DNA hypermethylation of cell cycle (p15 and p16) and apoptotic (p14, p53, DAPK and TMS1) genes in peripheral blood of leukemia patients.

Posted by rob on November 13, 2014 under Uncategorized | Comments are off for this article

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DNA hypermethylation of cell cycle (p15 and p16) and apoptotic (p14, p53, DAPK and TMS1) genes in peripheral blood of leukemia patients.

Asian Pac J Cancer Prev. 2014;15(1):75-84

Authors: Bodoor K, Haddad Y, Alkhateeb A, Al-Abbadi A, Dowairi M, Magableh A, Bsoul N, Ghabkari A

Abstract

Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

PMID: 24528084 [PubMed - indexed for MEDLINE]

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Assessment of changes in membrane properties of platelets from patients with chronic myeloid leukaemia in different stages of the disease.

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Assessment of changes in membrane properties of platelets from patients with chronic myeloid leukaemia in different stages of the disease.

Blood Coagul Fibrinolysis. 2014 Mar;25(2):142-50

Authors: Popov VM, Vladareanu AM, Bumbea H, Kovacs E, Moisescu MG, Onisai M, Iordache MM, Savopol T

Abstract

Patients with chronic myeloproliferative leukemia (CML) have frequent haemorrhage and/or thrombosis in their medical history. The mechanisms of these major and life-threatening complications remain unclear. Membrane organization influences many of the unique cellular functions and is strongly correlated, among other factors, to the membrane lipid composition; it may be evaluated by following up the membrane fluidity and aggregation properties of the platelet. In this study, we evaluated the platelet aggregation, the expression of platelet surface receptors, the membrane fluidity (as evaluated by fluorescence anisotropy) and its correlation to reactive oxygen species (ROS) production, in patients with chronic myeloid leukaemia (CML). It was found that the patients in accelerated and blastic phase of CML present an altered platelet aggregation response to all reagents except for ristocetin as compared with chronic phase group, which shows only epinephrine-altered response. We also found that BCR/ABL transcript leads to higher levels of ROS in accelerated and blastic CML phases. Patients without molecular remission have lower platelet membrane fluidity. We obtained a positive correlation between ROS level and membrane fluorescence anisotropy changes. The CD41 expression was decreased in CML patients and P selectin expression was found to be higher in these patients than in healthy volunteers. Platelets of CML patients have altered aggregation parameters in accelerated and blastic phases, in which BCR/ABL transcript level is increased. The increased level of ROS in CML patients without molecular remission is associated with a decrease in fluidity of platelet membrane and expression of CD41/CD61 receptors. These findings may contribute to understanding the mechanism of the altered platelet response reported in CML patients.

PMID: 24346354 [PubMed - indexed for MEDLINE]

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Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus.

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Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus.

Oncotarget. 2013 Dec;4(12):2249-60

Authors: Huang ZL, Gao M, Li QY, Tao K, Xiao Q, Cao WX, Feng WL

Abstract

The chimeric Bcr-Abl oncoprotein, which causes chronic myeloid leukemia, mainly localizes in the cytoplasm, and loses its ability to transform cells after moving into the nucleus. Here we report a new strategy to convert Bcr-Abl to be an apoptotic inducer by altering its subcellular localization. We show that a rapalog nuclear transport system (RNTS) containing six nuclear localization signals directs Bcr-Abl into the nucleus and that nuclear entrapped Bcr-Abl induces apoptosis and inhibits proliferation of CML cells by activating p73 and shutting down cytoplasmic oncogenic signals mediated by Bcr-Abl. Coupling cytoplasmic depletion with nuclear entrapment of Bcr-Abl synergistically enhances the inhibitory effect of nuclear Bcr-Abl on its oncogenicity in mice. These results provide evidence that direction of cytoplasmic Bcr-Abl to the nucleus offers an alternative CML therapy.

PMID: 24158537 [PubMed - indexed for MEDLINE]

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Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with nilotinib against BCR-ABL-positive leukemia cells involves the ABL kinase domain mutation.

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Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with nilotinib against BCR-ABL-positive leukemia cells involves the ABL kinase domain mutation.

Cancer Biol Ther. 2014 Feb;15(2):207-15

Authors: Okabe S, Tauchi T, Tanaka Y, Kitahara T, Kimura S, Maekawa T, Ohyashiki K

Abstract

Imatinib, an ABL tyrosine kinase inhibitor (TKI), has shown clinical efficacy against chronic myeloid leukemia (CML). However, a substantial number of patients develop resistance to imatinib treatment due to the emergence of clones carrying mutations in the protein BCR-ABL. The phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway regulates various processes, including cell proliferation, cell survival, and antiapoptosis activity. In this study, we investigated the efficacy of NVP-BEZ235, a dual PI3K and mTOR inhibitor, using BCR-ABL-positive cell lines. Treatment with NVP-BEZ235 for 48 h inhibited cell growth and induced apoptosis. The phosphorylation of the AKT kinase, eukaryotic initiation factor 4-binding protein 1 (4E-BP1), and p70 S6 kinase were decreased after NVP-BEZ235 treatment. The combination of NVP-BEZ235 with a BCR-ABL kinase inhibitor, imatinib, or nilotinib, induced a more pronounced colony growth inhibition, whereas the combination of NVP-BEZ235 and nilotinib was more effective in inducing apoptosis and reducing the phosphorylation of AKT, 4E-BP1, and S6 kinase. NVP-BEZ235 in combination with nilotinib also inhibited tumor growth in a xenograft model and inhibited the growth of primary T315I mutant cells and ponatinib-resistant cells. Taken together, these results suggest that administration of the dual PI3K and mTOR inhibitor NVP-BEZ235 may be an effective strategy against BCR-ABL mutant cells and may enhance the cytotoxic effects of nilotinib in ABL TKI-resistant BCR-ABL mutant cells.

PMID: 24100660 [PubMed - indexed for MEDLINE]

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Unusual case of simultaneous presentation of plasma cell myeloma, chronic myelogenous leukemia, and a jak2 positive myeloproliferative disorder.

Posted by rob on November 12, 2014 under Uncategorized | Comments are off for this article

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Unusual case of simultaneous presentation of plasma cell myeloma, chronic myelogenous leukemia, and a jak2 positive myeloproliferative disorder.

Case Rep Hematol. 2014;2014:738428

Authors: Maerki J, Katava G, Siegel D, Silberberg J, Bhattacharyya PK

Abstract

Background. Multiple articles discuss the rare incidence and potential causes of second hematologic disorders arising after treatment of Chronic Myelogenous Leukemia (CML), leading to the theory of imatinib, the current treatment regimen for CML, as a possible trigger for the development of secondary neoplasms. Our case eliminates the possibility of imatinib as the sole cause since our patient received a diagnosis of simultaneous plasma cell myeloma, CML, and a Jak2 mutation positive myeloproliferative disorder (MPD) arising de novo, prior to any treatment. We will further investigate into alternative theories as potential causes for multiple hematopathologic disorders. Case Report. There are currently no reported cases with the diagnosis of simultaneous plasma cell myeloma, chronic myelogenous leukemia, and Jak2 positive myeloproliferative disorder. We present a case of a 77-year-old male who was discovered to have these three concurring hematopathologic diagnoses. Our review of the literature includes a look at potential associations linking the three coexisting hematologic entities. Conclusion. The mechanism resulting in simultaneous malignancies is most likely multifactorial and potentially includes factors specific to the host, continuous stimulation of the immune system, previous chemotherapy or radiation, a potential common pluripotent stem cell, or, lastly, preexisting myeloma which may increase the susceptibility of additional malignancies.

PMID: 25386371 [PubMed]

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Structure, function, and resistance in chronic myeloid leukemia.

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Structure, function, and resistance in chronic myeloid leukemia.

Cancer Cell. 2014 Sep 8;26(3):305-6

Authors: Radich J

Abstract

Chronic myeloid leukemia (CML) is effectively treated by tyrosine kinase inhibitors (TKIs). Rarely, CML cases develop TKI resistance through acquisition of compound mutations. In this issue of Cancer Cell, Zabriskie and colleagues study how structural changes caused by compound mutations cause clinically relevant changes in TKI sensitivity.

PMID: 25203318 [PubMed - indexed for MEDLINE]

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BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.

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BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.

Cancer Cell. 2014 Sep 8;26(3):428-42

Authors: Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, Khoury HJ, Larson RA, Konopleva M, Cortes JE, Kantarjian H, Jabbour EJ, Kornblau SM, Lipton JH, Rea D, Stenke L, Barbany G, Lange T, Hernández-Boluda JC, Ossenkoppele GJ, Press RD, Chuah C, Goldberg SL, Wetzler M, Mahon FX, Etienne G, Baccarani M, Soverini S, Rosti G, Rousselot P, Friedman R, Deininger M, Reynolds KR, Heaton WL, Eiring AM, Pomicter AD, Khorashad JS, Kelley TW, Baron R, Druker BJ, Deininger MW, O’Hare T

Abstract

Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph(+)) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph(+) leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.

PMID: 25132497 [PubMed - indexed for MEDLINE]

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Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers.

Posted by rob on November 11, 2014 under Uncategorized | Comments are off for this article

Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers.

Nat Genet. 2014 Nov 10;

Authors: Core LJ, Martins AL, Danko CG, Waters CT, Siepel A, Lis JT

Abstract

Despite the conventional distinction between them, promoters and enhancers share many features in mammals, including divergent transcription and similar modes of transcription factor binding. Here we examine the architecture of transcription initiation through comprehensive mapping of transcription start sites (TSSs) in human lymphoblastoid B cell (GM12878) and chronic myelogenous leukemic (K562) ENCODE Tier 1 cell lines. Using a nuclear run-on protocol called GRO-cap, which captures TSSs for both stable and unstable transcripts, we conduct detailed comparisons of thousands of promoters and enhancers in human cells. These analyses identify a common architecture of initiation, including tightly spaced (110 bp apart) divergent initiation, similar frequencies of core promoter sequence elements, highly positioned flanking nucleosomes and two modes of transcription factor binding. Post-initiation transcript stability provides a more fundamental distinction between promoters and enhancers than patterns of histone modification and association of transcription factors or co-activators. These results support a unified model of transcription initiation at promoters and enhancers.

PMID: 25383968 [PubMed - as supplied by publisher]

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Monocyte chemoattractant protein-1 (MCP-1/CCL2) contributes to thymus atrophy in acute myeloid leukemia.

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Monocyte chemoattractant protein-1 (MCP-1/CCL2) contributes to thymus atrophy in acute myeloid leukemia.

Eur J Immunol. 2014 Nov 10;

Authors: Driss V, Quesnel B, Brinster C

Abstract

Recent studies on acute myelogenous leukemia (AML) patients have revealed the existence of T-cell immunodeficiencies, characterized by peripheral T lymphocytes that are unable to interact with blasts, reduced thymic emigrants and oligoclonal restricted repertoires. These observations suggest that there is a profound thymic dysregulation, which is difficult to study in AML patients. Using the C1498 AML mouse model, we demonstrated that leukemia development was associated with thymus atrophy, which was defined by abnormal organ weight and reduced cellularity. In addition, we observed a dramatic loss of peripheral CD4(+) and CD8(+) T-cell numbers with increased frequencies of CD4(+) FoxP3(+) regulatory and activated/memory T cells. Investigating the mechanisms leading to this atrophy, we observed a significant accumulation of the monocyte chemoattractant protein-1 (MCP-1/CCL2) in thymi of leukemic mice. Treatment of AML-bearing animals with a blocking anti-CCL2 antibody revealed a lower tumor burden, augmented anti-leukemic T-cell responses and improved survival rate compared with non-treated mice. These results were not observed when neutralization of CCL2 was performed in thymectomized mice. Altogether, we show that the CCL2 protein participates in thymic atrophy in AML mice, and this could have important implications for future immunotherapeutic strategies. This article is protected by copyright. All rights reserved.

PMID: 25382729 [PubMed - as supplied by publisher]

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Chronic myeloid leukemia in adolescents and young adults: patient characteristics, outcomes and review of the literature.

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Chronic myeloid leukemia in adolescents and young adults: patient characteristics, outcomes and review of the literature.

Acta Haematol. 2014;132(3-4):298-306

Authors: Pemmaraju N, Cortes J

Abstract

Over the past two decades, many improvements have been made in the management of patients with leukemia. Research in this field most often focuses on the youngest and oldest patient age groups. However, the population of patients in between those age groups has received relatively little attention with few studies specifically focusing on them. This important ‘age gap’ has demonstrated a unique, difficult-to-treat group of patients known as adolescents and young adults, or AYAs. Variably defined in the literature as patients from late teenage years to the age of up to 40 years, the AYA group of patients represents a vulnerable subset of patients now identified to require its own focus, development of therapeutic strategies and parallel emphasis on special support systems involving multidisciplinary psychosocial care. Despite the great advancements that have been realized for patients with chronic myeloid leukemia (CML), the AYA group has seldom been the focus of specific reports and studies, and the outcome appears to lag behind the general population. This review focuses on this subset of AYA patients with CML and summarizes the available data and recent developments, challenges and treatment options for this group of patients.

PMID: 25228555 [PubMed - indexed for MEDLINE]

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First-line treatment of 102 chronic myeloid leukemia patients with imatinib: a long-term single institution analysis.

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First-line treatment of 102 chronic myeloid leukemia patients with imatinib: a long-term single institution analysis.

Am J Hematol. 2014 Oct;89(10):E184-7

Authors: Viganò I, Di Giacomo N, Bozzani S, Antolini L, Piazza R, Gambacorti Passerini C

Abstract

Imatinib mesylate radically changed the natural history of chronic myeloid leukemia (CML). The recent availability of alternative tyrosine kinase inhibitors (TKIs) renders the clinical management of CML more complex. In this article, we summarize our long-term single institution experience. From 2003 to 2012, 102 patients with newly diagnosed chronic phase CML were referred to our institution and treated with imatinib mesylate as first-line therapy. All patients were followed inside a dedicated CML clinic. At 1 year, 82/95 patients (86.3%) achieved complete cytogenetic response (CCyR) using a treatment performed analysis (TPA); when using an intention to treat analysis, 85/102 patients (83.3%) obtained CCyR. At 3 months, 58 patients (64.4% TPA) obtained a BCR-ABL transcripts level <10%. A major molecular response (MMR) was obtained by 38% and 53% of patients at 1 and 2 years. Twenty patients (19.6%) discontinued treatment with imatinib; six of them did so in the initial 2 years of treatment (4 for resistance and 2 for adverse events). We observed seven deaths (6.86%). Overall survival (OS) at 6 years is 95.1% (95% C.I. 90-100%) and is not different from that of the general population. No patient experienced progression of disease (95% C.I.: 0-3%). Our results suggest that patient management is a crucial point to obtain a successful therapeutic outcome: at 1 year CCyR and MMR rates are similar to the results obtained with second generation TKIs and OS is not different from that of the general population.

PMID: 25041880 [PubMed - indexed for MEDLINE]

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BCR-ABL1 kinase domain mutational analysis of CD34+ stem/progenitor cells in newly diagnosed CML patients by next-generation sequencing.

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BCR-ABL1 kinase domain mutational analysis of CD34+ stem/progenitor cells in newly diagnosed CML patients by next-generation sequencing.

Am J Hematol. 2014 Oct;89(10):1016-7

Authors: Musilova M, Razga F, Jurcek T, Jeziskova I, Borsky M, Nemethova V, Zackova D, Culen M, Dvorakova D, Mayer J, Racil Z

PMID: 24984979 [PubMed - indexed for MEDLINE]

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Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia.

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Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia.

Am J Hematol. 2014 Oct;89(10):947-53

Authors: Gambacorti-Passerini C, Cortes JE, Lipton JH, Dmoszynska A, Wong RS, Rossiev V, Pavlov D, Gogat Marchant K, Duvillié L, Khattry N, Kantarjian HM, Brümmendorf TH

Abstract

Bosutinib, an orally active, Src/Abl tyrosine kinase inhibitor, has demonstrated clinical activity and acceptable tolerability in chronic phase chronic myeloid leukemia (CP CML). This updated analysis of the BELA trial assessed the safety profile and management of toxicities of bosutinib versus imatinib in adults with newly diagnosed (?6 months) CP CML after >30 months from accrual completion. Among patients randomized to bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252), 248 and 251, respectively, received ?1 dose of study treatment. Adverse events (AEs; any grade) with bosutinib versus imatinib were significantly more common for certain gastrointestinal events (diarrhea, 70% vs. 26%; P < 0.001; vomiting, 33% vs. 16%; P < 0.001), alanine aminotransferase (33% vs. 9%; P < 0.001) and aspartate aminotransferase (28% vs. 10%; P < 0.001) elevations, and pyrexia (19% vs. 12%; P = 0.046). AEs significantly less common with bosutinib included edema (periorbital, 2% vs. 14%; P < 0.001; peripheral, 5% vs. 12%; P = 0.006), musculoskeletal (myalgia, 5% vs. 12%; P = 0.010; muscle cramps, 5% vs. 22%; P < 0.001; bone pain, 4% vs. 11%; P = 0.003), increased creatine phosphokinase (8% vs. 20%; P < 0.001), neutropenia (13% vs. 30%; P < 0.001), and leukopenia (9% vs. 22%; P < 0.001). Between-group differences in the incidence of cardiac and vascular AEs were not significant. Diarrhea was typically transient, mostly Grade 1/2, occurring early during treatment, and was manageable with antidiarrheal medication. Despite higher rates of aminotransferase elevation with bosutinib, events were managed in most patients with dose modification and/or concomitant medication. Bosutinib had a manageable safety profile distinct from that of imatinib in patients with newly diagnosed CP CML.

PMID: 24944159 [PubMed - indexed for MEDLINE]

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Ponatinib circumvents FGF2-driven resistance to imatinib in CML.

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Ponatinib circumvents FGF2-driven resistance to imatinib in CML.

Cancer Discov. 2014 Mar;4(3):OF10

Authors:

Abstract

FGF2 induces imatinib resistance in CML cells via reactivation of FGFR3-RAS-MAPK signaling.

PMID: 24596204 [PubMed - indexed for MEDLINE]

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Biosimilar granulocyte colony-stimulating factor is effective in reducing the duration of neutropenia after autologous peripheral blood stem cell transplantation.

Posted by rob on November 9, 2014 under Uncategorized | Comments are off for this article

Biosimilar granulocyte colony-stimulating factor is effective in reducing the duration of neutropenia after autologous peripheral blood stem cell transplantation.

Transplant Proc. 2014;46(8):2882-4

Authors: Cioch M, Jawniak D, Kotwica K, Wach M, Ma?ko J, Gor?cy A, Klimek P, Mazurkiewicz E, Jarosz P, Hus M

Abstract

BACKGROUND: Autologous peripheral blood stem cell transplantation (APBSCT) is the standard of therapy for patients with multiple myeloma and refractory Hodgkin’s and non-Hodgkin’s lymphomas. Granulocyte colony-stimulating factor (G-CSF) is widely used to accelerate hematopoietic recovery after transplantation and to reduce the morbidity and mortality associated with prolonged neutropenia. Biosimilar G-CSF is approved for the same indications as the originator G-CSF. This is one of the first reported uses of a biosimilar G-CSF for neutrophil recovery after APBSCT.

METHODS: A total of 23 consecutive patients with hematological malignancy (multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphomas, and acute myelogenous leukemia) were recruited at the Department of Haematooncology and Bone Marrow Transplantation at the Medical University of Lublin. Patients (12 men and 11 women; median age, 47 ± 13 years) received biosimilar G-CSF (Zarzio, Sandoz Biopharmaceuticals) after myeloablative chemotherapy (primarily BiCnU, etoposide, cytarabine, and melphalan or melphalan 140/200 mg/m(2)) followed by PBSCT. The median number of transplanted CD34+ cells was 4.2 ± 0.8 × 10(6)/kg body wt. G-CSF therapy was started when absolute neutrophil count (ANC) was <0.5 × 10(9)/L and was continued until ANC reached >1.5 × 10(9)/L for 3 consecutive days. Hematopoietic recovery parameters were compared with those in the control group, which consisted of 23 consecutive patients transplanted in the period before the biosimilar G-CSF group and receiving originator G-CSF (Neupogen, Amgen).

RESULTS: The mean duration of treatment with biosimilar and originator G-CSF was 14.4 ± 5.1 and 18.6 ± 11.5 days, respectively (P = .43). The adverse event profile was comparable between the biosimilar G-CSF and originator G-CSF groups, with similar occurrence of neutropenic fever (5 versus 6 patients) and bone pain (7 patients in each group). One patient in the biosimilar group had neutropenic enterocolitis and sepsis. There was no case of death in either group. Granulocyte recovery in the study group was as follows: mean days to ANC >0.5 × 10(9)/L was 13.0 ± 4.0 days; to ANC >1.5 × 10(9)/L, 13.6 ± 4.5 days; and to ANC >1.5 × 10(9)/L, 14.0 ± 4.7 days. Mean duration until platelet recovery >20 × 10(9)/L was 16.1 ± 4.4 days. There were no statistically significant differences between the biosimilar and originator G-CSF groups in hematopoietic recovery parameters.

CONCLUSIONS: Biosimilar G-CSF is safe and effective in reducing the duration of neutropenia in patients undergoing myeloablative therapy followed by APBSCT and probably in cost savings in transplantation budgets.

PMID: 25380941 [PubMed - in process]

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Persistent suboptimal molecular response in a patient with chronic myelogenous leukemia and Klinefelter syndrome.

Posted by rob on November 8, 2014 under Uncategorized | Comments are off for this article

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Persistent suboptimal molecular response in a patient with chronic myelogenous leukemia and Klinefelter syndrome.

Korean J Intern Med. 2014 Nov;29(6):827-9

Authors: Chakraborty R, Mukkamalla SK, Singam K, Calderon N

PMID: 25378984 [PubMed - in process]

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How mRNA is misspliced in acute myelogenous leukemia (AML)?

Posted by rob on November 7, 2014 under Uncategorized | Comments are off for this article

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How mRNA is misspliced in acute myelogenous leukemia (AML)?

Oncotarget. 2014 Oct 30;5(20):9534-9545

Authors: Mohamed AM, Thénoz M, Solly F, Balsat M, Mortreux F, Wattel E

Abstract

Approximately one-third of expressed genes are misspliced in AML, opening the possibility that additional factors than splicing factor mutations might cause RNA missplicing in these diseases. AML cells harbor a constellation of epigenetic modifications and regularly express large amounts of WT1 transcripts. Histone acetylation/methylation and DNA CpG methylation favor either exon skipping or inclusion, mainly through interfering with RNA Pol II-mediated elongation. This can result either from the binding of various factors on Pol II or alternatively from the recruitment of DNA binding factors that create roadblocks to Pol II-induced elongation. WT1 exhibits pleiotropic effects on mRNA splicing, which mainly result from the binding properties of WT1 via its zinc fingers domains to DNA, RNA, and proteins. Through the repression of the kinase SRPK1, WT1 modifies the splicing of VEGF, which plays important roles in hematopoiesis and angiogenesis. At the protein level, WT1 interacts with the splicing factors U2AF2, WTAP, and RPM4. Therefore, AML cells appear to have acquired numerous properties known to interfere with mRNA splicing. The challenge is now to elucidate these links in order to trigger mRNA splicing at the therapeutic level.

PMID: 25375204 [PubMed - as supplied by publisher]

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Nonhematologic Toxicity of Imatinib Mesylate in Pediatric Patients With Chronic Myelogenous Leukemia: A Predominance of Musculoskeletal Pain.

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Nonhematologic Toxicity of Imatinib Mesylate in Pediatric Patients With Chronic Myelogenous Leukemia: A Predominance of Musculoskeletal Pain.

J Pediatr Hematol Oncol. 2014 Nov 4;

Authors: Heym KM, Gressett Ussery SM, Trinkman H, Philpot LM

Abstract

Therapy with the tyrosine kinase inhibitor imatinib mesylate has become standard initial treatment for adult and pediatric patients with chronic myelogenous leukemia. Long-term follow-up data are now available in the adult population, and the toxicity profile of imatinib mesylate among adults has been extensively studied and reported. Despite its increasing use in the pediatric population, there are limited data regarding adverse event profiles of imatinib mesylate in children, and few reports exist in the literature focusing on nonhematologic toxicity in this population. We reviewed our institutional experience with imatinib therapy for chronic myelogenous leukemia over an 8-year period of time. Nine pediatric patients began therapy with imatinib mesylate and were included in this review. We reviewed the occurrence of nonhematologic toxicity in this cohort and the impact of that toxicity on continuation of therapy. Eight patients experienced nonhematologic toxicity, including nausea/vomiting (44.4%) and musculoskeletal pain (88.9%). Three patients (33.3%) required discontinuation of imatinib therapy due to grade 3/4 musculoskeletal pain, a rate that is significantly higher than that seen in the adult population. As imatinib therapy becomes increasingly widespread in the treatment of pediatric malignancies, there may be different patterns of clinically significant nonhematologic toxicity, including higher grade musculoskeletal pain.

PMID: 25374285 [PubMed - as supplied by publisher]

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International patterns of childhood chronic myeloid leukemia: comparisons between the United States and resource-restricted nations.

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International patterns of childhood chronic myeloid leukemia: comparisons between the United States and resource-restricted nations.

Pediatr Blood Cancer. 2014 Oct;61(10):1774-8

Authors: Sadak KT, Fultz K, Mendizabal A, Reaman G, Garcia-Gonzalez P, Levine PH

Abstract

BACKGROUND: Chronic myeloid leukemia (CML) is a rare disease in children and represents approximately 2% of all childhood leukemia. This results in difficulty creating large cohorts of patients for pediatric CML research. The Glivec International Patient Assistance Program (GIPAP) is a patient-access program sponsored by Novartis Oncology and administered by The Max Foundation (MAX) that provides imatinib free of charge to patients in resource-restricted countries who are not able to afford this treatment.

PROCEDURES: GIPAP highlights a cohort of children (n?=?3,188) with CML that provides novel insight into international trends in diagnosis, treatment, and survival. These trends can be compared to outcomes in developed nations to crudely assess the impact of an extended access program for CML treatment such as GIPAP.

RESULTS: Overall survival values for children treated for CML within the GIPAP (89%) suggest that imatinib is very effective in middle and low-income countries.

CONCLUSIONS: This may allow for increased international awareness within the scientific community to consider possible reasons for the differences in overall survival in pediatric CML within the United States versus other nations with fewer resources.

PMID: 24976310 [PubMed - indexed for MEDLINE]

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NOCARDIA ASTEROIDES SUBRETINAL ABSCESS IN PATIENT WITH ACUTE MYELOGENOUS LEUKEMIA AFTER ALLOGENEIC STEM CELL TRANSPLANT.

Posted by rob on November 6, 2014 under Uncategorized | Comments are off for this article

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NOCARDIA ASTEROIDES SUBRETINAL ABSCESS IN PATIENT WITH ACUTE MYELOGENOUS LEUKEMIA AFTER ALLOGENEIC STEM CELL TRANSPLANT.

Retin Cases Brief Rep. 2014 Spring;8(2):113-115

Authors: Eisenberg MA, Wilker SC

Abstract

PURPOSE:: Nocardia asteroides is the most common bacterial cause of subretinal abscesses; however, the diagnosis is often delayed because of the lack of suspicion leading to poor visual prognosis and possible enucleation.

METHODS:: A 40-year-old man with a history of allogeneic stem cell transplant presents with decreased vision and a macular subretinal abscess.

RESULTS:: Examination revealed decreased vision at 20/100 with a peripapillary creamy subretinal lesion extending to the nasal margin of the fovea associated with intraretinal and subretinal hemorrhages without vitritis. Workup revealed disseminated N. asteroides, confirmed with a skin biopsy with the involvement of skin, eyes, lungs, and brain. Intravitreal amikacin and vancomycin were promptly given along with systemic vancomycin, sulfamethoxazole/trimethoprim, and meropenem. Vision improved rapidly to 20/40 with stabilization and eventual scarring of the lesion.

CONCLUSION:: This case illustrates that rapid diagnosis and treatment of subretinal N. asteroides can possibly have a good visual outcome and stabilization of the ocular manifestations.

PMID: 25372323 [PubMed - as supplied by publisher]

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