• Unable to resist.

• Differences among the polyadenylated RNA sequences of human leucocyte populations: an approach to the objective classification of human

• Cutaneous lesions and chronic myelocytic leukemia (CML) in progression.

• A case of hypoplastic chronic myelogenous leukemia initiating with pancytopenia.

• Generalized vitiligo after lymphocyte infusion for relapsed leukaemia.

• Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase

• Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase.

• Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of

• Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation.

• An overview of translocation-related oncogenesis in the chronic myeloid leukaemias.

• Cytogenetic and molecular monitoring of residual disease in chronic myeloid leukaemia.

• Cytogenetic and molecular genetic evolution of chronic myeloid leukemia.

• The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR-ABL positive chronic myeloid leukaemia cells: synergistic interactions with

• Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for

• Stem cell transplantation for chronic myeloid leukaemia: the role of infused marrow cell dose.

• Neutrophilic-chronic myeloid leukemia: low levels of p230 BCR/ABL mRNA and undetectable BCR/ABL protein may predict an indolent course.

• Molecular cytogenetic characterization of a novel additional chromosomal aberration in blast crisis of a Ph-positive chronic myeloid leukemia.

• Coexistence of chronic myeloid leukemia and hairy cell leukemia of common clonal origin.

• Monosomy 15 in chronic myelomonocytic leukemia. description of a case and review of the literature.

• Treatment options in chronic myelogenous leukemia.

• Interferon-alpha protects Philadelphia-negative progenitors from exhaustion in chronic myeloid leukemia patients with cytogenetic

• ABL gene fuses BCR during t(20;22) results in Philadelphia-negative, but BCR/ABL-positive chronic myeloid leukemia.

• Distinct genomic events in the myeloid and lymphoid lineages in simultaneous presentation of chronic myeloid leukemia and B-chronic

• Cerebral oedema as a possible complication of treatment with imatinib.

• Transgenic interleukin 2 secreted by CML dendritic cells stimulates autologous T(H)1 T cells.

• High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid

• Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.

• Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous

• Resistance to daunorubicin-induced apoptosis is not completely reversed in CML blast cells by STI571.

• Successful treatment of chronic myeloid leukemia during pregnancy with hydroxyurea.

• An epidemiologic study to screen for chronic myelocytic leukemia in war victims exposed to mustard gas.

• Doctors condemn NICE's guidance on leukaemia drug.

• Chronic neutrophilic leukemia--a case report.

• The importance of drug scheduling and recovery phases in determining drug activity. Improving etoposide efficacy in BCR-ABL-positive CML

• [Endogenous intoxication, immunological reactivity and erythrocyte membrane permeability in patients with chronic myelogenous leukemia]

1
UI - 12001985
AU - Brooksbank C
TI - Unable to resist.
SO - Nature Rev Cancer 2002 Apr;2(4):248

2
UI - 11894916
AU - Wiedemann LM; Burns JH; Birnie GD
TI - Differences among the polyadenylated RNA sequences of human leucocyte populations: an approach to the objective classification of human leukaemias.
SO - EMBO J 1983;2(1):9-13
AD - The Beatson Institute for Cancer Research, Bearsden, Glasgow, UK.
We have constructed a complementary DNA (cDNA) library representing expressed sequences of the white blood cells from a patient with chronic granulocytic leukaemia. The library was screened by colony hybridization of 32P-labelled cDNAs synthesized from the polyadenylated RNAs of the white blood cells from patients with chronic granulocytic or chronic lymphocytic leukaemia. The autoradiographic patterns were compared and 70 recombinants were selected to comprise a panel which distinguished between these two types of leukaemia. Hybridization of this panel with complementary DNAs transcribed from the polyadenylated RNAs of a variety of normal and neoplastic leucocyte populations showed that the RNA sequences in high abundance in leucocytes from chronic granulocytic leukaemias differ quite radically from those in other leucocytes. The patterns of hybridization seen when this panel was challenged with cDNAs representing the RNAs of normal and leukaemic leucocyte populations were sufficiently different to distinguish clearly the peripheral blood leucocytes of chronic granulocytic leukaemias from other populations of white blood cells, both normal and leukaemic. We suggest that this approach might provide additional markers useful in the classification of the acute leukaemias, especially the undifferentiated leukaemias whose identification by conventional methods is uncertain.

3
UI - 11904748
AU - Paydas S
TI - Cutaneous lesions and chronic myelocytic leukemia (CML) in progression.
SO - Ann Hematol 2002 Mar;81(3):178

4
UI - 11999367
AU - Matsuda M; Miyazato H; Ueda S; Morita Y; Sakaguchi M; Tatsumi Y; Maeda
TI - Y; Kanamaru A A case of hypoplastic chronic myelogenous leukemia initiating with pancytopenia.
SO - Int J Hematol 2002 Apr;75(3):335-6

5
UI - 11899125
AU - Au WY; Yeung CK; Chan HH; Lie AK
TI - Generalized vitiligo after lymphocyte infusion for relapsed leukaemia.
SO - Br J Dermatol 2001 Dec;145(6):1015-7
AD - Department of Medicine, Queen Mary Hospital, University of Hong Kong. auwing@hotmail.com
Vitiligo is an autoimmune disease caused by T-lymphocyte-mediated destruction of melanocytes. We describe two patients with generalized vitiligo caused iatrogenically after donor lymphocyte infusion (DLI) for leukaemia relapse over 3 years after bone marrow transplantation (BMT). Neither the sibling donor nor the recipient had vitiligo or other autoimmune diseases, and vitiligo did not occur after the first BMT. DLI was accompanied by skin graft-versus-host disease in both cases, which was controlled with immunosuppression. However, over several months, progressive generalized and persistent skin depigmentation occurred in both patients. Peripheral blood molecular studies showed the complete disappearance of host haematolymphopoiesis. The specific destruction of melanocytes in both patients was therefore probably mediated by new alloreactive lymphocytes infused from the donors.

6
UI - 11986204
AU - Sawyers CL; Hochhaus A; Feldman E; Goldman JM; Miller CB; Ottmann OG;
TI - Schiffer CA; Talpaz M; Guilhot F; Deininger MW; Fischer T; O'Brien SG; Stone RM; Gambacorti-Passerini CB; Russell NH; Reiffers JJ; Shea TC; Chapuis B; Coutre S; Tura S; Morra E; Larson RA; Saven A; Peschel C; Gratwohl A; Mandelli F; Ben-Am M; Gathmann I; Capdeville R; Paquette RL; Druker BJ Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.
SO - Blood 2002 May 15;99(10):3530-9
AD - Department of Medicine and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA. csawyers@mednet.ucla.edu
Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.

7
UI - 11986206
AU - Kantarjian HM; Cortes J; O'Brien S; Giles FJ; Albitar M; Rios MB; Shan
TI - J; Faderl S; Garcia-Manero G; Thomas DA; Resta D; Talpaz M Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase.
SO - Blood 2002 May 15;99(10):3547-53
AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. hkantarj@mdanderson.org
Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph(+) below 35%], and 4 minor [Ph(+), 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P =.001), longer median survival (7 versus 4 months, P =.04), and lower 4-week induction mortality (4% versus 15%, P =.07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.

8
UI - 11986238
AU - Holtz MS; Slovak ML; Zhang F; Sawyers CL; Forman SJ; Bhatia R
TI - Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation.
SO - Blood 2002 May 15;99(10):3792-800
AD - Division of Hematology and Bone Marrow Transplantation and the Department of Cytogenetics, City of Hope National Medical Center, Duarte, CA 91010, USA.
Imatinib mesylate (STI571) is a promising new treatment for chronic myelogenous leukemia (CML). The effect of imatinib mesylate on primitive malignant progenitors in CML has not been evaluated, and it is not clear whether suppression of progenitor growth represents inhibition of increased proliferation, induction of apoptosis, or both. We demonstrated here that in vitro exposure to concentrations of imatinib mesylate usually achieved in patients (1-2 microM) for 96 hours inhibited BCR/ABL-positive primitive progenitors (6-week long-term culture-initiating cells [LTCICs]) as well as committed progenitors (colony-forming cells [CFCs]). No suppression of normal LTCICs and significantly less suppression of normal CFCs were observed. A higher concentration of imatinib mesylate (5 microM) did not significantly increase suppression of CML or normal LTCICs but did increase suppression of CML CFCs, and to a lesser extent, normal CFCs. Analysis of cell division using the fluorescent dye carboxyfluorescein diacetate succinimidyl ester indicated that imatinib mesylate (1-2 microM) inhibits cycling of CML primitive (CD34(+)CD38(-)) and committed (CD34(+)CD38(+)) progenitors to a much greater extent than normal cells. Conversely, treatment with 1 to 2 microM imatinib mesylate did not significantly increase the percentage of cells undergoing apoptosis. Although a higher concentration of imatinib mesylate (5 microM) led to an increase in apoptosis of CML cells, apoptosis also increased in normal samples. In summary, at clinically relevant concentrations, imatinib mesylate selectively suppresses CML primitive progenitors by reversing abnormally increased proliferation but does not significantly increase apoptosis. These results suggest that inhibition of Bcr-Abl tyrosine kinase by imatinib mesylate restores normal hematopoiesis by removing the proliferative advantage of CML progenitors but that elimination of all CML progenitors may not occur.

9
UI - 11986250
AU - Olavarria E; Craddock C; Dazzi F; Marin D; Marktel S; Apperley JF;
TI - Goldman JM Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation.
SO - Blood 2002 May 15;99(10):3861-2
AD - Haematology Department, Hammersmith Hospital, London, England. e.olavarria@ic.ac.uk
Donor lymphocyte infusion (DLI) can restore durable molecular remission in a high percentage of patients with chronic myeloid leukemia (CML) who have relapses after allogeneic stem cell transplantation, but for patients who do not respond survival is poor. Imatinib mesylate (STI571) is a specific inhibitor of BCR-ABL tyrosine kinase that can induce hematologic and cytogenetic remissions in patients with CML. We report here a male patient who had a relapse to chronic phase after stem cell transplantation for CML, did not benefit from treatment with DLI, and then was administered STI571 at a dose of 400 mg daily. There was a rapid, complete hematologic response, and complete restoration of donor-type hematopoiesis (100% 46, XX marrow metaphases) was achieved after 6 months of therapy, though RT-PCR studies still detected BCR-ABL transcripts in the blood at low level. This case demonstrates that imatinib mesylate can be highly effective in the management of patients who have relapses after allograft for CML.

10
UI - 11919386
AU - Bain BJ
TI - An overview of translocation-related oncogenesis in the chronic myeloid leukaemias.
SO - Acta Haematol 2002;107(2):57-63
AD - Department of Haematology, Imperial College Faculty of Medicine, St Mary's Hospital, London, UK. b.bain@ic.ac.uk
The demonstration of the BCR-ABL fusion gene in patients with chronic granulocytic leukaemia and t(9;22)(q34;q11) represents the first recognition, in a human neoplasm, of a translocation leading to formation of an oncogenic fusion gene. Since this initial observation, this leukaemogenic mechanism has been increasingly recognized in chronic myeloid leukaemias. The fusion gene has often incorporated part of a gene encoding a receptor or cytoplasmic tyrosine kinase, particularly ABL, PDGFRB and FGFR1. This contrasts with the frequent involvement of genes encoding transcription factors or other nuclear proteins in acute myeloid leukaemia. Nevertheless, genes encoding tyrosine kinases have also been implicated in some cases of acute leukaemia. With the exception of the BCR-ABL fusion gene in chronic granulocytic leukaemia, all these fusion genes are uncommon or rare among cases of chronic myeloid leukaemia. The molecular mechanisms underlying the great majority of cases of Philadelphia-negative chronic myeloid leukaemia remain to be discovered. Copyright 2002 S. Karger AG, Basel

11
UI - 11919387
AU - Kaeda J; Chase A; Goldman JM
TI - Cytogenetic and molecular monitoring of residual disease in chronic myeloid leukaemia.
SO - Acta Haematol 2002;107(2):64-75
AD - Department of Haematology, Imperial College at Hammersmith Hospital, London, UK.
For patients with chronic myeloid leukaemia, methods for monitoring response to treatment have changed considerably in recent years. In the 1980s, the principal approach was repeated examination of bone marrow metaphases for the presence of the Ph chromosome in patients treated by interferon-alpha (IFN-alpha) or allogeneic stem cell transplantation. The use of fluorescence in situ hybridisation (FISH) techniques to detect the BCR-ABL fusion gene in Ph-positive leukaemia cells increased the sensitivity of cytogenetic studies to some degree. In the last 10 years, the reverse-transcriptase polymerase chain reaction (RT-PCR) has proved extremely valuable for assessing and monitoring minimal residual disease in patients who achieve Ph negativity after treatment with IFN-alpha or with the new Abl tyrosine kinase inhibitor imatinib mesylate or after allogeneic stem cell transplantation (SCT). Results are consistent with the notion that the majority of long-term survivors after allogeneic SCT are probably 'cured'; for other patients monitored serially in complete cytogenetic remission, rising numbers of BCR-ABL transcripts detected by RT-PCR can indicate the need for further therapy. Copyright 2002 S. Karger AG, Basel

12
UI - 11919388
AU - Johansson B; Fioretos T; Mitelman F
TI - Cytogenetic and molecular genetic evolution of chronic myeloid leukemia.
SO - Acta Haematol 2002;107(2):76-94
AD - Department of Clinical Genetics, Lund University Hospital, Sweden.
Chronic myeloid leukemia (CML) is genetically characterized by the presence of the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22 called the Philadelphia (Ph) chromosome. In 2-10% of the cases, this chimeric gene is generated by variant rearrangements, involving 9q34, 22q11, and one or several other genomic regions. All chromosomes have been described as participating in these variants, but there is a marked breakpoint clustering to chromosome bands 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13. Despite their genetically complex nature, available data indicate that variant rearrangements do not confer any specific phenotypic or prognostic impact as compared to CML with a standard Ph chromosome. In most instances, the t(9;22), or a variant thereof, is the sole chromosomal anomaly during the chronic phase (CP) of the disease, whereas additional genetic changes are demonstrable in 60-80% of cases in blast crisis (BC). The secondary chromosomal aberrations are clearly nonrandom, with the most common chromosomal abnormalities being +8 (34% of cases with additional changes), +Ph (30%), i(17q) (20%), +19 (13%), -Y (8% of males), +21 (7%), +17 (5%), and monosomy 7 (5%). We suggest that all these aberrations, occurring in >5% of CML with secondary changes, should be denoted major route abnormalities. Chromosome segments often involved in structural rearrangements include 1q, 3q21, 3q26, 7p, 9p, 11q23, 12p13, 13q11-14, 17p11, 17q10, 21q22, and 22q10. No clear-cut differences as regards type and prevalence of additional aberrations seem to exist between CML with standard t(9;22) and CML with variants, except for slightly lower frequencies of the most common changes in the latter group. The temporal order of the secondary changes varies, but the preferred pathway appears to start with i(17q), followed by +8 and +Ph, and then +19. Molecular genetic abnormalities preceding, or occurring during, BC include overexpression of the BCR/ABL transcript, upregulation of the EVI1 gene, increased telomerase activity, and mutations of the tumor suppressor genes RB1, TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in relation to treatment given during CP. For example, +8 is more common after busulfan than hydroxyurea therapy, and the secondary changes seen after interferon-alpha treatment or bone marrow transplantation are often unusual, seemingly random, and occasionally transient. Apart from the strong phenotypic impact of addition of acute myeloid leukemia/myelodysplasia-associated translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and t(15;17)(q22;q12-21), in CML BC, only a few significant differences between myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being more frequent in lymphoid BC. The prognostic significance of the secondary genetic changes is not uniform, although abnormalities involving chromosome 17, e.g., i(17q), have repeatedly been shown to be ominous. However, the clinical impact of additional cytogenetic and molecular genetic aberrations is most likely modified by the treatment modalities used. Copyright 2002 S. Karger AG, Basel

13
UI - 11986783
AU - Liu WM; Stimson LA; Joel SP
TI - The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR-ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents.
SO - Br J Cancer 2002 May 6;86(9):1472-8
AD - Barry Reed Oncology Laboratory, 4th Floor, 38 Little Britain, St. Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK. w.a.i.liu@qmul.ac.uk
Chronic myeloid leukaemia is typically characterised by the presence of dysregulated BCR-ABL tyrosine kinase activity, which is central to the oncogenic feature of being resistant to a wide range of cytotoxic agents. We have investigated whether the inhibition of this tyrosine kinase by the novel compound STI571 (formerly CGP57148B) would render K562, KU812 cell lines and chronic myeloid leukaemia-progenitor cells sensitive to induction of cell kill. Proliferation assays showed STI571 to be an effective cytotoxic agent in chronic myeloid leukaemia-derived cell lines (IC(50) on day 5 of 4.6 microg ml(-1) and 3.4 microg ml(-1) for K562 and KU812 respectively) and in leukaemic blast cells (per cent viability on day 3 at 4 microg ml(-1): 55.5+/-8.7 vs 96.4+/-3.7%). STI571 also appeared to specifically target bcr-abl expressing cells, as results from colony forming assays using the surviving cell fraction from STI571-treated peripheral CD34(+) chronic myeloid leukaemia blast cells, indicated a reduction in the expansion of colonies of myeloid lineage, but no effect on normal colony formation. Our data also showed synergy between STI571 and other anti-leukaemic agents; as an example, there were significant increases in per cent cell kill in cell lines cultured with both STI571 and etoposide compared to the two alone (per cent cell kill on day 3: 73.7+/-11.3 vs 44.5+/-8.7 and 17.8+/-7.0% in cultures with STI571 and etoposide alone respectively; P<0.001). This study confirms the central oncogenic role of BCR-ABL in the pathogenesis of chronic myeloid leukaemia, and highlights the role of targeting this tyrosine kinase as a useful tool in the clinical management of the disease. Copyright 2002 Cancer Research UK

14
UI - 11986785
AU - Topaly J; Fruehauf S; Ho AD; Zeller WJ
TI - Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning.
SO - Br J Cancer 2002 May 6;86(9):1487-93
AD - Department of Internal Medicine V, University of Heidelberg, Hospitalstrasse 3, D-69115 Heidelberg, Germany.
The tyrosine kinase activity of the BCR-ABL oncoprotein results in reduced apoptosis and thus prolongs survival of chronic myelogenous leukaemia cells. The tyrosine kinase inhibitor imatinib (formerly STI571) was reported to selectively suppress the proliferation of BCR-ABL-positive cells. Assuming that imatinib could be included in pretransplantation conditioning therapies, we tested whether combinations of imatinib and gamma-irradiation or alkylating agents such as busulfan or treosulfan would display synergistic activity in BCR-ABL-positive chronic myelogenous leukaemia BV173 and EM-3 cell lines. Further, primary cells of untreated chronic myelogenous leukaemia patients were assayed for colony forming ability under combination therapy with imatinib. Additionally, the cytotoxic effect of these combinations on BCR-ABL-negative cells was investigated. In the cell lines a tetrazolium based MTT assay was used to quantify growth inhibition after exposure to cytotoxic drugs alone or to combinations with imatinib. Irradiation was applied prior to exposure to imatinib. Interaction of drugs was analysed using the median-effect method of Chou and Talalay. The combination index was calculated according to the classic isobologram equation. The combination imatinib + gamma-irradiation proved to be significantly synergistic over a broad range of cell growth inhibition levels in both BCR-ABL-positive cell lines and produced the strongest reduction in primary chronic myelogenous leukaemia colony-forming progenitor cells. Combinations of imatinib + busulfan and imatinib + treosulfan showed merely additive to antagonistic effects. Imatinib did not potentiate the effects of irradiation or cytotoxic agents in BCR-ABL-negative cells. Our data provide the basis to further develop imatinib-containing conditioning therapies for stem cell transplantation in chronic myelogenous leukaemia. Copyright 2002 Cancer Research UK

15
UI - 11920259
AU - Pocock C; Szydlo R; Davis J; de La Fuente J; Craddock C; Cwynarski K;
TI - Olavarria E; Rezvani K; Kanfer E; Apperley J; Goldman J Stem cell transplantation for chronic myeloid leukaemia: the role of infused marrow cell dose.
SO - Hematol J 2001;2(4):265-72
AD - Department of Haematology, Hammersmith Hospital, Imperial College School of Medicine, London, UK.
INTRODUCTION: Allogeneic stem cell transplantation is a potentially curative option for patients with CML. The optimal donor is an HLA-identical sibling but transplants using unrelated volunteers can also be successful. The factors influencing survival after allogeneic SCT for CML are reasonably well defined. Recently however, the Seattle group have emphasised the influence of a high marrow cell dose on outcome following volunteer unrelated donor SCT for high risk acute leukaemia. MATERIALS AND METHODS: We have sought to define factors impacting on transplant related mortality (TRM) in a population of CML patients after allografting with matched sibling or alternative stem cell donors at a single centre over a 20-year period, with emphasis on infused marrow cell dose. Factors entered into a multivariate analysis were: recipient age, recipient CMV serostatus, disease phase, donor sex, cell dose and frequency of CTLP reactivity. RESULTS: In multivariate analysis four factors had an adverse effect on TRM when using a VUD: low marrow cell dose (<3.65 x 10(8) TNC/kg, relative risk 2.05, CI 1.08-3.90, P = 0.029), late disease phase (relative risk 1.68, CI 1.03-2.74, P = 0.038), patient CMV seropositivity (relative risk 1.98, CI 1.25-3.13, P = 0.004) and high frequency of CTLP (relative risk 1.93, CI 1.18-3.13, P = 0.008). For HLA-identical sibling donor transplants the only factor that adversely impacted on TRM was late disease phase (P = 0.0004 in univariate analysis). CONCLUSION: High infused cell dose is a new modifiable factor associated with reduced TRM following allogeneic SCT using an unrelated donor for the treatment of CML. The data support the recommendation that bone marrow harvest teams should aim to collect the highest possible number of nucleated cells for recipients of unrelated donor transplants.

16
UI - 12015767
AU - Verstovsek S; Lin H; Kantarjian H; Saglio G; De Micheli D; Pane F;
TI - Garcia-Manero G; Intrieri M; Rotoli B; Salvatore F; Guo JQ; Talpaz M; Specchia G; Pizzolo G; Liberati AM; Cortes J; Quackenbush RC; Arlinghaus RB Neutrophilic-chronic myeloid leukemia: low levels of p230 BCR/ABL mRNA and undetectable BCR/ABL protein may predict an indolent course.
SO - Cancer 2002 May 1;94(9):2416-25
AD - Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
BACKGROUND: Neutrophilic-chronic myeloid leukemia (CML-N) has been described as a CML variant associated both with a distinctive molecular defect of the Philadelphia chromosome and with a more benign clinical course than classic CML. The translocation (9;22) in CML-N results in the transcription of an e19/a2 type BCR/ABL mRNA that codes for a 230-kD BCR/ABL protein (p230). The indolence of the clinical course of patients with CML-N has been disputed. METHODS: The objectives of this study were to quantify and correlate with clinical outcome the p230 mRNA and protein in patients with CML-N, to describe six new patients and the follow-up (with molecular analysis) of five previously reported patients with CML-N, and to review characteristics of all patients with CML-N and p230 BCR/ABL reported to date in the literature. RESULTS: Quantitative polymerase chain reaction assays on specimens from the great majority of patients with CML-N revealed minimal numbers of molecules of p230 BCR/ABL transcripts per total RNA. This also was associated with a lack of detectable p230 BCR/ABL protein in patient specimens, even in one patient who was followed for 16 years after diagnosis. This may explain the milder leukemic phenotype in most patients with CML-N. A review of all 23 patients who had an e19/a2 type BCR/ABL translocation suggested that the low level of p230 BCR/ABL mRNA and the lack of detectable p230 BCR/ABL protein in patients with no additional cytogenetic abnormalities may predict their indolent clinical course. CONCLUSIONS: Patients with p230 positive CML-N have indolent course, probably as a result of low p230 mRNA and protein levels. This supports the need to conduct additional molecular studies, even if cytogenetic studies have revealed t(9;22), because of the prognostic importance of the molecular findings. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10490

17
UI - 12034521
AU - Storlazzi CT; Anelli L; Surace C; Rocchi M; Albano F; Pastore D; Liso V;
TI - Specchia G Molecular cytogenetic characterization of a novel additional chromosomal aberration in blast crisis of a Ph-positive chronic myeloid leukemia.
SO - Cancer Genet Cytogenet 2002 Apr 15;134(2):109-13
AD - Department of Pathologic Anatomy and Genetics, Section of Genetics, University of Bari, Piazza G. Cesare 11, Via Amendola 165/A, 70126, Bari, Italy.
We describe a novel chromosomal aberration acquired in blast crisis (BC) in a patient affected by Philadelphia-positive chronic myeloid leukemia (CML). Conventional cytogenetic studies at onset showed a classic t(9;22)(q34;q11.2) in all bone marrow cells, confirmed by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction (b3a2) analysis. In BC, the malignant clone developed a new additional cytogenetic abnormality consisting of a deletion of chromosome 21. To our knowledge, this is the first case of del(21) reported in literature associated with BC CML. The use of an appropriate set of BAC/PAC clones restricted the breakpoint to an interval of approximately 100 kb. Sequence analysis did not reveal any known gene in this interval. Oncosuppressor genes distal to the breakpoint could be hypothesized to be involved in the progression of disease toward BC. Identification of new chromosome abnormalities in CML may allow further understanding of specific molecular events leading to disease evolution.

18
UI - 12034522
AU - Pajor L; Kereskai L; Tamaska P; Vass JA; Radvanyi G
TI - Coexistence of chronic myeloid leukemia and hairy cell leukemia of common clonal origin.
SO - Cancer Genet Cytogenet 2002 Apr 15;134(2):114-7
AD - Department of Pathology, Medical Faculty, University of Pecs, Pecs, Hungary. pajor@pathology.pote.hu
The history of a forty year old patient is presented who was admitted with a clinical picture of chronic myeloid leukemia (CML). Laboratory findings, bone marrow morphology and molecular investigations supported this diagnosis, including b3/a2 as well as b2/a2 chimeric mRNA expression in support of a Philadelphia chromosome positive chronic myeloproliferation. In a fraction of the bone marrow content, however, an infiltrate different from that of CML could be seen. In addition, the morphology, cytochemistry, immunophenotyping and molecular analysis indicated that the coexisting neoplasia is hairy cell leukemia (HCL). Cell lineage specific interphase cytogenetic analysis proved a clonal relationship between the two neoplasias in a way that the HCL arose from one of the B-cells which, based on two cytogenetic markers, belonged to the original CML clone.

19
UI - 12034533
AU - Zamora L; Espinet B; Salido M; Florensa L; Woessner S; Pedro C; Serrtano
TI - S; Sole F Monosomy 15 in chronic myelomonocytic leukemia. description of a case and review of the literature.
SO - Cancer Genet Cytogenet 2002 Apr 15;134(2):165-7
AD - Laboratori de Citogenetica i Biologia Molecular, Departament de Patologia, Hospital del Mar, Pg Maritim, 25-29, 08003, Barcelona, Spain. e0037@imas.imim.es
We report a 89-year-old female diagnosed with chronic myelomonocytic leukemia (CMMoL) presenting with a monosomy 15. To our knowledge, this is the second reported case of CMMoL with monosomy 15. On the other hand, monosomy 15 in complex karyotypes is a frequent chromosome aberration in myelodysplastic syndromes, particularly in refractory anemia with excess of blasts.

20
UI - 11949629
AU - Copelan EA
TI - Treatment options in chronic myelogenous leukemia.
SO - Blood 2002 Apr 15;99(8):3070 -1; discussion 3071

21
UI - 11920230
AU - Frassoni F; Podesta M; Piaggio G; Rosti V; Pitto A; Soracco M; Figari O;
TI - Vassallo F; Fugazza G; Bergamaschi G; Bacigalupo A; Sessarego M; Cazzola M Interferon-alpha protects Philadelphia-negative progenitors from exhaustion in chronic myeloid leukemia patients with cytogenetic response.
SO - Hematol J 2001;2(1):26-32
AD - Divisione Ematologia II, Ospedale San Martino, Genova, Italy. frafrassoni@smartino.ge.it
INTRODUCTION: Normal immature hematopoietic progenitors are relatively well preserved in most patients newly diagnosed with chronic myeloid leukemia, but tend to decline rapidly with time. Such exhaustion could reflect a suppressive effect of the Philadelphia positive clone expansion and/or be induced by Interferon-alpha treatment. MATERIALS AND METHODS: A total of 51 CML patients were classified into three groups. Newly diagnosed untreated patients were group A (n=30). Of the 21 treated individuals with Interferon-alpha, for at least 12 months, 15 showed no cytogenetic response (group B) while six showed persisting major/complete response (group C). Patients belonging to groups A and B were mobilized with chemotherapy plus G-CSF while patients of group C received a short course of G-CSF only. RESULTS: Patients responding to IFN-alpha (group C) showed comparable numbers of bone marrow Ph- long-term culture initiating cells to those of newly diagnosed individuals (group A): 8.5 (<1-65)/10(6) MNC vs 10.5 (<1-30), while non-responders had markedly lower numbers: <1 (<1-5). The amount of Ph- LTC-IC collected was significantly lower in patients of group B 1.8 (0-325)x10(2)/kg than in patients of either group A 31.3 (0-952)x10(2)/kg (P<0.002) or group C 109 (8-259)x10(2)/kg (P<0.01). Interestingly, five patients of group B who had 100% Ph+ metaphases, but Ph- progenitors in their bone marrow, mobilized normal amounts of Ph(-) progenitors. CONCLUSION: These findings suggest that the decline of normal hematopoietic progenitors, currently observed in the majority of CML patients, is not induced by IFN-alpha treatment, but it is likely due to the expanding leukemic clone. They also indicate that normal hematopoietic reservoir is consistently preserved in patients given IFN-alpha early after diagnosis and achieving a stable cytogenetic response.

22
UI - 11986960
AU - Ito Y; Shimamoto T; Kuriyama Y; Nakajima A; Sumi M; Watanabe Y; Beppu H;
TI - Ohtsubo K; Ohyashiki K ABL gene fuses BCR during t(20;22) results in Philadelphia-negative, but BCR/ABL-positive chronic myeloid leukemia.
SO - Leukemia 2002 May;16(5):951-2

23
UI - 11986962
AU - Crescenzi B; Sacchi S; Marasca R; Temperani P; La Starza R; Matteucci C;
TI - Bonacorsi G; Romoli S; Martelli MF; Mecucci C; Emilia G Distinct genomic events in the myeloid and lymphoid lineages in simultaneous presentation of chronic myeloid leukemia and B-chronic lymphocytic leukemia.
SO - Leukemia 2002 May;16(5):955-6

24
UI - 12049868
AU - Ebnoether M; Stentoft J; Ford J; Buhl L; Gratwohl A
TI - Cerebral oedema as a possible complication of treatment with imatinib.
SO - Lancet 2002 May 18;359(9319):1751-2
AD - Division of Haematology, Department of Internal Medicine, University Hospital, Basel, Switzerland.
Imatinib is a potent drug used in treatment of chronic myeloid leukaemia (CML). It acts by inhibition of the CML-specific p210 BCR-ABL tyrosine kinase, but also blocks other pathways such as platelet-derived growth factor (PDGF) and c-kit receptor signalling. Clinical trials have confirmed the efficacy of imatinib, which has toxic effects in cells that express BCR-ABL. Side-effects, although frequent, are generally mild and include superficial oedema and fluid retention. Here, we describe two patients with cerebral oedema, which in one patient was fatal. The pathophysiological mechanisms remain unknown, although the drug could act through inhibition of the PDGF receptor.

25
UI - 12028832
AU - Dietz AB; Litzow MR; Bulur PA; Vuk-Pavlovic S
TI - Transgenic interleukin 2 secreted by CML dendritic cells stimulates autologous T(H)1 T cells.
SO - Cytotherapy 2001;3(2):97-105
AD - Stem Cell Laboratory, Mayo Clinic Cancer Center, Rochester, MN 55905, USA.
BACKGROUND: We investigated if dendritic cells (DC), derived from patients suffering from chronic myeloid leukemia (CML) could be modified by recombinant replication-defective adenoviruses to express functional interleukin 2 (IL-2). Such modification might confer onto antigen-presenting cells the ability to stimulate expansion of effector cells. METHODS: To quantify the infection efficiency of CML dendritic cells (CML-DC) by recombinant adenovirus, we measured the expression of green fluorescent protein (GFP) gene contained in the virus. In CML-DC infected with an adenovirus containing the IL-2 gene, we evaluated their ability to secrete IL-2 and stimulate proliferation of autologous T cells. RESULTS: Uninfected CML-DC and normal DC secreted similar amounts of IL-12 and stimulated similarly efficient autologous mixed leukocyte reaction. Immature CML-DC infected by an adenovirus containing the gene for IL-2 secreted large amounts of IL-2 and stimulated proliferation of autologous T cells more efficiently than the corresponding CML-DC alone. High levels of interferon eta, but not of IL-4, in cell culture supernates indicated that the proliferating cells were T(H)1. Infected mature CML-DC were more effective than infected immature CML-DC, showing that T cell stimulation by mature DC and by IL-2 was additive. DISCUSSION: CML-DC can be modified genetically and functionally by recombinant replication-defective adenoviruses, providing new possibilities for clinical trials in dendritic cell-based immunotherapy.

26
UI - 11964322
AU - Branford S; Rudzki Z; Walsh S; Grigg A; Arthur C; Taylor K; Herrmann R;
TI - Lynch KP; Hughes TP High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance.
SO - Blood 2002 May 1;99(9):3472-5
AD - Institute of Medical and Veterinary Science, Adelaide, Australia. branford@imvs.sa.gov.au
Point mutations were found in the adenosine triphosphate (ATP) binding region of BCR/ABL in 12 of 18 patients with chronic myeloid leukemia (CML) or Ph-positive acute lymphoblastic leukemia (Ph(+) ALL) and imatinib resistance (defined as loss of established hematologic response), but they were found in only 1 of 10 patients with CML with imatinib refractoriness (failure to achieve cytogenetic response). In 10 of 10 patients for whom samples were available, the mutation was not detected before the initiation of imatinib therapy. Three mutations (T315I, Y253H, and F317L present in 3, 1, and 1 patients, respectively) have a predicted role in abrogating imatinib binding to BCR/ABL, whereas 3 other mutations (E255K, G250E, and M351T, present in 4, 2, and 2 patients, respectively) do not. Thus we confirm a high frequency of mutations clustered within the ATP-binding region of BCR/ABL in resistant patients. Screening may allow intervention before relapse by identifying emerging mutations with defined impacts on imatinib binding. Certain mutations may respond to higher doses of imatinib, whereas other mutations may mandate switching to another therapeutic strategy.

27
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; Goldman J; O'Brien SG; Russell N; Fischer T; Ottmann O; Cony-Makhoul P; Facon T; Stone R; Miller C; Tallman M; Brown R; Schuster M; Loughran T; Gratwohl A; Mandelli F; Saglio G; Lazzarino M; Russo D; Baccarani M; Morra E; 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. hkantarj@mdanderson.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.

28
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.

29
UI - 12040447
AU - Tabrizi R; Mahon FX; Cony Makhoul P; Lagarde V; Lacombe F; Berthaud P;
TI - Melo JV; Reiffers J; Belloc F Resistance to daunorubicin-induced apoptosis is not completely reversed in CML blast cells by STI571.
SO - Leukemia 2002 Jun;16(6):1154-9
AD - Laboratoire d'Hematologie, Hopital Haut Leveque, Pessac, France.
The leukemogenic property of BCR-ABL in chronic myeloid leukemia (CML) is critically dependent on its protein tyrosine kinase activity. STI571 inhibits the BCR-ABL kinase activity, the growth and the viability of BCR-ABL expressing cells. In this study, we report the apoptotic effect of STI571 in combination with daunorubicin (DNR) on peripheral blood mononuclear cells from 11 CML patients and four BCR-ABL-positive cell lines: AR230, LAMA84, K562 and KCL22. Primary blast cells were identified by flow cytometry on the basis of their low CD45 expression. Nucleus fragmentation, exposure of phosphatidylserines and decrease in mitochondrial membrane potential were measured using acridine orange, FITC-annexin V and DiOC6(3), respectively, to evaluate apoptosis. On cell lines, the effect of DNR was negligible, whereas STI571 induced 10 to 35% of apoptosis in 18 h. STI571 sensitized AR230, LAMA84 and K562 cells to DNR when apoptosis was measured at the mitochondrial and membrane but not the nuclear levels. On CML blast cells, phosphatidyl serine exposure was significantly induced by both DNR and STI571 and was higher when these drugs were used in combination (P < 0.0003). However, the effects of this drug combination were only additive and no sensitization of blast cells to DNR by STI571 was observed. Interestingly, sensitization was evidenced in CML but not normal lymphocytes. These results suggest that other mechanisms additional to Bcr-Abl tyrosine kinase activity could be responsible for DNR resistance, and further investigations are needed to understand its origin.

30
UI - 12040456
AU - Fadilah SA; Ahmad-Zailani H; Soon-Keng C; Norlaila M
TI - Successful treatment of chronic myeloid leukemia during pregnancy with hydroxyurea.
SO - Leukemia 2002 Jun;16(6):1202-3

31
UI - 12003756
AU - Ghanei M; Vosoghi AA
TI - An epidemiologic study to screen for chronic myelocytic leukemia in war victims exposed to mustard gas.
SO - Environ Health Perspect 2002 May;110(5):519-21
AD - Chemical Warfare Victims Research Department, Baqiyatallah University of Medical Sciences, Tehran, Iran. m.ghanei@bmsu.ac.ir
Chemical agents such as mustard gas (or sulfur mustard), which has alkylating characteristics, were used against Iranian combatants in the Iraq-Iran war. Previous studies have not shown a strong link between these chemical agents and the development of chronic myelocytic leukemia (CML). The purpose of this study was to evaluate the increased risk of CML development in Iranian soldiers exposed to mustard gas during the war. Based on a descriptive study of 2,500 cases with documented exposure to various chemical warfare agents, 665 patients had documented exposure to mustard gas. We screened the latter using the leukocyte alkaline phosphatase (LAP) test and performed further cytochemical studies on cases with positive results. From among the 665 cases with documented exposure to mustard gas, 9 cases had LAP scores < 20; 2 of these 9 cases had CML and a score of zero (0.3%). We detected cytogenetic abnormalities in 7 patients with low LAP scores and atypical lymphocytes of 5-11% in 40 patients. The risk ratio of CML developing in victims exposed to mustard gas (cutaneous or respiratory) may be higher in comparison with the normal population, although confounding factors (e.g., the possibility of exposure to combined chemical agents, excluding patients who did not manifest blisters) limited our results. Because the increased development of CML in young patients with a documented history of exposure to mustard gas cannot be disregarded, further studies are needed.

32
UI - 12052793
AU - Mayor S
TI - Doctors condemn NICE's guidance on leukaemia drug.
SO - BMJ 2002 Jun 8;324(7350):1352

33
UI - 12035370
AU - Umashankar T; Venugopal N; Patil P
TI - Chronic neutrophilic leukemia--a case

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