National Cancer Institute®
Last Modified: May 1, 2002
UI - 11765724
AU - Anonymous
TI - Imatinib mesylate.
SO - Am J Health Syst Pharm 2001 Dec 1;58(23):2241-2
UI - 11960331
AU - Holyoake TL; Jiang X; Drummond MW; Eaves AC; Eaves CJ
TI - Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia.
SO - Leukemia 2002 Apr;16(4):549-58
AD - Departments of Medicine and Hematology, Glasgow Royal Infirmary, Glasgow, UK.
Chronic myeloid leukemia (CML) has been studied intensively for many years; yet its treatment remains problematic and its biology remains elusive. In chronic phase, the leukemic clone appears to be maintained by a small number of BCR-ABL-positive hematopoietic stem cells that differentiate normally and amplify slowly. In contrast, as these cells enter the intermediate stages of lineage restriction, their progeny are selectively expanded and generate an enlarged pool of neoplastic progenitors. Recent analyses of purified subsets of primitive CML cells have provided a coherent explanation for this dichotomous behavior of BCR-ABL-positive stem and progenitor cells based on the discovery of an unusual autocrine IL-3/G-CSF mechanism activated in them. This only partially counteracts in vivosignals that maintain normal stem cells in a quiescent state but, when active in CML stem cells, promotes their differentiation in favor of their self-renewal. In more differentiated CML progenitors, the same mechanism has a more potent mitogenic effect which is then extinguished when the cells enter the terminal stages of differentiation. Thus, further expansion of the clone is limited until inevitably additional mutations are acquired that further distort or override the regulatory mechanisms still operative in the chronic phase.
UI - 11960334
AU - Blagosklonny MV
TI - STI-571 must select for drug-resistant cells but 'no cell breathes fire out of its nostrils like a dragon'.
SO - Leukemia 2002 Apr;16(4):570-2
AD - Medicine Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Seemingly disappointing, the Bcr-Abl kinase inhibitor STI-571 shares an 'unfortunate' characteristic with conventional cancer drugs: the development of drug resistance. I argue that the resistance must develop even faster to STI-571 than to conventional drugs, because STI-571 is so effective. This is predictable, but is it inevitable? And how do mechanisms of resistance in relapse depend on a degree of remission. In addition to mutation rate and number of tumor cells, one additional factor determines relapse vs. 'extinction' of the leukemia cell population.
UI - 11960335
AU - Maloisel F; Guerci A; Guyotat D; Ifrah N; Michallet M; Reiffers J;
TI - Tertain G; Blanc M; Bauduer F; Briere J; Abgrall JF; Pegourie-Bandelier B; Solary E; Cambier N; Coso D; Vilque JP; Delain M; Harousseau JL; Rousselot P; Belhadj K; Morice P; Attal J; Chabin M; Chastang C; Guilhot J; Guilhot F; France Intergroupe des Leucemies Myeloides Chroniques Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase.
SO - Leukemia 2002 Apr;16(4):573-80
AD - Division of Hematology, University Hospital of Strasbourg, France.
Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.
UI - 11960336
AU - Schlenk RF; Hartmann F; Hensel M; Jung W; Weber-Nordt R; Gabler A; Haas
TI - R; Ho AD; Trumper L; Dohner H Less intense conditioning with fludarabine, cyclophosphamide, idarubicin and etoposide (FCIE) followed by allogeneic unselected peripheral blood stem cell transplantation in elderly patients with leukemia.
SO - Leukemia 2002 Apr;16(4):581-6
AD - Department of Internal Medicine III, University of Ulm, Ulm, Germany.
The objective of this study was to assess toxicity and feasibility of achieving engraftment of allogeneic blood progenitor cells following nonmyeloablative conditioning according to the FCIE protocol (fludarabine 25 mg/m(2)/day, days -7 to -3; cyclophosphamide 200 mg/m(2)/day, days -7 to -3; idarubicin 12 mg/m(2)/day, days -7 to -5; etoposide 250 mg/m(2)/day, days -4 to -3) in elderly patients with leukemia. Eleven patients were included in the study: six patients with acute myeloid leukemia (AML) in complete remission (CR); three patients with refractory or relapsed AML; one patient with chronic myeloid leukemia; one patient with acute lymphoblastic leukemia. The median age of the patients was 62 years. All patients received blood progenitor cells from an HLA-identical sibling with 8.8 x 10(6) CD34(+) cells/kg (median; range 4.7 to 26.2 x 10(6)/kg) and 5.5 x 10(8) CD3(+)cells/kg (median; range 4.5 to 7.9 x 10(8)/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and three courses of methotrexate. The median duration of white blood cell counts <1 x 10(9)/l was 17 days and of platelet counts <50 x 10(9)/l 20 days. In two patients acute GVHD grade I occurred. Nine of 10 patients analyzed developed mixed chimerism. Of seven patients transplanted in CR, three remained in CR 19 to 31 months after transplantation. Three patients with refractory leukemia did not achieve CR, while the patient with relapsed AML achieved a 3rd CR. After a median follow-up time of 22 months, chronic GVHD was mild and limited. The data from this pilot study in elderly patients with leukemia show that the combination of primarily immunosuppressive (FC) and antileukemic (IE) drugs for nonmyeloablative conditioning has moderate nonhematological toxicity and allows engraftment of allogeneic blood progenitor cells.
UI - 11960345
AU - Manabe A; Okamura J; Yumura-Yagi K; Akiyama Y; Sako M; Uchiyama H;
TI - Kojima S; Koike K; Saito T; Nakahata T; MDS Committee of the Japanese Society of Pediatric Hematology Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the International JMML Working Group.
SO - Leukemia 2002 Apr;16(4):645-9
AD - Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Prognostic factors of juvenile myelomonocytic leukemia (JMML) have not been clarified because of its very low incidence and inaccuracy in the diagnosis. The purpose of this study was to evaluate children with JMML given an allogeneic hematopoietic stem cell transplantation (SCT) and the role of different variables potentially influencing outcome in a nationwide survey in Japan based on the newly proposed criteria by the International JMML Working Group. The study patients were 27 children who underwent SCT among 55 JMML patients retrospectively collected in the survey. The source of grafts was HLA-identical siblings in 12 cases, HLA-matched unrelated individuals in 10 and others in five. Total body irradiation was used in 18 cases. Event-free and overall survival (OS) at 4 years after SCT were 54.2 +/- 11.2% (s.e.) and 57.9 +/- 11.0% (s.e.), respectively. Six patients died of relapse and three of complications. Patients with abnormal karyotypes showed a significantly lower OS than those with normal karyotypes (P < 0.001). Patients below 1 year of age showed a significantly higher OS than those of 1 year of age or more (P = 0.02). Patients with grade 0-1 acute graft-versus-host disease (GVHD) or chronic GVHD had a more favorable OS than those without them, although they were not statistically significant (P > 0.05). Other variables studied were not associated with OS. A multivariate analysis of these factors yielded the abnormal karyotype as the only significant risk factor for lower OS (risk ratio: 11.0; 95% CI: 2.7-45.1).
UI - 11960353
AU - Ferry-Dumazet H; Mamani-Matsuda M; Dupouy M; Belloc F; Thiolat D; Marit
TI - G; Arock M; Reiffers J; Mossalayi MD Nitric oxide induces the apoptosis of human BCR-ABL-positive myeloid leukemia cells: evidence for the chelation of intracellular iron.
SO - Leukemia 2002 Apr;16(4):708-15
AD - Bone Marrow Transplantation, CNRS UMR5540 and EA482, Bordeaux-2 University, Bordeaux, France.
Anti-leukemia activity of human macrophages involves the generation of nitric oxide (NO) derivatives. However, leukemic transformation may involve mechanisms that rescue cells from NO-mediated apoptosis. In the present work, we analyzed the effects of exogenous NO on the proliferation of BCR-ABL(+) chronic myelogenous leukemia (CML) cells. As normal leukocytes, the proliferation of leukemia cells was inhibited by SNAP (S-nitroso-N-acetyl-penicillamine), GEA (Oxatriazolium amino-chloride), and SIN-1 (Morpholino-sydnonimine), whereas SNP (sodium nitroprusside) had no effect on leukemia cell growth. SIN-1 induced higher anti-proliferation activity in BCR-ABL(+) cells, compared to normal hemopoietic cells. Inhibition of leukemia cell proliferation correlated with increased apoptosis and DEVDase activity. The simultaneous addition of exogenous iron reversed NO-mediated inhibition of cell growth, caspase activation and apoptosis in all BCR-ABL(+) cells tested. The quantification of intracellular iron levels in leukemia cells indicated that NO induced an early, dose-dependent decrease in ferric iron levels. Accordingly, elevation of intracellular iron protected leukemia cells from NO-mediated apoptosis. Together, the present work reveals the presence of an iron-dependant mechanism for leukemia cell rescue from NO-induced growth inhibition and apoptosis.
UI - 11920164
AU - Landolfo S; Guarini A; Riera L; Gariglio M; Gribaudo G; Cignetti A;
TI - Cordone I; Montefusco E; Mandelli F; Foa R Chronic myeloid leukemia cells resistant to interferon-alpha lack STAT1 expression.
SO - Hematol J 2000;1(1):7-14
AD - Centro CNR di Immunogenetica ed Oncologia Sperimentale, University of Torino, Torino, Italy.
INTRODUCTION: Interferon-alpha (IFN) plays a role in the management of different neoplasias, particularly those of hematological origin. The mechanisms of action of IFN are still poorly understood and the individual response is unpredictable. In the present study, the pattern of intracellular gene expression following in vitro and in vivo exposure of chronic myeloid leukemia (CML) cells to IFN was evaluated and correlated with the response to in vivo treatment with IFN. MATERIALS AND METHODS: CML patients in different phases of the disease were studied. The pattern of expression of two IFN-inducible proteins involved in IFN-mediated biological activities, the p91 and p84 proteins (STAT1alpha and STAT1beta), components of the IFN-stimulated gene factor 3 (ISGF3) complex and the enzyme 2'-5' oligoadenylate synthetase (2'-5' OASE) were investigated by Western blot in peripheral blood mononuclear cells stimulated or not in vitro by IFN. RESULTS AND CONCLUSIONS: In 6/9 patients evaluated before starting treatment, STAT1 was expressed either constitutively or after in vitro stimulation by IFN. In three cases, STAT1 remained negative even after in vitro activation. The pattern of protein expression correlated with the subsequent hematological response to prolonged in vivo IFN administration: the presence of STAT1 being associated with the clinical response to IFN and the absence and non-inducibility of STAT1 with resistance to IFN. This was further substantiated by studies carried out in ten patients analyzed at the time of a documented clinico-hematological response or resistance to the in vivo administration of IFN. Finally, in order to establish whether the pattern of response to IFN treatment could be predicted at diagnosis, cells cyropreserved at diagnosis from patients with a documented complete response, confirmed also by cytogenetic negativity, or resistance, were studied. While complete responders proved STAT1 positive, none of the four resistant cases ever expressed STAT1. The expression of 2'-5' OASE did not correlate with the clinical response to IFN. This study documents the pivotal role of STAT1 in the in vitro and in vivo responses of CML cells to IFN. The constitutive or induced presence or absence of STAT1 shows a predictive correlation with the response or resistance to treatment with IFN and could be utilized to identify, at diagnosis, resistant patients who may be spared an expensive and unnecessary prolonged IFN administration.
UI - 11792418
AU - Hashimoto S; Toba K; Tsuchiyama J; Abe T; Yano T; Momoi A; Okazuka K;
TI - Kanazawa N; Takahashi M; Aizawa Y CD56+, NKp46+ cell line (MZ93) expressing T-cell and myeloid antigens.
SO - Leuk Res 2002 Mar;26(3):289-95
AD - First Department of Internal Medicine, School of Medicine, Niigata University, Asahimachi-dori 1, Niigata City 951-8520, Japan.
The MZ93 cell line, established from a patient with CML, expressed CD4, CD7, CD13, CD25, CD33, CD34, CD56 and NKp46. The additional karyotype abnormality of the Ph-positive leukemia cells in vivo, 6p+, was also observed in MZ93. The early passages of MZ93 expressed CD3 in the cytoplasm, but the late passages did not. The cells did not express mature NK-markers as expected. The messenger RNAs of CD2 and NKp46 were detected and those of CD3varepsilon and CD3zeta were absent in the cells. Therefore, the cell line has the immunophenotype likely to NK and/or T cell precursor.
UI - 11965836
AU - Sarasombath P; Sumida K; Kaku DA
TI - Parkinsonism associated with interferon alpha therapy for chronic myelogenous leukemia.
SO - Hawaii Med J 2002 Mar;61(3):48, 57
AD - UH School of Medicine, 1356 Lusitana St., 7th Fl., Honolulu, HI 96813, USA. email@example.com
A 79 year-old man was treated with Interferon alpha for chronic myelogenous leukemia and developed severe parkinsonism that resolved after Interferon alpha was stopped. Carbidopa-levodopa was associated with early improvement, but discontinuation did not result in worsening of the parkinsonism.
UI - 11968584
AU - Tothova E
TI - [New views on the treatment of chronic myelocytic leukemia. Literature review]
SO - Vnitr Lek 2002 Mar;48(3):230-3
AD - Klinika hematologie LF UPJS a FNsP, Kosice, Slovenska republika.
The expansion of knowledge of molecular biology and pathophysiology of chronic myeloid leukaemia (CML) indicate a new therapeutic approaches of the disease. Besides less toxic nonmyeloablative regimes of allogenEic transplantation and the introduction of modified interpherone regimes attracts our interest therapy more specific, aimed to a primary reason of a disease, BCR/ABL gene, and its products, that are responsible for leukaemic transformation. The paper is a summary of experimental, as well as first clinical experiences with application of thyrosinkinase-inhibitors, farnesyl-transferase-inhibitors and vaccination therapy of CML. Even thought is allogeneic transplantation the only curative therapy of CML, first clinical experiences with thyrosinkinase inhibitors show, that these are the medicaments that can become in a near future its important alternative.
UI - 11425449
AU - Mohr B; Bornhauser M; Platzbecker U; Freiberg-Richter J; Naumann R;
TI - Prange-Krex G; Mohm J; Kroschinsky F; Ehninger G; Thiede C Problems with interphase fluorescence in situ hybridization in detecting BCR/ABL-positive cells in some patients using a novel technique with extra signals.
SO - Cancer Genet Cytogenet 2001 Jun;127(2):111-7
AD - Medizinische Klinik und Poliklinik I, Universitatsklinikum Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Germany.
Interphase fluorescence in situ hybridization (I-FISH) is frequently used to monitor the response to therapy in various hematological malignancies. We performed a comparison of I-FISH, metaphase FISH (C-FISH), conventional cytogenetics, spectral karyotyping (SKY) and PCR for the detection of the t(9;22) and the BCR/ABL rearrangement in 32 patients with chronic myelogenous leukemia (CML). FISH was done using a novel commercial probe set (VYSIS LSI BCR/ABL ES), which is designed to reduce the rate of false-positive results by marking the argininosuccinate synthetase (ASS) gene and thus providing an extra signal on chromosome 9. Our data indicate, that a substantial number of BCR/ABL-positive patients (n=5 patients, 3 with Ph, 2 with masked Ph) present negative results using this probe set in I-FISH analyses, because they did not fulfill the scoring criteria. In fact, the ASS region, which usually remains on 9q in Ph+ CML, appears to be lost or translocated. Due to these results we recommend that the initial diagnosis as well as the follow-up of patients with Ph+ leukemias should not be based on a single technique but should integrate results of cytogenetics and molecular biology.
UI - 11759071
AU - Muller L; Provenzani C; Pawelec G
TI - Generation of chronic myelogenous leukemia-specific T cells in cytokine-modified autologous mixed lymphocyte/tumor cell cultures.
SO - J Immunother 2001 Nov-Dec;24(6):482-92
AD - Section for Transplantation Immunology, Second Department of Internal Medicine, University of Tubingen Medical School, Germany. firstname.lastname@example.org
Chronic myelogenous leukemia (CML) may be amenable to cell-based adoptive immunotherapy, as suggested by the graft-versus-leukemia effect of bone marrow transplantation and the therapeutic benefit of donor leukocyte infusions. Specific adoptive immunotherapy without bone marrow transplantation might be more effective and less cost-intensive. Professional antigen-presenting cells, the dendritic cells, from patients with CML are derived from the malignant clone and may stimulate antileukemia T-cell responses. Autologous T cells may also be able to recognize tumor antigens on CML cells directly. Here, the authors show that CD4 and CD8 T-cell responses to autologous CML cells can be generated in vitro rapidly and effectively by performing modified autologous mixed lymphocyte/tumor cell cultures (MLTC) in serum-free medium in the presence of cytokines known to support dendritic cell differentiation. MLTC-sensitized T cells secreted large amounts of the type 1 cytokine interferon-gamma, as well as interleukin (IL)-2. However, they also secreted a variety of other cytokines, including the type 2-subtype cytokine IL-13 but not the classic type 2 cytokines IL-4, IL-5, and IL-10. Monoclonal populations of CML-specific CD4 cells could be derived from these lines in limited numbers but showed markedly enhanced reactivity. This suggests that CML-specific T cells are relatively rare in these autologous MTLC-derived sensitized populations, but that their isolation and propagation would yield much more potent antitumor effector cells for use in adoptive immunotherapy without the need for bone marrow transplantation.
UI - 11932803
AU - Nackley J 2nd; Barthel J; Coppola D
TI - Upper gastrointestinal bleeding from leukemic gastric implants.
SO - Endoscopy 2002 Apr;34(4):354
AD - Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612, USA. email@example.com
UI - 11996791
AU - Tong CR; Hong B; Qiu JY; Chen Z; Lu DP
TI - Significance of cytogenetic and fluorescence in situ hybridization analysis in evaluating antichronic myeloid leukemia efficacy of different immune effector cells.
SO - Cancer Genet Cytogenet 2002 Apr 1;134(1):21-4
AD - Cellular Therapy Center, Institute of Hematology, People's Hospital, Peking University, No. 11 South Street, Xi-Zhi-Men, 100044 Beijing, P. R. China. firstname.lastname@example.org
We report on the antileukemia effect of interleukin 2 (IL2) on different immune cells from 22 patients with chronic myeloid leukemia (CML). Bone marrow cells from these patients were first cultured in modified long-term bone marrow culture medium for several days, then separately cultured with lymphokine activated killer cells (LAK), cytokine-induced killer cells (CIK), and dendritic cell cocultured CIK (DC-CIK) for another 1-2 days. They were then detected for presence of the Philadelphia chromosome (Ph) by cytogenetic analysis and fluorescence in situ hybridization (FISH). The percentage of Ph-chromosome-positive cells in the bone marrow mononuclear cells after culturing with CIK and DC-CIK was significantly lower than that after culturing with IL2 or LAK. Our results demonstrate that cytogenetics and FISH are useful techniques for the evaluation of the anti-CML effect of immune cells and that CIK or DC-CIK can be appropriate candidates for adoptive immune cell therapy in vivo or for leukemia cell purging ex vivo.
UI - 11996803
AU - Yamamoto K; Nagata K; Kida A; Hamaguchi H
TI - Acquired gain of an X chromosome as the sole abnormality in the blast crisis of chronic neutrophilic leukemia.
SO - Cancer Genet Cytogenet 2002 Apr 1;134(1):84-7
AD - Department of Hematology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino, Tokyo 180-8610, Japan.
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder characterized by sustained neutrophilic leukocytosis and absence of the Philadelphia chromosome. Most patients with CNL have normal karyotypes, and no specific cytogenetic abnormality has been identified. We report here a patient with CNL that evolved to myeloid blast crisis. A 73-year-old man was admitted to the hospital because of marked leukocytosis (leukocyte count 112.5 x 10(9)/L with 91% segmented neutrophils) and massive hepatosplenomegaly that was diagnosed as CNL with a normal karyotype. After treatment with hydroxyurea for 7 months, the disease progressed to a blast crisis. Bone marrow showed myeloid hyperplasia with 21% myeloblasts, 15% promyelocytes, and marked dysplastic changes of neutrophils. Blastic cells were positive for CD10, CD13, CD14, CD33, CD34, and HLA-DR. Chromosome analysis of the bone marrow cells showed 46,XY,+X in all 20 metaphase spreads. We reviewed 15 cases of CNL terminating in the blast crisis and confirmed that all cases transformed into myeloid crises and had poor prognoses. Furthermore, to our knowledge, this is the first case showing the acquired gain of an extra X chromosome as a sole abnormality in CNL. The gain of an extra X chromosome may play an important role in the progression from chronic phase to the blast crisis of CNL.
UI - 11861264
AU - Baccarani M; Rosti G; de Vivo A; Bonifazi F; Russo D; Martinelli G;
TI - Testoni N; Amabile M; Fiacchini M; Montefusco E; Saglio G; Tura S; Italian Cooperative Study Group on Myeloid Leukemia A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia.
SO - Blood 2002 Mar 1;99(5):1527-35
AD - L. and A. Seragnoli Institute of Hematology and Medical Oncology, S. Orsola Hospital, University of Bologna, Italy. email@example.com
Interferon-alpha (IFN-alpha) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-alpha has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome-positive CML patients who were assigned at random to treatment with IFN-alpha 2a alone or in combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6) IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival (5-year survival, 68% versus 65%; P =.77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.
UI - 11861294
AU - Schultheis B; Carapeti-Marootian M; Hochhaus A; Weisser A; Goldman JM;
TI - Melo JV Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism.
SO - Blood 2002 Mar 1;99(5):1766-75
AD - Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom.
Constitutive activation of the BCR-ABL tyrosine kinase is fundamental to the pathogenesis of chronic myeloid leukemia (CML). STI571 inhibits this activity and modulates the transcription of several genes. It was shown by differential display that the suppressor of cytokine signaling-2 (SOCS-2) gene was down-regulated by STI571 treatment in 14 of 16 BCR-ABL-positive cell lines and in 2 BCR-ABL-transfected murine lines, but not in BCR-ABL-negative counterparts. The effect was maximal at 2 hours and persisted for at least 24 hours after exposure to 1 microM STI571, whereas SOCS-1 and SOCS-3 expression were unaffected. Baseline levels of SOCS-2 were significantly higher in BCR-ABL-positive as compared with BCR-ABL-negative cell lines. It was similar in leukocytes and CD34(+) cells from healthy persons (n = 44) and patients with CML in chronic phase (CP; n = 60) but significantly increased in patients with CML in blast crisis (BC; n = 20) (P <.0001). Mononuclear cells (MNCs) from 3 of 4 patients with CML in BC showed a 2-fold to 12-fold down-regulation of SOCS-2 levels on in vitro exposure to STI571; moreover, a 2-fold to 11-fold decrease in SOCS-2 was observed in MNCs from 7 of 8 patients with CML in BC who responded to treatment with STI571. Refractoriness to STI571 or relapse after initial response was accompanied by augmentation of SOCS-2 expression. Ectopic overexpression of SOCS-2 in 32Dp210 cells slowed growth, inhibited clonogenicity, and increased their motility and sensitivity to STI571. Overall, the results suggest that SOCS-2 is a component of a negative feedback mechanism; it is induced by Bcr-Abl but cannot reverse its overall growth-promoting effects in blastic transformation.
UI - 11916528
AU - Bruserud O; Gjertsen BT; Ulvestad E
TI - Expression of Fc(epsilon)-receptors by human acute myelogenous leukemia (AML) blasts: studies of high- and low- (CD23) affinity receptor expression and the effects of IgE-mediated receptor ligation on functional AML blast characteristics.
SO - Leuk Res 2002 May;26(5):515-21
AD - Division for Hematology, Medical Department, The Gade Institute, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway. firstname.lastname@example.org
Acute myelogenous leukemia (AML) blasts derived from 20 patients were examined for expression of high- (Fc(epsilon)RI) and low-affinity (Fc(epsilon)RII, CD23) IgE Fc(epsilon)-receptors. Fc(epsilon)RI expression was not detected for any patient. In contrast, expression of CD23 (at least 15% of the blasts stained positive) was detected for 6 out of the 20 patients. Acute lymphoblastic leukemia (ALL) blasts derived from 12 patients did not express CD23 (<1% positive cells for all patients). The functional effects of Fc(epsilon)R-receptor ligation were also examined for 20 patients, including the five patients with highest CD23 expression (30-55% positive cells) and five patients with verified low CD23 expression (
UI - 11836601
AU - Liu TC; Lin SF; Chen TP; Chang JG
TI - Polymorphism analysis of CYP3A5 in myeloid leukemia.
SO - Oncol Rep 2002 Mar-Apr;9(2):327-9
AD - Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
The human cytochrome P450 (CYP) metabolizes more than 100 structurally diverse exogenous and endogenous molecules. The CYP3A5 is a major P450 enzyme in the liver and represents 50% of the total hepatic CYP3A content in people expressing CYP3A5. The single nucleotide polymorphisms in CYP3A5*3 and CYP3A5*6 that resulted in the absence of CYP3A5 from tissues were noted in some people. Polymorphisms of potential relevance to leukemia and myelodysplastic syndrome (MDS) have been described for various CYP. The bone marrow and/or peripheral blood from 188 acute myeloid leukemia (AML) patients, 101 chronic myeloid leukemia (CML), 40 MDS, and 270 normal controls were analyzed by a PCR-RFLP assay to evaluate the association of the CYP3A5 polymorphisms with myeloid leukemia. Our data showed that 15/188 (8%), 8/101 (7.9%), and 3/40 (7.5%) of the patients (i.e., 188 AML, 101 CML, 40 MDS) were CYP3A5*1/*1; 88/188 (46.8%), 47/101 (46.5%), and 20/40 (50%) were CYP3A5*1/*3; and 85/188 (45.2%), 46/101 (45.5%), and 17/40 (42.5%) carried the CYP3A5*3/*3 genotype, respectively. CYP3A5*6 was not found in any of the patients' specimens. Similar frequencies of CYP3A5*3 were observed in the leukemic patients and normal controls. Consequently, the finding suggests that the CYP3A5 polymorphism was not associated with the risk of myeloid leukemia.
UI - 11847518
AU - Ribeiro EM; Rodriguez JM; Coser VM; Sotero MG; Fonseca Neto JM; Pasquini
TI - R; Cavalli IJ Microsatellite instability and cytogenetic survey in myeloid leukemias.
SO - Braz J Med Biol Res 2002 Feb;35(2):153-9
AD - Departamento de Genetica, Universidade Federal do Parana, Curitiba, PR, Brasil. email@example.com
Microsatellites are short tandem repeat sequences dispersed throughout the genome. Their instability at multiple genetic loci may result from mismatch repair errors and it occurs in hereditary nonpolyposis colorectal cancer. This instability is also found in many sporadic cancers. In order to evaluate the importance of this process in myeloid leukemias, we studied five loci in different chromosomes of 43 patients, 22 with chronic myelocytic leukemia (CML) in the chronic phase, 7 with CML in blast crisis, and 14 with acute myeloid leukemia (AML), by comparing leukemic DNA extracted from bone marrow and constitutional DNA obtained from buccal epithelial cells. Only one of the 43 patients (2.1%), with relapsed AML, showed an alteration in the allele length at a single locus. Cytogenetic analysis was performed in order to improve the characterization of leukemic subtypes and to determine if specific chromosome aberrations were associated with the presence of microsatellite instability. Several chromosome aberrations were observed, most of them detected at diagnosis and during follow-up of the patients, according to current literature. These findings suggest that microsatellite instability is an infrequent genetic event in myeloid leukemias, adding support to the current view that the mechanisms of genomic instability in solid tumors differ from those observed in leukemias, where specific chromosome aberrations seem to play a major role.
UI - 11769961
AU - Druker BJ
TI - ST1571: a paradigm for clinical trials of molecularly targeted agents.
SO - Biomed Pharmacother 2001 Nov;55(9-10):529-30
AD - Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland 97201, USA.
UI - 11858124
AU - Petukhov VI; Strozha IL; Bondare DK
TI - [Chronic myeloid leukemia: current pathogenetic aspects and new therapeutic approaches (a foreign literature review)]
SO - Ter Arkh 2001;73(12):96-101
UI - 11869959
AU - Piccinini L; Arigliano V; Artusi T
TI - Blast crisis merely lymph nodal of chronic myeloid leukemia.
SO - Haematologica 2002 Mar;87(3):EIM09
AD - Divisione di Oncologia, Dipartmento di Scienze mediche Oncologiche e Radiologiche Policlinico, Via del Pozzo 71, 41100 Modena, Italy. firstname.lastname@example.org
UI - 11877262
AU - Talpaz M; Silver RT; Druker BJ; Goldman JM; Gambacorti-Passerini C;
TI - Guilhot F; Schiffer CA; Fischer T; Deininger MW; Lennard AL; Hochhaus A; Ottmann OG; Gratwohl A; Baccarani M; Stone R; Tura S; Mahon FX; Fernandes-Reese S; Gathmann I; Capdeville R; Kantarjian HM; Sawyers CL Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study.
SO - Blood 2002 Mar 15;99(6):1928-37
AD - M. D. Anderson Cancer Center, Houston, Texas, USA. email@example.com
Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.
UI - 11877268
AU - Weisdorf DJ; Anasetti C; Antin JH; Kernan NA; Kollman C; Snyder D;
TI - Petersdorf E; Nelson G; McGlave P Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation.
SO - Blood 2002 Mar 15;99(6):1971-7
AD - University of Minnesota--Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA. firstname.lastname@example.org
Allogeneic bone marrow transplantation (BMT) offers the only curative therapy for chronic myelogenous leukemia. We compared prospectively collected results of 2464 unrelated donor (URD) transplantations with 450 HLA-identical, matched sibling donor (MSD) transplantations performed at collaborating National Marrow Donor Program institutions. A total of 63% of URDs were matched at HLA-A, -B, and at -DRB1 alleles; all MSDs were genotypically identical at major histocompatibility loci. URD recipients were younger (median 36 vs 39, P =.001) than MSDs and underwent BMT later after diagnosis (median 17 [0-325 months] vs 7 [1-118 months], P =.001) and less often in chronic phase (CP) (67% vs 82%, P =.001). Multivariate analysis demonstrated a significantly increased risk of graft failure and acute graft versus host disease after URD BMT. The risk of hematologic relapse was low after either matched URD or MSD transplantations. We observed significantly though modestly poorer survival and disease-free survival (DFS) after URD transplantations. However, for those undergoing transplantation during CP within 1 year from diagnosis, 5-year DFS was similar or only slightly inferior after matched URD versus MSD transplantation (age < 30: URD 61% +/- 8% vs MSD 68% +/- 15%, P =.18; 30-40: URD 57% +/- 9% vs MSD 67% +/- 10%, P =.05; > 40: URD 46% +/- 9% vs MSD 57% +/- 9%, P =.02). Delay from diagnosis to BMT in CP patients led to substantially poorer 5-year DFS after matched URD than MSD BMT (CP 1-2 years: URD 39% +/- 6% vs MSD 63% +/- 12%; beyond 2 years: URD 33% +/- 7% vs MSD 50% +/- 20%). Outcome of matched URD BMT for early CP chronic myelogenous leukemia yields survival and DFS approaching that of MSD transplantation. However, delay may compromise URD outcomes to a greater extent. Improvements in URD and MSD transplantation are still needed, and results of newer, nontransplantation therapies should be evaluated against the established curative potential of URD and MSD marrow transplantation.
UI - 11877286
AU - Baron F; Turhan AG; Giron-Michel J; Azzarone B; Bentires-Alj M; Bours V;
TI - Bourhis JH; Chouaib S; Caignard A Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression.
SO - Blood 2002 Mar 15;99(6):2107-13
AD - INSERM 487, Laboratoire de therapie cellulaire, Institut Gustave Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France.
Chronic myeloid leukemia is a clonal myeloproliferative expansion of transformed primitive hematopoietic progenitor cells characterized by high-level expression of BCR-ABL chimeric gene, which induces growth factor independence. However, the influence of BCR-ABL expression on cell-mediated cytotoxicity is poorly understood. In the present study, we asked whether BCR-ABL expression interferes with leukemic target sensitivity to natural killer (NK) cell cytolysis. Our approach was based on the use of 2 BCR-ABL transfectants of the pluripotent hematopoietic cell line UT-7 expressing low (UT-7/E8, UT-7/G6) and high (UT-7/9) levels of BCR-ABL. As effector cells, we used CD56(bright), CD16-, CD2- NK cells differentiated in vitro from CD34 cord blood progenitors. We demonstrated that BCR-ABL transfectants UT-7/9 were lysed by NK cells with a higher efficiency than parental and low UT-7/E8.1 and UT-7/G6 transfectants. This enhanced susceptibility to lysis correlated with an increase in expression of intercellular adhesion molecule 1 (ICAM-1) by target cells. Treatment of UT-7/9 cells by STI571 (a specific inhibitor of the abl kinase) resulted in a decrease in NK susceptibility to lysis and ICAM-1 down-regulation in target cells. Furthermore, the constitutive activation of nuclear factor-kappaB (NF-kappaB) detected in BCR-ABL transfectant UT-7/9, was significantly attenuated when cells were treated by STI571. Interestingly, inhibition of NF-kappaB activation by BAY11-67082 (a specific NF-kappaB inhibitor) resulted in down-regulation of ICAM-1 expression and a subsequent decrease in NK-induced killing of UT-7/9 transfectants. Our results show that oncogenic transformation by BCR-ABL may increase susceptibility of leukemic progenitors to NK cell cytotoxicity by a mechanism involving overexpression of ICAM-1 as a consequence of NF-kappaB activation.
UI - 11877311
AU - Verstovsek S; Kantarjian H; Manshouri T; Cortes J; Giles FJ; Rogers A;
TI - Albitar M Prognostic significance of cellular vascular endothelial growth factor expression in chronic phase chronic myeloid leukemia.
SO - Blood 2002 Mar 15;99(6):2265-7
AD - Department of Leukemia and Hematopathology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Box 72, Houston, TX 77030, USA.
The impact of elevated vascular endothelial growth factor (VEGF) expression on the course of chronic myeloid leukemia (CML) is unknown. By radioimmunoassay, we measured pretreatment cellular VEGF protein in bone marrow samples from 184 (148 chronic and 36 accelerated/blastic phases) CML patients and found the levels to be 1.6-fold higher than in 31 normal control bone marrow samples (P =.000 01). No significant differences were found in VEGF levels by different phases of CML (P =.1). VEGF levels correlated with older age (P =.01) and higher platelet count (P =.0003), but also with smaller spleen size (P =.004), lower white blood cell count (P =.0006), and lower percentage of peripheral blasts (P =.04). With the use of Cox proportional hazard model and VEGF levels as a continuous variable, high VEGF levels correlated with shorter survival of patients in chronic CML (P =.008). Multivariate analysis showed that VEGF was not independent of the synthesis stage (P =.09). These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML.
UI - 11990309
AU - Sharathkumar A; Thornley I; Saunders EF; Calderwood S; Freedman MH;
TI - Doyle J Allogeneic bone marrow transplantation in children with chronic myelogenous leukemia.
SO - J Pediatr Hematol Oncol 2002 Mar-Apr;24(3):215-9
AD - The Hospital for Sick Children, University of Toronto, Ontario, Canada.
PURPOSE: To determine the outcome of children undergoing allogeneic bone marrow transplantation for chronic myelogenous leukemia (CML) at the authors' institution. PATIENTS AND METHODS: Between 1985 and 1999, 18 allogeneic bone marrow transplantations were performed in 17 patients with CML at the Hospital for Sick Children in Toronto. Median age at diagnosis was 9.5 years (range 3-17). Fourteen patients had disease in the first chronic phase, one had disease in the second chronic phase, and two had disease in the accelerated phase. Preparative regimens varied, with radiation-based protocols used in eight patients. Thirteen donors were related (11 matched, 2 mismatched); four were unrelated (2 matched, 2 mismatched). Patients received T-cell-replete bone marrow a median of 7.5 months (range 2.2-22) from diagnosis. A median of 3.0 x 10(8)/kg nucleated cells was infused (range 1.6-6.7). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in 13 children. cyclosporine in three, and methotrexate in one. RESULTS: Primary graft failure occurred in one patient. Grade 2 acute GVHD or more developed in 11 of the 17 children (64%; grade 2 in 4, grade 3 in 7). Chronic GVHD occurred in 6 of the 16 patients at risk (37.5%; 5 extensive, 1 localized). No patient experienced overt or cytogenetic relapse. There were two deaths (12%): one from acute GVHD and cytomegalovirus pneumonia and the other from chronic GVHD. Probability of 5-year event-free survival was 87 +/- 9%. CONCLUSIONS: These results strongly support the practice of allotransplantation in children with CML, even in the setting of advanced disease and histoincompatibility. Efforts should be aimed at reducing the transplantation-related death rate.
UI - 11870247
AU - Savage DG; Antman KH
TI - Imatinib mesylate--a new oral targeted therapy.
SO - N Engl J Med 2002 Feb 28;346(9):683-93
AD - Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
UI - 11981005
AU - Kiss TL; Abdolell M; Jamal N; Minden MD; Lipton JH; Messner HA
TI - Long-term medical outcomes and quality-of-life assessment of patients with chronic myeloid leukemia followed at least 10 years after allogeneic bone marrow transplantation.
SO - J Clin Oncol 2002 May 1;20(9):2334-43
AD - Bone Marrow Transplant Service, Department of Medical Oncology and Hematology, Princess Margaret Hospital/University Health Network, Toronto, Ontario, Canada. email@example.com
PURPOSE: Benchmark analysis of patients with chronic myeloid leukemia (CML) alive for more than 10 years after allogeneic bone marrow transplantation (BMT) including data on disease status, bone marrow reserve, long-term complications, and quality of life (QOL). PATIENTS AND METHODS: Eighty-nine patients (46 in first chronic phase, 43 in advanced phase) received an allogeneic BMT for CML during the study period. Medical outcomes and QOL of patients were analyzed retrospectively. RESULTS: Twenty-eight (31.5%) of 89 patients were alive at 10 years and included in this analysis. Thirteen (46.4%) of 28 long-term survivors never relapsed. Fifteen patients relapsed between 0.5 and 16 years after transplantation. Ten patients showed a hematologic relapse and received salvage treatment. Five patients showed transient low levels of BCR-ABL-positive cells by Southern blot with no subseq