A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on October 30, 2005 under Uncategorized | 
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Koca E, Cetiner D, Goker H, Aksu S, Ozcebe OI, Haznedaroglu IC, Turgan C
Clin Nephrol. 2005 Oct ; 64(4): 324-6
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Aloisi A, DI Gregorio S, Stagno F, Guglielmo P, Mannino F, Sormani MP, Bruzzi P, Gambacorti-Passerini C, Saglio G, Venuta S, Giustolisi R, Messina A, Vigneri PG
Blood. 2005 Oct 25;
The BCR-ABL oncoprotein of Chronic Myelogenous Leukemia (CML) localizes to the cell cytoplasm where it activates proliferative and anti-apoptotic signaling pathways. We previously reported that the combination of the ABL kinase inhibitor Imatinib Mesylate (IM) and the nuclear export inhibitor Leptomycin B (LMB) traps BCR-ABL inside the nucleus, triggering the death of the leukemic cells. To evaluate the efficacy of the combination of IM and LMB on human cells we collected CD34-positive cells from 6 healthy donors and myeloid progenitors from 35 CML patients. The sequential addition of IM and LMB generated the strongest reduction in the proliferative potential of the leukemic cells, with limited toxicity to normal myeloid precursors. Furthermore, nested RT-PCR analysis on colonies representative of each experimental condition demonstrated that the combination of IM and LMB was the most effective regimen in reducing the number of BCR-ABL-positive colonies. The efficacy of the two-drug association was independent of the clinical characteristics of the patients. Our results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly-diagnosed and IM-resistant CML patients.
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Haltrich I, Kost-Alimova M, Kovács G, Kriván G, Dobos M, Imreh S, Fekete G
Magy Onkol. 2005; 49(2): 141-7
Cytogenetic syndrome involving bands 3q21 and 3q26, known as “3q21q26 syndrome” has been observed in adult patients with acute myelogenous leukemia (0.5-2%), chronic myelogenous leukemia in blast crisis (20%), myelodysplastic syndromes and myeloproliferative disorders. In the present study bone marrow samples from two boys (12 and 16 years), diagnosed with CML and AML respectively, were investigated using conventional cytogenetic methods, interphase “multipoint” fluorescence in situ hybridization (FISH), dual color-FISH and multiplex FISH. The “multipoint” FISH analysis identified in de novo childhood AML case an inv(3)(q21q26) and a complex 3q rearrangement including inversion and duplication in the CML case. The “3q21q26 syndrome” is associated with normal or elevated platelet counts with marked abnormalities of megakaryocytopoiesis, involvement of multiple hematopoietic lineages. The affected patients were resistant to conventional chemotherapy and had a short survival. This syndrome is very rare in de novo childhood AML, and simultaneous presence of 3q inversion and duplication, to our knowledge, has not yet been identified in hematological malignancies. The results of our study underline the importance of classical and modern cytogenetic analysis in the diagnosis of hematological malignancies, because in the majority of cases they can provide additional diagnostic information for the clinicians in deciding the best therapeutic approach, precise classification and prognosis of the disease.
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He Y, Feng SZ, Wang M, Wei JL, Qin TJ, Zhou Z, Zhai WJ, Qiu LG, Han MZ
Zhonghua Xue Ye Xue Za Zhi. 2005 Jul ; 26(7): 389-92
OBJECTIVE: To evaluate the treatment outcome of HLA-identical sibling allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia (CML) patients in first chronic phase (CP(1)). METHODS: Fifty-one patients with CML-CP(1) received HLA-identical sibling allo-HSCT with conditioning regimens of TBI plus Cy or Bu plus Cy. Allogeneic peripheral blood stem cell transplantation (PBSCT) and bone marrow transplantation (BMT) were performed for 28 and 23 patients, respectively. The median follow-up duration was 1434 (60 – 4062) days. RESULTS: Fifty (98.0%) patients were successfully engrafted. Transplant-related mortality occurred in 8 (15.7%) patients. Acute graft-versus-host disease (aGVHD) occurred in 35 (68.6%) patients and 11 (21.6%) patients were grade II-IV, while chronic GVHD (cGVHD) did in 17 (37.8%) patients. Five (7.4%) patients relapsed. The 5-year probability of disease-free survival (DFS) was (79.2 +/- 6.4)%. There was no significant difference in 5-year DFS, death rate and treatment related syndromes between the two conditioning regimens (P > 0.05), and in 5-year DFS, relapse rate and death rate between two transplant choices (P > 0.05). However, the rate of relapse was lower in Bu/Cy group (P [HLA-identical sibling allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia in first chronic phase. Analysis of 51 cases.]
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Geng SX, Li YQ, Chen SH, Yang LJ, Yin QS, Wu XL, Zhang XL
Zhonghua Xue Ye Xue Za Zhi. 2005 Jul ; 26(7): 413-6
OBJECTIVE: To analyze peripheral blood naive T cell level, its T cell receptor (TCR) Vbeta repertoire usage profile and clonality for evaluating the recent thymic output function and the expansion feature of TCR Vbeta subfamily T cells in patients with chronic myelogenous leukemia (CML). METHODS: Quantitative detection of T-cell receptor excision DNA circles (TRECs) in peripheral blood mononuclear cells (PBMNC) from 20 cases of CML was preformed by real-time PCR (TaqMan) analysis, and TRECs-number in T-cells was calculated from peripheral blood CD3-positive cell rate. The expression and clonality analysis were detected by RT-PCR and genescan technique in PBMNC from 14 out of the 20 patients. Nine normal individuals served as controls. RESULTS: A dramatic reduction of TRECs value in patients with CML was detected as compared with that in normal controls. The mean value of TRECs was 0.06 +/- 0.16 copy/1000 CD3(+) cells in CML patients while 6.84 +/- 4.71 copies/1000 CD3(+) cells in normal controls (P
[Peripheral blood naive T cell level and its T cell receptor Vbeta repertoire usage profile in patients with chronic myelogenous leukemia.]
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Hu SY, Chen ZX, Gu WY, Cen JN, Zhao Y, Gu M
Zhonghua Xue Ye Xue Za Zhi. 2005 Jul ; 26(7): 417-20
OBJECTIVE: To investigate retinoblastoma (Rb) associated protein 46 (RbAp46) gene expression levels in bone marrow (BM) cells of leukemia patients. METHODS: Real-time quantitative retroverse polymerase chain reaction (QRT-PCR) method was used for detecting RbAp46 expression levels in BM cells of 140 patients with acute leukemia (AL), 13 with chronic myelogenous leukemia in chronic phase (CML-CP), 7 with CML in blast crisis (CML-BC) and 32 with non-leukemic disorders. RESULTS: The M-Estimators of RbAp46 were higher in 98 newly diagnosed ALs and 5 relapsed ALs than in 28 ALs in complete remission (CR) and 32 non-leukemic controls (178.23 and 213.65 vs 85.89 and 88.08, respectively). No statistic difference was found between the CR group and control group, or between the newly diagnosed group and relapsed group. The M-Estimators of RbAp46 in patients with CML-CP was 58.27, similar to that in control, but much lower than that in CML-BC (173.24). Among 98 newly diagnosed ALs, the M-Estimators of RbAp46 in M(3) and M(4) were the lowest in all of the subtypes. Furthermore, the RbAp46 expression levels were not correlated with the expression of the fusion genes of bcr/abl, PML-RARalpha, and multidrug resistant gene (mdr1), but were positively correlated with Wilms’ tumor gene (WT1) expression levels and negatively with AML1/ETO fusion gene expression. CONCLUSION: RbAp46 expression levels in ALs and CML-BC were strikingly higher than that in non-leukemias and CML-CP, and might participate in leukemogenesis.
[Detection of RbAp46 expression in bone marrow cells of leukemia patients by real-time quantitative RT-PCR.]
Posted by rob on October 25, 2005 under Uncategorized | Be the First to Comment
D’Antonio J
Clin J Oncol Nurs. 2005 Oct ; 9(5): 535-8
Chronic myelogenous leukemia (CML) represents about 14% of all leukemias and occurs with a frequency of about 1 in 100,000. It is rare in children. Symptoms include fatigue, weight loss, sweating, and abdominal discomfort from an enlarged spleen. The white blood cell count can range from 100-600 ul. CML has three phases: the chronic phase, accelerated phase, and blast phase. Most patients are diagnosed during the chronic phase. Ionizing radiation has been implicated in some cases of CML, but in most individuals no cause is known. The Philadelphia chromosome, an acquired genetic mutation represented by a translocation of chromosome 22 and chromosome 9, drives the leukemic changes in CML. Imatinib mesylate, a tyrosine kinase inhibitor, was approved in 2002 for the treatment of all phases of CML. Because of its effectiveness, imatinib has become the treatment of choice for most patients with CML. Stem cell transplantation also is an option for eligible patients. It is the only curative treatment for CML. Two drugs under study for patients who cannot tolerate or who become resistant to imatinib are BMS-354825 and AMN107. Oncology nurses who are knowledgeable about new therapies for CML can be effective resources for their patients.
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Wu D, Nair-Gill E, Sher DA, Parker LL, Campbell JM, Siddiqui M, Stock W, Kron SJ
Anal Biochem. 2005 Sep 22;
There is a current and increasing demand for simple, robust, nonradioactive assays of protein tyrosine kinase activity with applications for clinical diagnosis and high-throughput screening of potential molecularly targeted therapeutic agents. One significant challenge is to detect and measure the activity of specific kinases with key roles in cell signaling as an approach to distinguish normal cells from cancer cells and as a means of evaluating targeted drug efficacy and resistance in cancer cells. Here, we describe a method in which kinase substrates fused to glutathione-S-transferase and immobilized on glutathione agarose beads are phosphorylated, eluted, and then assayed to detect kinase activity. The activity of recombinant, purified c-Abl kinase or Bcr-Abl kinase in whole cell extracts can be detected with equivalent specificity, sensitivity, and reproducibility. Similarly, inhibition of recombinant c-Abl or Bcr-Abl in cells or cell extracts by imatinib mesylate and other Bcr-Abl targeted kinase inhibitors is readily assayed. This simple kinase assay is sufficiently straightforward and robust for use in clinical laboratories and is potentially adaptable to high-throughput assay formats.
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Onitilo AA, Kio EA, Singh AK, Lazarchick J
Leuk Lymphoma. 2005 Nov ; 46(11): 1667-70
We report a 50-year-old patient with idiopathic hypereosinophilic syndrome with trisomy 8 who experienced a complete and durable hematological and cytogenetic remission with low-dose imatinib therapy. He also had a significant reversal of cardiac dysfunction with a reduction in cardiac hypertrophy, resolution of pericardial effusion and mitral and tricuspid regurgitation. He remained in remission 3 years after therapy.
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Piazza RG, Magistroni V, Franceschino A, Gambacorti-Passerini C
Leukemia. 2005 Oct 20;
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Khoury HJ, Loberiza FR, Ringden O, Barrett AJ, Bolwell BJ, Cahn JY, Champlin RE, Gale RP, Hale GA, Urbano-Ispizua A, Martino R, McCarthy PL, Tiberghien P, Verdonck LF, Horowitz MM
Blood. 2005 Oct 20;
Granulocyte-colony-stimulating factor (G-CSF) is often administered after hematopoietic cell transplantation (HCT) to accelerate neutrophil recovery, but it is unclear what impact G-CSF has on long-term transplant outcomes. We analyzed within the database of the Center for International Blood and Marrow Transplant Research, the impact of giving posttransplant G-CSF on the outcomes of allogeneic HCT for acute myelogenous leukemia and chronic myelogenous leukemia in 2,719 patients transplanted between 1995 and 2000. These included 1,435 recipients of HLA-identical sibling bone marrow (BM), 609 recipients of HLA-identical peripheral blood stem cells (PBSC), and 675 recipients of unrelated donor BM transplants. Outcomes were compared between patients receiving or not receiving G-CSF within 7 days of HCT according to graft type. Median follow-up was >30 mo (range, 2-87 mo). G-CSF shortened the post-transplant neutropenic period, but did not affect days +30 and +100 treatment-related mortality (TRM). Probabilities of acute and chronic graft-versus-host disease (GVHD), leukemia-free (LFS) and overall survival were similar whether or not G-CSF was given. Multivariate analyses confirmed that giving G-CSF did not affect the risk of GVHD, TRM, LFS, or survival. In conclusion, results of this study found no long-term benefit or disadvantage of giving G-CSF posttransplant to promote hematopoietic recovery.
Impact of posttransplant G-CSF on outcomes of allogeneic hematopoietic stem cell transplantation.
Posted by rob on October 23, 2005 under Uncategorized | Be the First to Comment
Posted by rob on October 22, 2005 under Uncategorized | Be the First to Comment
D’Antonio J
Clin J Oncol Nurs. 2005 Oct ; 9(5): 535-8
Chronic myelogenous leukemia (CML) represents about 14% of all leukemias and occurs with a frequency of about 1 in 100,000. It is rare in children. Symptoms include fatigue, weight loss, sweating, and abdominal discomfort from an enlarged spleen. The white blood cell count can range from 100-600 ul. CML has three phases: the chronic phase, accelerated phase, and blast phase. Most patients are diagnosed during the chronic phase. Ionizing radiation has been implicated in some cases of CML, but in most individuals no cause is known. The Philadelphia chromosome, an acquired genetic mutation represented by a translocation of chromosome 22 and chromosome 9, drives the leukemic changes in CML. Imatinib mesylate, a tyrosine kinase inhibitor, was approved in 2002 for the treatment of all phases of CML. Because of its effectiveness, imatinib has become the treatment of choice for most patients with CML. Stem cell transplantation also is an option for eligible patients. It is the only curative treatment for CML. Two drugs under study for patients who cannot tolerate or who become resistant to imatinib are BMS-354825 and AMN107. Oncology nurses who are knowledgeable about new therapies for CML can be effective resources for their patients.
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Hishida A, Terakura S, Emi N, Yamamoto K, Murata M, Nishio K, Sekido Y, Niwa T, Hamajima N, Naoe T
Asian Pac J Cancer Prev. 2005 Jul-Sep ; 6(3): 251-5
We conducted a prevalent case-control study with 51 chronic myelogenous leukemia (CML) cases and 476 controls to investigate the associations between glutathione S-transferase T1 (GSTT1), glutathione S-transferase M1 (GSTM1) deletions, and the NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism with risk of chronic myelocytic leukemia in Japanese. For the GSTT1 deletion, when the GSTT1 positive genotype was defined as the reference, the OR for the GSTT1 deletion genotype was 1.32 (95%CI; 0.74-2.36). For the GSTM1 deletion, when the GSTM1 positive genotype was defined as the reference, the OR for the GSTM1 deletion genotype was 0.95 (95%CI; 0.53-1.69). For NQO1 C609T polymorphism, when the NQO1 609CC genotype was defined as the reference, the ORs for the CT genotype, TT genotype, and CT and TT genotypes combined together were 2.37 (95%CI, 1.21-4.67, P=0.012), 1.44 (0.55-3.74, P=0.012) and 2.12 (1.10-4.08, P=0.025), respectively. The present study revealed that the risk of CML was modulated little by GSTT1 and GSTM1 deletions, but a statistically significant association between NQO1 C609T polymorphism and CML was observed for Japanese. Incidence case-control studies with a larger statistical power are now required to confirm our findings.
Posted by rob on October 20, 2005 under Uncategorized | Be the First to Comment
Cayuela JM, Rousselot P, Nicolini F, Espinouse D, Ollagnier C, Bui-Thi MH, Chabane K, Raffoux E, Callet-Bauchu E, Tigaud I, Magaud JP, Hayette S
Leukemia. 2005 Oct 13;
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Gruber FX, Lamark T, Anonli A, Sovershaev MA, Olsen M, Gedde-Dahl T, Hjort-Hansen H, Skogen B
Leukemia. 2005 Oct 13;
Resistance to imatinib during the treatment of chronic myeloid leukaemia (CML) is frequently associated with point mutations in the ABL gene encoding the ATP binding region likely to cause disease relapse. Early diagnosis and monitoring of these mutations may be important in order to prevent rapid expansion of resistant clones. We describe a quantitative mutation-specific PCR assay based on the readily available Taqman platform. Selectivity for the mutated target is conferred by mutation-specific primers destabilised by additional mismatches. The assay can be carried out in parallel to standard BCR-ABL quantification and is therefore more quickly compared to standard sequencing procedures. The sensitivity of the assay reaches 0.1%. It also allows for quantitative assessment of mutated clones. By analysing sequential samples of resistant subjects, we show how mutated clones were selected, maintained or deselected depending on the individual treatment setting. The high sensitivity and practical merits of this method makes it a good candidate for prospective molecular surveillance of patients at high risk for imatinib resistance.Leukemia advance online publication, 13 October 2005; doi:10.1038/sj.leu.2403983.
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Brazzelli V, Prestinari F, Roveda E, Barbagallo T, Bellani E, Vassallo C, Orlandi E, Passamonti F, Borroni G
J Am Acad Dermatol. 2005 Nov ; 53(5 Suppl 1): S240-3
Imatinib mesylate (IM) represents the first-line treatment for chronic myeloid leukemia (CML). We hereby relate 3 cases of an IM-induced pityriasis rosea (PR)-like cutaneous eruption. Patients developed an erythematous, slightly pruritic, macular skin eruption, with many lesions having a peripheral collarette of desquamation, confined to the trunk, limbs, and arms with a vaguely dermatomal diffusion. The histologic findings suggested a reactive process to the drug. Full dermatological recovery was obtained after IM discontinuation, but lesions reappeared upon restoring therapy, suggesting the drug-related nature of the rash. To our knowledge this is the first reported PR-like cutaneous eruption to IM.
Pityriasis rosea-like eruption during treatment with imatinib mesylate: description of 3 cases.
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Brusa G, Mancini M, Campanini F, Calabrò A, Zuffa E, Barbieri E, Santucci MA
Acta Haematol. 2005; 114(3): 150-154
In order to ascertain whether p53 has a role in chronic myeloid leukemia hematopoietic progenitor response to the innovative tyrosine kinase inhibitor STI571 (Imatinib), we overexpressed a wild type (wt) p53 construct in the K562 cell line, generated from a human blast crisis and lacking endogenous p53. Wt p53 overexpression was associated with a significant reduction of bcr-abl expression levels resulting, at least in part, from post-transcriptional events affecting the stability of p210 bcr-abl fusion protein. Moreover, we demonstrated that p53 overexpression enhances the commitment to the apoptotic death fate of K562 following its in vitro exposure to 1 muM STI571. Multiple mechanisms are involved in p53 impact on K562 survival: Most importantly, we found that a greater reduction of bcr-abl transcription by STI571 was associated with the overexpression of wt p53. Further studies are required to elucidate the mechanisms involved in the transcriptional repression of bcr-abl by STI571 and p53 and in their synergic effects on the clonal hematopoiesis of chronic myeloid leukemia. Copyright (c) 2005 S. Karger AG, Basel.
Tyrosine Kinase Inhibitor STI571 (Imatinib) Cooperates with Wild-Type p53 on K562 Cell Line to Enhance Its Proapoptotic Effects.
Posted by rob on October 15, 2005 under Uncategorized | Be the First to Comment
Jørgensen HG, Allan EK, Mountford JC, Richmond L, Harrison S, Elliott MA, Holyoake TL
Exp Hematol. 2005 Oct ; 33(10): 1140-6
OBJECTIVE: In chronic myeloid leukemia (CML), imatinib mesylate (IM; Gleevec, Glivec) induces a G0/G1 cell-cycle block in total CD34(+) cells without causing significant apoptosis. Bryostatin-1 (bryo), a protein kinase C (PKC) modulator, was investigated for its ability to increase IM-mediated apoptosis either through induction of cycling of G0/G1 Ph(+) cells or antagonism of the IM-induced cell-cycle block. METHODS: The Ph(+) K562 cell line and primary CD34(+) CML cells were studied for cell-cycle progression (PI staining), proliferation ((3)H thymidine uptake), and survival (dye exclusion). RESULTS: Following 48 hours exposure to IM, on average more than 80% of surviving K562 cells were in G0/G1 as compared to approximately 50% for untreated control cultures (p
Enhanced CML stem cell elimination in vitro by bryostatin priming with imatinib mesylate.
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Gleich GJ, Leiferman KM
Curr Opin Immunol. 2005 Oct 5;
In 1968, the term hypereosinophilic syndromes (HES) was coined to refer to a spectrum of eosinophil-associated diseases presumed to be caused by an underlying immunological pathology. In the 1990s, the identification of an HES subset with T lymphocyte clonality and production of cytokines, particularly IL-5, validated this concept. Then, in 2002, imatinib mesylate, which was introduced for the treatment of chronic myelogenous leukemia, effectively controlled another subgroup of HES patients. Imatinib’s target is a novel constitutively-active kinase. Most imatinib-responsive HES patients show an increased number of bone marrow mast cells and elevated serum tryptase; mast cells, lymphocytes and neutrophils express the novel kinase. This new information critically modifies our view of HES and indicates that several cell lines are altered and likely to contribute to HES pathophysiology.
