MedWorm: Chronic Myeloid Leukaemia

Imatinib and beyond - targeting activated tyrosine kinases in myeloproliferative disorders.

Onkologie — Mon, 06 Feb 2012 02:58:36 +0100

Authors: Hochhaus A, Reiter A, Ernst T, La Rosée P Abstract Tyrosine kinases (TKs) play a major role in cellular signal transduction. Deregulated TK activity has been observed in solid cancers and hematologic malignancies. Advances in the understanding of the oncogenic activation of TKs led to the identification of new kinase inhibitors with improved potency, specificity, and efficacy. With the advent of imatinib mesylate, a new era in the management of patients with BCR-ABL+ chronic myelogenous leukemia (CML), gastrointestinal stromal tumors, and myeloproliferative neoplasms including chronic myelomonocytic leukemia with PDGFRB gene rearrangements and hypereosinophilic syndrome has begun. CML represents a model for the rational design of TK inhibitors based on the insights into s...

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Recent developments and future perspectives of personalized oncology.

Onkologie — Mon, 06 Feb 2012 02:58:36 +0100

Authors: Grüllich C, von Kalle C Abstract Increasing understanding of molecular carcinogenesis has begun to change paradigms in oncology. On the diagnostic side, the characterization of key mutations and molecular pathways responsible for tumor development and progression has led to the identification of a large number of potential targets for diagnostic and therapeutic intervention. On the treatment and prevention side, molecular analysis will be of even greater importance for guiding individualized therapy. Diagnostics of molecular lesions present in each tumor will become a key feature of future clinical care. This will allow prediction of response with substantially increased accuracy, stratification of particular patient groups, and eventually personalization of therapy. Stri...

Persistent bloody tears as the initial manifestation of conjunctival chloroma associated with chronic myelogenous leukemia

Graefe's Archive for Clinical and Experimental Ophthalmology — Thu, 02 Feb 2012 06:54:29 +0100

Content Type Journal ArticleCategory Letter to the EditorPages 1-2DOI 10.1007/s00417-011-1924-1Authors Sonya B. Shah, Department of Ophthalmology (SBS) and Ocular Oncology Service (DAR, SEL, CLS), Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107, USADavid A. Reichstein, Department of Ophthalmology (SBS) and Ocular Oncology Service (DAR, SEL, CLS), Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107, USASara E. Lally, Department of Ophthalmology (SBS) and Ocular Oncology Service (DAR, SEL, CLS), Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107, USACarol L. Shields, Department of Ophthalmology (SBS) and Ocular Oncology Service (DAR, SEL, CLS), Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107, USA Journal Graefe's Archive for Cli...

Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION)

Blood — Thu, 02 Feb 2012 05:00:00 +0100

This study was registered at ClinicalTrials.gov: NCT00481247. (Source: Blood)

Overcoming CML acquired resistance by specific inhibition of Aurora A kinase in the KCL-22 cell model

Carcinogenesis — Thu, 02 Feb 2012 05:00:00 +0100

Serine/threonine kinase Aurora A is essential for regulating mammalian cell division and is overexpressed in many types of human cancer. However, the role of Aurora A in chemoresistance of chronic myelogenous leukemia (CML) is not well understood. Using the KCL-22 cell culture model we have recently developed for studying mechanisms of CML acquired resistance, we found that Aurora A expression was partially reduced in these cells upon treatment with the tyrosine kinase inhibitor imatinib, which accompanied the acquisition of BCR-ABL mutation for imatinib resistance. Gene knockdown of BCR-ABL also reduced Aurora A expression, and conversely, Aurora A expression increased in hematopoietic progenitor cells after BCR-ABL expression. Inhibition of Aurora A induced apoptosis of CML cells with or...

[News] NICE guidance on dasatinib, high-dose imatinib, and nilotinib for patients with CML who are resistant or intolerant to imatinib

The Lancet Oncology — Wed, 01 Feb 2012 05:00:00 +0100

On Jan 13, 2012, the UK National Institute for Health and Clinical Excellence (NICE) published guidance recommending nilotinib for the treatment of the chronic and accelerated phases of chronic myeloid leukaemia (CML) that is resistant or intolerant to standard-dose imatinib. Dasatinib, is not recommended for treatment of chronic, accelerated, or blast-crisis phase CML in adults with imatinib intolerance or whose CML is resistant to treatment with standard-dose imatinib. High-dose imatinib is not recommended for the treatment of chronic, accelerated, or blast-crisis phase Philadelphia-chromosome-positive CML that is resistant to standard-dose imatinib. (Source: The Lancet Oncology)

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Chronic Myeloid Leukemia: Clinical Impact of BCR-ABL1 Mutations and Other Lesions Associated With Disease Progression

Seminars in Oncology — Wed, 01 Feb 2012 05:00:00 +0100

The introduction of the tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, and nilotinib has dramatically improved the treatment of chronic myeloid leukemia (CML). However, a minority of CML patients in chronic phase (CP) and a substantial proportion of patients in advanced phase are either initially refractory to TKIs or eventually develop resistance. Rates of resistance and relapse directly correlate with disease progression. The most frequently identified mechanism of acquired TKI resistance is BCR-ABL1 kinase domain (KD) mutations that impair TKI binding by disrupting the drug contact sites or causing conformational changes that make the contact sites inaccessible. The underlying mechanisms of disease progression are heterogeneous and only poorly understood. So far the most frequen...

Chronic Myelomonocytic Leukemia and Atypical Chronic Myeloid Leukemia: Novel Pathogenetic Lesions

Seminars in Oncology — Wed, 01 Feb 2012 05:00:00 +0100

Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) are distinct, yet related, entities of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) characterized by morphologic dysplasia with accumulation of monocytes or neutrophils, respectively. Our understanding of the molecular pathogenesis of CMML and aCML has advanced, mainly due to the application of novel technologies such as array-based karyotyping and next-generation sequencing. In addition to previously known recurrent aberrations, somatic uniparental disomy affecting chromosomes 3, 4, 7, and 11 frequently occurs in CMML. Novel somatic mutations of genes, including those associated with proliferation signaling (CBL, RAS, RUNX1, JAK2 (V617F)) and with modification of epigenetic status (TET2, ASXL1, U...

Anticancer drugs: Keeping one step ahead

Nature Reviews Drug Discovery — Wed, 01 Feb 2012 05:00:00 +0100

Nature Reviews Drug Discovery 11, 108 (2012). doi:10.1038/nrd3664 Author: Darren J. Burgess Inhibiting the oncogenic kinase BCR–ABL1, which causes chronic myeloid leukaemia (CML), is a paradigm for clinically successful targeted therapy. However, drug-resistant mutations frequently emerge during clinical treatment. A new study shows that attempting to inhibit drug-resistant BCR–ABL1 mutants can result in a counterproductive activation of (Source: Nature Reviews Drug Discovery)

Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy

Cancer — Tue, 31 Jan 2012 05:00:00 +0100

CONCLUSIONS:The current results indicated that the prevalence of CML will continue to increase to reach a near plateau prevalence 35 times the annual incidence. These estimates should be considered in health care policies and in the design of future studies in CML. Cancer 2012. © 2012 American Cancer Society. (Source: Cancer)

Pfizer Announces FDA Acceptance Of New Drug Application For Bosutinib For Patients With Previously Treated Ph+ Chronic Myeloid Leukemia

Drugs.com - New Drug Applications — Mon, 30 Jan 2012 15:01:54 +0100

NEW YORK--(BUSINESS WIRE)--Jan 27, 2012 - Pfizer Inc. announced today that the U.S. Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for standard review of bosutinib as a treatment option for adult patients with... (Source: Drugs.com - New Drug Applications)

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Jak of all trades? Not of leukaemia therapy!

EurekAlert! - Medicine and Health — Mon, 30 Jan 2012 05:00:00 +0100

(University of Veterinary Medicine -- Vienna) Treatment of chronic myeloid leukaemia usually relies on inhibitors of the abnormal protein that causes the condition but some patients do not respond to treatment and efforts are underway to develop a supplementary approach, targeting the so-called JAK2 kinase. Recent results from a team of researchers from Vienna, Austria, have called this strategy into question. The work is published in advance in Nature Chemical Biology online and is of immediate relevance to leukaemia treatment. (Source: EurekAlert! - Medicine and Health)

Combining Nilotinib and Imatinib Improves the Outcome of Imatinib-Resistant Blast Phase CML.

Acta Haematologica — Fri, 27 Jan 2012 05:00:00 +0100

Authors: Zhu GR, Ji O, Ji JM, Zhang YC, Wu Y, Yu H, Jiang PJ, Shen Q Abstract Imatinib resistance is an important hurdle in the treatment of chronic myeloid leukemia (CML), and CML patients with this drug resistance are often given a dismal prognosis. In this case report, an imatinib-refractory blast phase CML patient was treated with a combination of imatinib and nilotinib. A complete hematologic response was achieved within 3 months, the drug combination was well tolerated, and there was a relatively long bone-marrow complete remission. These results suggest that combining imatinib and nilotinib treatment may improve the outcome of imatinib-resistant CML patients in the blast phase. We hypothesize regarding the possible mechanism for the effectiveness of the drug combination by r...

Splenic infarction in a child revealing chronic myeloid leukemia

European Journal of Pediatrics — Thu, 26 Jan 2012 06:44:12 +0100

Abstract A 7-year-old girl was admitted with a severe abdominal pain. Abdominal ultrasound and CT revealed a large splenic infarction, leading to the diagnosis of chronic myeloid leukemia. Content Type Journal ArticleCategory Images in PediatricsPages 1-2DOI 10.1007/s00431-012-1675-yAuthors David Drummond, Department of Pediatric Hematology and Oncology, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris (APHP), Université Pierre et Marie Curie (Paris 6), 26, avenue Arnold Netter, 75012 Paris, FranceMarion Lenoir, Department of Radiology, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris (APHP), Université Pierre et Marie Curie (Paris 6), 26, avenue Arnold Netter, 75012 Paris, FranceArnaud Y. Petit, Department of Pediatric Hematology and ...

Dasatinib: From Treatment of Imatinib-Resistant or -Intolerant Patients With Chronic Myeloid Leukemia to Treatment of Patients With Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia.

Clinical Therapeutics — Thu, 26 Jan 2012 05:00:00 +0100

CONCLUSIONS: Dasatinib was an effective treatment with the potential to improve long-term outcomes for patients with newly diagnosed CML-CP. PMID: 22285209 [PubMed - as supplied by publisher] (Source: Clinical Therapeutics)

Quality Of Life Issues For Patients With Chronic Myeloid Leukemia

Health News from Medical News Today — Tue, 24 Jan 2012 09:00:00 +0100

Although significant progress has been made in treating chronic myeloid leukemia, the disease cannot yet be eliminated in all patients, and that challenge must be addressed, states a commentary in CMAJ (Canadian Medical Association Journal).). Likening the journey to find a cure for chronic myeloid leukemia as a marathon, cancer expert Dr. Jorge Cortes, University of Texas, MD Anderson Cancer Center, Houston, Texas, writes, "The past half century has been an extraordinary run that has us on an excellent pace to not only complete the race to a cure, but to do so in record time... (Source: Health News from Medical News Today)

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The race against chronic myeloid leukemia not yet won

EurekAlert! - Social and Behavioral Science — Mon, 23 Jan 2012 05:00:00 +0100

(Canadian Medical Association Journal) Although significant progress has been made in treating chronic myeloid leukemia, the disease cannot yet be eliminated in all patients, and that challenge must be addressed, states a commentary in CMAJ. (Source: EurekAlert! - Social and Behavioral Science)

Chronic myeloid leukemia: The race is yet to be won.

cmaj — Mon, 23 Jan 2012 05:00:00 +0100

Authors: Cortes J PMID: 22271914 [PubMed - as supplied by publisher] (Source: cmaj)

Clinical cardiac safety profile of nilotinib.

Haematologica — Sun, 22 Jan 2012 05:00:00 +0100

Conclusions. Whereas new electrocardiographic abnormalities were recorded in twenty percent of all patients and some of them developed severe or even life-threatening coronary artery disease, QT prolongation, changes in left ventricular ejection fraction, and clinical cardiac adverse events were uncommon in patients treated with nilotinib. PMID: 22271904 [PubMed - as supplied by publisher] (Source: Haematologica)

Analysis of outcomes in adolescents and young adults with chronic myelogenous leukemia treated with upfront tyrosine kinase inhibitor therapy.

Haematologica — Sun, 22 Jan 2012 05:00:00 +0100

Conclusions: The unfavorable trend in outcome for adolescent and young adult with chronic myeloid leukemia is unexpected. Additional research in this population is required to better define outcomes, understand the cause of this difference, and to help make better treatment recommendations. PMID: 22271898 [PubMed - as supplied by publisher] (Source: Haematologica)

Analysis of non-HLA genomic risk factors in HLA-matched unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia.

Haematologica — Sun, 22 Jan 2012 05:00:00 +0100

Conclusions. We did not confirm that non-Human Leukocyte Antigen polymorphisms were associated with outcomes in myeloablative unrelated donor hematopoietic cell transplantation for Chronic Myeloid Leukemia, possibly due to the strong association between clinical variables and outcome that masked more subtle genetic effects. PMID: 22271889 [PubMed - as supplied by publisher] (Source: Haematologica)

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The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

Revista Brasileira de Hematologia e Hemoterapia — Fri, 20 Jan 2012 22:10:14 +0100

Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still cha...

Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia

Revista Brasileira de Hematologia e Hemoterapia — Fri, 20 Jan 2012 22:10:14 +0100

This article, a review of possible therapies used to overcome imatinib resistance, investigates the current position by searching the PubMed electronic database using the following keywords: imatinib, dasatinib, nilotinib, aurora kinase, SRC kinase, mutation, treatment, drugs and resistance. New tyrosine kinase inhibitors include BCR-ABL kinase selective inhibitors, dual ABL/SRC kinase inhibitors and aurora kinase inhibitors. Awareness of the spectrum of new drugs against mutations, in particular the T315I mutation, makes it possible to properly select the best therapy for each patient (Source: Revista Brasileira de Hematologia e Hemoterapia)

Successful treatment of a chronic-phase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa.

International Journal of Hematology — Fri, 20 Jan 2012 05:00:00 +0100

Authors: Itonaga H, Tsushima H, Hata T, Matsuo E, Imanishi D, Imaizumi Y, Kawaguchi Y, Fukushima T, Doi Y, Mori S, Kamihira S, Tomonaga M, Miyazaki Y Abstract The T315I BCR-ABL mutation in chronic myelogenous leukemia (CML) patients is responsible for up to 20% of all clinically observed resistance. This mutation confers resistance not only to imatinib, but also to second-generation BCR-ABL tyrosine kinases, such as nilotinib and dasatinib. A number of strategies have been implemented to overcome this resistance, but allogeneic stem cell transplantation remains the only established therapeutic option for a cure. A 61-year-old male was diagnosed with Philadelphia chromosome-positive chronic-phase CML in 2002. He was initially treated with imatinib and complete cytogenetic response (...

AWMSG issues Final Appraisal Recommendation on dasatinib (Sprycel®)

NeLM - Drug Specific Reviews — Thu, 19 Jan 2012 05:00:00 +0100

Source: All Wales Medicines Strategy Group (AWMSG) Area: Evidence > Drug Specific Reviews In its Final Appraisal Recommendation, the All Wales Medicines Strategy Group (AWMSG) does not support the use of dasatinib (Sprycel®) within NHS Wales for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia in the chronic phase. The group considered that the case for cost effectiveness had not been proven. (Source: NeLM - Drug Specific Reviews)

Pharmacokinetics of nilotinib in imatinib‐resistant/intolerant chronic myeloid leukemia patients on hemodialysis for chronic renal failure

American Journal of Hematology — Thu, 19 Jan 2012 05:00:00 +0100

(Source: American Journal of Hematology)

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ICB3E induces iNOS expression by ROS-dependent JNK and ERK activation for apoptosis of leukemic cells

Apoptosis — Wed, 18 Jan 2012 06:49:15 +0100

Abstract The role of c-Jun N terminal Kinase (JNK) has been well documented in various cellular stresses where it leads to cell death. Similarly, extracellular signal-regulated kinase (ERK) which was identified as a signalling molecule for survival pathway has been shown recently to be involved in apoptosis also. Recently we reported that ICB3E, a synthetic analogue of Piper betle leaf-derived apoptosis-inducing agent hydroxychavicol (HCH), possesses anti-chronic myeloid leukemia (CML) acitivity in vitro and in vivo without insight on mechanism of action. Here we report that ICB3E is three to four times more potent than HCH in inducing apoptosis of leukemic cells without having appreciable effects on normal human peripheral blood mononuclear cells, mouse fibroblast cell lin...

Not Only Response but Early Response to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia [EDITORIALS]

Journal of Clinical Oncology — Wed, 18 Jan 2012 05:00:00 +0100

(Source: Journal of Clinical Oncology)

Assessment of BCR-ABL1 Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors [Rapid Communication]

Journal of Clinical Oncology — Wed, 18 Jan 2012 05:00:00 +0100

Conclusion A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention. (Source: Journal of Clinical Oncology)

Allopurinol-induced palisaded neutrophilic and granulomatous dermatitis.

Cutaneous and Ocular Toxicology — Wed, 18 Jan 2012 05:00:00 +0100

We describe a 64-year-old man with past chronic myeloid leukemia. Palisading neutrophilic granulomatous dermatitis of the hands was diagnosed and related to recent allopurinol intake. Allopurinol is known to rarely cause granulomatous reactions, but this appears to be the first case of palisading neutrophilic granulomatous dermatitis induction. Possible mechanisms include immune complex deposition, an immune response directed against the metabolites of allopurinol, or allopurinol hypersensitivity exclusively localized to the skin. PMID: 22250812 [PubMed - as supplied by publisher] (Source: Cutaneous and Ocular Toxicology)

Absence of DNMT3A gene mutation in chronic myeloid leukemia patients in blast crisis

European Journal of Haematology — Tue, 17 Jan 2012 22:55:17 +0100

(Source: European Journal of Haematology)

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Imatinib/mycophenolate mofetil/tacrolimus: Elevated alkaline phosphatase levels and chronic myeloid leukaemia: 2 case reports

Reactions — Tue, 17 Jan 2012 19:08:18 +0100

(Source: Reactions)

Continuing Good News for Chronic Myeloid Leukemia Patients

Cancer Network — Tue, 17 Jan 2012 13:00:01 +0100

The results of the 2-year follow-up of the dasatinib DASISION phase III trial show the continued superiority of the drug compared to imatinib. The results provide further support for treatment of first-line chronic phase chronic myeloid leukemia patients that harbor the Philadelphia chromosome. (Source: Cancer Network)

Spotlight on Dasatinib in Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

BioDrugs — Fri, 13 Jan 2012 23:22:39 +0100

(Source: BioDrugs)

NICE issues costing statement for its guidance on dasatinib, high-dose imatinib and nilotinib for chronic myeloid leukaemia (CML)

NeLM - News — Fri, 13 Jan 2012 05:00:00 +0100

Source: NICE Area: News NICE has published guidance (Technology Appraisal 241) on the use of dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance. The costing statement notes that standard-dose imatinib is the current standard of care for first-line treatment of CML (as recommended in TA 70). Although the use of high-dose imatinib following resistance is recommended only in the context of research, specialists suggest that this, in addition to dasatinib and nilotinib, are used widely in the UK. This guidance recommends nilotinib fo...

NICE issues final guidance on dasatinib, high-dose imatinib and nilotinib for chronic myeloid leukaemia (CML)

NeLM - Guidelines — Fri, 13 Jan 2012 05:00:00 +0100

Source: NICE Area: Evidence > Guidelines NICE has published a technology appraisal (TA 241) on the use of dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance. The main recommendations regarding the use of these medicines within the NHS in England and Wales are as follows: . Nilotinib is recommended for the treatment of chronic or accelerated phase Philadelphia-chromosome-positive CML in adults whose CML is resistant to treatment with standard-dose imatinib or who have imatinib intolerance, as long as the manufacturer m...

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Bmi1 reprograms CML B-lymphoid progenitors to become B-ALL-initiating cells

Blood — Thu, 12 Jan 2012 05:00:00 +0100

We report that Bmi1 transforms and reprograms CML B-lymphoid progenitors into stem cell leukemia (Scl) promoter-driven, self-renewing, leukemia-initiating cells to result in B-lymphoid leukemia (B-ALL) in vivo. In vitro, highly proliferating and serially replatable myeloid and lymphoid colony-forming cultures could be established from BCR-ABL and Bmi1 coexpressing progenitors. However, unlike in vivo expanded CML B-lymphoid progenitors, hematopoietic stem cells, or multipotent progenitors, coexpressing BCR-ABL and Bmi1 did not initiate or propagate leukemia in a limiting dilution assay. Inducible genetic attenuation of BCR-ABL reversed Bmi1-driven B-ALL development, which was accompanied by induction of apoptosis of leukemic B-lymphoid progenitors and by long-term animal survival, suggesti...

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Blood — Thu, 12 Jan 2012 05:00:00 +0100

BCR-ABL overexpression and stem cell quiescence supposedly contribute to the failure of imatinib mesylate (IM) to eradicate chronic myeloid leukemia (CML). However, BCR-ABL expression levels of persisting precursors and the impact of long-term IM therapy on the clearance of CML from primitive and mature bone marrow compartments are unclear. Here, we have shown that the number of BCR-ABL–positive precursors decreases significantly in all bone marrow compartments during major molecular remission (MMR). More importantly, we were able to demonstrate substantially lower BCR-ABL expression levels in persisting MMR colony-forming units (CFUs) compared with CML CFUs from diagnosis. Critically, lower BCR-ABL levels may indeed cause IM insensitivity, because primary murine bone marrow cells en...

International Reporting Scale of BCR-ABL1 Fusion Transcript in Chronic Myeloid Leukemia: First Report from India.

Acta Haematologica — Thu, 12 Jan 2012 05:00:00 +0100

In this report, we explain the process and steps involved in obtaining a valid lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS. PMID: 22249155 [PubMed - as supplied by publisher] (Source: Acta Haematologica)

Prolonged Survival with Imatinib Mesylate Combined with Chemotherapy and Allogeneic Stem Cell Transplantation in de novo Ph+ Acute Myeloid Leukemia.

Acta Haematologica — Thu, 12 Jan 2012 05:00:00 +0100

Conclusions: Our cases indicate that IM combined with daunorubicin-based chemotherapy followed by allo-HSCT and IM maintenance treatment is associated with a favorable outcome for de novo Ph+ AML, especially when IM is used in an early phase of AML. PMID: 22248505 [PubMed - as supplied by publisher] (Source: Acta Haematologica)

Therapeutics: Keeping one step ahead

Nature Reviews Cancer — Thu, 12 Jan 2012 05:00:00 +0100

Nature Reviews Cancer 12, 82 (2012). doi:10.1038/nrc3211 Author: Darren J. Burgess A recent study proposes a new drug combination strategy to target drug-resistant chronic myeloid leukaemia. (Source: Nature Reviews Cancer)

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Four-channel asymmetric Real-Time PCR hybridization probe assay: A rapid pre-screening method for critical BCR-ABL kinase domain mutations.

Clinical Biochemistry — Thu, 12 Jan 2012 05:00:00 +0100

CONCLUSIONS: This new methodology detects in a few steps the presence of critical mutations associated to Imatinib resistance. PMID: 22266405 [PubMed - as supplied by publisher] (Source: Clinical Biochemistry)

Imatinib trough plasma levels do not correlate with the response to therapy in patients with chronic myeloid leukemia in routine clinical setting

Annals of Hematology — Tue, 10 Jan 2012 06:46:46 +0100

Abstract Association of trough imatinib plasma levels (IPL) with cytogenetic or molecular response to treatment in patients with chronic myeloid leukemia (CML) was repeatedly reported. We analyzed their value in the routine clinical setting in 131 patients with chronic phase CML in whom imatinib was applied as first- or second-line treatment. A total of 1,118 measurements were obtained by ultra-performance liquid chromatography–tandem mass spectrometry assay in patients treated with daily dose of imatinib ranging from 100 to 800 mg. Samples were obtained from 1 to 96 h after drug ingestion. High inter (36%) and intraindividual variability (9–33%) of IPL was observed. For analysis of correlation of IPL with treatment response, two sets of samples were selected...

CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression

Journal of Clinical Investigation — Mon, 09 Jan 2012 22:32:58 +0100

Chronic myelogenous leukemia (CML) results from a chromosomal translocation in hematopoietic stem or early progenitor cells that gives rise to the oncogenic BCR/ABL fusion protein. Clinically, CML has a chronic phase that eventually evolves into an accelerated stage and blast crisis. A CML-specific immune response is thought to contribute to the control of disease. Whether the immune system can also promote disease progression is not known. In the present study, we investigated the possibility that the TNF receptor family member CD27 is present on leukemia stem cells (LSCs) and mediates effects of the immune system on CML. In a mouse model of CML, BCR/ABL+ LSCs and leukemia progenitor cells were found to express CD27. Binding of CD27 by its ligand, CD70, increased expression of Wnt target ...

Perspectives on Targeted Therapies for Treatment of Human Cancers: Predictors of Response to Targeted Therapies for Gastrointestinal Stromal Tumors.

Archives of Pathology and Laboratory Medicine — Mon, 09 Jan 2012 05:00:00 +0100

Conclusions.-In gastrointestinal stromal tumors, the strongest predictor of response to targeted therapies is the mutational status of KIT or PDGFRA. Patients whose tumors harbor a KIT exon 11 mutation benefit the most from imatinib mesylate therapy, in terms of response rate, progression-free survival, and overall survival. Conversely, tumors without detectable mutations in either gene ("wild-type" gastrointestinal stromal tumors) are generally not responsive to imatinib mesylate. PMID: 22229850 [PubMed - as supplied by publisher] (Source: Archives of Pathology and Laboratory Medicine)

Undetectable molecular residual disease after omacetaxine and nilotinib combination therapy in an imatinib‐resistant chronic myeloid leukaemia patient harbouring the BCR‐ABL1 T315I gatekeeper mutation

British Journal of Haematology — Mon, 09 Jan 2012 05:00:00 +0100

(Source: British Journal of Haematology)

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Anti-leukemic effects of gallic acid on human leukemia K562 cells: Downregulation of COX-2, inhibition of BCR/ABL kinase and NF-κB inactivation.

Toxicology in Vitro — Sun, 08 Jan 2012 05:00:00 +0100

In conclusion, GA induced apoptosis in K562 cells involves death receptor and mitochondrial-mediated pathways by inhibiting BCR/ABL kinase, NF-κB activity and COX-2. PMID: 22245431 [PubMed - as supplied by publisher] (Source: Toxicology in Vitro)

Distinct graft-versus-leukemic stem cell effects of early or delayed donor leukocyte infusions in a mouse chronic myeloid leukemia model

Blood — Thu, 05 Jan 2012 05:00:00 +0100

Among hematologic neoplasms, chronic myeloid leukemia (CML) is exquisitely sensitive to graft-versus-leukemia (GVL) because patients relapsing after allogeneic hematopoietic stem-cell transplantation (alloHSCT) can be cured by donor leukocyte infusion (DLI); however, the cellular mechanisms and strategies to separate GVL from GVHD are unclear. We used a BCR-ABL1 transduction/transplantation mouse model to study the mechanisms of DLI in MHC-matched, minor histocompatibility antigen–mismatched allogeneic chimeras with CML-like leukemia, in which DLI can be administered at the time of transplantation (early) or after recovery of hematopoiesis (delayed). After early DLI, CML-like leukemia cannot be transferred into immunocompetent secondary recipients as soon as 4 days after primary tran...

Fish Oil May Hold Key To Leukemia Cure

Health News from Medical News Today — Tue, 03 Jan 2012 08:00:00 +0100

A compound produced from fish oil that appears to target leukemia stem cells could lead to a cure for the disease, according to Penn State researchers. The compound -- delta-12-protaglandin J3, or D12-PGJ3 -- targeted and killed the stem cells of chronic myelogenous leukemia, or CML, in mice, said Sandeep Prabhu, associate professor of immunology and molecular toxicology in the Department of Veterinary and Medical Sciences. The compound is produced from EPA -- Eicosapentaenoic Acid -- an Omega-3 fatty acid found in fish and in fish oil, he said... (Source: Health News from Medical News Today)

Photoinduced dermatitis and oral lichenoid reaction in a chronic myeloid leukemia patient treated with imatinib mesylate

Photodermatology, Photoimmunology and Photomedicine — Sun, 01 Jan 2012 07:43:51 +0100

ConclusionSkin changes are the most common non‐hematologic side effects to IM treatment and are usually dose dependent. In particular, patients with IM therapy reported a lightening and depigmentation of the skin, that may alter the skin protection against ultraviolet exposure, with a possible subsequent intolerance to sun exposure, as reported in our patient, and higher risk of skin cancer. They are frequently self‐limited or easily managed; nevertheless, in some cases, the therapy needs to be discontinued or may only be continued with concomitant oral steroid. (Source: Photodermatology, Photoimmunology and Photomedicine)

[News] NICE approves nilotinib for chronic myeloid leukaemia

The Lancet Oncology — Sun, 01 Jan 2012 05:00:00 +0100

On Dec 6, 2011, in the UK, NICE issued draft new guidance on first-line treatment of chronic myeloid leukaemia (CML). NICE already recommends imatinib, a standard dose of which costs about £20 000. “We are happy to now include nilotinib as a treatment option” a NICE spokesperson told The Lancet Oncology. “Although nilotinib is expensive at over £30 000 per patient per year, the manufacturer offered to provide the drug to the NHS at a discounted price meaning the committee could recommend it.” The size of the discount was not revealed. (Source: The Lancet Oncology)

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Design and Analytic Validation of BCR-ABL1 Quantitative Reverse Transcription Polymerase Chain Reaction Assay for Monitoring Minimal Residual Disease.

Archives of Pathology and Laboratory Medicine — Sun, 01 Jan 2012 05:00:00 +0100

Conclusions.-Validation of laboratory-developed quantitative molecular tests requires careful planning and execution to adequately address all required analytic performance parameters. How these are addressed depends on the potential for technical errors and confidence required for a given test result. We demonstrate how one laboratory validated and clinically implemented a quantitative BCR-ABL1 assay that can be used for the management of patients with chronic myelogenous leukemia. PMID: 22208485 [PubMed - in process] (Source: Archives of Pathology and Laboratory Medicine)

Drug development: portals of discovery.

Cell Research — Sun, 01 Jan 2012 05:00:00 +0100

Authors: Bates SE, Amiri-Kordestani L, Giaccone G Abstract A British humorist said, "There is much to be said for failure. It is much more interesting than success." This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non-small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a num...

[Acquired ichthyosis and haematological malignancies: Five cases].

Annales de Dermatologie et de Cenereologie — Sun, 01 Jan 2012 05:00:00 +0100

CONCLUSION: Acquired ichthyosis should prompt the clinician to search for a neoplastic condition, primarily a haematological disorder, guided by other associated signs, given that in our study, skin lesions generally appear to precede signs of the blood disease. PMID: 22225737 [PubMed - in process] (Source: Annales de Dermatologie et de Cenereologie)

An update on imatinib mesylate therapy in chronic myeloid leukaemia patients in a teaching hospital in Malaysia.

Singapore Medical Journal — Sun, 01 Jan 2012 05:00:00 +0100

Conclusion: The majority of our chronic myeloid leukaemia patients did well with imatinib therapy. The adverse effects in our patients were tolerable, and no patient had to stop treatment permanently. PMID: 22252185 [PubMed - in process] (Source: Singapore Medical Journal)

Mucosal Pigmentation Caused by Imatinib: Report of Three Cases

Head and Neck Pathology — Fri, 30 Dec 2011 16:49:59 +0100

Abstract Imatinib mesylate (STI-571, Gleevec®), a tyrosine kinase inhibitor, is a first-line medication for treating chronic myeloid leukemia (CML). Clinical studies revealed very good hematological responses without significant side effects. However, imatinib may lead to mucosal pigmentation. Three patients, two males aged 64 and 53 and one female aged 29 presented with a painless, diffuse, grey-blue pigmentation of the mucosa of the hard palate. Both male patients had a history of CML and had been on imatinib for 4 and 10 years, respectively. The female patient had been on imatinib for 4 years for pelvic fibromatosis. Histopathologically, deposition of fine, dark-brown, spherical granules was noted within the connective tissue. There was no inflammation or hemo...

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A new dic(7;12)(p12.21;p12.2) and i(12)(q10) during the lymphoid blast crisis of patient with Ph+ chronic myeloid leukemia

Medical Oncology — Fri, 30 Dec 2011 16:43:29 +0100

Abstract Chronic myelogenous leukemia (CML) is a common myeloproliferative disease that is characterized by the clonal expansion of marrow stem cells, and is associated with the Philadelphia chromosome. As the disease progresses, additional chromosome abnormalities may arise. The prognostic impact of secondary chromosomal abnormalities in CML is complex, heterogeneous, and sometimes related to previous treatment. Here, we describe a CML patient in lymphoid blast crisis associated with a new chromosomal abnormality identified, dic(7;12)(p12.21;p12.2) and i(12)(q10) using classical cytogenetics and spectral karyotype analysis. To the best of our knowledge, this is the first report of t(7;12)(p11.1;q11.1) and i(12)(q10) in a CML patient with lymphoid evolution. Content Ty...

Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase

European Journal of Clinical Pharmacology — Fri, 30 Dec 2011 07:09:47 +0100

Conclusions There is a less than proportional dose-exposure relationship between nilotinib 300 mg and 400 mg twice-daily doses. Blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed CML treated with nilotinib. Content Type Journal ArticleCategory Pharmacokinetics and DispositionPages 1-11DOI 10.1007/s00228-011-1200-7Authors Richard A. Larson, University of Chicago, Chicago, IL, USAOphelia Q. P. Yin, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USAAndreas Hochhaus, Universitätsklinikum Jena, Jena, GermanyGiuseppe Saglio, University of Turin, Orbassano, ItalyRichard E. Clark, Royal Liverpool University Hospital, Liverpool, UKHirohisa Nakamae, Osaka City University, Osaka, JapanNeil J....

Chronic phase chronic myeloid leukemia patients with low OCT-1 activityrandomised to high-dose imatinib achieve better responses, and lower failure rates, than those randomized to standard-dose.

Haematologica — Thu, 29 Dec 2011 05:00:00 +0100

Conclusions. High dose imatinib leads to superior molecular responses in patients with low OCT-1 activity. In this group trough imatinib levels may define a group with inferior outcomes. For high OCT-1 activity patients higher imatinib dosing or monitoring of imatinib trough levels were not found to be of significant clinical value. Hence OCT-1 activity determined prior to the start of therapy in newly diagnosed CML patients provides a valuable prognostic tool to determine the optimal up-front dose of imatinib in newly diagnosed chronic phase chronic myeloid leukaemia patients. PMID: 22207690 [PubMed - as supplied by publisher] (Source: Haematologica)

Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a src-dependent fashion

Angiogenesis — Tue, 27 Dec 2011 17:01:16 +0100

Abstract Exosomes, microvesicles of endocytic origin released by normal and tumor cells, play an important role in cell-to-cell communication. Angiogenesis has been shown to regulate progression of chronic myeloid leukemia (CML). The mechanism through which this happens has not been elucidated. We isolated and characterized exosomes from K562 CML cells and evaluated their effects on human umbilical endothelial cells (HUVECs). Fluorescent-labeled exosomes were internalized by HUVECs during tubular differentiation on Matrigel. Exosome localization was perinuclear early in differentiation, moving peripherally in cells undergoing elongation and connection. Exosomes move within and between nanotubular structures connecting the remodeling endothelial cells. They stimulated angiot...

Imatinib in chronic myeloid leukemia elderly patients.

Aging — Tue, 27 Dec 2011 05:00:00 +0100

Authors: Gugliotta G, Castagnetti F, Palandri F, Baccarani M, Rosti G Abstract Second generation tyrosine kinase inhibitors (dasatinib and nilotinib) as front-line therapy showed higher response rates and lower toxicities compared to IM; probably these results will be confirmed also in elderly patients. Importantly, extra-hematologic toxicities are distinct between IM, dasatinib and nilotinib, allowing the selection of the more appropriate drug in relation to the presence of co-morbidities. Although data on dasatinib and nilotinib in elderly patients are still few and the follow-up is still short, these second generation tyrosine kinase inhibitors will probably further improve the outcome of CML elderly patients. PMID: 22203437 [PubMed - as supplied by publisher] (Source: Aging...

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Therapeutic additions and possible deletions in oncology in 2011.

Clinical Pharmacology and Therapeutics — Sun, 25 Dec 2011 12:31:20 +0100

Authors: Holstein SA, Hohl RJ Abstract Approval of agents for the treatment of cancers by the US Food and Drug Administration (FDA) was granted to only six new chemical entities in the three years spanning 2008 to 2010. By contrast, in the first nine months of 2011, six new chemical entities were approved for use in cancer. This approval rate is unprecedented and reflects the advances in science since the approval of the first monoclonal antibody (rituximab) in 1997 and the first targeted small-molecule tyrosine kinase inhibitor (imatinib) in 2001 for non-Hodgkin's lymphoma and chronic myelogenous leukemia, respectively. Here we briefly discuss the newly approved agents, a possible deletion from the therapeutic armamentarium, and the use of the FDA accelerated approval process. ...

Two New Winners for CML?Two New Winners for CML?

Medscape Today Headlines — Fri, 23 Dec 2011 15:40:44 +0100

The drugs keep coming -- and the results remain impressive -- for treatment of chronic myeloid leukemia. Medscape Hematology-Oncology (Source: Medscape Today Headlines)

Leukemic spleen cells are more potent than bone marrow-derived cells in a transgenic mouse model of CML

Leukemia — Fri, 23 Dec 2011 05:00:00 +0100

Authors: M Schemionek, T Spieker, L Kerstiens, C Elling, M Essers, A Trumpp, W E Berdel, C Müller-Tidow & S Koschmieder (Source: Leukemia)

Operational Cures After Interferon-Alpha in Patients with Chronic Myeloid Leukemia in Central and Northern Moravia

Journal of Interferon — Thu, 22 Dec 2011 20:01:30 +0100

Journal of Interferon & Cytokine Research , Vol. 0, No. 0. (Source: Journal of Interferon)

Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV

Blood — Thu, 22 Dec 2011 05:00:00 +0100

The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome–positive (Ph+) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (–Y) and 41 patients (3.6%) had ACAs except –Y; 16 of these (1.4%) were major route (second Philadelphia [Ph] chromosome, tr...

{Delta}12-prostaglandin J3, an omega-3 fatty acid-derived metabolite, selectively ablates leukemia stem cells in mice

Blood — Thu, 22 Dec 2011 05:00:00 +0100

Targeting cancer stem cells is of paramount importance in successfully preventing cancer relapse. Recently, in silico screening of public gene-expression datasets identified cyclooxygenase-derived cyclopentenone prostaglandins (CyPGs) as likely agents to target malignant stem cells. We show here that 12-PGJ3, a novel and naturally produced CyPG from the dietary fish-oil -3 polyunsaturated fatty acid eicosapentaenoic acid (EPA; 20:5) alleviates the development of leukemia in 2 well-studied murine models of leukemia. IP administration of 12-PGJ3 to mice infected with Friend erythroleukemia virus or those expressing the chronic myelogenous leukemia oncoprotein BCR-ABL in the hematopoietic stem cell pool completely restored normal hematologic parameters, splenic histology, and enhanced surviva...

Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models.

International Journal of Hematology — Thu, 22 Dec 2011 05:00:00 +0100

Authors: Doki N, Kitaura J, Uchida T, Inoue D, Kagiyama Y, Togami K, Isobe M, Ito S, Maehara A, Izawa K, Kato N, Oki T, Harada Y, Nakahara F, Harada H, Kitamura T Abstract The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph(+)) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph(+) leuk...

Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib

Leukemia — Tue, 20 Dec 2011 05:00:00 +0100

Authors: E Weisberg, A K Azab, P W Manley, A L Kung, A L Christie, R Bronson, I M Ghobrial & J D Griffin (Source: Leukemia)

Design, synthesis, and in vitro antiproliferative activity of novel Dasatinib derivatives.

Bioorganic and Medicinal Chemistry Letters — Tue, 20 Dec 2011 05:00:00 +0100

Authors: Cai J, Zhang S, Zheng M, Wu X, Chen J, Ji M Abstract Two series of novel Dasatinib derivatives have been designed and synthesized, with their in vitro cytostatic effect screened on human chronic myeloid leukemia cell line K562 and human myeloid leukemia cell line U937. Some target compounds demonstrated significant inhibitory activities against both cell lines. Compared to the contrast drug Dasatinib, 1b, 1c, 1d, 1e and 1f were found to demonstrate more potent antitumor activities. The structures of all the newly synthesized compounds were determined by (1)H NMR and (13)C NMR. PMID: 22217877 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)

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Subcutaneous Omacetaxine Effective in Chronic- or Accelerated-Phase CML Resistant to 2 or More TKIs Including Imatinib

Clinical Care Options Oncology - Leukemia — Mon, 19 Dec 2011 12:28:43 +0100

Capsule Summary - Novel, first-in-class cetaxine demonstrates efficacy in heavily pretreated patients with chronic- or accelerated-phase chronic myeloid leukemia. (Source: Clinical Care Options Oncology - Leukemia)

BCR‐ABL1 kinase domain mutations: methodology and clinical evaluation

American Journal of Hematology — Sat, 17 Dec 2011 05:00:00 +0100

AbstractThe introduction of tyrosine kinase inhibitors (TKIs), starting with Imatinib and followed by second and third generation TKIs, has significantly changed the clinical management of Chronic Myeloid Leukaemia (CML) patients. Despite their unprecedented clinical success, a proportion of patients fail to achieve complete cytogenetic remission by 12 months of treatment (primary resistance) while others experience progressive resistance after an initial response (secondary resistance). BCR‐ABL1 kinase domain (KD) mutations have been detected in a proportion of patients at the time of treatment failure, and therefore their identification and monitoring plays an important role in therapeutic decisions particularly when switching TKIs. When monitoring KD mutations in a clinical laboratory...

STIM Trial: Imatinib Safely Discontinued After Sustained Complete Molecular Remission in Patients With Chronic Myeloid Leukemia

Clinical Care Options Oncology - Leukemia — Fri, 16 Dec 2011 11:42:39 +0100

Capsule Summary - Sokal score and duration of imatinib therapy were identified as independent predictors of relapse among patients with CML who discontinued imatinib therapy after sustaining complete molecular remission for 2 or more years. (Source: Clinical Care Options Oncology - Leukemia)

Astragalus membranaceus lectin (AML) induces caspase‐dependent apoptosis in human leukemia cells

Cell Proliferation — Fri, 16 Dec 2011 05:00:00 +0100

Conclusions: Our results suggest that AML could act as a potential anti‐cancer drug. (Source: Cell Proliferation)

Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia.

Haematologica — Fri, 16 Dec 2011 05:00:00 +0100

Authors: Takahashi N, Kyo T, Maeda Y, Sugihara T, Usuki K, Kawaguchi T, Usui N, Okamoto S, Ohe Y, Ohtake S, Kitamura K, Yamamoto M, Teshima H, Motoji T, Tamaki T, Sawada K, Ohyashiki K Abstract It was recently recognized that some chronic myeloid leukemia patients with a complete molecular response could sustain that response after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase chronic myeloid leukemia patients who could discontinue imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated chronic myeloid leukemia patients, 50 were identified who discontinued imatinib for at least 6 months; of those, 43 were analyzed. Molecular recurrence was detected in 19 patients, and a complete molecular response rate was...

Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study

Blood — Thu, 15 Dec 2011 05:00:00 +0100

Patients with chronic myeloproliferative neoplasms, including essential thrombocythemia (ET), polycythemia vera (PV), and chronic myeloid leukemia (CML), are at increased risk of new hematologic malignancies, but their risk of nonhematologic malignancies remains unknown. In the present study, we assessed the risk of both types of malignancies after an ET, PV, or CML diagnosis. We linked 2 population-based nationwide registries, the Danish National Registry of Patients, covering all Danish hospitals and the Danish Cancer Registry, and assessed subsequent cancer risk in a cohort of all 7229 patients diagnosed with a chronic myeloproliferative neoplasm during 1977-2008. We compared the incidence of subsequent cancer in this cohort with that expected on the basis of cancer incidence in the gen...

Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Blood — Thu, 15 Dec 2011 05:00:00 +0100

Dasatinib is a potent BCR-ABL inhibitor effective in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL) resistant/intolerant to imatinib. In the GIMEMA LAL1205 protocol, patients with newly diagnosed Ph+ ALL older than 18 years (with no upper age limit) received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy. Postremission therapy was free. Fifty-three patients were evaluable (median age, 53.6 years). All patients achieved a complete hematologic remission (CHR), 49 (92.5%) at day 22. At this time point, 10 patients achieved a BCR-ABL reduction to < 10–3. At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. A significant difference in DFS was observed between patients wh...

Shedding Light On Lymphoma Evolution With The Help Of Two Sisters

Health News from Medical News Today — Wed, 14 Dec 2011 08:00:00 +0100

When a 41-year-old woman was diagnosed with chronic-phase chronic myeloid leukemia, she received a bone marrow transplant and subsequent leukocyte infusion from her sister. These treatments controlled her leukemia, but seven years later, both sisters developed follicular lymphoma. Although the phenomenon of a donor passing a malignancy to a recipient is well documented and considered a minimal risk to those in the transplant community, this case gave scientists the unique opportunity to understand the genetic abnormalities that led to follicular lymphoma in both cases... (Source: Health News from Medical News Today)

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In vitro evaluation of the anti-proliferative activities of the wood essential oils of three Cedrus species against K562 human chronic myelogenous leukaemia cells.

Natural Product Research — Wed, 14 Dec 2011 05:00:00 +0100

Authors: Saab AM, Lampronti I, Borgatti M, Finotti A, Harb F, Safi S, Gambari R Abstract There are four kinds of Cedar: Cedrus libani naturally occurring in Lebanon, Syria and Turkey, Cedrus atlantica in Morocco and Algeria, Cedrus brevefolia in Cyprus Island and Cedrus deodara which is distributed in Himalayan Mountains. Wood essential oils obtained from C. libani, C. atlantica and C. deodara were tested for the inhibition of K562 cell proliferation and for the induction of erythroid differentiation. The wood essential oils of C. libani, C. atlantica and C. deodara inhibited the proliferation of the K562 cell line exhibiting IC(50) values 23.38 ± 1.7, 59.37 ± 2.6 and 37.09 ± 1.4 µg mL(-1), respectively. Meanwhile, C. libani wood oils induced a percentage of ery...

How Lymphoma Evolves - A Study Of Two Sisters

Health News from Medical News Today — Tue, 13 Dec 2011 17:00:00 +0100

A 41-year-old woman with chronic-phase chronic myeloid leukemia received a bone marrow transplant and subsequent leukocyte infusion from her sister to control her leukemia, however seven years on, both sisters developed follicular lymphoma. Cases whereby donors pass on a malignancy to their recipients are well documented and usually of minimal risk to those in the transplant community, however this case presented scientists with the opportunity to study genetic abnormalities, which led to follicular lymphoma in both cases... (Source: Health News from Medical News Today)

Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase

Leukemia — Tue, 13 Dec 2011 05:00:00 +0100

Authors: F J Giles, H M Kantarjian, P D le Coutre, M Baccarani, F-X Mahon, R E Blakesley, N J Gallagher, K Gillis, S L Goldberg, R A Larson, A Hochhaus & O G Ottmann (Source: Leukemia)

Nilotinib and MEK Inhibitors Induce Synthetic Lethality through Paradoxical Activation of RAF in Drug-Resistant Chronic Myeloid Leukemia

Cancer Cell — Tue, 13 Dec 2011 00:00:00 +0100

Leisl M. Packer, Sareena Rana, Robert Hayward, Thomas O'Hare, Christopher A. Eide, Ana Rebocho, Sonja Heidorn, Matthew S. Zabriskie, Ion Niculescu-Duvaz, Brian J. Druker, Caroline Springer, Richard Marais. We show that imatinib, nilotinib, and dasatinib possess weak off-target activity against RAF and, therefore, drive paradoxical activation of BRAF and CRAF in a RAS-dependent manner. Critically, be.... (Source: Cancer Cell)

Cancer-Related Pathway Reveals Potential Treatment Target For Rare Pediatric Disease Cherubism

Health News from Medical News Today — Mon, 12 Dec 2011 08:00:00 +0100

Cancer researchers studying genetic mutations that cause leukemia have discovered a connection to the rare disease cherubism, an inherited facial bone disorder in children. The link is the enzyme Tankyrase and its pivotal role in switching on or off the protein that controls two known cancer genes. In normal cells, the protein is vital for bone development. In abnormal cells, it is thought to be involved in two common types of blood cancer - chronic myelogenous leukemia and acute myeloid leukemia. The findings, published online today in CELL (DOI: 10.1016/j.cell.2011.10... (Source: Health News from Medical News Today)

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Treatment with Interferon alpha prior to discontinuation of Imatinib in patients with chronic myeloid leukemia.

Cytokine — Mon, 12 Dec 2011 05:00:00 +0100

This study is registered with ClinicalTrials.gov, number NCT00297570. PMID: 22169779 [PubMed - as supplied by publisher] (Source: Cytokine)

Imatinib has the potential to exert its antileukemia effects by down-regulating hERG1 K+ channels in chronic myelogenous leukemia

Medical Oncology — Fri, 09 Dec 2011 17:08:35 +0100

Abstract Imatinib is a powerful protein tyrosine kinase (PTK) inhibitor that specifically targets BCR-ABL, KIT, and PDGFR kinases, has become the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Beside PTKs, PTK inhibitors alter the activity of a large number of voltage-dependent ion channels. hERG1 K+ channels are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis. The present study explored a possible regulatory effect of imatinib upon hERG1 K+ channels as a means to uncover new molecular events involved in the antileukemic activity of this PTK inhibitor in CML. The results demonstrated that hERG1 was highly detected in K562 cells and primary CML cells, and down-regulated by imatinib at mRNA...

Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

BMC Cancer — Fri, 09 Dec 2011 05:00:00 +0100

Conclusions: Our data reveal that BCR-ABL can regulate TA at multiple levels, including transcription, post-translational level, and proper localization. Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment may be partially due to TA inhibition. Additionally, we have identified STAT5a as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells, suggesting that targeting STAT5a may be a promising therapeutic strategy for BCR-ABL positive CML patients. (Source: BMC Cancer)

Residual normal stem cells can be detected in newly diagnosed chronic myeloid leukemia patients by a new flow cytometric approach and predict for optimal response to imatinib

Leukemia — Fri, 09 Dec 2011 05:00:00 +0100

Authors: J J W M Janssen, W Deenik, K G M Smolders, B J van Kuijk, W Pouwels, A Kelder, J J Cornelissen, G J Schuurhuis & G J Ossenkoppele (Source: Leukemia)

The role of body mass index and other body composition parameters in early post-transplant complications in patients undergoing allogeneic stem cell transplantation with busulfan-cyclophosphamide conditioning.

International Journal of Hematology — Fri, 09 Dec 2011 05:00:00 +0100

This study was conducted to determine whether body mass index (BMI) and other body composition parameters, such as lean body mass index (LBMI) and body fat mass (BFM), are associated with early post-transplantation toxicity and mortality in allogeneic HSCT recipients. The records of 71 patients diagnosed with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or myelodysplastic leukemia (MDS) who had undergone allogeneic HSCT with a conditioning regimen of busulfan-cyclophosphamide (Bu-Cy), between September 2003 and January 2009 at the Stem Cell Transplantation Unit of Gazi University Hospital were retrospectively evaluated. BMI was found to be negatively correlated with the NCI grade of mucositis, cardiotoxicity, emesis, and hyperglycemia, a...

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Effect of siRNA targeting Ets2 gene on chemosensitization of human acute monocytic leukemic cell line SHI-1

The Chinese-German Journal of Clinical Oncology — Thu, 08 Dec 2011 18:17:30 +0100

Conclusion The high-level expression of Ets2 transcription factor in leukemia cells were connected with proliferation and anti-apoptosis of leukemia cells. with proliferation and anti-apoptosis of leukemia cells. SiRNA mediated Ets2 gene silencing induced cell apoptosis and enhanced in vitro sensitivity to chemotherapy (VP-16) of SHI-1 cells. in vitro sensitivity to chemotherapy (VP-16) of SHI-1 cells. It speculated the high-level expression of Ets2 may actually be an unfavorable determinant of chemotherapy sensitivity in leukemia. be an unfavorable determinant of chemotherapy sensitivity in leukemia. Content Type Journal ArticlePages 726-729DOI 10.1007/s10330-011-0864-xAuthors Chun Huang, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong ...

NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights

Blood — Thu, 08 Dec 2011 05:00:00 +0100

Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodoma...

Antileukemic effects of AMPK activators on BCR-ABL-expressing cells

Blood — Thu, 08 Dec 2011 05:00:00 +0100

We report that AMPK activators, such as metformin and 5-aminoimidazole-4-carboxamide ribonucleotide, suppress activation of the mTOR pathway in BCR-ABL–expressing cells. Treatment with these inhibitors results in potent suppression of chronic myeloid leukemia leukemic precursors and Ph+ acute lymphoblastic leukemia cells, including cells expressing the T315I-BCR-ABL mutation. Altogether, our data suggest that AMPK is an attractive target for the treatment of BCR-ABL–expressing malignancies and raise the potential for use of AMPK activators in the treatment of refractory chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. (Source: Blood)

Molecular Pathways: BCR-ABL.

Clinical Cancer Research — Thu, 08 Dec 2011 05:00:00 +0100

Authors: Cilloni D, Saglio G Abstract Aberrant Tyrosine kinase (TK) activity is critical in many hematological disorders, including chronic myeloid leukemia (CML) characterized by the constitutive activity of BCR-ABL. ABL therefore represented a crucial target for new therapeutic strategies. The molecular pathways abnormally activated by the oncoprotein are summarized and they may represent additional opportunities to develop new drugs to overcome the resistance to TK inhibitors. Among them the PI3K/Akt pathway can be effectively blocked by mTOR inhibitors, or RAS pathway, resulting MEK1/2 and MAPK activation can be targeted. Furthermore, mitotic kinases can be blocked by Aurora kinase inhibitors or Pim kinases by selective serine-threonine kinase inhibitors. Finally, the abnormal ...

Analysis of altered proteins related to blast crisis in chronic myeloid leukemia by proteomic study.

International Journal of Laboratory Hematology — Wed, 07 Dec 2011 05:00:00 +0100

Conclusion: A group of proteins associated with BC can be obtained and the result of this study might provide clues for further research. PMID: 22145801 [PubMed - as supplied by publisher] (Source: International Journal of Laboratory Hematology)

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NICE issues preliminary recommendations (ACD) on dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia

NeLM - News — Tue, 06 Dec 2011 05:00:00 +0100

Source: NICE Area: News The National Institute for Health and Clinical Excellence (NICE) is producing guidance on using dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia (CML) within the NHS in England and Wales. Preliminary recommendations have now been published for consultation, as follows: . Nilotinib is recommended as an option for the first-line treatment of chronic phase Philadelphia-chromosome-positive CML in adults if the manufacturer continues to make nilotinib available with the discount agreed as part of the patient access scheme. . Standard-dose imatinib is recommended as an option for the first-line treatment of adults with chronic phase Philadelphia-chromosome-positive CML. ...

Hematological cancer: BCR-ABL1 level at 3 months predicts outcome

Nature Clinical Practice Oncology — Tue, 06 Dec 2011 05:00:00 +0100

Nature Reviews Clinical Oncology 9, 4 (2012). doi:10.1038/nrclinonc.2011.194 A single measurement of BCR-ABL1 transcripts 3 months after imatinib treatment is the best way to identify the patients who will not respond well, according to a study of 282 patients with chronic-phase chronic myeloid leukemia. Patients with elevated transcript levels at 3 months (Source: Nature Clinical Practice Oncology)

Does Hypereosinophilic Syndrome Precede Common B Acute Lymphoblastic Leukaemia in Childhood? A Case Report.

Acta Haematologica — Tue, 06 Dec 2011 05:00:00 +0100

Authors: Ayhan AC, Timur C, Ayhan Y, Cakır B, Erguven M Abstract Hypereosinophilic syndrome (HES) and the association of hypereosinophilia with acute lymphoblastic leukaemia (ALL) are both rare in children. Some acute myelogenous leukaemias can present with eosinophilia, but the relationship between HES and ALL is not well known and is rarer than the relationship between HES and acute myelogenous leukaemia. Patients are diagnosed with HES when no cause is found to explain the eosinophilia leading to end organ damage. For this reason, it is recommended that patients presenting with hypereosinophilia be carefully assessed to exclude any malignant clonal proliferation. HES may present with severe clinical manifestations such as high leucocyte count, anaemia, thrombocytopaenia, hepato...

Inhibition of the NADPH oxidase regulates heme oxygenase 1 expression in chronic myeloid leukemia

Cancer — Fri, 02 Dec 2011 05:00:00 +0100

CONCLUSIONS:BCR‐ABL1 expression up‐regulated HO‐1, a survival factor for CML cells. This up‐regulation was more pronounced in blast crisis CML relative to early stage disease and was mediated by the NADPH oxidase components Rac1 and p47phox. The expression of p47phox was increased in BCR‐ABL1–expressing cells. Cancer 2011. © 2011 American Cancer Society. (Source: Cancer)

Imatinib does not impair gonadal function

Leukemia Research — Fri, 02 Dec 2011 05:00:00 +0100

The Bcr-Abl tyrosine kinase inhibitor, imatinib, was introduced into the armamentarium for the treatment of chronic myeloid leukemia (CML) and has revolutionized the management and significantly improved the long term prognosis of the disease. Durable clinical responses are now achievable in a significant number of chronic phase CML patients and their projected survival is expected to be more than 10–15 years . Imatinib is generally well tolerated and many patients can expect to have a normal quality of life. A recent report has also suggested that imatinib can possibly be interrupted safely in patients who have had sustained complete molecular responses . This positive outlook has raised the expectations of many patients in the childbearing age group who may want to parent children. (So...

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Identification of Side Effects Associated With Intolerance to BCR-ABL Inhibitors in Patients With Chronic Myeloid Leukemia.

Clinical Journal of Oncology Nursing — Thu, 01 Dec 2011 05:00:00 +0100

Authors: Rios MB, Ault P Abstract Clinical intolerance occurs when the toxicity of a medication outweighs its clinical benefit. Early recognition of clinical intolerance to BCR-ABL inhibitors used for chronic myeloid leukemia (CML) is important for maximizing patient benefit. In CML, most side effects associated with BCR-ABL inhibitor therapy are mild and easily managed, so recognizing, monitoring, and addressing serious side effects may ensure optimal outcome. However, a subset of patients will be intolerant to first-line imatinib. Patients who experience unresponsive grade 3 or any grade 4 nonhematologic side effects to imatinib may require discontinuation and switching to second-line therapies, such as dasatinib or nilotinib, after identification of intolerance. The most common ...

Analysis of altered proteins related to blast crisis in chronic myeloid leukemia by proteomic study

Clinical and Laboratory Haematology — Thu, 01 Dec 2011 05:00:00 +0100

Conclusion: A group of proteins associated with BC can be obtained and the result of this study might provide clues for further research. (Source: Clinical and Laboratory Haematology)

Overexpression of SET is a recurrent event associated with poor outcome that contributes to protein phosphatase 2A inhibition in acute myeloid leukemia.

Haematologica — Thu, 01 Dec 2011 05:00:00 +0100

Conclusions. These findings suggest that SET overexpression represents a key mechanism to inhibit PP2A in acute myeloid leukemia, and that EVI1 overexpression contributes to deregulate SET. Furthermore, SET overexpression is associated with poor outcome in acute myeloid leukemia, and it can be used to identify a subgroup of patients that could benefit from future treatments based on PP2A activators. PMID: 22133779 [PubMed - as supplied by publisher] (Source: Haematologica)

Efficacy of combining dasatinib and intensive chemotherapy for patients with chronic myeloid leukemia in blastic transformation.

Haematologica — Thu, 01 Dec 2011 05:00:00 +0100

Authors: Milojkovic D, Ibrahim A, Reid A, Foroni L, Apperley J, Marin D Abstract In this paper we show that dasatinib can be safely combined with conventional chemotherapy and although this approach should be tested in a larger number of patients the combination seems to induce deep remissions in patients with CML in blastic phase allowing for further therapeutic strategies to enable a continuing response. PMID: 22133777 [PubMed - as supplied by publisher] (Source: Haematologica)

Targeting the Microenvironment in Hematological Malignancies: How to Condition both Stromal and Effector Cells to Overcome Cancer Spreading.

Current Medicinal Chemistry — Thu, 01 Dec 2011 05:00:00 +0100

In this study, the effects of cholesterol synthesis inhibitors, such as statins, on the interaction between BMSC and T lymphocytes or on natural killer cell-mediated functions is analyzed and compared with other drugs known to act on BMSC, including thalidomide or lenalidomide. Besides lowering the plasma lipid levels, statins indeed show strong anti-inflammatory and immunomodulatory effects. On the other hand, these drugs can affect growth and survival of solid tumour and leukaemic cells, thus they have been proposed in the treatment of multiple myeloma, in association with drugs, as thalidomide, known to act on the cancer microenvironment.Kabelitz and co-workers move to the control of the balance between effector T (Teff) and regulatory T cells (Tregs). In particular they present data su...

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Chronic myeloid leukemia: the basis of treatment for tomorrow.

Haematologica — Thu, 01 Dec 2011 05:00:00 +0100

Authors: Carella AM, Goldman JM, Martinelli G, Melo JV, Perrotti D PMID: 22147770 [PubMed - in process] (Source: Haematologica)

Imatinib plasma trough levels in chronic myeloid leukaemia: results of a multicentre study CSTI571AIL11TGLIVEC

Hematological Oncology — Thu, 01 Dec 2011 05:00:00 +0100

In this study, IMPLs were analysed in 191 patients with CML and were compared with achievement of molecular and cytogenetic responses (CyR). IMPLs were also correlated with renal and hepatic dysfunction. Additionally, self‐reported adherence was monitored. The median and mean IMPLs were 994 ng/mL and 1070 ± 686 ng/mL, respectively, with 96 patients (50%) achieving plasma levels >1000 ng/mL. Self‐reported patient compliance was 98%. Patients who achieved a complete CyR (CCyR) had significantly higher IMPLs (1078 ± 545 ng/mL) than those without CyR (827 ± 323 ng/mL, p = 0.045). When grouped together, patients who achieved a CCyR or partial CyR had significantly higher IMPLs than patients who achieved a minimal CyR or did not achieve a CyR (1066 ng/mL vs ...

Sequential transient novel chromosomal translocations in a patient with chronic myelogenous leukemia in complete cytogenetic remission after therapy with imatinib mesylate

Cancer Genetics and Cytogenetics — Thu, 01 Dec 2011 05:00:00 +0100

Imatinib mesylate (IM) is the first tyrosine kinase inhibitor (TKI) introduced for the treatment of chronic myelogenous leukemia (CML) with remarkable high rates of complete hematologic and cytogenetic response and an acceptable safety and toxicity profile. Clonal aberrations (CAs) in Philadelphia (Ph)-chromosome negative metaphases have been reported in patients with CML after treatment with IM, with a varying frequency between series (1.6–20.6%) . Most CAs are numerical aberrations, whereas structural aberrations, in particular, balanced translocations are much less frequent . (Source: Cancer Genetics and Cytogenetics)

DOK2 as a Marker of Poor Prognosis of Patients with Gastric Adenocarcinoma After Curative Resection

Annals of Surgical Oncology — Wed, 30 Nov 2011 18:52:36 +0100

Conclusions Our data suggest the potential usefulness of DOK2 as a marker of poor prognosis in patients with gastric cancer after curative resection. Content Type Journal ArticleCategory Gastrointestinal OncologyPages 1-8DOI 10.1245/s10434-011-2157-6Authors Hiromichi Miyagaki, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, JapanMakoto Yamasaki, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, JapanTsuyoshi Takahashi, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, JapanYukinori Kurokawa, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, JapanHiroshi Miyata, Department of Gastroent...

ABCB1 haplotype is associated with major molecular response in chronic myeloid leukemia patients treated with standard-dose of imatinib.

Blood Cells, Molecules and Diseases — Tue, 29 Nov 2011 05:00:00 +0100

CONCLUSIONS: The ABCB1 1236CT/2677GT/3435CT haplotype is positively associated with the major molecular response to IM in CML patients. PMID: 22134106 [PubMed - as supplied by publisher] (Source: Blood Cells, Molecules and Diseases)

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Characterization of binding mode of imatinib to human α(1)-acid glycoprotein.

International Journal of Biological Macromolecules — Tue, 29 Nov 2011 05:00:00 +0100

Authors: Fitos I, Simon A, Zsila F, Mády G, Bencsura A, Varga Z, Orfi L, Kéri G, Visy J Abstract Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α(1)-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases ...

Live birth with vitrified-warmed oocytes of a chronic myeloid leukemia patient nine years after allogenic bone marrow transplantation

Journal of Assisted Reproduction and Genetics — Thu, 24 Nov 2011 17:49:49 +0100

Content Type Journal ArticleCategory Fertility PreservationPages 1-4DOI 10.1007/s10815-011-9681-yAuthors Mi Kyoung Kim, Department of Obsterics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, 606-13 Yeoksam-dong, Gangnam-gu, Seoul, 135-081 South KoreaDong Ryul Lee, Department of Biomedical Science, Fertility Center of CHA Gangnam Medical Center, CHA University, 606-13 Yeoksam-dong, Gangnam-gu, Seoul, 135-081 South KoreaJi Eun Han, Department of Obsterics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, 606-13 Yeoksam-dong, Gangnam-gu, Seoul, 135-081 South KoreaYou Shin Kim, Department of Obsterics and Gynecology, Fertility Center of CHA Gangnam Medical Center, CHA University, 606-13 Yeoksam-dong, Gangnam-gu, Seoul, 135-081 ...

Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improve GVL and immune reconstitution

Blood — Thu, 24 Nov 2011 05:00:00 +0100

Donor T cells contribute to the success of allogeneic hematopoietic stem cell transplantation (alloSCT). Alloreactive donor T cells attack leukemia cells, mediating the GVL effect. Donor T cells, including the memory T cells (TM) that are generated after infection, also promote immune reconstitution. Nonetheless, leukemia relapse and infection are major sources of treatment failure. Efforts to augment GVL and immune reconstitution have been limited by GVHD, the attack by donor T cells on host tissues. One approach to augmenting GVL has been to infuse ex vivo–generated T cells with defined specificities; however, this requires expertise that is not widely available. In the present study, we tested an alternative approach, adoptive immunotherapy with CD8+ TM from donors vaccinated agai...

Expression of the novel NUP98/PSIP1 fusion transcripts in myelodysplastic syndrome with t(9;11)(p22;p15)

European Journal of Haematology — Tue, 22 Nov 2011 10:25:00 +0100

Conclusions: The fusion genes combining NUP98 exon 11/12 with PSIP1 exon 8, which have never been detected in other AML/CML cases, may be implicated in the pathogenesis of MDS. Furthermore, RQ‐PCR for NUP98/PSIP1 could be useful to monitor minimal residual disease. (Source: European Journal of Haematology)

Small GTPase RAB45-mediated p38 activation in apoptosis of chronic myeloid leukemia progenitor cells

Carcinogenesis — Fri, 18 Nov 2011 05:00:00 +0100

In this study, we found that treatment with ABL kinase inhibitors or depletion of BCR-ABL induced the expression of RAB45 messenger RNA and protein and induced apoptosis via reduction of mitochondrial membrane potential and p38 activation in CML cell lines and BCR-ABL+ progenitor cells from CML patients. Overexpressed RAB45 induced the activation of caspases-3 and -9 and reduced the expression of Survivin, XIAP, c-IAP1 and c-IAP2 in CML cells. Moreover, in colony-forming cells derived from CML-aldehyde dehydrogenasehi/CD34+ cells, treatment with ABL kinase inhibitors induced RAB45 expression and reduced mitochondrial membrane potential, resulting in inhibited colony formation of Bcr-Abl+ progenitor cells. The overexpression of RAB45 significantly decreased colony numbers and induced apopto...

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State of the Fight: Pancreatic Cancer

Stand Up 2 Cancer — Thu, 17 Nov 2011 20:08:21 +0100

During the week I graduated from high school, my mother was diagnosed with chronic myelogenous leukemia (CML). Today, patients with CML are treated with imatinib and do remarkably well, but at the time, there was no effective treatment available and my mother passed away three years later. Watching her battle with cancer spurred my interest in medical research. I currently study pancreatic cancer. read more (Source: Stand Up 2 Cancer)

Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment

Blood — Thu, 17 Nov 2011 05:00:00 +0100

Imatinib mesylate treatment markedly reduces the burden of leukemia cells in chronic myelogenous leukemia (CML) patients. However, patients remain at risk for relapse on discontinuing treatment. We have previously shown that residual BCR-ABL+ progenitors can be detected in CML patients within the first 2 years of imatinib treatment. However, reduced rates of relapse and continued decline of BCR-ABL levels with prolonged treatment, together with the ability of selected patients to maintain remission after discontinuing treatment, led us to investigate whether prolonged imatinib exposure resulted in reduction or elimination of BCR-ABL+ stem cells. We evaluated BCR-ABL expression in CD34+CD38+ (38+) committed progenitors and CD34+CD38– (38–) stem/primitive progenitor cells in samp...

Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

Blood — Thu, 17 Nov 2011 05:00:00 +0100

We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABLT315I mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome–positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had ...

Dasatinib Overrides Imatinib Resistance Mediated by the F359I Residue Mutation in Two Patients with Chronic Myeloid Leukemia.

Acta Haematologica — Thu, 17 Nov 2011 05:00:00 +0100

Authors: Serpa M, Sanabani SS, Dorlhiac-Llacer PE, Nardinelli L, de Barros Ferreira P, Borges Martins TF, Seguro F, Bendit I Abstract Despite the beneficial effects of imatinib mesylate, some patients may either not respond or respond suboptimally. Here, we report two chronic myelogenous leukemia patients; one had a suboptimal response according to European LeukemiaNet criteria (a major molecular response was not achieved after 18 months of standard-dose imatinib therapy) and the other had failure with a standard dose of imatinib. At the time of the suboptimal response in patient 1 and the failure in patient 2, we were able to detect the F359I mutation in the BCR-ABL tyrosine kinase domain using DNA sequencing in both patients. Therefore, it was decided to change the therapeutic re...

Primary myelofibrosis: 2012 update on diagnosis, risk stratification, and management

American Journal of Hematology — Thu, 17 Nov 2011 01:32:36 +0100

AbstractDisease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell‐derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.Diagnosis: Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation or +9/13q‐ cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute my...

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Enhanced ABL-inhibitor-induced MAPK-activation in T315I-BCR-ABL-expressing cells: a potential mechanism of altered leukemogenicity

Journal of Cancer Research and Clinical Oncology — Wed, 16 Nov 2011 16:45:24 +0100

Conclusions Aberrant MAPK-activation triggered by ABL-inhibitors and positively regulated by BCR-ABL kinase mutation T315I might be an experimental explanation for the clinical observation that patients carrying high-resistance mutations show a highly aggressive course of their disease when tyrosine kinase inhibitor treatment is not discontinued in time. Content Type Journal ArticleCategory Original PaperPages 1-10DOI 10.1007/s00432-011-1086-xAuthors Nicolai Härtel, III. Medizinische Universitätsklinik, Universitätsmedizin Mannheim der Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, GermanyThomas Klag, Klinik f. Innere Medizin II, Abt. f. Hämatologie/Onkologie, Universitätsklinikum Jena, Erlanger Allee 101, 07740 Jena, GermanyBenjamin Hanfstei...

Dasatinib Overrides Imatinib Resistance Mediated by the F359I Residue Mutation in Two Patients with Chronic Myeloid Leukemia

Karger Publishers — Wed, 16 Nov 2011 16:30:31 +0100

Acta Haematol 2012;127:56–59 (DOI:10.1159/000333092) (Source: Karger Publishers)

Effects of BCR-ABL Inhibitors on Anti-Tumor Immunity.

Current Medicinal Chemistry — Wed, 16 Nov 2011 05:00:00 +0100

Authors: Krusch M, Salih HR Abstract In chronic myeloid leukemia (CML), BCR-ABL-mediated oncogenic signaling can be successfully targeted with the BCRABL- inhibitors imatinib, nilotinib, and dasatinib leading to complete cytogenetic (Philadelphia chromosome not detectable upon cytogenetic testing of bone marrow) and even complete molecular (BCR-ABL not detectable by PCR in peripheral blood) responses. However, CML apparently can not be cured by BCR-ABL inhibitors alone, likely due to treatment-resistance of CML stem/progenitor cells, which provokes a relapse of disease after cessation of therapy. Evidence from patients treated with allogenic stem cell transplantation or IFN-α points to an important role of anti-tumor immunity for durable control of CML disease. Data from multiple ...

IL-6 Controls Leukemic Multipotent Progenitor Cell Fate and Contributes to Chronic Myelogenous Leukemia Development

Cancer Cell — Tue, 15 Nov 2011 00:00:00 +0100

Damien Reynaud, Eric Pietras, Keegan Barry-Holson, Alain Mir, Mikhail Binnewies, Marion Jeanne, Olga Sala-Torra, Jerald P. Radich, Emmanuelle Passegué. Using a mouse model recapitulating the main features of human chronic myelogenous leukemia (CML), we uncover the hierarchy of leukemic stem and progenitor cells contributing to disease pathogenesi.... (Source: Cancer Cell)

Aberrant expressions of leptin and adiponectin receptor isoforms in chronic myeloid leukemia patients.

Cytokine — Sat, 12 Nov 2011 05:00:00 +0100

CONCLUSION: While the decrease in leptin receptor levels in CML patients was confirmed, the increase in AdipoR1 levels and relevant decrease in AdipoR2 levels depicted their possible involvement in CML pathogenesis. This suggests different functions of adiponectin receptors in CML development. PMID: 22082804 [PubMed - as supplied by publisher] (Source: Cytokine)

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Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results

Leukemia — Fri, 11 Nov 2011 05:00:00 +0100

Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results Leukemia advance online publication, November 11, 2011. doi:10.1038/leu.2011.323 Authors: P D le Coutre, F J Giles, A Hochhaus, J F Apperley, G J Ossenkoppele, R Blakesley, Y Shou, N J Gallagher, M Baccarani, J Cortes & H M Kantarjian (Source: Leukemia)

Reversible opacification of a hydrophilic acrylic intraocular lens

Journal of Cataract and Refractive Surgery — Fri, 11 Nov 2011 05:00:00 +0100

A 56-year-old woman with diabetic retinopathy and chronic myelogenous leukemia had phacoemulsification cataract removal and hydrophilic acrylic intraocular lens (IOL) (Akreos MI-60) implantation in both eyes. One month after surgery, significant IOL opacity and severe cystoid macular edema were observed in both eyes. After bilateral intravitreal injection of bevacizumab (Avastin) to control macular edema, central clearing of the IOL opacity was observed in both eyes. Two months after the injection, the IOL opacity had almost disappeared from both eyes. To our knowledge, this is the first case of early postoperative bilateral IOL opacity in a hydrophilic acrylic IOL cleared after anti-vascular endothelial growth factor (VEGF) intravitreal injection. The role of anti-VEGF therapy in clearing...

Metabolic syndrome in adult cancer survivors: A meta-analysis

Diabetes Research and Clinical Practice — Fri, 11 Nov 2011 05:00:00 +0100

Conclusions: Our meta-analyses of cross-sectional studies found that adult cancer survivors with hematologic malignancies were at an increased risk of metabolic syndrome. (Source: Diabetes Research and Clinical Practice)

Chronic Myeloid Leukemia

Cancer Network — Thu, 10 Nov 2011 12:00:00 +0100

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of the primitive hematopoietic stem cell. (Source: Cancer Network)

Blood consult: high Sokal risk chronic myeloid leukemia and suboptimal response

Blood — Thu, 10 Nov 2011 05:00:00 +0100

(Source: Blood)

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The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Blood — Thu, 10 Nov 2011 05:00:00 +0100

We present cell-based and biochemical evidence establishing that BCR-ABL35INS is kinase-inactive and does not contribute to TKI resistance, and we find that detection of BCR-ABL35INS does not consistently track with or explain resistance in clinical samples from chronic myeloid leukemia patients. (Source: Blood)

Characterization of ABL exon 7 deletion by molecular genetic and bioinformatic methods reveals no association with imatinib resistance in chronic myeloid leukemia

Medical Oncology — Tue, 08 Nov 2011 19:14:51 +0100

Abstract In chronic myeloid leukemia (CML), the best characterized imatinib resistance mechanisms are BCR-ABL tyrosine kinase domain mutations and clonal evolution, but recently alternative splicing of BCR-ABL was also proposed as a mechanism for imatinib resistance. Among recently reported BCR-ABL splice variants, exon 7 deletion (Δexon7) was characterized in this study. The frequency of Δexon7 was investigated in 30 healthy controls and in 76 CML patients at different time points of the disease course by four different molecular genetic methods (direct sequencing, fragment analysis, allele-specific and quantitative PCR). The functionality and viability of the variant protein was tested by bioinformatic prediction. The Δexon7 was abundantly detected with similar freque...

Sensitive Detection of BCR-ABL1 Mutations in Patients With Chronic Myeloid Leukemia After Imatinib Resistance Is Predictive of Outcome During Subsequent Therapy [Hematologic Malignancies]

Journal of Clinical Oncology — Tue, 08 Nov 2011 05:00:00 +0100

Conclusion Detection of low-level mutations after imatinib resistance offers critical information to guide subsequent therapy selection. If an inappropriate kinase inhibitor is selected, there is a high risk of treatment failure with clonal expansion of the resistant mutant. (Source: Journal of Clinical Oncology)

Front-Line Therapy With Second-Generation Tyrosine Kinase Inhibitors in Patients With Early Chronic Phase Chronic Myeloid Leukemia: What Is the Optimal Response? [Hematologic Malignancies]

Journal of Clinical Oncology — Tue, 08 Nov 2011 05:00:00 +0100

Conclusion The use of second-generation TKIs as initial therapy in CML induces high rates of CCyR at early time points. The ELN definitions of response proposed for imatinib therapy are not applicable in this setting. We propose that achievement of CCyR and partial cytogenetic response at 3 months should be considered optimal and suboptimal responses, respectively. The achievement of MMR offered no advantage over CCyR in defining long-term outcome in patients with newly diagnosed CML treated with second-generation TKIs. (Source: Journal of Clinical Oncology)

Successful treatment of lymphoid blastic crisis in chronic myelogenous leukemia with the additional bcr/abl transcript using imatinib-combined chemotherapy and high-dose chemotherapy with allogeneic bone marrow stem cell transplantation.

International Journal of Hematology — Tue, 08 Nov 2011 05:00:00 +0100

We describe the case of a 37-year-old woman who had CML and pain in the extremities. She was diagnosed with lymphoid blast crisis of CML on the basis of the following findings: presence of promyelocytes, myelocytes, and metamyelocytes in peripheral blood smear; detection of major and minor BCR/ABL transcripts by polymerase chain reaction analysis; proliferation of lymphoblastic cells with abnormal B-cell phenotype; and aberrant expression of myeloid antigens in the bone marrow. The patient underwent one course of idarubicin and cytosine arabinose therapy combined with imatinib followed by daunorubicin/cyclophosphamide plus vincristine and prednisone/L: -asparaginase (DNR/COP/L: -ASP) therapy, high-dose cytosine arabinose, and CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and pr...

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Dasatinib as Salvage Therapy for Steroid Refractory and Imatinib Resistant or Intolerant Sclerotic Chronic Graft-versus-Host Disease

Biology of Blood and Marrow Transplantation — Mon, 07 Nov 2011 05:00:00 +0100

We present here the first direct clinical evidence, from 3 patients treated in a small single-center series, suggesting that dasatinib can be a therapeutic option for patients with severe scGVHD resistant or intolerant to imatinib. All patients achieved partial response, with improvement in scGHVD target organs severity, joint mobility, lung impairment, and deep fibrotic lesions. This clinical response has remained stable or continued to improve after a median of 22 months (20-25) on dasatinib treatment, with very good tolerance. In addition, corticosteroids could be discontinued or significantly reduced in all patients. This clinical evidence suggests that dasatinib could be a safe and effective alternative for scGVHD patients refractory to corticosteroids and resistant or intolerant to i...

Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation

Infectious Diseases in Obstetrics and Gynecology — Fri, 04 Nov 2011 01:31:20 +0100

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a “difficult-to-manage” state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the ...

Good adherence to imatinib therapy among patients with chronic myeloid leukemia—a single-center observational study

Annals of Hematology — Wed, 02 Nov 2011 16:58:15 +0100

Abstract Previous studies have suggested that adherence to imatinib therapy can be an obstacle among patients with chronic myeloid leukemia (CML). We studied adherence to imatinib therapy among CML patients treated at the Sahlgrenska University Hospital. We identified all CML patients that were alive at the 1st of January 2010 (n = 70). Nineteen patients were excluded due to a history of allogenic hematopoietic stem cell transplantation, and nine were excluded due to treatment with other tyrosine kinase inhibitors. Thirty-eight out of 42 patients (90%) treated with imatinib accepted inclusion in the study. The patients were interviewed in a structured way, and adherence was evaluated in a standardized way using the nine-item Morisky Medication Adherence Scale that range...

Imatinib has adverse effect on growth in children with chronic myeloid leukemia

Pediatric Blood and Cancer — Wed, 02 Nov 2011 04:00:00 +0100

ConclusionsGrowth retardation is a significant adverse effect of imatinib in children with CML. The failure to gain appropriate height was most discernible when imatinib was initiated in the prepubertal period. Etiology and remedial measures need to be investigated. Pediatr Blood Cancer © 2011 Wiley Periodicals, Inc. (Source: Pediatric Blood and Cancer)

Gynecomastia during imatinib mesylate treatment for gastrointestinal stromal tumor: a rare adverse event

BMC Gastroenterology — Wed, 02 Nov 2011 04:00:00 +0100

Conclusions: Testosterone levels were not decreased in the six GIST patients with gynecomastia. Three patients had increased serum estradiol level which suggests that imbalance of sex hormones may be the cause of gynecomastia during treatment with imatinib mesylate. (Source: BMC Gastroenterology)

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Tyrosine kinase inhibitor therapy for acute myeloid leukemia with late-appearing Philadelphia chromosome

Leukemia Research — Wed, 02 Nov 2011 04:00:00 +0100

Although Philadelphia chromosome (Ph) is most commonly associated with chronic myelogenous leukemia (CML) and precursor B acute lymphoblastic leukemia, in rare instances patients with acute myeloid leukemia (AML) have been reported to be carrying this chromosomal anomaly, with occurrences found to be fewer than 1% of all newly diagnosed AML . Selective BCR-ABL1 tyrosine kinase inhibitors (TKIs) induce a high molecular response rate in patients with CML. TKIs have also been reported to be effective in patients with Ph positive (Ph+) de novo AML, especially in patients undergoing post-remission therapy . While Ph chromosome can also appear in the course of AML, late-appearing Ph+ AML is extremely rare and the efficacy of TKIs in such patients remains unclear. (Source: Leukemia Research)

Enhancement of specific cellular immune response induced by glycosyl-phosphatidylinositol-anchored BCR/ABL and mIL-12.

Cancer Biology and Therapy — Tue, 01 Nov 2011 09:10:46 +0100

In this study, we sought to enhance cellular immunity by co-expression of BCR/ABL and murine IL-12 gene on the tumor cell surface as a glycosyl-phosphatidylinositol (GPI)-form. The successfully constructed plasmid pBudCE4.1-BCR/ABL-GPI-mIL12 resulted in high levels of splenocyte proliferative responses, significant levels of IL-2 and IFN-γ, and strong cytotoxic T lymphocyte (CTL) responses in vitro. In a murine transplant model, the vaccinated mice showed decreased infiltration of leukemia cells and reduced expression of BCR/ABL transcripts and protein in bone marrow cells. Results of the present study indicated that this novel immunization strategy is useful in enhancing immune protection in mice, which would provide new insights into the development of effective vaccines for treating CM...

Myelodysplastic/myeloproliferative neoplasms

Seminars in Diagnostic Pathology — Tue, 01 Nov 2011 04:00:00 +0100

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include clonal myeloid neoplasms that overlap the MDS and MPN categories and at the time of initial diagnosis exhibit some clinical, laboratory, or morphologic features supporting the diagnosis of myelodysplastic syndrome (MDS) and at the same time show proliferative features in keeping with the diagnosis of a myeloproliferative neoplasm (MPN). Although the clinical, morphologic, and laboratory findings vary along a continuum from MDS to MPN, distinctive features are usually present that allow assignment of most of the cases to 1 of 3 distinct subtypes recognized by the 2008 World Health Organization (WHO) classification: chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR-ABL-(aCML, BCR-ABL1-), and juven...

Six-year follow up of imatinib therapy for newly diagnosed chronic myeloid leukemia in Iranian patients.

Archives of Iranian Medicine — Tue, 01 Nov 2011 04:00:00 +0100

DISCUSSION: Our findings showed the efficacy and safety of imatinib mesylate among Iranian patients with chronic myeloid leukemia by hematological and molecular response. PMID: 22039840 [PubMed - in process] (Source: Archives of Iranian Medicine)

Aberrant Activation of the Hedgehog Signaling Pathway in Hematological Neoplasms.

The American Journal of Pathology — Tue, 01 Nov 2011 04:00:00 +0100

Authors: Ok CY, Singh RR, Vega F Abstract The hedgehog (HH) signaling pathway is a highly regulated signaling pathway that is important not only for embryonic development, tissue patterning, and organogenesis but also for tissue repair and the maintenance of stem cells in adult tissues. In the adult hematopoietic system, HH signaling regulates intrathymic T-cell development, and it is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in germinal center B cells. HH signaling is required for primitive hematopoiesis; however, conflicting data have been reported regarding the role of the HH pathway in adult hematopoiesis. Inappropriate activation of the HH signaling pathway occurs in several human cancers, including hematopoietic neoplasms. Emergin...

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Development of an effective therapy for chronic myelogenous leukemia.

Cancer Journal — Tue, 01 Nov 2011 04:00:00 +0100

Authors: Woessner DW, Lim CS, Deininger MW Abstract ABSTRACT: Targeted small-molecule drugs have revolutionized treatment of chronic myeloid leukemia (CML) during the last decade. These agents interrupt a constitutively active BCR-ABL, the causative agent for CML, by interfering with adenosine 5' triphosphate-dependent ABL tyrosine kinase. Although the efficacy of tyrosine kinase inhibitors (TKIs) has resulted in overall survival of greater than 90%, TKIs are not curative. Moreover, no currently approved TKIs are effective against the T315I BCR-ABL variant. However, a new generation of TKIs with activity against T315I is on the horizon. We will highlight the clinical utility of historical CML therapeutics, those used today (first- and second-generation TKIs), and discuss treatment ...

Evolution of therapies for chronic myelogenous leukemia.

Cancer Journal — Tue, 01 Nov 2011 04:00:00 +0100

Authors: Santos FP, Kantarjian H, Quintás-Cardama A, Cortes J Abstract ABSTRACT: The clinical outcome for patients with chronic myelogenous leukemia (CML) has changed dramatically in the past 15 years. This has been due to the development of tyrosine kinase inhibitors (TKIs), compounds that inhibit the activity of the oncogenic BCR-ABL1 protein. Imatinib was the first TKI developed for CML, and it led to high rates of complete cytogenetic responses and improved survival for patients with this disease. However, approximately 35% of patients in chronic phase treated with imatinib will develop resistance or intolerance to this drug. The recognition of the problem of imatinib failure led to the design of second-generation TKI (dasatinib, nilotinib, and bosutinib). These drugs are high...

Leaf extracts from Nitraria retusa promote cell population growth of human cancer cells by inducing apoptosis

Cancer Cell International — Mon, 31 Oct 2011 04:00:00 +0100

Conclusion: Our results indicate that the tested compounds have a significant antiproliferative effect which may be due to their involvement in the induction of the extrinsic apoptosic pathway. (Source: Cancer Cell International)

TMTP1, a novel tumor-homing peptide, specifically targets hematological malignancies and their metastases

Journal of Huazhong University of Science and Technology -- Medical Sciences -- — Fri, 28 Oct 2011 16:51:18 +0100

In this study, TMTP1 was assessed for its ability to specifically target the malignant hematopoietic cells and metastatic lesions of hematological malignancies. FITC-TMTP1 was chemically synthesized. Immunofluorescence assay and competitive test were carried out to determine the specific binding capacity of TMTPl to hematological malignant cell lines, including HL60, k562, SHI-1, Jurkat, Raji, El–4 and umbilical cord blood mononuclear cells. Mononuclear cells were isolated from the bone marrow of healthy subjects and patients with chronic myeloid leukemia. Then the cells were co-clutured with TMTP1 or scrambled peptides and the binding and affinity of TMTP1 peptide to the primary cells of hematological malignancies were flow cytometrically analyzed. The binding specificity of TMTP1...