National Cancer Institute®
Last Modified: October 1, 2002
UI - 10845939
AU - Verfuerth S; Peggs K; Vyas P; Barnett L; O'Reilly RJ; Mackinnon S
TI - Longitudinal monitoring of immune reconstitution by CDR3 size spectratyping after T-cell-depleted allogeneic bone marrow transplant and the effect of donor lymphocyte infusions on T-cell repertoire.
SO - Blood 2000 Jun 15;95(12):3990-5
AD - Department of Haematology, University College London, London, United Kingdom.
Delayed immune reconstitution after allogeneic bone marrow transplantation (BMT) with associated infection is a major cause of morbidity and mortality. We used third complementarity region (CDR3) size spectratyping as a tool for monitoring T-cell repertoire reconstitution in 19 patients over a median time of 40 months after T-cell-depleted allogeneic BMT for chronic myeloid leukemia (CML). Furthermore, the effect of donor lymphocyte infusions (DLI) for the treatment of relapse in 18 of the 19 patients was analyzed. All BMT recipients had irregular spectratypes in the first 3- to -6 months after transplant. These evolved to more normal patterns by 12 months after transplant and continued to improve thereafter. In approximately a third of the patients, it took 2 to 3 years for all spectratypes to normalize, whereas in the other two thirds, some abnormal spectratypes persisted even after several years. In 9 patients, there was no immediate change in the CDR3 size profiles after DLI. In 3 patients, spectratypes improved slightly after DLI, whereas in 6 patients, spectratypes became more restricted and irregular. Overall, T-cell spectratypes in BMT patients were characterized by instability over time and in patients with graft-versus-host disease (GVHD), this was even more exaggerated. Several factors, such as pre-BMT conditioning, T-cell depletion of the donor marrow, loss of thymic function in adults, exposure to infectious agents, GVHD, and immunosuppressive treatment, are likely contributors to the delay in T-cell-repertoire reconstitution. (Blood. 2000;95:3990-3995)
UI - 11301187
AU - Kondo Y; Shiobara S; Nakao S
TI - Identification of T-cell clones showing expansion associated with graft-vs-leukemia effect on chronic myelogenous leukemia in vivo and in vitro.
SO - Exp Hematol 2001 Apr;29(4):471-6
AD - Third Department of Medicine, Kanazawa University School of Medicine, 13-1 Takaramachi, Kanazawa, Ishikawa, Japan 920-8641.
Although the graft-vs-leukemia (GVL) effect induced by donor leukocyte infusion (DLI) is thought to be mediated by T cells, their features, as well as target molecules, remain unknown. To characterize T cells that mediate the GVL effect on chronic myelogenous leukemia (CML), we studied T-cell repertoire in peripheral blood (PB) of two patients treated with DLI for relapsed CML after allogeneic bone marrow transplantation.Peripheral blood mononuclear cells (PBMCs) were obtained at 2-week intervals following DLI and examined for the presence of antigen-driven T-cell proliferation using complementarity-determining region (CDR) 3 size spectratyping of T-cell receptor beta chain subfamilies.Both patients exhibited transient proliferation of a limited number of T cells at a certain point in time (day 132 for patient 1 and day 75 for patient 2) after DLI in association with a decrease in the proportion of Philadelphia chromosome (Ph)-positive cells. In patient 2, who showed expansion of a BV16(+) T cell in PB, expansion of BV16(+) T cells with a similar CDR3 motif containing QDR to that of PB was demonstrated in the bone marrow (BM) sampled on day 33 and in the buccal mucosal tissue, showing chronic graft-vs-host disease (GVHD) on day 138 after DLI. When PBMCs obtained from patient 2 in remission were cultured with cryopreserved CML cells for 2 weeks, proliferation of a BV16(+) T cell with a CDR3 motif of QIR was induced in vitro.These findings indicate that transient proliferation of a limited number of T cells detected in PB 3-5 months after DLI probably reflects the GVL response against CML cells and may serve as a marker for the appearance of the GVL effect induced by DLI.
UI - 11583030
AU - Takubo T; Fujino H; Hino M; Yamane T; Ohta K; Koh KR; Kumura T;
TI - Hashimoto S; Nakao T; Nakamae H; Aoyama Y; Nishiki S; Kinoshita Y; Kamitani T; Tatsumi N; Hojo S; Fujita J Expression of KL-6 antigen on leukemia cells of a patient with chronic myelocytic leukemia in blastic phase.
SO - Haematologia (Budap) 2001;31(2):173-6
AD - Department of Clinical and Laboratory Medicine, Osaka City University Medical School, Osaka, Japan. email@example.com
UI - 12203776
AU - Barbouti A; Johansson B; Hoglund M; Mauritzson N; Strombeck B; Nilsson
TI - PG; Tanke HJ; Hagemeijer A; Mitelman F; Fioretos T Multicolor COBRA-FISH analysis of chronic myeloid leukemia reveals novel cryptic balanced translocations during disease progression.
SO - Genes Chromosomes Cancer 2002 Oct;35(2):127-37
AD - Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. Aikaterini.Barmpouti@klingen.lu.se
During the initial indolent chronic phase of chronic myeloid leukemia (CML), the t(9;22)(q34;q11), resulting in the Philadelphia chromosome (Ph), is usually the sole cytogenetic anomaly, but as the disease progresses into the accelerated phase (AP), and eventually into aggressive blast crisis (BC), secondary aberrations, mainly unbalanced changes such as +8, i(17q), and +Ph, are frequent. To date, molecular genetic studies of CML BC have mainly focused on alterations of well-known tumor-suppressor genes (e.g., TP53, CDKN2A, and RB1) and oncogenes (e.g., RAS and MYC), whereas limited knowledge is available about the molecular genetic correlates of the unbalanced chromosomal abnormalities. Balanced secondary changes are rare in CML AP/BC, but it is not known whether cryptic chromosomal translocations, generating fusion genes, may be responsible for disease progression in a subgroup of CML. To address this issue, we used multicolor combined binary ratio fluorescence in situ hybridization (FISH), which allows the simultaneous visualization of all 24 chromosomes in different colors, verified by locus-specific FISH in a series of 33 CML cases. Two cryptic balanced translocations, t(7;17)(q32-34;q23) and t(7;17)(p15;q23), were found in two of the five cases showing the t(9;22) as the only cytogenetic change. Using several BAC clones, the breakpoints at 17q23 in both cases were mapped within a 350-kb region. In the case with the 7p15 breakpoint, a BAC clone containing the HOXA gene cluster displayed a split signal, suggesting a possible creation of a fusion gene involving a member of the HOXA family. Furthermore, one case with a partially cryptic t(9;11)(p21-22;q23) and an MLL rearrangement as well as a previously unreported t(3;10)(p22;p12-13) were identified. Altogether, a refined karyotypic description was achieved in 12 (36%) of the 33 investigated cases, illustrating the value of using multicolor FISH for identifying pathogenetically important aberrations in CML AP/BC. Copyright 2002 Wiley-Liss, Inc.
UI - 12194088
AU - Shaikh A; Parulekar M; James B
TI - Acute suprachoroidal haemorrhage with acute angle closure glaucoma as a presenting sign of chronic myelomonocytic leukemia.
SO - Eye 2002 Sep;16(5):651-3
UI - 1584598
AU - Pozsonyi T; Jakab L; Jakab L; Onody K; Cseh K; Kalabay L
TI - [Effect of estrogen on the blast transformation of lymphocytes and interleukin-2 production in lupus erythematosus]
SO - Orv Hetil 1992 May 10;133(19):1167-71
AD - Semmelweis Orvostudomanyi Egyetem III., Budapest.
The mitogenic response of peripheral lymphocytes was investigated in 12 patients with systemic lupus erythematosus and in healthy female volunteers who were on 11 and without 9 contraceptive pills. The effect of estrogen (ethinyl-estradiol 10(-5)-10(-6)-10(-7)M) was studied on Phytohaemagglutinin and Pokeweed mitogen induced blastogenic transformation and interleukin-2 production of peripheral lymphocytes in vitro. We observed a significantly depressed Phytohaemagglutinin induced lymphoblastic transformation both in patients and women taking oral contraceptive in presence of 10(-5)M estrogen as compared to normal controls. However there was no significant alteration neither in the response of lymphocyte nor in the production of interleukin-2 using of Pokeweed mitogen. The stimulataneous inhibition of the interleukin-2 production proved to be moderate. Marked significant correlation (r greater than = 0.8) vas detected between lymphoblastic transformation and interleukin-2 production in healthy females. Correlation coefficient measured in females taking oral contraceptive (r less than = 0.64) and patients with systemic lupus erythematosus (r less than = 0.34) suggest that in these groups the inhibition of lymphoblastic transformation is due to the inhibition effect of estrogen on the interleukin-2 production.
UI - 8703818
AU - Johnson RJ; Owen RG; Child JA; Morgan GJ; Barnard DL; Dickinson H;
TI - Ricketts S; Rawstron A; Evans P; Woodhead V; Major K; Robinson F; Smith GM Mobilization of Philadelphia-negative peripheral blood mononuclear cells in chronic myeloid leukaemia using hydroxyurea and G-CSF (filgrastim).
SO - Br J Haematol 1996 Jun;93(4):863-8
AD - General Infirmary at Leeds.
A relatively simple and non-toxic out-patient-based regimen for the mobilization of Philadelphia-negative (Ph-ve) mononuclear cells in chronic myeloid leukaemia (CML) was evaluated in 10 patients, nine in stable chronic phase and one in accelerated phase. They received oral hydroxyurea at a mean dose of 3.5 g/m2 daily for 7 d, followed by 300 micrograms of G-CSF daily until the last day of harvesting. In the nine chronic-phase patients the mean number of days from the end of hydroxyurea to the commencement of harvesting was 14.5 (range 10-18). The patient in accelerated phase recovered and was harvested after 6 d. The mean number of aphereses performed was 3.4. Adequate numbers of stem cells were obtained in 9/10 patients judged by our usual criteria. Side-effects were mild in comparison to published intravenous schedules. No patients lost their hair. Five (50%) patients required admission with neutropenic fever which responded to antibiotics in all cases. Four (40%) patients developed a transient rash and four (40%) experienced mild oral mucostis. This level of toxicity enabled half of the patients to be treated entirely on an out-patient basis. The harvest products were analysed for cells belonging to the leukaemic clone by conventional cytogenetics, FISH and PCR. All were PCR positive. The mean Ph positivities by cytogenetics and FISH were comparable at 18.1% and 15% respectively. Half the patients had > 98% normal metaphases. We conclude that this approach is comparable in efficacy to published intravenous regimens and significantly less toxic. It can be safely used at diagnosis before interferon therapy commences.
UI - 8857964
AU - Carella AM; Frassoni F
TI - ICE, mini-ICE or high-dose hydroxyurea to mobilize Philadelphia (Ph1)-negative PBPC in chronic myelogenous leukaemia.
SO - Br J Haematol 1996 Oct;95(1):213-5
UI - 12004084
AU - Peled A; Hardan I; Trakhtenbrot L; Gur E; Magid M; Darash-Yahana M;
TI - Cohen N; Grabovsky V; Franitza S; Kollet O; Lider O; Alon R; Rechavi G; Lapidot T Immature leukemic CD34+CXCR4+ cells from CML patients have lower integrin-dependent migration and adhesion in response to the chemokine SDF-1.
SO - Stem Cells 2002;20(3):259-66
AD - Hadassah University Hospital, Gene Therapy Institutem, Jerusalem, Israel. firstname.lastname@example.org
Chronic myelogenous leukemia (CML), a malignant myeloproliferative disorder originating from a pluripotent stem cell expressing the bcr-abl oncogene, is characterized by abnormal release of the expanded, malignant stem cell clone from the bone marrow (BM) into the circulation. Moreover, immature CD34+ CML cells have lower adhesion to stromal cells and fibronectin as well as lower engraftment potential in severe combined immunedeficient (SCID) and nonobese diabetic (NOD)/SCID mice than normal CD34+ cells. We report in this study that leukemic Philadelphia chromosome-positive (Ph+)CD34+ cells from newly diagnosed CML patients that express the chemokine receptor CXCR4 migrate in response to stromal-derived factor-1 (SDF-1). However, normal Ph-CD34+CXCR4+ cells derived from the same patient have significantly higher migration levels toward SDF-1. In contrast to their transwell migration potential, the SDF-1-mediated integrin-dependent polarization and migration of the Ph+CD34+CXCR4+ cells through extracellular matrix-like gels were significantly lower than for normal cells. Concomitantly, binding of these cells to vascular cell adhesion molecule-1 or fibronectin, in the presence of SDF-1, was also substantially lower. These findings suggest a major role for SDF-1-mediated, integrin-dependent BM retention of Ph+CD34+ cells.
UI - 12221673
AU - Kanamori H; Tanaka M; Kawaguchi H; Yamaji S; Fujimaki K; Tomita N;
TI - Fujisawa S; Ishigatsubo Y Resolution of psoriasis following allogeneic bone marrow transplantation for chronic myelogenous leukemia: case report and review of the literature.
SO - Am J Hematol 2002 Sep;71(1):41-4
AD - First Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan. email@example.com
We describe a case of a 49-year-old man with chronic myelogenous leukemia (CML) whose coincidental psoriasis resolved following allogeneic bone marrow transplantation (BMT). The patient had suffered from psoriasis for 20 years and was treated with corticosteroid ointment. He was diagnosed as having CML in 1998, and his psoriasis BMT from an HLA-identical sister after undergoing a conditioning regimen involving busulfan, cytosine arabinoside, and cyclophosphamide. Prophylaxis of acute graft-versus-host disease was done using short-term methotrexate and cyclosporin A. His psoriasis improved immediately and disappeared completely on day 70 after BMT. For 2.5 years, his CML remains in remission and he is free of psoriasis without undergoing immunosuppressive therapy. This case suggests the potential benefits of the treatment of immune-mediated diseases with allogeneic BMT. Copyright 2002 Wiley-Liss, Inc.
UI - 12189460
AU - Espinosa G; Font J; Munoz-Rodriguez FJ; Cervera R; Ingelmo M
TI - Myelodysplastic and myeloproliferative syndromes associated with giant cell arteritis and polymyalgia rheumatica: a coincidental coexistence or a causal relationship?
SO - Clin Rheumatol 2002 Aug;21(4):309-13
AD - Service of Autoimmune Diseases, Institut Clinic d'Infeccions i Immunologia, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain.
A variety of systemic autoimmune disorders have been reported in patients with myelodysplastic and myeloproliferative syndromes. A possible association with polymyalgia rheumatica and giant cell arteritis has also been recognised. We report another case of polymyalgia rheumatica and one of giant cell arteritis associated with a myelodysplastic syndrome and the two first cases of giant cell arteritis associated with essential thrombocytaemia and chronic myelomonocytic leukaemia, respectively. It seems that there is a relationship between these entities, but the nature of this association is still unknown.
UI - 11937267
AU - Bhatia R; Williams AD; Munthe HA
TI - Contact with fibronectin enhances preservation of normal but not chronic myelogenous leukemia primitive hematopoietic progenitors.
SO - Exp Hematol 2002 Apr;30(4):324-32
AD - Division of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA 91010, USA. firstname.lastname@example.org
OBJECTIVE: Coculture with stromal cells enhances preservation and self-renewal of primitive progenitor potential in hematopoietic cells during ex vivo culture with growth factors (GF). However, the respective roles of growth factors, stromal contact, and extracellular matrix (ECM) ligands in this effect are not clear. Here we investigated the role of direct contact with stroma and the ECM protein fibronectin (FN) in these effects, and investigated whether abnormal integrin receptor function in chronic myelogenous leukemia (CML) progenitors was associated with perturbation in these responses. METHODS: Normal bone marrow CD34+ cells were cultured in GF-containing medium with or without contact with stromal layers, glutaraldehyde-fixed stromal layers (stroma-contact), or integrin-binding FN fragments for 7 days. Progeny cells were assayed for primitive progenitors in week-6 long-term culture-initiating cell (LTC-IC) and week-10 extended LTC-IC (ELTC-IC) assays. RESULTS: Increased LTC-IC and ELTC-IC preservation was seen following coculture with stroma, and was also observed after culture in contact with fixed stromal layers and FN. Both alpha4beta1 and alpha5beta1-integrin binding FN fragments enhanced LTC-IC preservation. Analysis of single CD34+CD38- cells showed that coculture with FN resulted in significantly reduced cell division, but enhanced retention of LTC-IC capacity in divided cells. FN also increased LTC-IC frequency in undivided cells. CML progenitors demonstrate deficient integrin-mediated adhesion, migration, and signaling. Coculture of CML CD34+ cells with stroma and FN failed to enhance LTC-IC preservation. CONCLUSION: We conclude that beta1 integrin-FN interactions enhance normal primitive progenitor preservation with or without cell division, and that these mechanisms are impaired in CML primitive progenitors.
UI - 11856743
AU - Mc Gee MM; Campiani G; Ramunno A; Nacci V; Lawler M; Williams DC;
TI - Zisterer DM Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells.
SO - J Biol Chem 2002 May 24;277(21):18383-9
AD - Department of Biochemistry, Trinity College, Dublin 2, Ireland.
The mitogen-activated protein (MAP) kinase family is activated in response to a wide variety of external stress signals such as UV irradiation, heat shock, and many chemotherapeutic drugs and leads to the induction of apoptosis. A novel series of pyrrolo-1,5-benzoxazepines have been shown to potently induce apoptosis in chronic myelogenous leukemia (CML) cells, which are resistant to many chemotherapeutic agents. In this study we have delineated part of the mechanism by which a representative compound known as PBOX-6 induces apoptosis. We have investigated whether PBOX-6 induces activation of MAP kinase signaling pathways in CML cells. Treatment of K562 cells with PBOX-6 resulted in the transient activation of two JNK isoforms, JNK1 and JNK2. In contrast, PBOX-6 did not activate the extracellular signal-regulated kinase (ERK) or p38. Apoptosis was found to occur independently of the small GTPases Ras, Rac, and Cdc42 but involved phosphorylation of the JNK substrates, c-Jun and ATF-2. Pretreatment of K562 cells with the JNK inhibitor, dicoumarol, abolished PBOX-6-induced phosphorylation of c-Jun and ATF-2 and inhibited the induced apoptosis, suggesting that JNK activation is an essential component of the apoptotic pathway induced by PBOX-6. Consistent with this finding, transfection of K562 cells with the JNK scaffold protein, JIP-1, inhibited JNK activity and apoptosis induced by PBOX-6. JIP-1 specifically scaffolds JNK, MKK7, and members of the mixed-lineage kinase (MLK) family, implicating these kinases upstream of JNK in the apoptotic pathway induced by PBOX-6 in K562 cells.
UI - 11235567
AU - Tong X; Luo S; Hong W
TI - [Expression of beta 2 integrins and L-selectin on CML cells after treatment with IFN-alpha and allo-bone marrow transplantation]
SO - Zhonghua Zhong Liu Za Zhi 2000 Nov;22(6):474-6
AD - Department of Hematology, First Affiliated Hospital of Sun Yat-sen University of Medical Sciences, Guangzhou 510080, China.
OBJECTIVE: To study the expression of L-selectin, Mac-1, LFA-1 on CML progenitor cells in relation to CML progression and therapeutic effect. METHODS: The expression of adhesion molecules (LFA-1, Mac-1, L-selectin) on bone marrow CD34+ cells from 34 CML patients were analyzed by three-color flow cytometry. RESULTS: The mean percentage of expression of L-selectin, and LFA-1 on CD34+ CD38-(-)+ cells from untreated CML patients was significantly lower than that from normal controls. Among 8 CML patients treated with IFN-alpha, the expression of L-selectin and LFA-1 on CD34+ CD38- cell (37.6 +/- 5.3%, 42.1 +/- 13.1%) was comparable to that from normal controls (38.2 +/- 9.4%, 48.2 +/- 12.2%). L-selectin expression in CD34+ CD38- cells from CML patients was inversely correlated with the percentage of Ph'(+) cells. In 2 CML patients treated with allo-bone marrow transplantation, the expression rate of L-selectin, IFA-1 and Mac-1 on CD38+ CD38- cells was comparable to that from normal controls. CONCLUSION: The data suggest that decreased expression of L-selectin and LFA-1 in CML CD34+ cells reflects one of the features of malignant CML progenitors. IFN-alpha and allo-BMT restore the expression of Mac-1, L-selectin and LFA-1 to normal on CML CD34+ cells.
UI - 12006504
AU - Cohen MH; Williams G; Johnson JR; Duan J; Gobburu J; Rahman A; Benson K;
TI - Leighton J; Kim SK; Wood R; Rothmann M; Chen G; U KM; Staten AM; Pazdur R Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia.
SO - Clin Cancer Res 2002 May;8(5):935-42
AD - Division Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA. email@example.com
PURPOSE: Chronic myelogenous leukemia (CML) results from the breakpoint cluster region-Abl fusion gene product, a tyrosine kinase involved in cell division and apoptosis. Imatinib, an orally administered inhibitor of the breakpoint cluster region-Abl tyrosine kinase, is capable of blocking proliferation and inducing apoptosis in CML cell lines. In this report, we describe the preclinical profile of imatinib and the data submitted in the New Drug Application that led to its marketing approval. EXPERIMENTAL DESIGN: Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. Results of Phase I and Phase II clinical studies in patients with CML in blast crisis (CML-BC), in accelerated phase (CML-AP), and in chronic phase disease-resistant or intolerant to IFN-alpha (CML-CP) are summarized. The basis for marketing approval and postmarketing commitments by the pharmaceutical company are discussed. RESULTS: Toxicology studies in the rat, dog, and monkey show the hematological, renal, and hepatobiliary toxicity of imatinib. Pharmacokinetic studies in patients with CML demonstrate 98% imatinib bioavailability. The elimination half-lives of the parent drug and the major active metabolite, CGP74588, from plasma are approximately 18 and 40 h, respectively. Approximately 81% of the drug is eliminated in 7 days, 68% in the feces and 13% in the urine. Cytochrome P-450 3A4 is the main enzyme responsible for imatinib metabolism. Phase I and II clinical studies were conducted. The Phase I study, in 83 CML patients, evaluated oral imatinib doses from 25 to 1000 mg/day. Dose-limiting toxicity was not observed. The three Phase II studies, in CML-CP, CML-AP, and CML-BC, enrolled 1027 patients. CML-CP patients received 400 mg/day imatinib, whereas CML-AP and CML-BC patients generally received 600 mg/day imatinib. Primary study endpoints were cytogenetic response rate (CML-CP) and hematological response rate (CML-AP and CML-BC). The cytogenetic response rate for CML-CP patients was 49%. The hematological response rate of CML-AP and CML-BC patients was 63 and 26%, respectively. The most common imatinib adverse events were nausea, vomiting, myalgia, edema, and diarrhea. Elevated liver enzymes and/or bilirubin were reported in 27 patients (2.6%). CONCLUSIONS: On May 10, 2001, imatinib mesylate (Gleevec, formerly known as STI-571 and Glivec), manufactured and distributed by Novartis Pharmaceuticals, East Hanover, NJ, was approved by the United States Food and Drug Administration for the treatment of CML in three clinical settings: CML-BC, CML-AP, and CML-CP. This report summarizes the Food and Drug Administration's review of the New Drug Application.
UI - 12194684
AU - Artigas CG; Melo A; Roa JC; Paez E; Vittini C; Arriagada M; Gonzalez L;
TI - Pflaumer E; Roa I [Detection of BCR-ABL gene sequences using RT-PCR in patients with leukemia in the IX region. Chile]
SO - Rev Med Chil 2002 Jun;130(6):623-30
AD - Departamento Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Casilla 54-D, Temuco-Chile. firstname.lastname@example.org
BACKGROUND: The BCR-ABL fusion gene is the molecular expression of the Philadelphia chromosome. This cytogenetic aberration is the most frequent alteration found in leukemias, which is produced by the translocation t(9;22). Two different fusion proteins are produced depending on the break point (210 kD and 190 kD). The detection of this gene has both diagnostic and prognostic importance, associated with poor prognosis in acute lymphoblastic leukemia (ALL). AIM: To detect BCR-ABL gene sequences in patients with leukemia from the IX Region of Chile. MATERIAL AND METHODS: We studied 58 patients: 5 chronic myeloid leukemia (CML), 35 ALL, 15 acute myeloid leukemia (AML) and 3 biphenotypic leukemia. The gene sequences were detected using reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: BRC-ABL gene sequences were positive in all patients with CML, 2 of 35 ALL (one child and one adult). The remaining patients were negative. We found p210 and p190 co-expression in 2 CML and 1 ALL. CONCLUSIONS: Our results are in agreement with other reports. The detection of these and other genetic alterations will allow us to have invaluable diagnostic and prognostic information from our patients with leukemia.
UI - 12357373
AU - Ohyashiki K; Kuriyama Y; Nakajima A; Tauchi T; Ito Y; Miyazawa H; Kimura
TI - Y; Serizawa H; Ebihara Y Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis.
SO - Leukemia 2002 Oct;16(10):2160-1
UI - 11000992
AU - Pigneux A; Mahon FX; Reiffers J
TI - Autologous peripheral blood stem cell transplantation for chronic myelocytic leukaemia, using unmanipulated grafts.
SO - Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):193-8
AD - Service d'Hematologie, Hopital du Haut Leveque, Bordeaux, France.
In chronic myeloid leukaemia (CML) allogeneic stem cell transplantation can be proposed to a minority of patients who are both less than 50 years of age and have an HLA-identical donor. Recombinant alpha-interferon induces cytogenetic responses (and prolongation of survival) in only 25-40% of patients. Thus, alternative treatments need to be proposed. When performed in chronic phase with unmodified stem cells, autologous stem cell transplantation is followed by cytogenetic responses in about 40% of cases, and some data suggest that these responder patients could have a prolongation of survival. This now needs to be demonstrated prospectively. If so, further studies could be performed in order to define the best source of stem cells (purged or unpurged) to be used.
UI - 11000993
AU - Frassoni F; Podesta M; Piaggio G
TI - Normal and leukaemic haematopoiesis in bone marrow and peripheral blood of patients with chronic myeloid leukaemia.
SO - Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):199-208
AD - Dipartimento di Ematologia, Divisione Ematologia II, Ospedale San Martino, Genoa, Italy.
In the majority of newly diagnosed patients with chronic myeloid leukaemia (CML), the bone marrow contains consistent numbers of normal Ph-negative surrogate stem cells (LTC-IC) which seem to decline rapidly with time. This is confirmed by mobilization studies showing that early after diagnosis is the optimal time to collect Ph-negative progenitor to be utilized for restoring Ph-negative haematopoiesis. In the marrow of the majority of CML patients at diagnosis Ph-positive LTC-IC are found at a lower frequency than Ph-negative LTC-IC and, unexpectedly, they do not show a tendency to increase with time as long as patients remain in chronic phase. Therefore, the decline of normal haematopoiesis does not seem related to a parallel increase in Ph-positive stem cells.
UI - 11000994
AU - Carella AM; Cavaliere M; Lerma E; Corsetti MT
TI - Autologous peripheral blood haematopoietic stem cell transplantation for chronic myelogenous leukaemia.
SO - Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):209-17
AD - Haematology and ABMT Unit, Azienda Ospedaliera e Cliniche, Universitarie Convenzionate, Ospedale San Martino, Genoa, Italy.
In these last four decades there has been extraordinary progress in our understanding of the biology of, and therapeutic approach to, chronic myelogenous leukaemia (CML). During these decades new observations arising from studies of the biological behaviour of diploid and leukaemic stem cells and, recently, from clinical investigations have received the most attention. From a clinical point of view, allografting is still the only procedure which is able to cure CML. For patients without HLA-compatible donors, current therapeutic options include conventional chemotherapy (hydroxyurea), interferon-alpha (IFN-alpha) and autografting. While IFN-alpha (+/- low-dose ARA-C) must be considered the first-line therapy, autografting, according to our approach, or other procedures, raises the question of an ideal sequential strategy in the management of CML patients (diploid stem cell mobilization, autografting, IFN-alpha). Because it seems that the diploid haematopoietic reservoir declines with time, it may be desirable to mobilize and collect diploid stem cells in order to store them as soon as diagnosis is possible when the WBC count has been controlled by hydroxyurea.
UI - 12171771
AU - Spiers AS
TI - Management of the chronic leukemias: special considerations in the elderly patient. Part III rarer chronic myeloid leukemias.
SO - Hematology 2002 Feb;7(1):1-8
AD - Department of Haematology, John Radcliffe Hospital, Oxford, UK.
The manifestations, diagnosis and management of the rarer chronic myeloid leukemias are reviewed, with special attention to problems that affect elderly patients. The spectrum of disorders includes atypical myeloproliferative syndrome, so-called Ph-negative CGL, chronic myelomonocytic leukemia, and leukemias characterized by chronic proliferation of neutrophil, eosinophil, or basophil leukocytes. These latter are sometimes difficult to differentiate from chronic nonleukemic proliferations of the index cells. Termination in an acute myeloid leukaemia that is usually refractory to treatment may occur in any of the above disorders but is not a constant event.
UI - 12365015
AU - Onida F; Ball G; Kantarjian HM; Smith TL; Glassman A; Albitar M;
TI - Scappini B; Rios MB; Keating MJ; Beran M Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia.
SO - Cancer 2002 Oct 15;95(8):1673-84
AD - Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
BACKGROUND: Up to 5% of patients with chronic myelogenous leukemia (CML) do not have the Philadelphia (Ph) translocation t(9;22)(q34;q11) or a bcr/abl molecular rearrangement. Although the diagnostic criteria of this entity are still under debate, there is general agreement that patients with Ph negative, bcr/abl negative CML have a severe clinical course that is not affected significantly by current treatment options. METHODS: A population of 76 patients with bcr/abl negative CML who had received minimal or no previous therapy was characterized carefully with the intent of investigating clinical and hematologic variables and their association with survival by univariate, correlation, and multivariate analyses. A group of 73 patients with Ph negative CML who were not tested for the bcr/abl rearrangement (bcr/abl unknown) was analyzed separately and used for extension of the analysis. RESULTS: In the bcr/abl negative patient population, the median overall survival was 24 months. At the time of the analysis, 38 patients (50%) had died, and blastic transformation preceded death in 31%. Chromosomal abnormalities were found in 30% of the 76 patients, with trisomy 8 the most common abnormality. Complex chromosomal abnormalities were rare, and monosomy 7 was not observed. Survival was not affected significantly by treatment. Multivariate analysis identified older age (> 65 years), anemia (hemoglobin < 10 g/dL), and severe leukocytosis (white blood cells > 50 x 10(9)/L) as variables with independent prognostic significance for poor survival. A prognostic scoring system stratified patients into a low-risk group (53%) and a high-risk group (47%), with median survivals of 38 months and 9 months, respectively. CONCLUSIONS: Bcr/abl negative CML is a distinct clinical entity associated with very poor prognosis. Two risk categories are identifiable using a simple scoring system based on age, hemoglobin level, and leukocyte number. Copyright 2002 American Cancer Society.
UI - 12011769
AU - Prejzner W
TI - Relationship of the BCR gene breakpoint and the type of BCR/ABL transcript to clinical course, prognostic indexes and survival in patients with chronic myeloid leukemia.
SO - Med Sci Monit 2002 May;8(5):BR193-7
AD - Department of Hematology, Medical University of Gdansk, Poland.
BACKGROUND: Chronic myeloid leukemia is characterized by the presence of the Philadelphia chromosome. At the molecular level a fusion of part of the ABL and BCR genes is observed. The breakpoint locations in the BCR gene fall between exons b2a2 or b3a2 (5' and 3', respectively). Depending on the BCR gene breakpoint two types of mRNA are created. Differences in the types of transcripts and/or the breakpoint site may have an influence on the clinical course of the disease. This prompted the present author to separate subtypes of chronic myeloid leukemia on the molecular level. MATERIAL/METHODS: 71 patients diagnosed with chronic myeloid leukemia in the chronic phase were enrolled in the study. In 61 patients the type of BCR/ABL transcript was determined, and in 27 patients BCR breakpoints were established. Possible correlations between the clinical course, prognostic indexes, survival and the type of transcript and breakpoint were examined. RESULTS: No correlation between the clinical course, prognostic index, or survival was observed in patients with 5' and 3' breakpoints. The patients with b3a2 transcript experienced longer survival than the patients expressing b2a2 transcript. However, no significant differences were observed in the duration of the chronic phase between the two groups. CONCLUSIONS: The type of BCR gene breakpoint seems to have no prognostic value in patients with chronic myeloid leukemia. The longer survival of patients expressing the b3a2 transcript may be caused by the less aggressive course of the accelerated or blastic phase.
UI - 12296996
AU - Shim MJ; Kim HJ; Yang SJ; Lee IS; Choi HI; Kim T
TI - Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase.
SO - J Biochem Mol Biol 2002 Jul 31;35(4):377-83
AD - Department of Biomedical Laboratory Science, College of Health Science, Yonsei University, Wonju 220-710, Korea. Kimtu@dragon.yonsei.ac.kr
Arsenic trioxide (As(2)O(3)) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As(2)O(3) might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As(2)O(3) to induce apoptosis in K562 cells. In vitro cytotoxicity of As(2)O(3) was evaluated in K562 cells by a MTT assay; the IC(50) value for As(2)O(3) was determined to be 10 microM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 microM As(2)O(3) for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 microM As(2)O(3) by a Western blot analysis. Next, we examined the MAP kinase-signaling pathway of As(2)O(3)-induced apoptosis in K562 cells. As(2)O(3) at 10 microM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As(2)O(3) induced apoptotic cell death. These results suggest that As(2)O(3) is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.
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