National Cancer Institute®
Last Modified: March 1, 2002
UI - 11526594
AU - Sawyers CL
TI - Implications of signal transduction inhibition for the treatment of chronic myeloid leukemia.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):1-2
AD - Department of Medicine, Division of Hematology and Oncology, Molecular Biology Institute, University of California Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
UI - 11526597
AU - Sawyers CL
TI - Molecular studies in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):15-21
AD - Department of Medicine, Division of Hematology and Oncology, Molecular Biology Institute, University of California Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) blocks the constitutively activated Bcr-Abl tyrosine kinase that is characteristic of chronic myeloid leukemia (CML). Molecular analysis for the presence of residual Bcr-Abl-positive cells in patients with a cytogenetic response following treatment with imatinib mesylate reveals that some patients have undetectable disease using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assays capable of detecting 1 in 10(5) Philadelphia chromosome-positive (Ph(+)) cells. To examine whether the leukemia is still Bcr-Abl-dependent in patients who have responded to imatinib mesylate but have relapsed, a quantitative assay that directly measures enzymatic activity of Bcr-Abl toward one of its major signaling substrates has been developed. This assay allows monitoring both of the imatinib mesylate sensitivity of patient cells in vitro, and of the endogenous inhibition of Bcr-Abl kinase activity during imatinib mesylate treatment and relapse. Studies show that imatinib mesylate resistance is associated with restored activation of the Bcr-Abl signal transduction pathway in the majority of cases, indicating that Bcr-Abl remains a valid target for therapeutic intervention. Understanding resistance mechanisms of Ph(+) leukemia to imatinib mesylate will allow design of therapies to overcome such barriers to efficacy. Copyright 2001 by W.B. Saunders Company.
UI - 11526598
AU - Talpaz M
TI - Interferon-alfa-based treatment of chronic myeloid leukemia and implications of signal transduction inhibition.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):22-7
AD - Division of Medicine, Department of Bioimmunotherapy, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
The cytokine interferon-alfa (IFN-alpha) has substantial activity in chronic myeloid leukemia (CML) and is the nontransplant standard of care for chronic-phase disease. When used as front-line therapy, IFN-alpha induces a state of tumor dormancy and delays progression to advanced phase. Unfortunately, IFN-alpha is associated with substantial toxicity at therapeutic doses. The introduction of pegylated IFN-alpha (PEG-IFN-alpha), a modified form of the protein that permits weekly administration, may alleviate some of the problems observed with IFN-alpha. Combination regimens of IFN-alpha with other drugs such as cytarabine (Ara-C) appear to enhance efficacy and are currently under investigation. The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) also is efficacious in chronic-phase CML, with a low toxicity profile. However, its potential to cure CML remains unknown even though it achieves frequent cytogenetic responses. To enhance treatment outcome, a combination of IFN-alpha and imatinib mesylate therapies is proposed. Low-dose IFN-alpha may be given after imatinib mesylate-induced remission as a specific immune stimulant to consolidate the remission. Recent data showing a possible additive effect of imatinib mesylate and IFN-alpha suggest that concurrent use of these agents may also be more effective than single use, particularly in advanced stages of CML where imatinib mesylate has activity but resistance develops. Copyright 2001 by W.B. Saunders Company.
UI - 11526599
AU - Goldman J
TI - Implications of imatinib mesylate for hematopoietic stem cell transplantation.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):28-34
AD - Department of Haematology, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
The ability of allogeneic bone marrow or blood stem cell transplantation (SCT) to induce long-term remission or cure of chronic myeloid leukemia (CML) is well established. However, the use of this treatment is limited by the availability of suitable human leukocyte antigen (HLA) identical siblings or matched unrelated donors (MUD). As a consequence only a relatively small proportion of CML patients are eligible for a transplant, and of these not all are cured. The preliminary results of trials using the new Bcr-Abl kinase inhibitor imatinib mesylate (formerly CGP57-148B, STI571, Gleevec) to treat CML are very encouraging. However, a number of important questions cannot yet be answered: Can imatinib mesylate induce durable molecular remissions? Can the drug prolong survival in comparison with other nontransplant treatments? and, can it actually cure CML patients? Until answers to these questions are available, SCT and use of interferon-alfa (IFN-alpha) alone or in combination (perhaps with imatinib mesylate) must remain major therapeutic options. I summarize here the advantages and disadvantages associated with currently available therapy. I review three different approaches to initial treatment of the CML patient diagnosed in chronic phase, and make a tentative recommendation for one of these options. It is likely that the situation will alter considerably in the foreseeable future. Copyright 2001 by W.B. Saunders Company.
UI - 11526600
AU - Appelbaum FR
TI - Perspectives on the future of chronic myeloid leukemia treatment.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):35-42
AD - Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA 98109-1024, USA.
Chronic myeloid leukemia (CML) is probably the best understood human malignancy at the molecular level, but among the hardest to explain to patients concerning appropriate treatment options. At present, we do not know the long-term outcome of promising new therapies such as the tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) and nonmyeloablative transplants. There is also no reliable way to predict which patients will respond to a particular therapy. The development of methods to predict therapeutic response will be of major benefit to patients, and the newly emerging science of gene array analysis may provide such a tool. In this context, given the proven likelihood of cure with allogeneic transplantation and the negative effects of delay, in Seattle we continue to suggest transplantation as the initial form of therapy for patients below age 55 years with matched sibling donors. For patients without matched donors below the age of 40, we would suggest an unrelated donor search and only proceed directly to transplant for those with allele-level matches. For younger patients without matches and those aged 40 to 55, an initial trial of imatinib mesylate might be preferred. For patients over age 55 with CML, initial therapy with imatinib mesylate, possibly an interferon-containing regimen or nonmyeloablative allogeneic transplantation may be considered. Copyright 2001 by W.B. Saunders Company.
UI - 11526596
AU - Druker B
TI - Signal transduction inhibition: results from phase I clinical trials in chronic myeloid leukemia.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):9-14
AD - Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97201, USA.
The tyrosine kinase inhibitor, imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) showed significant antileukemic activity with minimal toxicity in preclinical studies. Based on these data, a phase I clinical trial was conducted in patients with chronic myeloid leukemia (CML) who failed other treatment options. Once therapeutic doses were attained, 53 of 54 patients (98%) in the chronic phase achieved hematologic remissions. With prolonged therapy of 2 to 5 months duration, a growing percentage of patients achieved cytogenetic responses. Imatinib mesylate also has activity as a single agent in CML blast crisis and in patients with Ph(+) acute lymphocytic leukemia (ALL). Although responses tend not to be durable, 20% of patients with myeloid blast crisis are in continuous remission for periods up to 1 year. Ongoing clinical studies are directed at optimizing the use of imatinib mesylate. Copyright 2001 by W.B. Saunders Company.
UI - 11843818
AU - Bhatia R; Munthe HA; Forman SJ
TI - Abnormal growth factor modulation of beta1-integrin-mediated adhesion in chronic myelogenous leukaemia haematopoietic progenitors.
SO - Br J Haematol 2001 Dec;115(4):845-53
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
Abnormal progenitor circulation and extramedullary haematopoiesis are characteristic features of chronic myelogenous leukaemia (CML). Growth factor (GF) and beta1-integrin interactions play an important role in regulation of progenitor trafficking to and from the marrow space. CML progenitors demonstrate abnormal beta1-integrin-mediated adhesion to fibronectin (FN). In the present study we investigated whether GF modulation of beta1-integrin-mediated adhesion and migration was altered in CML progenitors. Culture with low concentrations of GF enhanced normal progenitor adhesion to FN compared with no GF, but failed to enhance CML progenitor adhesion to FN. Similarly, high concentrations of selected GF rapidly enhanced beta1-integrin-mediated adhesion of normal progenitors to FN through a phosphotidylinositol-3 (PI-3) kinase-dependent mechanism, but failed to increase CML progenitor adhesion. Exposure to a BCR-ABL tyrosine kinase inhibitor restored GF modulation of CML progenitor adhesion. CML colony-forming cells (CFC) demonstrated increased migration across FN-coated transwells compared with normal CFC in the absence of GF. The addition of stem cell factor resulted in enhanced migration of CML and normal CFC on FN. In conclusion, GF stimulation failed to enhance integrin-mediated adhesion but enhanced migration in CML progenitors on FN. BCR-ABL induced abnormalities in GF-integrin interactions could contribute to abnormal circulation and microenvironmental localization of CML progenitors.
UI - 11806985
AU - Onida F; Kantarjian HM; Smith TL; Ball G; Keating MJ; Estey EH; Glassman
TI - AB; Albitar M; Kwari MI; Beran M Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients.
SO - Blood 2002 Feb 1;99(3):840-9
AD - Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by wide heterogeneity of clinical presentation and course. CMML shares myelodysplastic characteristics with features of myeloproliferative disorders. No treatment has proven effective in modifying the natural course of the disease. To improve the prognostic assessment of clinical outcome, the associations of patient and disease characteristics with survival times of 213 patients with CMML was investigated retrospectively. Median survival was 12 months. Univariate analysis identified low hemoglobin level; low platelet count; high white blood cell, monocyte, and lymphocyte counts; presence of circulating immature myeloid cells, high percentage of marrow blasts, low percentage of marrow erythroid cells, abnormal cytogenetics, and high levels of serum lactate dehydrogenase and beta(2)-microglobulin as characteristics associated with shorter survival. Hemoglobin level below 120 g/L (12 g/dL), presence of circulating immature myeloid cells, absolute lymphocyte count above 2.5 x 10(9)/L, and marrow blasts 10% or more were independently associated with shorter survival by multivariate analysis and were used to generate a prognostic score. The model identified 4 subgroups of patients with median survival of 24, 15, 8, and 5 months for low, intermediate-1, intermediate-2, and high risk, respectively. Researchers could not confer objective evidence suggesting that arbitrary divisions of CMML by white blood cell counts into "dysplastic" and "proliferative" categories reflect clinical entities differing in the risk of acute leukemia development, although a trend of shorter survival in patients with leukocytosis was observed. The prognostic model was compared with 6 previously published scoring systems for myelodysplastic syndrome/CMML. The reported results should provide an improved assessment of prognosis in CMML.
UI - 11841395
AU - Reilly JT
TI - Chronic neutrophilic leukaemia: a distinct clinical entity?
SO - Br J Haematol 2002 Jan;116(1):10-8
AD - Molecular Haematology Unit, Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, Sheffield, UK. email@example.com
UI - 11841409
AU - Voskaridou E; Terpos E; Komninaka V; Eftyhiadis E; Mantzourani M;
TI - Loukopoulos D Chronic myeloid leukaemia with marked thrombocytosis in a patient with thalassaemia major: complete haematological remission under the combination of hydroxyurea and anagrelide.
SO - Br J Haematol 2002 Jan;116(1):155-7
AD - Unit of Thalassaemia, Laikon General Hospital, Athens, Greece. firstname.lastname@example.org
The co-existence of thalassaemia major and chronic myeloid leukaemia (CML) is a very rare event. We report a 32-year-old man with thalassaemia major whose progressively increasing leukocytosis and thrombocytosis led to the diagnosis of CML confirmed by the characteristic t(9;22)(q34;q11) chromosomal translocation and the bcr-abl (b3a2) DNA fusion. The patient was treated with hydroxyurea and anagrelide. This combination resulted in the satisfactory control of both the white blood cell and platelet counts, which has continued over the past 14 months with no major side-effects, albeit with no molecular response. The administration of hydroxyurea was also associated with a significant HbF increase.
UI - 11841411
AU - Marley SB; Davidson RJ; Goldman JM; Gordon MY
TI - Effects of combinations of therapeutic agents on the proliferation of progenitor cells in chronic myeloid leukaemia.
SO - Br J Haematol 2002 Jan;116(1):162-5
AD - Leukaemia Research Fund Centre for Adult Leukaemia, Department of Haematology, Imperial College School of Medicine, London, UK. email@example.com
Combination of STI571, a tyrosine kinase inhibitor, with other drugs may be beneficial in the treatment of chronic myeloid leukaemia (CML). We measured the effects of STI571, AG490, farnesyltransferase inhibitor (FTI), interferon alpha (IFN-alpha), cytosine arabinoside (Ara-C) and all-trans retinoic acid (ATRA), singly and in combination, on clonogenic leukaemic cell proliferation. STI571, IFN-alpha and ATRA each reduced proliferation by 50-60%; AG490, FTI and Ara-C had less effect. Comparing the observed and expected (i.e. additive) effects of drug combinations showed STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA were additive; STI571 + IFN-alpha, IFN-alpha + Ara-C and STI571 + AG490 + FTI were less than additive. Thus, STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA may be better combination therapies for CML than STI571 + IFN-alpha, IFN-alpha + Ara-C or STI571 + AG490 + FTI.
UI - 11841417
AU - Pigneux A; Tanguy ML; Michallet M; Jouet JP; Kuentz M; Vernant JP;
TI - Milpied N; Ifrah N; Cahn JY; Gratecos N; Reman O; Cure H; Caillot D; Witz F; Pillier-Loriette C; Tron P; Reiffers J; Societe Francaise de Greffe de Moelle Prior treatment with alpha interferon does not adversely affect the outcome of allogeneic transplantation for chronic myeloid leukaemia.
SO - Br J Haematol 2002 Jan;116(1):193-201
AD - Service d'Hematologie, Hopital du Haut Leveque, CHU Bordeaux, Pessac, France.
The timing of transplantation in chronic myeloid leukaemia is still debated and previous treatment with interferon (IFN) alpha has been reported to be deleterious. We have analysed the outcome of 438 allogeneic transplants performed between 1984 and 1995 and reported to the Societe Francaise de Greffe de Moelle (SFGM) registry. One hundred and two patients (group I) received IFN for more than 6 weeks (median = 9 months) before transplant. Their outcome was compared with 336 other patients (group II) not pretreated with IFN. There were no significant differences between the groups for engraftment and chronic graft-versus-host disease (GVHD) incidence. However, other significant differences included the incidence of acute GVHD > or = 2 at 3 months which was higher in group I (65 +/- 10%) than in group II (38 +/- 5%; P = 0.01). Moreover, disease-free survival (DFS) and overall survival (OS) at 5 years were significantly shorter for group I than for group II (33 +/- 10% vs. 41 +/- 6%; P = 0.005)(95% CI) and (41 +/- 10% vs. 55 +/- 6%; P = 0.002)(95% CI) respectively. After adjustment for patient and transplant covariables in a multivariate analysis, prior IFN was not found to adversely affect transplant outcome.
UI - 11848092
AU - Keung YK; Pettenati M; Hurd DD; Powell BL; Buss DH
TI - Allogenic marrow grafts from unrelated donors with congenital pericentric inversion of chromosome 9.
SO - Br J Haematol 2002 Jan;116(1):237-8
UI - 11865642
AU - Uehara E; Uesugi T; Tasaka T; Matsuhashi Y; Tamura T; Kuwajima M; Nagai
TI - M [Reversible cardiomyopathy secondary to interferon-alpha in chronic myelogenous leukemia]
SO - Gan To Kagaku Ryoho 2002 Feb;29(2):317-21
AD - Division of Internal Medicine, Kagawa Prefectural Central Hospital.
Interferon-alpha (IFN-alpha) has been accepted as an effective agent in the treatment of chronic myelogenous leukemias (CML). Cardiac toxicity of IFN-alpha has rarely been reported in cases of CML. A 62-year-old woman with a two-year history of chronic myelogenous leukemia who had been treated with IFN-alpha (10 million U/3 days/week) given subcutaneously with oral hydroxycarbamide 500 mg, presented with chest pain, dyspnea and subconsciousness. Chest X-ray revealed cardiomegaly and congestion, and ultrasonography showed diffuse hypokinesis of the heart with decreased left ventricular ejection fraction (LVEF) 34%. She was diagnosed cardiomyopathy caused by IFN-alpha administration. She was treated with furosemide, dobutamine hydrochloride, milrinone and carperitide. The administration of IFN-alpha was terminated. LVEF was improved to 50% within one month from the onset of events, and the patient was discharged. We discuss herein the cardiomyopathy caused by IFN-alpha in CML.
UI - 11870241
AU - Kantarjian H; Sawyers C; Hochhaus A; Guilhot F; Schiffer C;
TI - Gambacorti-Passerini C; Niederwieser D; Resta D; Capdeville R; Zoellner U; Talpaz M; Druker B; The International STI571 CML Study Group Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.
SO - N Engl J Med 2002 Feb 28;346(9):645-52
AD - M.D. Anderson Cancer Center, Houston, TX 77030, USA. firstname.lastname@example.org
BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.
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 - 11642601
AU - Claxton DF; McMannis J; Champlin R; Choudhury A
TI - Therapeutic potential of leukemia-derived dendritic cells: preclinical and clinical progress.
SO - Crit Rev Immunol 2001;21(1-3):147-55
AD - Division of Hematology/Oncology, Milton S. Hershey Medical Center, Hershey, PA 17033, USA. email@example.com
Human leukemia-derived dendritic cells show potential as tools for therapy. Leukemic cells of patients with chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and chronic myelomonocytic leukemia (CMML) will all undergo substantial differentiation toward dendritic cells (DC) and may be used to drive autologous T cells to acquire anti-leukemic cytotoxicity. This article describes the use of these human leukemia-derived dendritic cells for stimulation of allogeneic donor lymphocytes and presents a clinical trial of autologous CML DC-stimulated lymphocytes.
UI - 11803360
AU - Mohty M; Faucher C; Gaugler B; Vey N; Sainty D; Arnoulet C; Mozziconacci
TI - MJ; Isnardon D; Gastaut JA; Maraninchi D; Olive D; Blaise D Large granular lymphocytes (LGL) following non-myeloablative allogeneic bone marrow transplantation: a case report.
SO - Bone Marrow Transplant 2001 Dec;28(12):1157-60
AD - Laboratoire d'Immunologie des Tumeurs, Institut Paoli-Calmettes, Universite de la Mediterranee, Marseille, France.
We report here the first case of large granular lymphocytes (LGL) expansion following non-myeloablative allo-BMT for chronic myeloid leukemia. We characterized the morphologic, phenotypic and functional features of the LGL subset amplified in vivo 14 months after allo-BMT. Our results indicate that LGL can mediate in vitro a cytolytic activity on tumor cells. In vivo, the timing of the LGL expansion was associated with a sustained complete molecular remission. These observations suggest that LGL are a subset with the properties of effector lymphocytes which may contribute to the graft-versus-tumor effect.
UI - 11872078
AU - Stentoft J; Pallisgaard N; Kjeldsen E; Holm MS; Nielsen JL; Hokland P
TI - Kinetics of BCR-ABL fusion transcript levels in chronic myeloid leukemia patients treated with STI571 measured by quantitative real-time polymerase chain reaction.
SO - Eur J Haematol 2001 Nov-Dec;67(5-6):302-8
AD - Department of Hematology, Arhus University Hospital, Arhus, Denmark.
The activated tyrosine kinase, which arises as a result of the balanced t(9,22) translocation in chronic myeloid leukemia (CML), is thought to be essential for the development of the leukemic phenotype. Recently, designer drugs have been introduced which specifically inhibit such specific kinases. Among these, STI571 (Glivec) has entered clinical trials and shown promising activities in chronic phase (CP), accelerated phase (AP) and blast crisis (BC) as evidenced by significant hematological and cytogenetic responses in CML patients. To evaluate the effect of STI571 at the molecular level we have employed quantitative real-time PCR (RQ-PCR) to measure the amount of BCR-ABL fusion transcript in a series of 19 patients treated with STI571, either in CP(11) or in (AP)(8) of the disease for 3--9 months (median 6 months). Employing this method, which is able to detect at least one BCR-ABL+ cell in 500,000, in serial blood and bone marrow specimens we found decreases in transcript levels in 10/11 CP patients, but only in 1/8 of the AP patients. When present such decreases were gradual and became evident only after 3 months of STI571 treatment, and their kinetics in blood closely mirrored those seen in parallel marrow samples. Moreover, decreases were between 10- and 100-fold in 11/13 patients, with only two patients reaching residual disease levels below 10(-2) (a 900-fold decrease). Thus, no patient reached PCR negativity. We conclude that the RQ-PCR method is a highly suitable tool for following the effect of STI571 in CML and that further validation of the method, performed in a prospective manner, will contribute significantly to the elucidation of the proper role of STI571 in CML.
UI - 11872080
AU - Patel M; Ezzat W; Pauw KL; Lowsky R
TI - Bronchiolitis obliterans organizing pneumonia in a patient with chronic myelogenous leukemia developing after initiation of interferon and cytosine arabinoside.
SO - Eur J Haematol 2001 Nov-Dec;67(5-6):318-21
AD - Department of Medical Oncology, Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada.
A 59-yr-old man developed fevers, shortness of breath, persistent cough and weight loss, shortly after initiation of therapy with interferon-alpha 2a and cytosine arabinoside for treatment of chronic myelogenous leukemia. Radiologic pulmonary infiltrates and lung tissue biopsy were consistent with bronchiolitis obliterans organizing pneumonia (BOOP). After discontinuation of the chemotherapeutic drugs, the pneumonic symptoms and chest roentgenogram infiltrates resolved. This report suggests that treatment with interferon-alpha, in combination with cytosine arabinoside, may produce the rare complication of BOOP.
UI - 10578166
AU - Machida U; Kami M; Kanda Y; Takeuchi K; Akahane M; Yamaguchi I; Kakiuchi
TI - C; Takeda N; Tanaka Y; Chiba S; Honda H; Hirai H Aspergillus tracheobronchitis after allogeneic bone marrow transplantation.
SO - Bone Marrow Transplant 1999 Nov;24(10):1145-9
AD - The Department of Hematology and Oncology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
We describe a patient who developed Aspergillus tracheobronchitis after BMT. She complained of progressive dyspnea on day +165 and her respiratory function deteriorated rapidly. Although neither early chest X-rays nor CT scans were negative, bronchoscopy revealed formation of a pseudomembrane around the bronchial walls. Based upon pathological and microbiological examinations, she was diagnosed as having invasive Aspergillus tracheobronchitis. Retrospectively analyzed, the Aspergillus circulating antigen detection tests became positive before clinical symptoms developed, and may be beneficial for early diagnosis of Aspergillus tracheobronchitis. This form of aspergillosis should be regarded as one of the serious complications after BMT.
UI - 11603003
AU - Benthin M; Dallmann I; Atzpodien J
TI - 13cis- and all-trans retinoic acid have antiproliferative effects on CML cells and render IFN alpha antiproliferative potency after combined treatment in vitro.
SO - Cancer Biother Radiopharm 2001 Aug;16(4):323-31
AD - Medizinische Hochschule Hannover, Germany.
The treatment of CML with IFN alpha is limited due to resistance against this substance. Recent studies with different cells than chronic myelogenous leukemic cells revealed a synergistic effect of a combined use of Retinoids (RA) and IFN alpha. The purpose of the study was to detect possible interactions of IFN alpha and RA in CML considering also the effect of the BCR-ABL gene-product. Therefore, we investigated three CML cell lines in their proliferation after incubation with IFN alpha and Retinoids alone and in combination. We measured low susceptibility to IFN alpha but a marked influence of the Retinoids. In combination, the growth inhibition was enhanced potentially in response to an increased efficacy of IFN alpha. Even solely, ineffective concentrations of both substances lead to decreased proliferation.
UI - 11852815
AU - Wajs J; Zabielski S; Trawinski J
TI - [Neoplastic skin infiltration in chronic myelomonocytic leukemia]
SO - Pol Merkuriusz Lek 2001 Nov;11(65):427-9
AD - Klinika Chorob Wewnetrznych i Hematologii z Osrodkiem Transplantacji Szpiku, Warszawa.
Chronic myelomonocytic leukemia has been associated with various nonspecific cutaneous manifestations. Rarely has the leucaemia been reported to directly affect the skin. We present a case of 53-year old man with CMML who showed neoplastic cutaneous lesions. The occurrence of these lesions may be the presenting feature of the disease or may herald its progression to acute leukemia. Early diagnosis have therapeutic and prognostic significance.
UI - 11706876
AU - Stark G; O'Brien SG
TI - An update on chronic myeloid leukaemia.
SO - Clin Med 2001 Sep-Oct;1(5):354-7
AD - School of Clinical Science, Department of Haematology University of Newcastle, Newcastle upon Tyne, UK.
The therapy of CML is clearly 'work in progress' Although long-term follow-up data for patients treated with STI571 are not yet available, preliminary results are encouraging. STI571 is likely to be licensed in late 2001/early 2002 and will certainly find a place in the treatment of CML. Current therapeutic considerations are summarised in Fig 2. At all stages of treatment it is vital that the patient is fully aware of treatment options, their risks and benefits. In some cases there is little evidence to suggest that one treatment option is better than another; in these situations, treatment is likely to depend on a patient's individual circumstances and preferences.
UI - 11845064
AU - Denizon N; Beraud JJ; Mourad G; Blanc P; Bureau JP; Navarro M;
TI - Lavabre-Bertrand T [Hemolitic uremic syndrome with hypertransaminasemia following treatment by interferon for chronic myeloid leukemia]
SO - Gastroenterol Clin Biol 2001 Nov;25(11):1039-40
UI - 11523404
AU - Stromskaia TP; Rybalkina EIu; Turkina AG; Zabotina TN; Logacheva NP;
TI - Zakharova ES; Mechetner EB; Baryshnikov AIu; Khoroshko ND; Stavrovskaia AA [Functional activity and expression of P-glycoprotein in chronic myeloid leukemia]
SO - Ter Arkh 2001;73(7):20-5
AIM: To evaluate the prognostic significance of P-glycoprotein (Pgp) in chronic myeloid leukemia (CML). MATERIALS AND METHODS: Functional activity (rhodamine 123 test) and expression of Pgp (binding of UIC2 monoclonal antibodies by cells) were evaluated by flow cytofluorometry. A total of 141 samples of peripheral blood from 121 patients with various stages of CML were examined. RESULTS: The number of patients whose cells express functionally active Pgp increases during the blast crisis (BC) in comparison with the chronic phase (CP). Repeated testing of patients with BC and CP showed that Pgp-expressing cells can disappear from the peripheral blood of patients despite the treatment by Pgp preparations and substrates. However the number of cases with expression and functional activity of Pgp increases in the course of BC. Several patients in whom functionally active Pgp was not detected during diagnosis of BC had longer BC phase than patients with the active protein. CONCLUSION: These data suggest that active Pgp contributes to CML BC (presumably to patient's response to therapy) but this contribution is not decisive.
UI - 11523405
AU - Vinogradova OA; Savchenko VG; Neverova AL; Diachenko LV; Domracheva EV;
TI - Liubimova LS; Mendeleeva LP [Study of the time course of mixed chimerism by fluorescent in situ hybridization in patients with chronic myeloid leukemia after allogenic transplantation of bone marrow]
SO - Ter Arkh 2001;73(7):26-34
AIM: To determine the type of chimerism in patients with chronic myeloid leukemia (CML) in various periods after allogenic transplantation of bone marrow (TBM) and its association with subsequent relapse. MATERIALS AND METHODS: Ten patients were examined after allogenic TBM, which was performed during the chronic phase of CML in 9 patients and during acceleration phase in 1. Two patients received therapy with donor lymphocytes during relapse after transplantation. Time course of chimerism and minimum residual illness was studied by standard cytogenetic methods, fluorescent in situ hybridization (FISH) with DNA probes to centromer sites of X and Y chromosomes and BCR and ABL genes. The studies were carried out 30, 60, 90, 180 days, 9 months, 1 year, and then every 6 months after transplantation. RESULTS: Mixed chimerism was observed in all patients during 9 months after TBM. The count of host cells was 0.1-5.8% in 8 patients; later the count of autologous cells was less than 1% in 5 patients, and in 3 patients complete donor chimerism was observed. Clinical hematological remission was stable in these patients. Relapses of leukemia with 40 and 83.1% host cells occurred in 2 patients 13 and 23 months after transplantation, respectively. Donor lymphocytes were transfused in order to induce the graft versus host effect, and in patient No. 2 restoration of donor hemopoiesis was attained. CONCLUSION: Highly sensitive FISH method with DNA probe to centromer sites of X and Y chromosomes detects early relapse of the disease and demonstrates the time course of donor hemopoiesis recovery after transfusion of donor lymphocytes. The data indicate that 9 months after transplantation molecular cytogenetic studies should be carried out more often (once a month), particularly in patients with poor prognosis, for earlier detection of the relapse and beginning of immunotherapy.
UI - 11683803
AU - Subudhi CP; Adedeji A; Kaufmann ME; Lucas GS; Kerr JR
TI - Fatal Roseomonas gilardii bacteremia in a patient with refractory blast crisis of chronic myeloid leukemia.
SO - Clin Microbiol Infect 2001 Oct;7(10):573-5
UI - 11878573
AU - Felice M S; Zubizarreta P A; Alfaro E M; Sackmann-Muriel F
TI - Childhood acute lymphoblastic leukemia: prognostic value of initial peripheral blast count in good responders to prednisone.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):411-5
AD - Hematology/Oncology Department, Hospital de Pediatria SAMIC Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina. firstname.lastname@example.org
PURPOSE: To assess the value of initial peripheral blast count in patients with acute lymphoblastic leukemia (ALL) and prednisone good 1995, 403 consecutive patients with newly diagnosed ALL were enrolled in the authors' protocol 1-ALL90-BFM/HPG. Prednisone good response was defined as a blast count of less than 1,000/microL and a prednisone poor response (PPR) as a blast count of at least 1,000/microL, both in peripheral smears, after 7 days of oral prednisone (60 mg/m2 per day) and one intrathecal dose of methotrexate. In the PGR group, patients were divided into two subgroups: patients who had less than 1,000 blasts/microL at diagnosis and those with at least 1,000 blasts/microL at diagnosis. RESULTS: Three-hundred thirty-seven patients (90%) had PGR and 37 had (10%) PPR. At 5-year follow-up, event-free survival estimates were 67 +/- 3.8% and 38 +/- 8% for PGR and PPR, respectively (P = 0.0001). In the PGR group, 114 patients (34%) had an initial blast count of less than 1,000/microL and 223 (66%) had an initial blast count of at least 1,000/microL. The authors compared the clinical and laboratory characteristics of these subgroups at diagnosis and outcome and detected significant differences in white cell count, incidence of T immunophenotype, and presence of mediastinal or spleen enlargement. However, there were no differences in response to induction treatment, death in complete remission, relapses, or event-free survival probability. CONCLUSIONS: In the PGR group, regardless of the initial blast count, both subgroups had the same outcome. The PGR group with an initial blast count of at least 1,000/microL had significantly higher white cell counts. T markers, and mediastinal or spleen enlargement at diagnosis. Response to prednisone is a practical, inexpensive, and good prognostic factor in childhood ALL.
UI - 11693465
AU - Lyseng-Williamson K; Jarvis B
TI - Imatinib.
SO - Drugs 2001;61(12):1765-74; discussion 1775-6
AD - Adis International Limited, Mairangi Bay, Auckland, New Zealand. email@example.com
Imatinib inhibits the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukaemia (CML). Complete haematological responses were achieved in 88% of patients and major cytogenetic responses were detected in 49% of patients with chronic phase CML treated with oral imatinib 400 mg/day in a multicentre noncomparative study of 532 patients. Administration of oral imatinib 400 or 600 mg/day to 235 patients with accelerated phase CML in a multicentre noncomparative study resulted in haematological responses in 63% of patients and major cytogenetic responses in 21% of patients. 26% of the 260 patients with blast crisis CML receiving imatinib 400 or 600 mg/day in a multicentre noncomparative trial sustained a haematological response and 13.5% of patients had a major cytogenetic response. Imatinib 400 or 600 mg/day orally achieved ahaematological response in 19 of 32 patients with Ph+ acute lymphoblastic leukaemia in a pilot study. Clinical improvement was demonstrated in 89% of 36 patients with gastrointestinal stromal tumours unresponsive to standard chemotherapy during treatment with 400 or 600 mg/day oral imatinib in a noncomparative phase II trial. Adverse events were frequent in clinical trials of imatinib but most events were mild or moderate in severity. Serious adverse events reported include severe fluid retention, cytopenias and hepatotoxicity.
UI - 11766235
AU - Egyed M; Mihalyfalvi Z; Kollar B; Rumi G; Keller E; Vass J; Fekete S
TI - [Effect of retinoic acid on the cytogenetic remission in the first chronic phase of chronic myeloid leukemia treated with interferon]
SO - Orv Hetil 2001 Nov 4;142(44):2421-5
AD - Belgyogyaszati Osztaly, Kaposi Mor Megyei Korhaz, Kaposvar. firstname.lastname@example.org
Cytogenetic responses of 11 chronic myeloid leukemic (CML) patients during the first chronic phase, treated with the combination of all-trans retinoic acid (ATRA) + interferon (IFN) were compared to 9 other CML patients of phase one, treated with interferon monotherapy. Metaphase and interphase cytogenetics and a semiquantitative polymerase chain reaction (PCR) were used to evaluate the cytogenetic responses. Two of the 11 patients in the ATRA + interferon treated group were withdrawn, one of them because of interferon intolerance, and the other because of compliance failure. Among the 9 ATRA + interferon treated patients 6 major cytogenetic responses could be detected and 3 of them were complete. Of the 9 patients treated with IFN monotherapy only 2 major cytogenetic responses could be registered. No severe adverse effects were observed. The first results suggest that the ATRA + interferon combination may be superior in achieving cytogenetic remission in the first chronic phase of CML.
UI - 11855148
AU - Xu L; Guo N; Huang X
TI - [Effect of interferon-alpha on the prognosis of bone marrow transplantation in chronic myeloid leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 2001 Nov;22(11):589-91
AD - Institute of Hematology, People's Hospital, Beijing University, Beijing 100044, China.
OBJECTIVE: To investigate whether prior interferon alfa (IFN-alpha) treatment affects the outcome of allogeneic bone marrow transplantation. METHODS: The outcome of 85 patients with chronic myelogenous leukemia (CML) in first chronic phase received transplants from an HLA-identical sibling donor was analyzed. Of the 85 patients, 30 did not receive IFN-alpha, whereas 30, 15 and 10 patients received IFN-alpha 3 x 10(6) units 3-4 times per week for < 6, 6-12 and > 12 months before transplant combined with hydroxyurea and/or HA regimen (H: Harringtonine; A: Ara-C) respectively. RESULTS: Pretransplant IFN-alpha therapy for > or = 6 months was associated with an increased risk of severe (grade III-IV) acute graft-versus-host disease (GVHD) (P < 0.01) as compared to that in < 6 months or no IFN-alpha therapy. No influence of pretransplant IFN-alpha treatment on engraft, cGVHD, VOD, relapse and TRM (transplant-related mortality) was found. Survival rate of IFN-alpha therapy < 6 months group (90.0%) was higher than that of no IFN-alpha group (68.9%) or > 12 months group(60.0%) (P < 0.05). CONCLUSION: It was found that there was a trend towards an improved survival in the IFN-alpha < 6 months group. Pretransplant IFN-alpha therapy for > or = 6 months was associated with an increased risk of severe aGVHD.
UI - 11831068
AU - Fischer T
TI - [Results up to now of administration of STI-571 (Glivec) in recurrence after allogenic and autologous stem cell transplantation in chronic myeloid leukemia]
SO - Med Klin 2002 Jan 15;97 Suppl 1():22-7
AD - III. Medizinische Klinik und Poliklinik, Hamatologie und Onkologie, Johannes-Gutenberg-Universitat Mainz. email@example.com
BACKGROUND: Gleevec (STI-571) is s selective inhibitor of the bcr/abl tyrosine kinase. Recent phase I and phase II studies in patients with bcr/abl positive CML and ALL showed a low rate of grade III/IV toxicity and good clinical efficacy. This report describes the preliminary results in patients relapsing post autologous or allogeneic peripheral blood stem cell transplantation. The focus of this analysis will include toxicity, feasibility and clinical efficacy. THERAPY AND RESULTS: 18 of 18 patients with cytogenetic and/or hematologic relapse in chronic phase CML post autologous stem cell transplantation achieved a complete hematologic remission upon therapy with Gleevec. The cytogenetic response rate was 75% with a complete cytogenetic response rate of 50%. After allogeneic stem cell transplantation, patients in cytogenetic or hematologic relapse also experienced high hematologic and cytogenetic response rates upon therapy with Gleevec. In these patients, Gleevec was shown to induce mixed chimerism. Overall, Gleevec was well tolerated after autologous and allogeneic stem cell transplantation. Most common side effects were mild to moderate gastrointestinal discomfort and edema. No symptoms of chronic extensive or > grade I acute GvHD could be observed. Hematologic toxicity was dependent on stage of disease. Grade III/IV granulocytopenia and/or thrombopenia could be observed in 50% of patients with transformed phases of CML. Management of these patients required frequent controls of peripheral blood counts and transfusion of blood products. CONCLUSION: These results show a new approach in treatment of patients with Philadelphia-chromosome-positive leukemia relapsing post autologous or allogeneic stem cell transplantation. Gleevec is able to induce mixed chimerism without induction of severe GvHD. The data suggest that early start of STI-571 therapy in MRD-positive patients is a promising approach. Recently, a multicenter phase II study to evaluate the toxicity and efficacy of Gleevec in CML patients with minimal residual disease post allogeneic transplantation was started.