently introduced and used for the treatment of chronic or accelerated phase CML patients, intolerant or resistant to imatinib. This treatment represents and important step forward for the disease control of such patients but can lead to side effects, sometimes serious, which can limit its optimal use. We propose here some guidelines that might be of help in daily practice, in order to manage properly these side effects.
PMID: 20529767 [PubMed - as supplied by publisher]
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Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo.
Br J Cancer. 2010 May 11;102(10):1474-82
Authors: Bright SA, McElligott AM, O’Connell JW, O’Connor L, Carroll P, Campiani G, Deininger MW, Conneally E, Lawler M, Williams DC, Zisterer DM
BACKGROUND: Imatinib is a direct and potent inhibitor of the constitutively active tyrosine kinase, breakpoint cluster region-Abelson (Bcr-Abl), which is central to the pathogenesis of chronic myeloid leukaemia (CML) patients. As such, imatinib has become the front-line treatment for CML patients. However, the recent emergence of imatinib resistance, commonly associated with point mutations within the kinase domain, has led to the search for alternative drug treatments and combination therapies for CML. METHODS: In this report, we analyse the effects of representative members of the novel pro-apoptotic microtubule depolymerising pyrrolo-1,5-benzoxazepines or PBOX compounds on chemotherapy-refractory CML cells using a series of Bcr-Abl mutant cell lines, clinical ex vivo patient samples and an in vivo mouse model. RESULTS: The PBOX compounds potently reduce cell viability in cells expressing the E225K and H396P mutants as well as the highly resistant T315I mutant. The PBOX compounds also induce apoptosis in primary CML samples including those resistant to imatinib. We also show for the first time, the in vivo efficacy of the pro-apoptotic PBOX compound, PBOX-6, in a CML mouse model of the T315I Bcr-Abl mutant. CONCLUSION: Results from this study highlight the potential of these novel series of PBOX compounds as an effective therapy against CML.
PMID: 20407438 [PubMed - indexed for MEDLINE]
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Background: Imatinib mesylate (Gleevec) is a medication that was developed to treat chronic myelogenous leukemia as well as gastrointestinal stromal tumors (GISTS). The most common ocular side effect is periorbital edema. However, more serious ocular side effects have been reported, including optic nerve edema, optic nerve damage, and glaucoma. Hence, it is important that optometrists be familiar with Gleevec and its potential vision-threatening complications. (Source: Optometry – Journal of the American Optometric Association)
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Abstract: Coexistence of inv(16) and t(9;22) is a rare chromosomal aberration, one that has been described in chronic myelogenous leukemia (CML), mainly in myeloid blast crisis, and de novo acute myeloid leukemia (AML). Approximately 14 cases have been reported, including only 1 pediatric case. Here we present the case of a 13-year-old boy with a new diagnosis of AML with some features of monocytic differentiation. Conventional cytogenetic analyses on unstimulated blood showed three related abnormal clones with inv(16) in the stemline: 46,XY,inv(16)(p13.1q22)[2]/46,idem,del(7)(q22q32)[16]/46,idem,t(9;22;19)(q34;q11.2;p13.1)[2]. Fluorescence in situ hybridization (FISH) studies on interphase nuclei and previously G-banded metaphases showed a 3?CBFB deletion and confirmed the presence of …
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Abstract We investigated the efficacy of the induction therapy involving granulocyte colony-stimulating factor (G-CSF) and low-dose
homoharringtonine as well as standard-dose imatinib, which we called the G-CSF?+?homoharringtonine?+?imatinib (GHI) regimen,
in patients with chronic myelogenous leukemia (CML) in blast crisis who have failed prior single-agent therapy with imatinib.
Twelve patients were enrolled. The GHI regimen consisted in a unique induction course where imatinib was administered at 400 mg day?1 until remission, together with homoharringtonine (1 mg/m2?s.c. twice daily for 14 days every 28 days), and G-CSF, which was administered 1 day before chemotherapy (5 µg/kg s.c. daily).
Patients who failed to obtain …
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Conclusion:
To our knowledge, this is the first report to show that pristimerin is effective in vitro and in vivo against CML cells, including those with the T315I mutation. The mechanisms may involve inhibition of NF-kappaB and Bcr-Abl. We concluded that pristimerin could be a lead compound for further drug development to overcome imatinib resistance in CML patients. (Source: BioMed Central)
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New research discovers a combination of drugs that may prove to be a more effective treatment for a lethal form of leukemia. The study, published by Cell Press in the May issue of the journal Cancer Cell, reports that the new therapeutic strategy effectively targets notoriously intractable leukemia stem cells that often escape standard treatment and are a main factor in disease relapse. Chronic myelogenous leukemia (CML) is a deadly form of leukemia that is associated with chromosome rearrangements that result in the expression of the BCR-ABL oncoprotein… (Source: Health News from Medical News Today)
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Bin Zhang, Adam C. Strauss, Su Chu, Min Li, Yinwei Ho, Keh-Dong Shiang, David S. Snyder, Claudia S. Huettner, Leonard Shultz, Tessa Holyoake, Ravi Bhatia. Imatinib mesylate (IM) induces remission in chronic myelogenous leukemia (CML) patients but does not eliminate leukemia stem cells (LSCs), which remain a potential source of relapse. Here we inves…. (Source: Cancer Cell)
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Posted by rob on June 5, 2010 under Uncategorized |
Phase IV study evaluating efficacy of escalated dose of imatinib in chronic myeloid leukemia patients showing suboptimal response to standard dose imatinib.
Ann Hematol. 2010 Jul;89(7):725-31
Authors: Koh Y, Kim I, Yoon SS, Kim BK, Kim DY, Lee JH, Lee KH, Park E, Kim HJ, Sohn SK, Joo YD, Kim SJ, Chung J, Shin HJ, Kim SH, Kim CS, Song HS, Kim MK, Hyun MS, Ahn JS, Jung CW, Park S,
The aim of this phase IV study was to (1) to define efficacy of escalating dose imatinib in chronic myeloid leukemia (CML) patients showing suboptimal response to standard dose imatinib and (2) to find markers that predict the response to escalating doses of imatinib. CML patients in chronic phase (CP) who failed to achieve optimal response with 400 mg/day imatinib or patients in accelerated phase (AP) or blast crisis (BC) who failed to achieve complete hematologic response after 3 months of 400-600 mg/day imatinib were enrolled. CP patients received 600 mg/day, while AP/BC patients received 600-800 mg/day imatinib. Patients received imatinib for at least 12 months or until the disease progression or intolerable toxicity. Along with cytogenetic response (CyR), molecular response was assessed with BCR-ABL/ABL ratio. Baseline BCR-ABL gene mutation test was performed. Seventy-one patients (median age, 49.0 years, M:F = 50:21) received escalated dose imatinib. Grade 3 edema in two patients was the only nonhematologic toxicities more than grade 2. For evaluable patients, 30.8% of patients achieved CCyR at 6 months, and median time to treatment failure (TTFx) was 18.0 months. TTFx was longer in patients who achieved greater than 50% reduction in BCR-ABL/ABL within 6 months (early molecular responder (EMR)) compared with those who did not (non-EMR; p < 0.001). Of 31 patients who had mutational status data, three had mutation. All mutants failed to achieve CCyR. In conclusion, escalated dose imatinib shows considerable efficacy with tolerable toxicity in CML patients showing suboptimal response to standard dose imatinib. EMR is an early predictive marker for positive imatinib response.
PMID: 20179930 [PubMed - indexed for MEDLINE]
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Central nervous system immune reconstitution inflammatory syndrome (IRIS) after hematopoietic SCT.
Bone Marrow Transplant. 2010 Mar;45(3):593-6
Authors: Airas L, Päivärinta M, Röyttä M, Karhu J, Kauppila M, Itälä-Remes M, Remes K
PMID: 19684631 [PubMed - indexed for MEDLINE]
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Outcome of patients developing GVHD after DLI given to treat CML relapse: a study by the Chronic Leukemia Working Party of the EBMT.
Bone Marrow Transplant. 2010 Mar;45(3):558-64
Authors: Chalandon Y, Passweg JR, Schmid C, Olavarria E, Dazzi F, Simula MP, Ljungman P, Schattenberg A, de Witte T, Lenhoff S, Jacobs P, Volin L, Iacobelli S, Finke J, Niederwieser D, Guglielmi C,
We studied GVHD after donor lymphocyte infusion (DLI) in 328 patients with relapsed CML between 1991 and 2004 . A total of 122 patients (38%) developed some form of GVHD. We analyzed GVHD by clinical presentation (acute or chronic GVHD) and onset time after the first DLI (early (< or =45 days) or late (>45 days)). There was a significant overlap between onset time and clinical presentation. Some form of GVHD occurred at a median of 104 days, acute GVHD at 45 days and chronic GVHD at 181 days after DLI. The clinical presentation was acute GVHD in 71 patients, of whom 31 subsequently developed chronic GVHD subsequently. De novo chronic GVHD was seen in 51 patients. OS for all patients was 69% (95% confidence interval (CI) 63-75) at 5 years, DLI-related mortality was 11% (95% CI 8-15) and disease-related mortality was 20% (95% CI 16-25). Risk factors for developing GVHD after DLI were T-cell dose at first DLI, the time interval from transplant to DLI and donor type. In time-dependent multivariate analysis, GVHD after DLI was associated with a risk of death of 2.3-fold compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were associated with increased mortality.
PMID: 19633691 [PubMed - indexed for MEDLINE]
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P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia.
J Hematol Oncol. 2008;1:15
Authors: Cang S, Liu D
Imatinib was the first BCR-ABL-targeted agent approved for the treatment of patients with chronic myeloid leukemia (CML) and confers significant benefit for most patients; however, a substantial number of patients are either initially refractory or develop resistance. Point mutations within the ABL kinase domain of the BCR-ABL fusion protein are a major underlying cause of resistance. Of the known imatinib-resistant mutations, the most frequently occurring involve the ATP-binding loop (P-loop). In vitro evidence has suggested that these mutations are more oncogenic with respect to other mutations and wild type BCR-ABL. Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib. Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop. Data from clinical trials suggest that dasatinib may be more effective vs. nilotinib for treating patients harboring P-loop mutations. Other mutations that are differentially sensitive to the second-line tyrosine kinase inhibitors (TKIs) include F317L and F359I/V, which are more sensitive to nilotinib and dasatinib, respectively. P-loop status in patients with CML and the potency of TKIs against P-loop mutations are key determinants for prognosis and response to treatment. This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.
PMID: 18828913 [PubMed - indexed for MEDLINE]
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Background: Imatinib mesylate (Gleevec) is a medication that was developed to treat chronic myelogenous leukemia as well as gastrointestinal stromal tumors (GISTS). The most common ocular side effect is periorbital edema. However, more serious ocular side effects have been reported, including optic nerve edema, optic nerve damage, and glaucoma. Hence, it is important that optometrists be familiar with Gleevec and its potential vision-threatening complications. (Source: Optometry – Journal of the American Optometric Association)
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