MedWorm: Chronic Leukemia

Chronic Lymphocytic Leukemia

Clinical Care Options Oncology - Leukemia — Tue, 07 Feb 2012 15:36:47 +0100

Learning Module - In this CME-certified slideset, John C. Byrd, MD, and Kanti Rai, MD, explore the most compelling data in chronic lymphocytic leukemia presented in San Diego. (Source: Clinical Care Options Oncology - Leukemia)

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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...

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...

[Comment] XMRV and CFS—the sad end of a story

LANCET — Sat, 04 Feb 2012 05:00:00 +0100

Scientific papers on chronic fatigue syndrome (CFS) often evoke much debate and emotional reaction, as exemplified by the recent discussions in The Lancet on the PACE trial. Also, the potential role of a retrovirus in CFS kindled a fierce controversy which has recently culminated. In 2009, in Science, Lombardi and colleagues described the occurrence of the xenotropic murine leukaemia virus (MLV)-related virus (XMRV), a gammaretrovirus, in white blood cells in 67% of patients with CFS and in 3·7% of healthy controls. (Source: LANCET)

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...

Growth factor‐associated graft‐versus‐host disease and mortality 10 years after allogeneic bone marrow transplantation

British Journal of Haematology — Thu, 02 Feb 2012 05:00:00 +0100

This study analysed the effects of growth factor on outcome after haematopoietic stem‐cell transplantation (HSCT) with >9 years follow‐up. Of 1887 adult patients with acute leukaemia who received bone marrow from human leucocyte antigen (HLA)‐identical siblings and were treated with myeloablative conditioning, 459 (24%) were treated with growth factor. Growth factor hastened engraftment of neutrophils (P < 0·0001), but reduced platelet counts (P = 0·0002). Graft‐versus‐host disease (GVHD)‐free survival (no acute GVHD grade II–IV or chronic GVHD) at 10 years was 12 ± 2% (±SE) in the growth factor group, as opposed to 17 ± 2% in the controls [hazard ratio (HR) 0·81, P = 0·001]. Similar differences in GVHD‐free survival were seen in patients with or wi...

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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)

Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia

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

Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition–induced expression of miR-1...

The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

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

In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhib...

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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Integration of Next-Generation Sequencing Into Clinical Practice: Are We There Yet?

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

Next-generation sequencing (NGS) platforms have evolved to provide an accurate and comprehensive means for the detection of molecular mutations in heterogeneous tumor specimens. Here, we review potential applications of this novel laboratory technology. In particular, we focus on the utility of amplicon deep-sequencing assays in characterizing myeloid neoplasms where the number of molecular markers applied for disease classification, patient stratification, and individualized monitoring of minimal residual disease is constantly increasing. We highlight the potential of this technology by discussing data from a recent study on chronic myelomonocytic leukemia (CMML). Although many facets of this assay need to be taken into account, eg, the preparation of sequencing libraries with molecular b...

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...

Pathologic and Molecular Genetic Features of Chronic Lymphocytic Leukemia

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

Chronic lymphocytic leukemia (CLL) is an indolent B-cell leukemia. While many patients may not require therapy, some patients will suffer a progressive course and die of their disease. This clinical heterogeneity is reflected in the molecular genetic heterogeneity that is becoming apparent through studies of immunoglobulin heavy chain gene mutational status, chromosomal numerical abnormalities, microRNA abnormalities, and genetic abnormalities identified by whole genome sequencing. Indeed, many of these studies are becoming routine in the assessment of patients with CLL or being incorporated into clinical trials to further stratify patients for appropriate therapies. Here, we will review the morphologic, immunophenotypic, and molecular genetic features of CLL and touch upon the concept of ...

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)

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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)

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)

IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia

Journal of Translational Medicine — Mon, 30 Jan 2012 05:00:00 +0100

Conclusions: Data indicate that IGHV mutational status and 17p deletion may be integrated with clinical-demographic variables in new prognostic tools to estimate overall survival. (Source: Journal of Translational Medicine)

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...

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Obesity in patients with Acute Lymphoblastic Leukemia in childhood

Italian Journal of Pediatrics — Fri, 27 Jan 2012 05:00:00 +0100

Acute lymphoblastic leukemia is the most common malignancy in childhood. Continuous progress in risk-adapted treatment for childhood acute lymphoblastic leukemia has secured 5-year event-free survival rates of approximately 80% and 8-year survival rates approaching 90%. Almost 75% of survivors, however, have a chronic health condition negatively impacting on cardiovascular morbidity and mortality. Obesity can be considered one of the most important health chronic conditions in the general population, with an increasing incidence in patients treated for childhood cancers and especially in acute lymphoblastic leukemia survivors who are, at the same time, more at risk of experiencing precocious cardiovascular and metabolic co-morbidities. The hypothalamic-pituitary axis damage secondary to ca...

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 ...

Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

Blood — Thu, 26 Jan 2012 05:00:00 +0100

Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal c...

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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Caregiving Burden, Stress, and Health Effects Among Family Caregivers of Adult Cancer Patients [Grand Rounds]

JAMA — Tue, 24 Jan 2012 05:00:00 +0100

This report describes a case that exemplifies caregiving burden and discusses the importance of identifying caregivers at risk of negative health outcomes and intervening to attenuate the stress associated with the caregiving experience. (Source: JAMA)

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)

No Link Between XMRV and Chronic Fatigue Syndrome

Sound Medicine — Sun, 22 Jan 2012 05:00:00 +0100

At the end of 2011, two prestigious scientific journals, Science and Proceedings of the National Academy of Sciences, both retracted papers on a reported an association between a mouse leukemia virus called XMRV and Chronic Fatigue Syndrome. UC San Francisco virus expert Jay Levy, MD, the man who first discovered XMRV back in the 1970s, was one of the early skeptics. Today on Sound Medicine.... (Source: Sound Medicine)

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)

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Flavopiridol treatment of patients aged 70 or older with refractory or relapsedchronic lymphocytic leukemia is a feasible and active therapeutic approach.

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

Authors: Stephens D, Ruppert AS, Blum K, Jones J, Flynn J, Johnson A, Ji J, Phelps M, Grever M, Byrd J Abstract Older chronic lymphocytic leukemia patients have poor outcomes with standard treatments and are underrepresented in clinical trials. We retrospectively reviewed outcomes of refractory chronic lymphocytic leukemia patients in two age categories [≥70, <70 years] treated with single-agent flavopiridol, a drug active in genomically high-risk patients, during two trials. No significant difference between older and younger patients was observed in response rates (43% versus 47%) or progression-free survival (median=8.7 versus 9.9 months, p>0.80). Although overall survival was worse in older patients (median=2.1 versus 2.4 years, p=0.02), when adjusted for other factors,...

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)

ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor proliferation and differentiation into eosinophils: role of NF-κB.

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

Conclusions. We show that human CD34+ cells expressing PDGF receptor fusion oncogenes proliferate autonomously and differentiate towards the eosinophil lineage in a process that requires NF-κB. These results suggest new treatment possibilities for imatinib-resistant myeloid neoplasms associated with PDGF receptor mutations. PMID: 22271894 [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)

“Best of ASH” Features Two Studies with Contributions from US Oncology Research 01-20-2012

McKesson News — Fri, 20 Jan 2012 23:06:24 +0100

Studies focused on treatment of Chronic Lymphocytic Leukemia (CLL) recognized by the American Society of Hematology (Source: McKesson News)

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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)

Risk factors and treatment of childhood and adolescent Burkitt lymphoma/leukaemia

British Journal of Haematology — Fri, 20 Jan 2012 05:00:00 +0100

SummaryBurkitt lymphoma/leukaemia is the most common (40%) form of non‐Hodgkin lymphoma that occurs in children and adolescents. The prognosis of advanced (disseminated) Burkitt lymphoma/leukaemia in children and adolescents three decades ago had a 5‐year event‐free survival (EFS) of <40%, and required combination chemotherapy and radiation therapy over a 1–2 year period. Currently, the prognosis for the same advanced stage has a 5‐year EFS of 85–90% with <6 months of chemotherapy only. Radiation therapy has been eliminated for children and adolescents with Burkitt lymphoma/leukaemia except in emergencies, such as superior vena cava syndrome and acute neurological impairment or in patients with relapse/progression. Current risk factors in the prognosis of childhood and ...

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 (...

Longitudinal genome-wide analysis of patients with chronic lymphocytic leukemia reveals complex evolution of clonal architecture at disease progression and at the time of relapse

Leukemia — Fri, 20 Jan 2012 05:00:00 +0100

Authors: E Braggio, N E Kay, S VanWier, R C Tschumper, S Smoley, J E Eckel-Passow, T Sassoon, M Barrett, D L Van Dyke, J C Byrd, D F Jelinek, T D Shanafelt & R Fonseca (Source: Leukemia)

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The scientific method at work: xenotropic murine leukemia virus-related virus is neither a cause of chronic fatigue syndrome nor a threat to the blood supply.

Transfusion — Fri, 20 Jan 2012 01:19:27 +0100

Authors: Karafin MS, Stramer SL PMID: 22239209 [PubMed - in process] (Source: Transfusion)

Development and application of a high-throughput microneutralization assay: lack of xenotropic murine leukemia virus-related virus and/or murine leukemia virus detection in blood donors.

Transfusion — Fri, 20 Jan 2012 01:18:59 +0100

CONCLUSION: A microneutralization assay was developed for detection of XMRV and can be applied in a high-throughput format for large-scale studies. Although a proportion of blood donors demonstrated the ability to block XMRV envelope-mediated infection, we found no evidence that this inhibition was mediated by specific antibodies elicited by exposure to XMRV or MLV. It is likely that this moderate neutralization is mediated through another, nonspecific mechanism. PMID: 22239212 [PubMed - in process] (Source: Transfusion)

Composite Hodgkin lymphoma and chronic lymphocytic leukemia: A rare case

Journal of Cancer Research and Therapeutics — Thu, 19 Jan 2012 05:00:00 +0100

Krishnakumar Rathnam, Shashidhar Karpurmath, Sanju Cyriac, Sagar Tenali Gnana, Shirley SundersinghJournal of Cancer Research and Therapeutics 2011 7(4):484-485 (Source: Journal of Cancer Research and Therapeutics)

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)

EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases

Blood — Thu, 19 Jan 2012 05:00:00 +0100

EBV-associated T/NK–cell lymphoproliferative disease (T/NK-LPD) is defined as a systemic illness characterized by clonal proliferation of EBV-infected T or NK cells. We prospectively enrolled 108 nonimmunocompromised patients with this disease (50 men and 58 women; median onset age, 8 years; age range, 1-50 years) evidenced by expansion of EBV+ T/NK cells in the peripheral blood; these were of the T-cell type in 64 cases and of the NK-cell type in 44, and were clinically categorized into 4 groups: 80 cases of chronic active EBV disease, 15 of EBV-associated hemophagocytic lymphohistiocytosis, 9 of severe mosquito bite allergy, and 4 of hydroa vacciniforme. These clinical profiles were closely linked with the EBV+ cell immunophenotypes. In a median follow-up period of 46 months, 47 pa...

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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)

An Increased Number of Individuals with Clinically Recognized Monoclonal B-Cell Lymphocytosis Characterizes a Recent Database of Chronic Lymphocytic Leukemia Rai Stage 0.

Acta Haematologica — Thu, 19 Jan 2012 05:00:00 +0100

Authors: Molica S, Gentile M, Mauro FR, Brugiatelli M, Federico M, Sperduti I, Neri A, Ferrarini M, Foà R, Morabito F Abstract No abstract available. PMID: 22262125 [PubMed - as supplied by publisher] (Source: Acta Haematologica)

Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia

Leukemia — Thu, 19 Jan 2012 05:00:00 +0100

Authors: S J L Knight, C Yau, R Clifford, A T Timbs, E Sadighi Akha, H M Dréau, A Burns, C Ciria, D G Oscier, A R Pettitt, S Dutton, C C Holmes, J Taylor, J-B Cazier & A Schuh (Source: Leukemia)

Study Published On Novel Treatment For Skin Lymphoma

Health News from Medical News Today — Wed, 18 Jan 2012 10:00:00 +0100

Promising findings on a novel combination treatment approach for a chronic type of skin lymphoma are published in JAMA's Archives of Dermatology by clinical researchers from Seidman Cancer Center at University Hospitals (UH) Case Medical Center and Case Western Reserve University School of Medicine. The article outlines findings from a first-of-its-kind study showing that O6-benzylguanine is successful in treating cutaneous T-Cell lymphoma by enhancing the efficacy of topical chemotherapy (carmustine)... (Source: Health News from Medical News Today)

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...

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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)

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)

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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)

Expression of natural killer cell activating receptors in patients with chronic lymphocytic leukaemia

Immunology — Tue, 17 Jan 2012 11:21:23 +0100

(Source: Immunology)

The assessment of minimal residual disease in chronic lymphocytic leukaemia: comparison of multi-colour flow cytometry and bone marrow trephine biopsy

Journal of Hematopathology — Tue, 17 Jan 2012 07:07:47 +0100

Abstract We investigated the value and degree of agreement between a sensitive four-colour flow cytometry (FC) method and bone marrow trephine (BMT) biopsy for detecting minimal residual disease (MRD) in 82 chronic lymphocytic leukaemia (CLL) cases. Concordance was 85%, with 15% of cases discrepant (six BMT-positive/FC-negative and six BMT-negative/FC-positive cases). FC-positive/BMT-negative cases had a low-level MRD by FC (0.05–0.9%), whereas BMT-positive/FC-negative cases had significant residual nodular disease. We conclude that FC and BMT biopsy are complementary investigations for MRD assessment in CLL, and both should be considered in the routine setting to assess MRD in CLL. Content Type Journal ArticleCategory Original ArticlePages 1-5DOI 10.1007/s12308-011-...

Effects of Vitamin D3 on the Expression of Growth‐Related Oncogene‐α in THP‐1 Cells and Human Primary Monocytes

Journal of Food Science — Tue, 17 Jan 2012 05:00:00 +0100

In conclusion, the opposite effects of 1α, 25‐(OH)2D3 on GRO‐α expression in THP‐1 cells and human primary monocytes indicated that the data from THP‐1 cells should be further confirmed by human primary monocytes. Moreover, vitamin D3 may have potentiality in treating GRO‐α‐related chronic inflammatory diseases, like asthma and autoimmune diseases. (Source: Journal of Food Science)

Genetics: Splicing the pieces of the chronic lymphocytic leukemia puzzle

Nature Clinical Practice Oncology — Tue, 17 Jan 2012 05:00:00 +0100

Nature Reviews Clinical Oncology 9, 66 (2012). doi:10.1038/nrclinonc.2011.216 Author: M. Teresa Villanueva B-cell chronic lymphocytic leukemia (CLL) is the most common type of leukemia and it is characterized by the accumulation of impaired mature B lymphocytes in the blood and bone marrow. Although it progresses slowly in many cases and these patients may have normal active lives (Source: Nature Clinical Practice Oncology)

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Cancer Risk in Patients With Chronic Urticaria: A Population-Based Cohort Study [Evidence-Based Dermatology: Study]

Archives of Dermatology — Mon, 16 Jan 2012 05:00:00 +0100

Conclusions Patients with chronic urticaria are at increased risk of cancer, especially hematologic malignant tumors. Further studies are needed to delineate the associations. (Source: Archives of Dermatology)

Diagnosis of immunophenotyping of chronic lymphoproliferative syndromes by flow cytometry at HEMOPA blood center

Jornal Brasileiro de Patologia e Medicina Laboratorial — Sat, 14 Jan 2012 16:50:49 +0100

CONCLUSION: Based on the antibody panel recommended in this investigation, the immunophenotyping method by flow cytometry associated with morphological characterization of peripheral blood samples is a reliable, rapid, feasible, and non-invasive procedure for the diagnosis of chronic lymphoproliferative syndromes. (Source: Jornal Brasileiro de Patologia e Medicina Laboratorial)

Blues Singer Etta James Loses Battle With Leukemia

About.com Lymphoma — Sat, 14 Jan 2012 05:00:00 +0100

Blues singer Etta James passed away on Friday from complications of chronic leukemia. She was 73 years old. Ms. James came on the music scene in the 1950's and had a long and successful career and was very influential on more recent artists such as Beyonce and Christina Aguilera....Read Full Post (Source: About.com Lymphoma)

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...

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Outcome of patients with relapsed or refractory chronic lymphocytic leukemia treated with flavopiridol: impact of genetic features

Leukemia — Fri, 13 Jan 2012 05:00:00 +0100

Authors: J A Woyach, G Lozanski, A S Ruppert, A Lozanski, K A Blum, J A Jones, J M Flynn, A J Johnson, M R Grever, N A Heerema & J C Byrd (Source: Leukemia)

A role for Danazol in chronic lymphocytic leukemia

Leukemia — Fri, 13 Jan 2012 05:00:00 +0100

Authors: S Tung & D E Spaner (Source: Leukemia)

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...

SOCS1 is significantly up-regulated in Nutlin-3-treated p53wild-type B chronic lymphocytic leukemia (B-CLL) samples and shows an inverse correlation with miR-155

Investigational New Drugs — Thu, 12 Jan 2012 06:43:03 +0100

Summary The basal SOCS1 mRNA levels were significantly lower in p53mutated BJAB and MAVER leukemic cell lines with respect to p53wild-type SKW6.4 and JVM-2 leukemic cell lines, p53wild-type primary B chronic lymphocytic leukemia (B-CLL) cells and primary normal peripheral blood mononuclear cells (PBMC). Moreover, the MDM2 small molecule inhibitor Nutlin-3 significantly increased the levels of SOCS1 mRNA in both primary p53wild-type B-CLL cells as well as in p53wild-type B leukemic cell lines, but not in p53mutated B leukemic cell lines nor in primary PBMC. Of note, a significant inverse correlation was observed between SOCS1 mRNA and miR-155 levels in Nutlin-3-treated primary B-CLL cells and PBMC, suggesting that the miRNA-155/SOCS1 axis represents a potentially important the...

NOTCH1 mutations in CLL associated with trisomy 12

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

Two recent studies reported wholegenome sequencing of chronic lymphocytic leukemia (CLL) samples and found repeated mutations in the XPO1 and NOTCH1 genes. XPO1 was found mutated in 2.4% of cases, while NOTCH1 was found mutated in 12.2% or 15.1% of CLL samples. Here we report the results of sequencing of XPO1 and NOTCH1 in 186 CLL cases. Our results confirmed frequency of XPO1 mutations. However, we found only 5 NOTCH1 mutations in 127 IGVH unmutated/ZAP70+ CLL samples (4%), and one mutation was found in IGVH mutated/ZAP70– CLL for a total percentage of 1.5%. Because 4 of 6 mutated samples also showed trisomy 12, we sequenced NOTCH1 in an additional 77 cases with trisomy 12 CLLs, including 47 IGVH unmutated/ZAP70+ cases. Importantly, we found 41.9% NOTCH1 mutation frequency in aggres...

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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...

Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia

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

Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P < .001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed...

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)

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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)

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)

Mechanisms and consequences of the loss of PHLPP1 phosphatase in chronic lymphocytic leukemia (CLL)

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

Authors: M O'Hayre, M Niederst, J F Fecteau, V M Nguyen, T J Kipps, D Messmer, A C Newton & T M Handel (Source: Leukemia)

Can Prognostic Factors Be Used to Direct Therapy in Chronic Lymphocytic Leukemia?

Current Hematologic Malignancy Reports — Wed, 11 Jan 2012 17:56:53 +0100

Abstract Chronic lymphocytic leukemia (CLL) shows a heterogeneous clinical course, which can be explained in part by prognostic factors. Most patients do not need treatment at the time of first diagnosis. The identification of prognostic factors is of major interest if strategies can be devised to treat patients according to their individual risk profile or biological subgroup. Currently, in spite of a wealth of prognostic factors, individualized treatment approaches in different genetic or risk groups are the exemption in CLL. This review summarizes the most important prognostic and predictive factors in CLL, with particular emphasis on factors affecting treatment decisions in clinical trials and routine practice. Content Type Journal ArticleCategory Chronic Lymphocyt...

Haploidentical stem cell transplantation for children with high‐risk leukemia

Pediatric Blood and Cancer — Wed, 11 Jan 2012 05:00:00 +0100

ConclusionsHI‐HSCT is feasible in our setting, offers a rational treatment option, and expands the donor pool significantly for children with high‐risk leukemia in a developing country. This information is especially relevant to other ethnically diverse populations that are poorly represented in international donor registries. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc. (Source: Pediatric Blood and Cancer)

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Mantle cell lymphoma displays a homogenous methylation profile: A comparative analysis with chronic lymphocytic leukemia

American Journal of Hematology — Wed, 11 Jan 2012 05:00:00 +0100

AbstractMantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5+ B‐cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e. IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high‐resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor‐prognostic IGHV unmutated subset #1 and 15 good‐prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset d...

Chronic Lymphocytic Leukemia

Clinical Care Options Oncology - Leukemia — Wed, 11 Jan 2012 00:00:00 +0100

CCO Slideset - In this downloadable slideset, John C. Byrd, MD, and Kanti Rai, MD, review the most compelling data in the treatment of chronic lymphocytic leukemia presented at the 2011 American Society of Hematology Annual Meeting. (Source: Clinical Care Options Oncology - Leukemia)

Treatment of Older Patients with Chronic Lymphocytic Leukemia

Current Hematologic Malignancy Reports — Tue, 10 Jan 2012 16:49:22 +0100

Abstract Chronic lymphocytic leukemia (CLL) is typically a disease of older individuals. Yet most of the literature on various chemotherapeutic regimens includes patients who are 10 to 15 years younger than the median age at diagnosis of this disease. The older patient population is grossly underrepresented in clinical trials. Currently available therapies are often too toxic for this older patient population, so their efficacy is reduced. This review discusses some of the results of treatment in older patients with CLL. A discussion of factors that often affect outcome, such as comorbidities, renal function, bone marrow reserve, and infection, are also reviewed, along with quality of life. Content Type Journal ArticleCategory Chronic Lymphocytic Leukemia (S O'Bri...

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...

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Population Pharmacokinetics of Rituximab in Patients With Chronic Lymphocytic Leukemia.

The Journal of Clinical Pharmacology — Tue, 10 Jan 2012 05:00:00 +0100

Authors: Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, Mangat R, Joshi A, Visich J Abstract This retrospective analysis characterizes rituximab population pharmacokinetics in combination with fludarabine and cyclophosphamide and its effect on fludarabine and cyclophosphamide disposition in chronic lymphocytic leukemia (CLL) patients. Rituximab concentration data were well described by a 2-compartment model comprising a time-varying clearance component related to the target-mediated clearance pathway and a constant clearance component reflecting catabolic elimination pathway. Marked differences were observed compared to pharmacokinetic parameters for non-Hodgkin lymphoma (NHL) obtained previously: in CLL, time-varying clearance at time zero (CL(2)) was faster, volumes of ...

Hepatitis B reactivation despite entecavir prophylaxis in a patient with chronic lymphocytic leukaemia receiving bendamustine

Journal of Antimicrobial Chemotherapy — Tue, 10 Jan 2012 05:00:00 +0100

(Source: Journal of Antimicrobial Chemotherapy)

Histone Deacetylase in Chronic Lymphocytic Leukemia.

Oncology — Tue, 10 Jan 2012 05:00:00 +0100

Conclusions: These results suggest: (1) in CLL, elevated HDAC isoenzyme activity is not restricted to one class, and therefore, HDACi therapy may need to be directed to more than one specific class of HDAC; (2) higher HDAC expression activity may indicate a poor prognosis and more advanced disease stage (through indirect evidence), since higher values were found in patients with ZAP-70+ and higher CD44 expression levels. PMID: 22237050 [PubMed - as supplied by publisher] (Source: Oncology)

Hematological cancer in 2011: New therapeutic targets and treatment strategies

Nature Clinical Practice Oncology — Tue, 10 Jan 2012 05:00:00 +0100

Authors: Paula Cramer & Michael Hallek 2011 saw improvements in our understanding of B-cell malignancies: insights into the genomic basis of chronic lymphocytic leukemia were achieved; reduced treatment intensity caused fewer toxic effects in early-stage Hodgkin lymphoma; first-line rituximab maintenance therapy improved outcome in follicular lymphoma; and selected patients with diffuse large-cell lymphoma benefited from the addition of bortezomib. (Source: Nature Clinical Practice Oncology)

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 ...

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Immune Reconstitution in Chronic Lymphocytic Leukemia

Current Hematologic Malignancy Reports — Mon, 09 Jan 2012 19:39:48 +0100

This article reviews the immune defect in CLL and discusses strategies aimed at repairing or circumventing this defect. In particular, it focuses on recent developments in the areas of CD40 ligand (CD40L/CD154) gene therapy, immunomodulatory agents such as lenalidomide, and adoptive transfer of T cells bearing chimeric antigen receptors. Content Type Journal ArticleCategory Chronic Lymphocytic Leukemia (S O'Brien, Section Editor)Pages 1-8DOI 10.1007/s11899-011-0106-xAuthors John C. Riches, Barts Cancer Institute, Queen Mary University of London, 3rd Floor John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ UKAlan G. Ramsay, Barts Cancer Institute, Queen Mary University of London, 3rd Floor John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ UKJohn G. Gribbe...

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)

Monoclonal B‐cell lymphocytosis is closely related to chronic lymphocytic leukaemia and may be better classified as early‐stage CLL

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

This study analysed 298 MBL patients by multi‐parameter flow cytometry, chromosome banding analysis (CBA)/fluorescence in situ hybridization (FISH), and IGHV mutation status and compared them with 356 CLL patients. In MBL, CBA more frequently revealed a normal karyotype and FISH identified less frequently del(6q), del(13q) (as sole alterations), and del(17)(p13). Within the MBL cohort, a shorter time to treatment (TTT) was found for ZAP‐70‐positivity, 14q32/IGH‐translocations (CBA), del(11)(q22·3) (FISH) and unmutated IGHV status. Higher CD38 and ZAP‐70 expression, del(11)(q22·3) (FISH), trisomy 12 (FISH), and 14q32/IGH‐translocations (CBA) were correlated with a shorter TTT in the combined cohort (MBL + CLL); a sole del(13)(q14) (FISH) correlated with longer TTT. Regardi...

Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results

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

SummaryPatients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p‐) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p‐ CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p‐ CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27–98) years at the time of fluorescence in situ hybridization analysis. After 17p‐ documentation, 52% received treatment, achieving an overall response ...

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Individualized Fludarabine-Based Regimen in Elderly Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Advances in Therapy — Mon, 09 Jan 2012 05:00:00 +0100

CONCLUSION: The individual regimen of fludarabine combined with rituximab demonstrated marked clinical efficacy and acceptable toxicity in elderly patients with CLL/SLL. PMID: 22249944 [PubMed - as supplied by publisher] (Source: Advances in Therapy)

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)

Histone deacetylase inhibitors are unable to synergize with ABT-737 in killing primary chronic lymphocytic leukaemia cells in vitro

Leukemia — Fri, 06 Jan 2012 05:00:00 +0100

Authors: R Ralli, K M Banks, A P Wiegmans, D Carney, J F Seymour, R W Johnstone & A E Alsop (Source: Leukemia)

Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells

Leukemia — Fri, 06 Jan 2012 05:00:00 +0100

Authors: A H Daneshmanesh, M Hojjat-Farsangi, A S Khan, M Jeddi-Tehrani, M M Akhondi, A A Bayat, R Ghods, A-R Mahmoudi, R Hadavi, A Österborg, F Shokri, H Rabbani & H Mellstedt (Source: Leukemia)

The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells

Leukemia — Fri, 06 Jan 2012 05:00:00 +0100

The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells Leukemia advance online publication, January 6, 2012. doi:10.1038/leu.2011.369 Authors: A Zucchetto, T Vaisitti, D Benedetti, E Tissino, V Bertagnolo, D Rossi, R Bomben, M Dal Bo, M I Del Principe, A Gorgone, G Pozzato, G Gaidano, G Del Poeta, F Malavasi, S Deaglio & V Gattei (Source: Leukemia)

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Surface IgM stimulation induces MEK1/2-dependent MYC expression in chronic lymphocytic leukemia cells

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

Although long considered as a disease of failed apoptosis, it is now clear that chronic lymphocytic leukemia (CLL) cells undergo extensive cell division in vivo, especially in progressive disease. Signaling via the B-cell receptor is thought to activate proliferation and survival pathways in CLL cells and also has been linked to poor outcome. Here, we have analyzed the expression of the proto-oncoprotein MYC, an essential positive regulator of the cell cycle, after stimulation of surface IgM (sIgM). MYC expression was rapidly increased after sIgM stimulation in a subset of CLL samples. The ability of sIgM stimulation to increase MYC expression was correlated with sIgM-induced intracellular calcium fluxes. MYC induction was partially dependent on the MEK/ERK signaling pathway, and MYC and p...

Tcl1 interacts with Atm and enhances NF-{kappa}B activation in hematologic malignancies

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

The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IBα phosphorylation and ubiquitination and subsequent activation of ...

The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms

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

The somatically acquired V600E mutation of the BRAF gene has been recently described as a molecular marker of hairy cell leukemia (HCL). We developed an allele-specific PCR for this mutation and studied 62 patients with HCL, 1 with HCL variant, 91 with splenic marginal zone lymphoma, 29 with Waldenström macroglobulinemia, and 57 with B-cell chronic lymphoproliferative disorders. The BRAF V600E mutation was detected in all HCL cases and in only 2 of the remaining 178 patients. These 2 subjects had B-cell chronic lymphoproliferative disorders that did not fulfill the diagnostic criteria for HCL. Despite the positive PCR finding, the mutation could not be detected by Sanger sequencing in these 2 cases, suggesting that it was associated with a small subclone. We conclude that the BRAF V60...

Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation

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

In this study, we describe a new, simple, and inexpensive test for genetics-based diagnosis of HCL in whole-blood samples that detects BRAF-V600E through a sensitive allele-specific PCR qualitative assay followed by agarose-gel electrophoresis. This approach detected BRAF-V600E in all 123 leukemic HCL samples investigated containing as few as 0.1% leukemic cells. BRAF-V600E was detected at different time points during the disease course, even after therapy, pointing to its pivotal role in HCL pathogenesis and maintenance of the leukemic clone. Conversely, 115 non-HCL chronic B-cell neoplasms, including 79 HCL-like disorders, were invariably negative for BRAF-V600E. This molecular assay is a powerful tool for improving the diagnostic accuracy in HCL. (Source: Blood)

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...

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Expression of ERp5 and GRP78 on the membrane of chronic lymphocytic leukemia cells: association with soluble MICA shedding

Cancer Immunology, Immunotherapy — Wed, 04 Jan 2012 06:47:57 +0100

In conclusion, these results uncover a molecular mechanism which regulates MICA protein shedding and immune evasion in CLL. Content Type Journal ArticleCategory Original ArticlePages 1-10DOI 10.1007/s00262-011-1195-zAuthors Leticia Huergo-Zapico, Functional Biology Department. Instituto Universitario Oncologico del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, SpainAna P. Gonzalez-Rodriguez, Hematology Department, Hospital Cabueñes, Gijón, SpainJuan Contesti, Hematology Department, Hospital Cabueñes, Gijón, SpainEsther Gonzalez, Hematology Department, Hospital Cabueñes, Gijón, SpainAlejandro López-Soto, Functional Biology Department. Instituto Universitario Oncologico del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, SpainAzahara Fernandez-G...

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)

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)

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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...

ATM and chronic lymphocytic leukemia: mutations, and not only deletions, matter.

Haematologica — Sun, 01 Jan 2012 05:00:00 +0100

Authors: Rossi D, Gaidano G PMID: 22210328 [PubMed - in process] (Source: Haematologica)

[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....

No evidence of cross-species transmission of mouse retroviruses to animal workers exposed to mice.

Transfusion — Fri, 30 Dec 2011 05:00:00 +0100

CONCLUSIONS: There was no evidence of human infection with XMRV/MLV among a cohort of individuals highly exposed to mice. These data suggest that the likelihood of cross-species transmission events of MLV from mice to humans is low. PMID: 22212105 [PubMed - as supplied by publisher] (Source: Transfusion)

New Class of Drug May Vanquish CLLNew Class of Drug May Vanquish CLL

Medscape Today Headlines — Thu, 29 Dec 2011 23:06:42 +0100

The novel small molecule navitoclax blocks the function of Bcl-2, a protein essential for the growth of chronic lymphocytic leukemia cells, and may represent a "revolution" in the treatment of CLL. Medscape Medical News (Source: Medscape Today Headlines)

Bone marrow stromal cell-derived vascular endothelial growth factor (VEGF) rather than chronic lymphocytic leukemia (CLL) cell-derived VEGF is essential for the apoptotic resistance of cultured CLL cells.

Molecular Medicine — Thu, 29 Dec 2011 07:24:03 +0100

In this study, the VEGF status in CLL was assessed by enzyme-linked immunosorbent assay and immunofluorescence. VEGF receptor 2 (VEGFR2) phosphorylation was determined flow cytometrically and by immunofluorescence. For co-culture, CLL cells were cultivated on a monolayer of the bone marrow-derived stromal cell (BMSC) line HS5. Secreted VEGF was neutralized using the monoclonal antibody mAb293 (R&D Systems, Minneapolis, MN, USA). To block protein secretion, we used Brefeldin A. VEGF was downregulated in BMSCs by small interfering RNA (siRNA), and we assessed survival by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. CLL cells express and secrete VEGF and possess phosphorylated VEGFR2. This positive VEGF status is not sufficient to prevent spontaneous apoptos...

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Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course

Annals of Hematology — Thu, 29 Dec 2011 06:42:41 +0100

In conclusion, CLL/PLL with MYC translocations is a rare entity, which seems to be associated with adverse prognostic features and unfavorable outcome. Content Type Journal ArticleCategory Original ArticlePages 1-11DOI 10.1007/s00277-011-1393-yAuthors Natalie Put, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, BelgiumKatrien Van Roosbroeck, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, BelgiumPeter Konings, Department of Electrical Engineering/IBBT-K.U. Leuven Future Health Department, Catholic University of Leuven, Leuven, BelgiumPeter Meeus, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, BelgiumCaroline Brusselmans, Department of Clinical Biology, University Hospit...

NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL.

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

Authors: Del Giudice I, Rossi D, Chiaretti S, Marinelli M, Tavolaro S, Gabrielli S, Laurenti L, Marasca R, Rasi S, Fangazio M, Guarini A, Gaidano G, Foa' R Abstract Trisomy 12, the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), confers an intermediate prognosis. In our cohort of 104 untreated patients carrying +12, NOTCH1 mutations occurred in 24% of cases and were associated to unmutated IGHV genes (p=.003) and +12 as a sole cytogenetic abnormality (p=.008). NOTCH1 mutations in +12 CLL associated with a ~2.4 fold increase in the death risk, a significant survival shortening (p<.001) and proved an independent predictor of survival in multivariate analysis. Analogous to +12 CLL with TP53 disruption or del(11q), NOTCH1 mutations in +12 CLL confer...

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)

Physical contact with endothelial cells through β1- and β2- integrins rescues chronic lymphocytic leukemia from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile on leukemic cells.

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

ConclusionOur study supports the notion that endothelial cells are major players in chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly sustains survival, protects from drug-induced apoptosis and widely modifies gene expression profile of leukemic cells. PMID: 22207686 [PubMed - as supplied by publisher] (Source: Haematologica)

Multiple myeloma shows no intra-disease clustering of immunoglobulin heavy chain genes.

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

Conclusions. Analysis of multiple myeloma immunoglobulin repertoire does not support a pathogenetic role for antigen selection in this tumor. PMID: 22207685 [PubMed - as supplied by publisher] (Source: Haematologica)

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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...

Spliceosome mutations in hematopoietic malignancies

Nature Genetics — Tue, 27 Dec 2011 05:00:00 +0100

Authors: Christopher N Hahn & Hamish S Scott Recent studies, including two in this issue, report heterozygous missense mutations in the U2AF1 and SF3B1 genes that encode spliceosome subunits. U2AF1 is frequently mutated in myeloid hematopoietic malignancies, especially in myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL). (Source: Nature Genetics)

High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment [Medical Sciences]

Proceedings of the National Academy of Sciences — Tue, 27 Dec 2011 05:00:00 +0100

The primary cause of poor outcome following allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is disease recurrence. Detection of increasing minimal residual disease (MRD) following HCT may permit early intervention to prevent clinical relapse; however, MRD quantification remains an uncommon diagnostic test because of logistical and financial barriers to widespread use. Here we describe a method for quantifying CLL MRD using widely available consensus primers for amplification of all Ig heavy chain (IGH) genes in a mixture of peripheral blood mononuclear cells, followed by high-throughput sequencing (HTS) for disease-specific IGH sequence quantification. To achieve accurate MRD quantification, we developed a systematic bioinformatic methodology to a...

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...

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. ...

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Leukemia and Related Disorders

Springer Medicine titles — Sun, 25 Dec 2011 03:57:57 +0100

Integrated Treatment Approachesseries:Contemporary HematologyFrom the world renowned Fred Hutchinson Cancer Research Center, this book is written for all physicians who treat patients with acute or chronic leukemias or myelodysplasia. It is designed to answer questions about treatment approaches that commonly arise in day-to-day practice. In keeping with the Center’s groundbreaking research in bone marrow transplantation, the book provides ... (Source: Springer Medicine titles)

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)

Role of Bcl-3 in solid tumors

Molecular Cancer — Fri, 23 Dec 2011 05:00:00 +0100

Bcl-3 is an established oncogene in hematologic malignancies, such as B-cell chronic lymphocytic leukemias. Nevertheless, recent research has shown that it also participates in progression of diverse solid tumors. The present review summarizes the current knowledge of Bcl3 role in solid tumors progression, including some new insights in its possible molecular mechanisms of action (Source: Molecular Cancer)

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)

Science Journal Retracts Chronic Fatigue Syndrome Paper

NYT Health — Thu, 22 Dec 2011 20:55:49 +0100

Some data in the 2009 study, which linked a mouse leukemia retrovirus to chronic fatigue syndrome and was published in the journal Science, were retracted in September on grounds of laboratory contamination. (Source: NYT Health)

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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...

Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness

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

The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10 of 59 (17%) fludarabine-refractory cases, with a frequency significantly greater than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; P = .002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted 3 hotspots (codons 662, 666, and 700),...

{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...

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Reduced mast cell and basophil numbers and function in Cpa3-Cre; Mcl-1fl/fl mice

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

It has been reported that the intracellular antiapoptotic factor myeloid cell leukemia sequence 1 (Mcl-1) is required for mast cell survival in vitro, and that genetic manipulation of Mcl-1 can be used to delete individual hematopoietic cell populations in vivo. In the present study, we report the generation of C57BL/6 mice in which Cre recombinase is expressed under the control of a segment of the carboxypeptidase A3 (Cpa3) promoter. C57BL/6-Cpa3-Cre; Mcl-1fl/fl mice are severely deficient in mast cells (92%-100% reduced in various tissues analyzed) and also have a marked deficiency in basophils (58%-78% reduced in the compartments analyzed), whereas the numbers of other hematopoietic cell populations exhibit little or no changes. Moreover, Cpa3-Cre; Mcl-1fl/fl mice exhibited marked reduc...

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...

[Rare association between chronic lymphocytic leukemia and systemic lupus erythematosus.]

Presse Medicale — Thu, 22 Dec 2011 05:00:00 +0100

Authors: Dieval C, Herrador C, Guiboux AL, Haramburu F, Mercié P PMID: 22197401 [PubMed - as supplied by publisher] (Source: Presse Medicale)

[Acute lymphoblastic leukaemia initially diagnosed and treated as chronic juvenile arthritis.]

Anales de Pediatria — Thu, 22 Dec 2011 05:00:00 +0100

Authors: Pérez Rodríguez T, Lassaletta Atienza A, González-Vincent M, Alonso Canal L, Madero López L PMID: 22196917 [PubMed - as supplied by publisher] (Source: Anales de Pediatria)

Expansion of a CD8+PD-1+ replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression.

Clinical Cancer Research — Wed, 21 Dec 2011 05:00:00 +0100

CONCLUSIONS: Our data show that the emergence of CD8+PD-1+ replicative senescence phenotype in early stage CLL patients is associated with more aggressive clinical disease. Importantly, these findings were independent of tumor cell prognostic markers and could not be accounted for by patient age, changes in regulatory T cell frequency or cytomegalovirus serostatus. PMID: 22190592 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

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Diagnostic Usefulness and Prognostic Impact of CD200 Expression in Lymphoid Malignancies and Plasma Cell Myeloma.

American Journal of Clinical Pathology — Tue, 20 Dec 2011 15:14:08 +0100

Authors: Alapat D, Coviello-Malle J, Owens R, Qu P, Barlogie B, Shaughnessy JD, Lorsbach RB Abstract The membrane glycoprotein MRC OX-2 (CD200) is expressed in several lymphoid malignancies. However, the diagnostic usefulness and potential prognostic importance of CD200 expression have not been rigorously examined. We show that CD200 is uniformly expressed in chronic lymphocytic leukemia (CLL) and absent in mantle cell lymphoma (MCL). It is important to note that expression of CD200 is retained even in CLLs with immunophenotypic aberrancies, making CD200 a particularly useful marker for discrimination between these cases and MCL. CD200 is expressed in nearly all precursor B-lymphoblastic leukemias, with aberrant overexpression or underexpression compared with normal B-cell progenit...

Characteristics of chronic lymphocytic leukemia with somatically acquired mutations in NOTCH1 exon 34

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

Authors: K Shedden, Y Li, P Ouillette & S N Malek (Source: Leukemia)

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)