Reply: the BIM deletion polymorphism cannot account for intrinsic TKI resistance of Chinese individuals with chronic myeloid leukemia.

Posted by rob on December 18, 2014 under Uncategorized | Comments are off for this article

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Reply: the BIM deletion polymorphism cannot account for intrinsic TKI resistance of Chinese individuals with chronic myeloid leukemia.

Nat Med. 2014 Oct;20(10):1090-1

Authors: Ong ST, Chuah CT, Ko TK, Hillmer AM, Lim WT

PMID: 25295933 [PubMed - indexed for MEDLINE]

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The BIM deletion polymorphism cannot account for intrinsic TKI resistance of Chinese individuals with chronic myeloid leukemia.

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The BIM deletion polymorphism cannot account for intrinsic TKI resistance of Chinese individuals with chronic myeloid leukemia.

Nat Med. 2014 Oct;20(10):1090

Authors: Chen X, Liu H, Xing H, Sun H, Zhu P

PMID: 25295932 [PubMed - indexed for MEDLINE]

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Assessment of treatment and monitoring patterns and subsequent outcomes among patients with chronic myeloid leukemia treated with imatinib in a community setting.

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Assessment of treatment and monitoring patterns and subsequent outcomes among patients with chronic myeloid leukemia treated with imatinib in a community setting.

Curr Med Res Opin. 2014 Apr;30(4):529-36

Authors: Saleh MN, Haislip S, Sharpe J, Hess T, Gilmore J, Jackson J, Sail KR, Ericson SG, Chen L

Abstract

INTRODUCTION: Real-world treatment and monitoring patterns have not been well documented among imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients. Thus, we evaluated these patterns and responses to imatinib in CP-CML patients.

METHODS: This retrospective study, based on the Georgia Cancer Specialists’ electronic medical record (EMR) system, identified CP-CML patients initiating treatment with imatinib from 01/01/2002 to 11/01/2011 who were subsequently followed for ?6 months.

RESULTS: A total of 177 patients met the study criteria. Imatinib dose modification occurred in 59 patients (33%). Rates of treatment interruption, discontinuation, and switching to another therapy were 16%, 24%, and 23%, respectively. Of 27 patients discontinuing imatinib for lack of efficacy, 9 (33%) had initial dose escalation; 26 patients (96%) eventually switched to a second-generation tyrosine kinase inhibitor. By 3 months, 168 patients remained on imatinib, of whom 96 (57%) had undergone cytogenetic and/or molecular testing. The frequency of response monitoring fluctuated over time, with rates as high as 28% for cytogenetic and 69% for molecular testing. Cumulative response rates steadily increased; 18 month rates were 47% for complete cytogenetic response and 26% for major or complete molecular response. There were no cases of progression and/or death among 38 patients who were regularly monitored for molecular response within the first 12 months of imatinib. Ten of 98 patients (10%) not regularly monitored had progressed or died.

CONCLUSIONS: Almost one-third of patients initiating imatinib for CP-CML required dose modification, treatment interruption, or discontinuation. Opportunities for improved monitoring in this setting were identified. Limitations include those inherent to retrospective analyses based on EMR and the uncertain extrapolability of the results.

PMID: 24156689 [PubMed - indexed for MEDLINE]

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[Bioinformatic analysis of chronic myeloid leukemia progression and preliminary experimental verification].

Posted by rob on December 15, 2014 under Uncategorized | Comments are off for this article

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[Bioinformatic analysis of chronic myeloid leukemia progression and preliminary experimental verification].

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Aug;22(4):909-13

Authors: Zhang JF, Liu XL, Lin YD, Pan JW, Xu N

Abstract

This study was aimed to explore the progression mechanism of chronic myeloid leukemia, so as to provide the new molecular markers for evaluation of CML clinical outcome and selection of treatment. The microarray data of genes related with progression from different phase of chronic myeloid leukemia (CML) were collected from public data depository GEO (Gene expression datasets). SAM analysis, fold change filtering, cross comparison were used to analyze the data and identify different genes. Moreover, MeV and pSTIING sofewares were used to analyze the key differential genes and signal pathways. At last, Q-PCR were used to confirm the predicted key gene. The results indicated that after comparison, 9 genes were differentially expressed from AP to BC, and the integrin-mediated cell adhesion , focal adhesion, regulation of actin cytoskeleton were the principal pathways during CML progression. Network construction analysis found that AP-related genes or pathways may be the original signals; and MLLT4, WDR35 and EPHB4 were the key genes for CML progression. EPHB4 was confirmed by Q-PCR in CML BC patients and CP patients. It is concluded that MLLT4, WDR35, EPHB4, integrin-mediated cell adhesion, focal adhesion and regulation of actin cytoskeleton are the principal genes and pathways during CML progression.

PMID: 25130802 [PubMed - indexed for MEDLINE]

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Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib.

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Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib.

Leukemia. 2014 Oct;28(10):1988-92

Authors: Hanfstein B, Shlyakhto V, Lauseker M, Hehlmann R, Saussele S, Dietz C, Erben P, Fabarius A, Proetel U, Schnittger S, Krause SW, Schubert J, Einsele H, Hänel M, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Pfirrmann M, Hasford J, Hofmann WK, Hochhaus A, Müller MC, SAKK and the German CML Study Group

Abstract

UNLABELLED: Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection.

RESULTS: (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.

PMID: 24798484 [PubMed - indexed for MEDLINE]

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Development and immunological evaluation of HLA-specific chronic myeloid leukemia polyepitope vaccine in Chinese population.

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Development and immunological evaluation of HLA-specific chronic myeloid leukemia polyepitope vaccine in Chinese population.

Vaccine. 2014 Jun 12;32(28):3501-8

Authors: Dong W, Zhang J, Shao N, Tian T, Li L, Jian J, Zang S, Ma D, Ji C

Abstract

BACKGROUND: BCR/ABL and Wilms’ tumor 1 (WT1) are an ideal tumor associated antigens which can be used to develop a potential chronic myeloid leukemia (CML) dentritic cell (DC) vaccine. Here, we constructed a novel polyepitope vaccine which used recombinant lentiviral vector carrying BCR/ABL and WT1 genes, and determined the immunological effects of this vaccine in vitro.

METHODS: The DC vaccine was constructed using lentiviral vector transduced DCs. T lymphocytes were stimulated with DC vaccine and then co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) from CML or ALL patients, respectively. The cytotoxicity of proliferous cytotoxic T lymphocytes (CTLs) was determined by the LDH assay. The IFN-? production of CTLs was detected using ELISPOT assay.

RESULTS: We constructed an lentiviral vector encoding 50 different epitopes from BCR/ABL and WT1 antigens, and transferred it into DCs to prepare the DC vaccine successfully. The in vivo stimulation of CTLs with this DC vaccine were proved to show strong cytotoxicity and produce high level of IFN-?.

CONCLUSIONS: The novel recombinant lentiviral polyepitope DC vaccine is a promising candidate for clinical trials and may be an effective approach for CML immunotherapy.

PMID: 24793940 [PubMed - indexed for MEDLINE]

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NKT cell-infiltrating aseptic meningitis on the central nervous system in Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib.

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NKT cell-infiltrating aseptic meningitis on the central nervous system in Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib.

Ann Hematol. 2014 Nov;93(11):1935-6

Authors: Imataki O, Arai T, Yamaoka G, Matsuoka A, Uemura M

PMID: 24756695 [PubMed - indexed for MEDLINE]

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Real-time quantification assay to monitor BCR-ABL1 transcripts in chronic myeloid leukemia.

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Real-time quantification assay to monitor BCR-ABL1 transcripts in chronic myeloid leukemia.

Methods Mol Biol. 2014;1160:115-24

Authors: Foskett P, Gerrard G, Foroni L

Abstract

The BCR-ABL1 fusion gene, the causative lesion of chronic myeloid leukemia (CML) in >95 % of newly presenting patients, offers both a therapeutic and diagnostic target. Reverse-transcription quantitative polymerase chain reaction technology (RT-qPCR), utilizing primer-probe combinations directed to exons flanking the breakpoint junctional region, offers very high levels of both specificity and sensitivity, in a scalable, robust, and cost-effective assay.

PMID: 24740226 [PubMed - indexed for MEDLINE]

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Study protocol of the RAND-study: a multicenter, prospective cohort study investigating response and adherence to nilotinib treatment in chronic myeloid leukemia.

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Study protocol of the RAND-study: a multicenter, prospective cohort study investigating response and adherence to nilotinib treatment in chronic myeloid leukemia.

BMC Cancer. 2014;14:247

Authors: Boons CC, Swart EL, Timmers L, van de Ven PM, Janssen JJ, Hugtenburg JG

Abstract

BACKGROUND: The antitumor drug nilotinib has a large inter- and intra individual variability in pharmacokinetics. Adherence to treatment may substantially influence plasma levels and has been recognized as the most important determinant of treatment failure in chronic myeloid leukemia (CML). A better understanding of the various factors contributing to the efficacy of treatment is essential for the development of interventions to optimize the treatment of chronic phase CML (CP-CML) with a protein kinase inhibitor like nilotinib.

METHODS/DESIGN: In this multicenter prospective observational cohort study 70 adult patients with CP-CML starting treatment with nilotinib will be followed up for at least 12 months. Response to treatment is evaluated after 3, 6 and 12 months. Adherence is primarily assessed by counting the daily intake of nilotinib capsules by means of a medication event monitoring system (MEMS). Before the start of nilotinib treatment and after 3, 6 and 12 months, patients are asked to fill in a comprehensive questionnaire including topics on quality of life, side effects, attitude towards disease and medication, the patients’ appreciation of information received about the medication, and discontinuation, and trough plasma levels of nilotinib are measured.

DISCUSSION: The present study aims to get more insight into the efficacy of treatment with nilotinib and the various aspects that govern optimal response, of which adherence is a primary endpoint. We hypothesize that patients who experience inadequate response levels to nilotinib are less adherent. In addition, their plasma levels of nilotinib may be lower. We expect that our findings will be useful for health care professionals to support patients with the use of nilotinib in order to derive optimal benefit from their medication.

TRIAL REGISTRATION: Netherlands Trial Registry NTR3992.

PMID: 24712728 [PubMed - indexed for MEDLINE]

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Studies on microRNAs that are correlated with the cancer stem cells in chronic myeloid leukemia.

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Studies on microRNAs that are correlated with the cancer stem cells in chronic myeloid leukemia.

Mol Cell Biochem. 2014 May;390(1-2):75-84

Authors: Zhu X, Lin Z, Du J, Zhou X, Yang L, Liu G

Abstract

Accumulating data indicate that cancer stem cells play an important role in tumorigenesis and are underlying cause of tumor recurrence and metastasis, specifically in chronic myeloid leukemia (CML). We aim to detect the miRNAs that are correlated with the cancer stem cells in CML to provide theoretical basis for clinical application. We first analyzed microRNA expression profiles of CML leukemia patients compared with normal controls by microarray analysis and validated the results by real-time PCR. A single microRNA signature classified CML from normal was detected. We also determined the absolute copy numbers of these three microRNAs in normal adults. The results showed that three microRNAs (miR-150, miR-23a, and miR-130a) were identified to significantly decrease in expanded 38 CML patients compared with 90 normal controls. Molecular and statistical analysis showed that the decreased microRNAs were significant in clinical analysis. All these results indicated that those three microRNAs could act as a tumor suppressor and their decreased expression might be one of the causes of leukemia. Accordingly, clarifying their regulatory mechanisms might delineate their potentials as drug targets of gene therapy for CML.

PMID: 24385111 [PubMed - indexed for MEDLINE]

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Heparin-mediated inhibition of PCR in the accelerated phase of chronic myeloid leukaemia characterised by abundant basophilia.

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Heparin-mediated inhibition of PCR in the accelerated phase of chronic myeloid leukaemia characterised by abundant basophilia.

Eur J Haematol. 2014;92(5):456-7

Authors: Satoh Y, Masuda A, Jona M, Nannya Y, Yokota H, Kurokawa M, Yatomi Y

PMID: 24373003 [PubMed - indexed for MEDLINE]

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Imatinib and pegylated IFN-?2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response.

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Imatinib and pegylated IFN-?2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response.

Eur J Haematol. 2014;92(5):413-20

Authors: Koskenvesa P, Kreutzman A, Rohon P, Pihlman M, Vakkila E, Räsänen A, Vapaatalo M, Remes K, Lundán T, Hjorth-Hansen H, Vakkila J, Simonsson B, Mustjoki S, Porkka K

Abstract

OBJECTIVES: Previous studies indicate that 40-50% of patients with chronic myeloid leukemia in prolonged complete molecular remission may discontinue imatinib therapy without imminent relapse. The combination of pegylated interferon-alpha (Peg-IFN-?2b) and imatinib may increase the rate of successful discontinuation.

METHODS: In this pilot study, we prospectively stopped imatinib from patients (n = 12) who had achieved major molecular response (MMR) after ?12 months of treatment with either imatinib or imatinib+Peg-IFN-?2b. Molecular monitoring was carried out monthly for BCR-ABL1. In addition, analyses of lymphocyte immunophenotype, function, and plasma cytokines were performed.

RESULTS: In the monotherapy group, 5/6 patients lost MMR within 4 months. One patient remains to date in MR(4.0) 61 months after discontinuation. In the combination therapy group, 2/6 patients relapsed within 4 months while still receiving Peg-IFN-?2b. Four of six patients were able to discontinue both treatments, but three of these patients relapsed after 3 months. One patient is still in sustained MR(4.0) at 58 months off all treatment. All relapsed patients re-responded to imatinib. The two successfully discontinued patients had either an increased number of NK-cells or functionally active T-cells.

CONCLUSIONS: A higher frequency of relapsed patients in our study in comparison with other studies may be due to the shorter duration of imatinib treatment prior to discontinuation. However, in selected patients with an active immune system, even a short duration of TKI therapy (<2 yr) may allow for therapy discontinuation but this needs to be confirmed in larger prospective studies.

PMID: 24372965 [PubMed - indexed for MEDLINE]

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Large granular lymphocytosis during dasatinib therapy.

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Large granular lymphocytosis during dasatinib therapy.

Cancer Biol Ther. 2014 Mar 1;15(3):247-55

Authors: Qiu ZY, Xu W, Li JY

Abstract

Dasatinib is a second generation tyrosine kinase inhibitor (TKI) approved for clinical use in patients with imatinib-resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). Large granular lymphocytes (LGLs) are medium to large cells with eccentric nuclei and abundant cytoplasm with coarse azurophilic granules. LGL lymphocytosis is caused by a proliferation of cytotoxic (CD8+) T cells and/or NK cells. In a proportion of CML and Ph(+) ALL patients, there is a significant expansion of LGLs during dasatinib therapy. LGL lymphocytosis is seen in some cases with fevers, colitis, and pleural effusions (PE), suggesting an aberrant immune response mediated by these LGLs. LGLs may participate in the elimination of the residual leukemic cells, and LGL clonal expansion is associated with excellent, long-lasting therapy responses in dasatinib-treated patients. For a more comprehensive analysis, we analyzed the morphologic, phenotypic, clinical, and functional features of the LGL subsets amplified in vivo during dasatinib therapy.

PMID: 24352048 [PubMed - indexed for MEDLINE]

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Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond.

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Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond.

Hematology Am Soc Hematol Educ Program. 2013;2013:189-200

Authors: Ahmed W, Van Etten RA

Abstract

In patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.

PMID: 24319181 [PubMed - indexed for MEDLINE]

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Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when is this a safe option to consider?

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Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when is this a safe option to consider?

Hematology Am Soc Hematol Educ Program. 2013;2013:184-8

Authors: Sweet K, Oehler V

Abstract

Mrs G is a 54-year-old woman with a diagnosis of chronic-phase chronic myeloid leukemia dating back 8 years. She had a low-risk Sokal score at diagnosis and was started on imatinib mesylate at 400 mg orally daily within one month of her diagnosis. Her 3-month evaluation revealed a molecular response measured by quantitative RT-PCR of 1.2% by the International Scale. Within 6 months of therapy, she achieved a complete cytogenetic response, and by 18 months, her BCR-ABL1 transcript levels were undetectable using a quantitative RT-PCR assay with a sensitivity of ? 4.5 logs. She has maintained this deep level of response for the past 6.5 years. Despite her excellent response to therapy, she continues to complain of fatigue, intermittent nausea, and weight gain. She is asking to discontinue imatinib mesylate and is not interested in second-line therapy. Is this a safe and reasonable option for this patient?

PMID: 24319180 [PubMed - indexed for MEDLINE]

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Update on current monitoring recommendations in chronic myeloid leukemia: practical points for clinical practice.

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Update on current monitoring recommendations in chronic myeloid leukemia: practical points for clinical practice.

Hematology Am Soc Hematol Educ Program. 2013;2013:176-83

Authors: Oehler VG

Abstract

Excellent therapeutic options exist for the treatment of chronic-phase chronic myeloid leukemia (CML) patients. Therefore, managing CML patients has become a more common practice for many physicians. Most chronic-phase CML patients achieve durable cytogenetic and molecular responses on first-line tyrosine kinase inhibitor therapy. However, careful monitoring and assessment of adherence are essential for successful outcomes and to identify patients at risk for failing therapy. The European LeukemiaNet and National Comprehensive Cancer Network provide guidance and strategies for monitoring and managing patients treated with TKIs. These recommendations continue to evolve as approved treatment options expand to include second- and third-generation tyrosine kinase inhibitors. How measurements of response are defined and data supporting recent recommended changes to monitoring are reviewed here. These changes include increasing recognition of the importance of early response. The relevance of achieving deep molecular responses will also be addressed.

PMID: 24319179 [PubMed - indexed for MEDLINE]

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Which TKI? An embarrassment of riches for chronic myeloid leukemia patients.

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Which TKI? An embarrassment of riches for chronic myeloid leukemia patients.

Hematology Am Soc Hematol Educ Program. 2013;2013:168-75

Authors: Hughes T, White D

Abstract

With the approval in many countries of nilotinib and dasatinib for frontline therapy in chronic myeloid leukemia, clinicians now have to make a difficult choice. Because none of the 3 available tyrosine kinase inhibitors (TKIs) have shown a clear survival advantage, they all represent reasonable choices. However, in individual patients, the case may be stronger for a particular TKI. In the younger patient, in whom the prospect of eventually achieving treatment-free remission is likely to be of great importance, dasatinib or nilotinib may be preferred, although their advantage over imatinib in this setting remains to be proven. In patients with a higher risk of transformation (which is currently based on prognostic scoring), the more potent TKIs may be preferred because they appear to be more effective at reducing the risk of transformation to BC. However, imatinib still represents an excellent choice for many chronic myeloid leukemia patients. All of these considerations need to be made in the context of the patient’s comorbidities, which may lead to one or more TKIs being ruled out of contention. Whatever first choice of TKI is made, treatment failure or intolerance must be recognized early because a prompt switch to another TKI likely provides the best chance of achieving optimal response.

PMID: 24319178 [PubMed - indexed for MEDLINE]

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Correlations between cytogenetic and molecular monitoring among patients with newly diagnosed chronic myeloid leukemia in chronic phase: post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study.

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Correlations between cytogenetic and molecular monitoring among patients with newly diagnosed chronic myeloid leukemia in chronic phase: post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study.

Arch Pathol Lab Med. 2014 Sep;138(9):1186-92

Authors: Akard LP, Cortes JE, Albitar M, Goldberg SL, Warsi G, Wetzler M, Ericson SG, Radich JP

Abstract

CONTEXT: Although bone marrow (BM) karyotyping has been the standard in monitoring patients with chronic myeloid leukemia, peripheral blood (PB) monitoring methods may be more convenient.

OBJECTIVE: To conduct post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study to evaluate correlations between results of cytogenetic testing and molecular monitoring from BM and PB during the first 18 months of high-dose imatinib therapy, and between early and late molecular responses.

DESIGN: Newly diagnosed patients with chronic-phase chronic myeloid leukemia received imatinib 400 mg twice daily and were monitored quarterly for up to 18 months. Cytogenetic testing was performed by karyotyping using BM or by fluorescence in situ hybridization using PB. Molecular testing was performed by quantitative reverse transcriptase polymerase chain reaction using BM and PB.

RESULTS: Significant pairwise correlations were found between results obtained by karyotyping, fluorescence in situ hybridization, and quantitative reverse transcriptase polymerase chain reaction using PB or BM (all pairwise correlations >0.8; P < .001). At 12 months, cytogenetic response by karyotyping correlated well with response by fluorescence in situ hybridization. A median 2.579-log reduction in BCR-ABL1 level from a standardized baseline correlated with fluorescence in situ hybridization-negative status. Patients with greater than 2-log reduction in BCR-ABL1 level at 3, 6, and 9 months were more likely to achieve major molecular response at 18 months than those with 2-log reduction or less.

CONCLUSIONS: Our findings support the feasibility of molecular monitoring using PB and suggest that molecular monitoring conducted at a single reliable reference laboratory can adequately track response without invasive BM testing. Our findings are consistent with other work indicating that early response to imatinib predicts favorable long-term outcome.

PMID: 24308645 [PubMed - indexed for MEDLINE]

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OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients.

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OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients.

Eur J Haematol. 2014 Apr;92(4):283-8

Authors: Koren-Michowitz M, Buzaglo Z, Ribakovsky E, Schwarz M, Pessach I, Shimoni A, Beider K, Amariglio N, le Coutre P, Nagler A

Abstract

OBJECTIVES: One third of CML patients treated with first line imatinib have suboptimal responses or treatment failures with increased risk for disease progression. Imatinib is actively transported into cells by the SLC22A1 transporter (hOCT1) and its genetic variants may affect intracellular drug import. We studied the effect of SLC22A1 genetic variants on long-term outcomes of imatinib treated patients.

METHODS: A total of 167 patients, 94% in chronic phase, were analyzed for rs41267797, rs683369, rs12208357, and rs628031 variants using the Sequenom MassARRAY platform.

RESULTS: Rates of CHR, MCyR, CCyR, and MMolR were not significantly different according to allelic variants. However, patients with AA or GA rs628031 genotypes had a higher incidence of poor response to imatinib compared to the GG genotype (47% compared to 29%, P = 0.06), and a higher rate of KD mutation discovery (8/16 vs. 5/27, P = 0.04), suggesting that secondary resistance was more common in these genotypes. Median EFS was shorter for rs628031 genotype AA/AG compared with the GG genotype (61 months and not reached, respectively, P = 0.05), and 5 yr OS rates were lower for patients with the rs628031 genotypes AA/AG compared with the GG genotype (88% and 97%, respectively, P = 0.03). Patients with AA/GA rs628031 and additional rare genotypes had worse EFS and OS compared to patients with only AA/GA rs628031 (P = 0.02 for EFS and 0.01 for OS). There was no difference in pretreatment SLC22A1 mRNA expression levels in patients with rs628031 genotypes GG/AA or GA.

CONCLUSIONS: Studying SLC22A1 genetic variants prior to TKI initiation could influence treatment decisions.

PMID: 24215657 [PubMed - indexed for MEDLINE]

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Fenretinide targets chronic myeloid leukemia stem/progenitor cells by regulation of redox signaling.

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Fenretinide targets chronic myeloid leukemia stem/progenitor cells by regulation of redox signaling.

Antioxid Redox Signal. 2014 Apr 20;20(12):1866-80

Authors: Du Y, Xia Y, Pan X, Chen Z, Wang A, Wang K, Li J, Zhang J

Abstract

AIMS: We have recently shown that fenretinide preferentially targets CD34(+) cells of acute myeloid leukemia (AML), and here, we test whether this agent exerts the effect on CD34(+) cells of chronic myeloid leukemia (CML), which are refractory to imatinib.

RESULTS: As tested by colony-forming cell assays using clinical specimens, both number and size of total colonies derived from CD34(+) CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and more primitive pluripotent/multipotent progenitors were highly sensitive to fenretinide/fenretinide plus imatinib. Accordantly, fenretinide appeared to induce apoptosis in CD34(+) CML cells, particularly with regard to the cells in the subpopulation of CD34(+)CD38(-). Through cell quiescent assays, including Ki-67 negativity test, we added evidence that nonproliferative CD34(+) CML cells were largely eliminated by fenretinide. Transcriptome and molecular data further showed that mechanisms underlying the apoptosis in CD34(+) CML cells were highly complex, involving multiple events of oxidative stress responses.

INNOVATION AND CONCLUSION: As compared with CD34(+) AML cells, the apoptotic effects of fenretinide on CD34(+) CML cells were more prominent whereas less varied among the samples of different patients, and also various stress-responsive events appeared to be more robust in fenretinide-treated CD34(+) CML cells. Thus, the combination of fenretinide with imatinib may represent a more sophisticated strategy for CML treatment, in which imatinib mainly targets leukemic blast cells through the intrinsic pathway of apopotosis, whereas fenretinide primarily targets CML stem/progenitor cells through the oxidative/endoplasmic reticulum stress-mediated pathway.

PMID: 24021153 [PubMed - indexed for MEDLINE]

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