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NCI CANCERLIT® Search: Chronic Myelogenous Leukemia - October 2001
National Cancer Institute®
Last Modified: November 21, 2001
Table of Contents
1
UI - 21378684
AU - Gorre ME; Mohammed M; Ellwood K; Hsu N; Paquette R; Rao PN; Sawyers CL
TI -
Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene
mutation or amplification.
SO - Science 2001 Aug 3;293(5531):876-80
AD - Department of Medicine, Molecular Biology Institute, University of
California, Los Angeles, CA 90095, USA.
Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in
chronic myeloid leukemia demonstrate that many patients with advanced
stage disease respond initially but then relapse. Through biochemical
and molecular analysis of clinical material, we find that drug
resistance is associated with the reactivation of BCR-ABL signal
transduction in all cases examined. In six of nine patients, resistance
was associated with a single amino acid substitution in a threonine
residue of the Abl kinase domain known to form a critical hydrogen bond
with the drug. This substitution of threonine with isoleucine was
sufficient to confer STI-571 resistance in a reconstitution experiment.
In three patients, resistance was associated with progressive BCR-ABL
gene amplification. These studies provide evidence that genetically
complex cancers retain dependence on an initial oncogenic event and
suggest a strategy for identifying inhibitors of STI-571 resistance.
2
UI - 21240464
AU - Sercan HO; Sercan ZY; Kizildag S; Undar B; Soydan S; Sakizli M
TI -
Consistent loss of heterozygosity at 14Q32 in lymphoid blast crisis of
chronic myeloid leukemia.
SO - Leuk Lymphoma 2000 Oct;39(3-4):385-90
AD - Department of Medical Biology, Dokuz Eylul University Faculty of
Medicine Izmir, Turkey. ogun.sercan@deu.edu.tr
Little is understood about the basic biological mechanisms that underlie
the reasons for acute transformation in chronic myeloid leukemia (CML).
Progression of disease may include inactivation of one or more tumor
suppressor genes (TSGs). A widely used methodology for indirectly
detecting somatic inactivation of TSGs is searching loss of
heterozygosity (LOH) for polymorphic loci located in or near the gene(s)
of interest. We aimed to analyze DNA of chronic phase and blastic phase
archive material of 15 CML patients for LOH using D1S430, D2S123,
D3S1611, D11S29, D14S65, D17S520, BAT 40 markers, the dinucleotide
repeat located in the ABL gene and the trinucleotide repeat located in
the BCR gene (amplification of the trinucleotide in the BCR gene could
not be succeeded). LOH was identified by a %50 lost of one of the
alleles intensity. LOH was detected with the ABL dinucletide repeat and
D2S123 marker in two patients and with the D14S65 marker in three
patients. The three patients exhibiting LOH at the D14S65 locus, all
proceeded through lymphoid blast crisis. The D14S65 marker is located at
the 14q32 locus which contains the immunglobulin heavy chain gene and
the TCL1 oncogene. 14q32 abnormalities at the molecular level, may be
predictive for lymphoid blast crisis, whether or not they are detectable
cytogenetically
3
UI - 21240471
AU - Lucero G; Birman V; Colimodio E; Bertinetti CM; Kotliar N; Murolo P;
TI -
Irusta O; Klimovsky J; Koziner B
Nodal T cell blast crisis in chronic myeloid leukemia.
SO - Leuk Lymphoma 2000 Oct;39(3-4):435-40
AD - Unidad de Investigaciones Oncohematologicas "Nelly Arrieta de Blaquier".
We report the case of a 54 year old male with an original diagnosis of
chronic myeloid leukemia (CML) who developed a nodal T cell blast crisis
(BC) while he was in a complete hematological remission (CR). We
describe the clinical presentation and the histological,
immunophenotypic and molecular characterization of the lymph node blast
cells. Our case, together with other rare similar reports in the
literature, argue that a T cell nodal blast crisis of CML resembles the
presentation of a T-cell non-Hodgkin's lymphoma.
4
UI - 21240494
AU - Tannir NM; Talpaz M; Ghazal H; Proothi S; Kantarjian HM
TI -
Acute pancreatitis associated with interferon alpha therapy for chronic
myelogenous leukemia.
SO - Leuk Lymphoma 2000 Nov;39(5-6):647-50
AD - Department of Leukemia, the University of Texas MD Anderson Cancer
Center, Houston, Texas 77030 USA.
Acute pancreatitis related to interferon alpha therapy is very rare. We
report two patients with chronic myelogenous leukemia (CML) who
developed acute pancreatitis following treatment with interferon alpha.
A review of the literature on the association of pancreatitis and
interferon alpha is provided. Possible pathophysiologic mechanisms are
also discussed.
5
UI - 21303121
AU - Drummond MW; Holyoake TL
TI -
Tyrosine kinase inhibitors in the treatment of chronic myeloid
leukaemia: so far so good?
SO - Blood Rev 2001 Jun;15(2):85-95
AD - Academic Transfusion Medicine Unit, University Department of Medicine,
Glasgow Royal Infirmary, Glasgow, UK. mwd3z@clinmed.gla.ac.uk
Chronic myeloid leukaemia (CML) is characterized by marked expansion of
the myeloid series, and is thought to arise as a direct result of the
bcr-abl fusion-gene. The BCR-ABL oncoprotein is a constitutively active
protein tyrosine kinase (PTK), which results in altered cell signalling
and is responsible for the changes that characterize the malignant cells
of CML. It has been shown that the increased tyrosine kinase activity of
BCR-ABL is a requirement for transformation and is, therefore, a
legitimate target for pharmacological inhibition. Several compounds have
now been identified as relatively selective inhibitors of BCR-ABL,
including members of the tyrphostin family, herbimycin A and most
importantly the 2-phenylaminopyrimidine ST1571. Having established the
efficacy of this agent in vitro, phase I trials using an oral
formulation were commenced in the USA in mid 1998. Early data from an
interferon-alpha (IFN) resistant/refractory or intolerant cohort
demonstrated good patient tolerance and effective haematological control
at doses above 300 mg. More promising was its ability to induce
cytogenetic responses in this pretreated group of patients. Phase II
data, albeit far from complete, appear to confirm its efficacy even in
the context of advanced disease and phase III clinical trials are
currently underway in many countries. Recent laboratory evidence,
however, suggests that the development of drug resistance is a
possibility (via amplification of the bcr-abl fusion gene,
overexpression of P-glycoprotein or binding of ST1571 to alpha1 acid
glycoprotein) and that combination therapy including ST1571 should be
considered. Copyright 2001 Harcourt Publishers Ltd.
6
UI - 21416670
AU - Martindale D
TI -
Cancer in the crosshairs.
SO - Sci Am 2001 Sep;285(3):19-20
7
UI - 21451184
AU - Barthe C; Cony-Makhoul P; Melo JV; Mahon JR
TI -
Roots of clinical resistance to STI-571 cancer therapy.
SO - Science 2001 Sep 21;293(5538):2163
AD - Laboratoire Greffe de Moelle, Universite Victor Segalen, Bordeaux,
France.
8
UI - 21451303
AU - Hochhaus A; Kreil S; Corbin A; La Rosee P; Lahaye T; Berger U; Cross NC;
TI -
Linkesch W; Druker BJ; Hehlmann R; Gambacorti- Passerini C; Corneo G;
D'Incalci M
Roots of clinical resistance to STI-571 cancer therapy.
SO - Science 2001 Sep 21;293(5538):2163
AD - III. Medizinische Universitatsklinik, Fakultat fur Klinische Medizin
Mannheim, Universitat Heidelberg, Mannheim, Germany. hochhaus@uni-hd.de
9
UI - 21259466
AU - Sanz GF; Saavedra S; Jimenez C; Senent L; Cervera J; Planelles D;
TI -
Bolufer P; Larrea L; Martin G; Martinez J; Jarque I; Moscardo F; Plume
G; Andreu R; de la Rubia J; Barragan E; Solves P; Soler MA; Sanz MA
Unrelated donor cord blood transplantation in adults with chronic
myelogenous leukemia: results in nine patients from a single
institution.
SO - Bone Marrow Transplant 2001 Apr;27(7):693-701
AD - Bone Marrow Transplantation Unit, Department of Hematology, Hospital
Universitario La Fe, Av. Campanar 21, 46009 Valencia, Spain.
The potential role of unrelated donor cord blood transplantation
(UD-CBT) in adults is not well established. We report the results of
UD-CBT in nine adult patients with chronic myeloid leukemia (CML). The
median age was 27 years (range, 19-41 years), and the median weight was
62 kg (range, 45-78 kg). At transplant, six patients were in chronic
phase (five in first, and one in second), two in blast crisis, and one
in accelerated phase. Eight had received intensive chemotherapy, and
three had undergone autologous peripheral blood hematopoietic stem cell
transplantation. Four had received interferon with no cytogenetic
response, and only three underwent UD-CBT within 1 year of diagnosis.
After serological typing for class I antigens, and high-resolution DNA
typing for DRB1, the degree of HLA match between patients and cord blood
(CB) units was 4/6 in six cases and 5/6 in three cases. The median
number of nucleated cells infused was 1.7 x 10(7)/kg (range, 1.2 to 4.9
x 10(7)/kg), and was above 2 x 10(7)/kg in only two cases. All patients
received thiotepa, busulfan, cyclophosphamide and anti-thymocyte
globulin as conditioning; cyclosporine and prednisone for
graft-versus-host disease (GVHD) prophylaxis; and G-CSF from day +7
until engraftment. All seven evaluable cases engrafted. The median time
to reach an absolute neutrophil count > or =0.5 x 10(9)/l and > or =1 x
10(9)/l was 22 days (range, 19-52 days) and 28 days (range, 23-64 days),
respectively. In the four patients evaluable for platelet recovery time
to levels of > or =20 x 10(9) platelets/l, > or =50 x 10(9) platelets/l,
and > or =100 x 10(9) platelets/l, these ranged from 50 to 128 days, 60
to 139 days, and 105 to 167 days, respectively. Three patients developed
acute GVHD above grade II, and three of the five patients at risk
developed extensive chronic GVHD. Four patients, all transplanted in
chronic phase, remain alive in molecular remission more than 18, 19, 24
and 42 months after transplantation. These preliminary results suggest
that UD-CBT may be considered a reasonable alternative in adults with
CML who lack an appropriate bone marrow donor.
10
UI - 21365353
AU - Pfirrmann M; Hasford J
TI -
Testing Sokal's and the new prognostic score for chronic myeloid
leukaemia treated with alpha-interferon: comments.
SO - Br J Haematol 2001 Jul;114(1):241-3
11
UI - 21390872
AU - Sui X; Su L; Chu J
TI -
[Expression of bcl-2 gene in the evolution of chronic myelogenous
leukemia to blast crisis and its implication]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Jan;20(1):27-9
AD - Institute of Hematology, State Key Laboratory of Experimental
Hematology, CAMS and PUMC, Tianjin 300020.
OBJECTIVE: To investigate the expression of bcl-2 gene and cell
apoptosis and cell cycle in bone marrow of chronic myelogenous leukemia
(CML). METHODS: APAAP assay and in situ hybridization were used for the
expression of BCL-2 protein and bcl-2 mRNA in fresh bone marrow samples
from 60 cases of CML. Flow cytometry was used to assess the extent of
apoptosis and cell cycle percentage. RESULTS: The expression of bcl-2
gene had no statistical difference between CMLs at presentation and in
chronic phase, but was much lower in blast crisis (P < 0.05). The
percentage of bcl-2 mRNA positive cells was consistent with BCL-2
protein expression. In addition, BCL-2 protein was related to the Hb
levels, BPC, and immature cells in the peripheral blood and bone marrow.
Notably, the extent of apoptosis in accelerated phase/blast crisis was
much lower than that in chronic phase(P = 0.028), while the cell cycle
had no difference. CONCLUSION: High level of bcl-2 gene expression and
low extent of apoptosis in bone marrow cells of CML might partially be
the mechanism of poor prognosis of blast crisis, and this provides a new
experimental basis for early diagnosis and treatment of CML blast
crisis.
12
UI - 21390876
AU - Xiong H; Chen X
TI -
[Progress on the study of related genes in patients with blast crisis of
chronic myelocytic leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Jan;20(1):49-51
13
UI - 21418711
AU - Thiele J; Kvasnicka HM; Schmitt-Graeff A; Diehl V; Niederle N; Schaefer
TI -
HE
Bone marrow histopathology predicting blast crisis in chronic myeloid
leukemia.
SO - Acta Haematol 2001;105(4):244-6
AD - Institute of Pathology, University of Cologne, Joseph-Stelzmannstrasse
9, D-50924 Cologne, Germany. j.thiele@uni-koeln.de
14
UI - 21426506
AU - Radich JP; Gooley T; Bryant E; Chauncey T; Clift R; Beppu L; Edmands S;
TI -
Flowers ME; Kerkof K; Nelson R; Appelbaum FR
The significance of bcr-abl molecular detection in chronic myeloid
leukemia patients "late," 18 months or more after transplantation.
SO - Blood 2001 Sep 15;98(6):1701-7
AD - Clinical Research Division, Fred Hutchinson Cancer Research Center, the
University of Washington School of Medicine, Seattle, WA, USA.
jradich@fhcrc.org
The bcr-abl chimeric messenger RNA is frequently detected in chronic
myeloid leukemia (CML) patients after bone marrow transplantation. It
was previously reported that the relapse risk of bcr-abl detection 6 to
12 months after transplantation was greater than 40%. This risk
decreased as the time between transplantation and detection increased.
To further define the relapse risk associated with bcr-abl molecular
detection in "late" CML survivors, 379 consecutive CML patients alive at
18 months after transplantation or later were studied. Ninety of 379
patients (24%) had at least one positive bcr-abl test 18 months after
transplantation or later; 13 of 90 bcr-abl-positive patients (14%) and 3
of 289 bcr-abl-negative patients (1.0%) relapsed. The median time from
bcr-abl detection to relapse was 916 days (range, 251-2654 days). The
hazard ratio of relapse associated with bcr-abl detection was 19.2 (P
<.0001). The stage of disease, chronic graft-versus-host disease, and
the donor type did not alter the association between bcr-abl and
relapse. Quantification of bcr-abl was performed on 344 samples from 85
bcr-abl-positive patients by means of a real-time quantitative reverse
transcriptase-polymerase chain reaction assay. The median bcr-abl change
of patients who relapsed was significantly greater than those that
remained in remission (P =.002). The median bcr-abl level at relapse was
40 443 bcr-abl copies per microg RNA (range, 960-299 552). Of 73
bcr-abl-positive patients who failed to relapse, 69% had only one
positive test at a median of 24 copies bcr-abl per microg RNA. The
detection of bcr-abl is common following transplantation. The prognostic
significance of a qualitative bcr-abl can be refined by quantitative
assays and thus may target patients who would benefit from early
intervention.
15
UI - 21426507
AU - Talpaz M; O'Brien S; Rose E; Gupta S; Shan J; Cortes J; Giles FJ; Faderl
TI -
S; Kantarjian HM
Phase 1 study of polyethylene glycol formulation of interferon alpha-2B
(Schering 54031) in Philadelphia chromosome-positive chronic myelogenous
leukemia.
SO - Blood 2001 Sep 15;98(6):1708-13
AD - Department of Bioimmunotherapy, M. D. Anderson Cancer Center, Houston,
TX, USA.
Interferon alpha (IFN-alpha) therapy improves prognosis in Philadelphia
chromosome (Ph)-positive chronic myelogenous leukemia (CML).
Polyethylene glycol (PEG) attached to IFN-alpha prolongs its half-life
and may offer better therapy. The aims of this phase 1 study were to
define the maximal tolerated dose (MTD), dose-limiting toxicities
(DLTs), and response with PEG IFN-alpha-2b. Twenty-seven adults with
Ph(+) CML in chronic or accelerated phases, in whom IFN-alpha treatment
had failed, were studied. Patients had hematologic (9 patients) or
cytogenetic resistance (12 patients) or intolerance to IFN-alpha (6
patients). PEG IFN-alpha-2b was given as a weekly subcutaneous injection
starting at 0.75 microg/kg weekly and escalating to 1.5, 3, 4.5, 6, 7.5,
and 9.0 microg/kg. The MTD was defined at 7.5 to 9 microg/kg; DLT
included severe fatigue, neurotoxicity, liver function abnormalities,
and myelosuppression. Longer administration of PEG IFN-alpha-2b resulted
in chronic side effects not observed earlier, which defined the MTD and
DLT. The proposed phase 2 dose of PEG IFN-alpha-2b was 6 microg/kg
weekly. Among 19 patients with active disease, 7 (37%) achieved complete
hematologic response (CHR); 2 (11%) had a cytogenetic response
(complete). Among 8 patients treated in CHR, 7 (87%) improved
cytogenetic response to complete (4 patients) or partial (3 patients).
All 6 patients intolerant to IFN-alpha tolerated PEG IFN-alpha-2b; 4
improved their cytogenetic response. The results show that PEG
IFN-alpha-2b is easier to deliver (once weekly), better tolerated, and
perhaps more effective than IFN-alpha.
16
UI - 21426511
AU - Huntly BJ; Reid AG; Bench AJ; Campbell LJ; Telford N; Shepherd P; Szer
TI -
J; Prince HM; Turner P; Grace C; Nacheva EP; Green AR
Deletions of the derivative chromosome 9 occur at the time of the
Philadelphia translocation and provide a powerful and independent
prognostic indicator in chronic myeloid leukemia.
SO - Blood 2001 Sep 15;98(6):1732-8
AD - Department of Hematology, University of Cambridge, Cambridge, United
Kingdom.
Chronic myeloid leukemia (CML) is characterized by formation of the
BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph)
translocation between chromosomes 9 and 22. Large deletions on the
derivative chromosome 9 have recently been reported, but it was unclear
whether deletions arose during disease progression or at the time of the
Ph translocation. Fluorescence in situ hybridization (FISH) analysis was
used to assess the deletion status of 253 patients with CML. The
strength of deletion status as a prognostic indicator was then compared
to the Sokal and Hasford scoring systems. The frequency of deletions was
similar at diagnosis and after disease progression but was significantly
increased in patients with variant Ph translocations. In patients with a
deletion, all Ph(+) metaphases carried the deletion. The median survival
of patients with and without deletions was 38 months and 88 months,
respectively (P =.0001). By contrast the survival difference between
Sokal or Hasford high-risk and non-high-risk patients was of only
borderline significance (P =.057 and P =.034). The results indicate that
deletions occur at the time of the Ph translocation. An apparently
simple reciprocal translocation may therefore result in considerable
genetic heterogeneity ab initio, a concept that is likely to apply to
other malignancies associated with translocations. Deletion status is
also a powerful and independent prognostic factor for patients with CML.
The prognostic significance of deletion status should now be studied
prospectively and, if confirmed, should be incorporated into management
decisions and the analysis of clinical trials.
17
UI - 21449247
AU - Heller P; Kornblihtt LI; Cuello MT; Larripa I; Najfeld V; Molinas FC
TI -
BCR-ABL transcripts may be detected in essential thrombocythemia but
lack clinical significance.
SO - Blood 2001 Sep 15;98(6):1990
18
UI - 21437191
AU - Carter A; Dann EJ; Katz T; Shechter Y; Oliven A; Regev R; Eytan E; Rowe
TI -
JM; Eytan GD
Cells from chronic myelogenous leukaemia patients at presentation
exhibit multidrug resistance not mediated by either MDR1 or MRP1.
SO - Br J Haematol 2001 Sep;114(3):581-90
AD - Haematology Department and Blood Bank, Rambam Medical Centre, Haifa,
Israel.
Tetramethylrosamine (TMR) is excluded from P-glycoprotein
(MDR1)-enriched cell lines, but it stains efficiently MDR1-poor parent
lines. Application of the TMR resistance assay to cells obtained from
chronic myelogenous leukaemia (CML) patients revealed, in all
individuals, a significant resistance compared with healthy donors (P <
0.001). Cells from the same patients at later phases exhibited a further
increase in TMR resistance. Doxorubicin was excluded from all cell
samples obtained from CML patients at presentation. The resistance to
TMR and doxorubicin was energy-dependent, and was not modulated by
inhibitors of MDR1 and multidrug-resistance protein-1 (MRP1).
Transcription of mRNAs suspected as relevant to multidrug resistance was
assessed using comparative reverse transcription polymerase chain
reaction. All cells from the CML patients transcribed high levels of
MRP3, MRP4 and MRP5 compared with healthy donors. Low levels of MDR1,
MRP1, MRP2, MRP6, lung resistance-related protein and anthracycline
resistance-associated protein were equally transcribed in cells from
healthy donors and CML patients. These results indicated that neither
MDR1 nor MRP1 mediate the resistance in these cells. Our results shed
light on a resistance mechanism operative in CML patients, which,
together with the resistance to apoptosis, is responsible for the lack
of response of CML patients to induction-type protocols used to treat
acute myeloid leukaemia patients.
19
UI - 21437198
AU - Roman J; Jimenez A; Barrios M; Castillejo JA; Maldonado J; Torres A
TI -
E1A3 as a unique, naturally occurring BCR-ABL transcript in an indolent
case of chronic myeloid leukaemia.
SO - Br J Haematol 2001 Sep;114(3):635-7
AD - Haematology Department, Reina Sofia Hospital, Cordoba, Spain.
peperosa@teleline.es
A woman with Ph-positive chronic myeloid leukaemia (CML) with an
atypical e1a3 BCR-ABL hybrid gene is described. To our knowledge, this
is the first report of this transcript type as a unique naturally
occurring BCR-ABL fusion in a CML patient. This case was characterized
by a low leucocyte count and a very indolent course without treatment.
Because the deletion of ABL exon 2 sequences results in deletion of an
essential part of the ABL SH3 domain, our case suggests that this ABL
SH3 domain is not absolutely necessary for efficient induction of a
myeloproliferative disease in the context of BCR-ABL/p190.
20
UI - 21443312
AU - Sun B; Jiang G; Zaydan MA; La Russa VF; Safah H; Ehrlich M
TI -
ABL1 promoter methylation can exist independently of BCR-ABL
transcription in chronic myeloid leukemia hematopoietic progenitors.
SO - Cancer Res 2001 Sep 15;61(18):6931-7
AD - Tulane Cancer Center, Human Genetics Program, Tulane Medical School, New
Orleans, Louisiana 70112, USA.
Formation of the hybrid BCR-ABL gene is responsible for >95% of chronic
myeloid leukemia (CML). The alternative, downstream ABL promoter (Pa),
which is usually retained in this chimeric oncogene, was reported to be
methylated in many CML patients, but there has been controversy as to
whether this methylation is a frequent change in bone marrow (BM) in
early chronic phase (CP) or only past this stage. Also, the relevance of
Pa promoter methylation to BCR-ABL expression in CML is unclear. We
examined methylation of the ABL Pa promoter in uncultured BM samples and
in colonies derived from their hematopoietic precursor cells by
bisulfite and PCR-based assays (combined bisulfite restriction analysis
and methylation-specific PCR). BM from seven CP CML patients at
diagnosis had about 20-60% of the copies of the ABL Pa promoter
methylated. No Pa methylation was detected in normal BMs or colonies
derived from them. In contrast, most colonies from CP CML patients had
Pa methylation. Surprisingly, 18-49% of the CML-derived colonies with
this methylation reproducibly had no detectable BCR-ABL RNA on nested
reverse transcription-PCR. Furthermore, the percentage of BCR-ABL
RNA-positive colonies was almost same among the colonies not displaying
Pa methylation as among the colonies in which this methylation was
found. We conclude that ABL Pa methylation is often an early marker of
CML in hematopoietic precursors and in total mononuclear BM cells but
that it is not associated with an increased frequency of BCR-ABL
RNA-positive cells. This methylation might be emblematic of
cancer-associated hypermethylation elsewhere in the genome with the
consequent silencing of tumor suppressor genes seen in many
malignancies.
21
UI - 21445100
AU - Sawyers CL
TI -
Cancer treatment in the STI571 era: what will change?
SO - J Clin Oncol 2001 Sep 15;19(18 Suppl):13S-16S
AD - Division of Hematology-Oncology, Department of Medicine, and Molecular
Biology Institute, University of California Los Angeles, Los Angeles, CA
90095-1678, USA. csawyers@mednet.ucla.edu
22
UI - 21464085
AU - Ohnishi K
TI -
[Chronic myelogenous leukemia]
SO - Gan To Kagaku Ryoho 2001 Sep;28(9):1199-205
AD - Department of Medicine III, Hamamatsu University School of Medicine,
1-20-1 Handayama, Hamamatsu 431-3192, Japan.
STI571, a BCA-ABL tyrosine kinase inhibitor, has appeared in molecular
targeted therapy as a new treatment option for patients with chronic
myelogenous leukemia (CML) through rational drug development. In a phase
I study in the USA, adverse effects were minimal. Complete hematologic
response was observed in 98% of patients with chronic phase CML treated
with a daily dose of 300 mg or more, and cytogenetic response was seen
in 31% of patients. STI571 has substantial activity in the blast crisis
of CML and Ph + ALL. Stem cell transplantation (SCT) may be compared
with interferon-alpha (IFN-alpha) therapy from three analyses reported
according to risk assessment. These studies indicated that SCT increased
survival only in patients who were younger and at intermediate or high
risk; however, survival with SCT in older patients at higher risk was no
better than with IFN-alpha therapy in a Japanese prospective study. An
individualized risk assessment-based approach is useful in prioritizing
SCT and IFN-alpha in patients with chronic phase CML.
23
UI - 21471000
AU - Ohnishi K; Ino T; Kishimoto Y; Usui N; Shimazaki C; Ohtake S; Taguchi H;
TI -
Kusumoto S; Kuriyama K; Hotta T; Ohno R
Multicenter prospective study of interferon-alpha versus bone marrow
transplantation for newly diagnosed patients with chronic myelogenous
leukemia: a preliminary analysis.
SO - Cancer Chemother Pharmacol 2001 Aug;48 Suppl 1():S59-64
AD - Department of Medicine III, Hamamatsu University School of Medicine,
Handayama, Japan. kohnishi@hama-med.ac.jp
Interferon-alpha (IFN-alpha) therapy was compared with bone marrow
transplantation (BMT) in patients with chronic myelogenous leukemia
(CML) in a multicenter, prospective study. Of 254 evaluable patients,
175 received IFN-alpha and 79 received allogeneic BMT, 50 of whom
received transplants from human leukocyte antigen (HLA)-identical
related donors and 29 from HLA-matched unrelated donors. Complete
hematologic response was achieved by 148 patients (89%) in the IFN-alpha
group and 53 (78%) in the BMT group. In the IFN-alpha group, a complete
cytogenetic response was induced in 25 patients (15%), a partial
cytogenetic response in 37 (23%), and a minor cytogenetic response in 41
(25%). At a median follow-up of 38 months, in the IFN-alpha group the
predicted 5-year survival rate was 79%, and the predicted 5-year rate of
remaining in chronic phase was 66%. In the BMT group the predicted
5-year survival rate was 72% for related-donor BMT and 67% for
unrelated-donor BMT. Among low Sokal-risk patients, 5-year survival did
not differ between IFN-alpha therapy and BMT, irrespective of age. In
higher Sokal-risk patients, survival for related-donor BMT and
unrelated-donor BMT tended to be better than that with IFN-alpha therapy
in younger patients. On the other hand, in older patients, survival in
the BMT group, especially for those receiving unrelated-donor BMT,
appeared to be inferior to that in the IFN-alpha group. Unrelated-donor
BMT can be recommended for high-risk younger patients. However, for
older patients, it should be performed after careful consideration of
prognostic factors such as age, Sokal score, and response to IFN-alpha.
24
UI - 21471003
AU - Mauro MJ; O'Dwyer ME; Druker BJ
TI -
ST1571, a tyrosine kinase inhibitor for the treatment of chronic
myelogenous leukemia: validating the promise of molecularly targeted
therapy.
SO - Cancer Chemother Pharmacol 2001 Aug;48 Suppl 1():S77-8
AD - Leukemia Program, Oregon Health Sciences University, Portland 97201,
USA.
The deregulated tyrosine kinase activity of the Bcr-Abl fusion protein
has been established as the causative molecular event in chronic
myelogenous leukemia (CML). Thus the Bcr-Abl tyrosine kinase is an ideal
target for pharmacologic inhibition. ST1571 (formerly CGP57148B), is an
Abl-specific tyrosine kinase inhibitor that in preclinical studies
selectively kills Bcr-Abl-containing cells in vitro and in vivo. The
results of clinical studies have demonstrated the potential of
molecularly targeted therapies, and ST1571 is emerging as a new
therapeutic agent for CML.
25
UI - 21396275
AU - Inokuchi K; Dan K
TI -
Philadelphia chromosome-negative, bcr/abl-positive chronic myelogenous
leukemia.
SO - J Nippon Med Sch 2001 Aug;68(4):292-3
AD - Third Department of Internal Medicine, Nippon Medical School, Japan.
26
UI - 21447773
AU - Anonymous
TI -
[Hypertension, abdominal aortic aneurysm, chronic bronchitis and myeloid
leukemia]
SO - Medicina (B Aires) 2001;61(4):447-51
27
UI - 21466981
AU - Robak T; Gora-Tybor J
TI -
Cladribine combined with mitoxantrone in the treatment of blastic phase
of chronic myeloid leukemia.
SO - Neoplasma 2001;48(3):203-7
AD - Department of Hematology, Medical University of Lodz, Poland.
A phase II clinical study was performed to evaluate the effectiveness
and toxicity of cladribine (2-CdA) combined with mitoxantrone (CM
regimen) in the treatment of chronic myeloid leukemia in blastic phase
(CML BP). A total of 12 adult patients with CML BP were included in this
study. 2-CdA was given at a dose 0.12 mg/kg in 2-hour iv infusion on
days 1-5 and mitoxantrone 10 mg/m2 i.v. day 1. The cycles were repeated
at 4 week intervals in most cases. Complete remission (CR) was defined
as the presence of < 5% of blasts in a normo- or hypercellular bone
marrow in addition to normal peripheral blood counts and with normal
physical examination. A partial response (PR) required normal peripheral
blood counts but 5 to 25% marrow blasts. Toxicity was assessed according
to WHO criteria. The patients received 21 courses of CM (median 2, range
1-3). Of 12 patients only 2 (17%), achieved PR. Responses were observed
in patients with myeloid BP, after 3 and 2 courses, respectively.
Myelosuppression was the main toxicity. Four patients (33.3%) had grade
3 or 4 neutropenia and 3 (25%) had grade 3 or 4 thrombocytopenia.
Infections occurred in 4 patients (33.3%) and 2 of them died of sepsis
shortly after CM treatment. This preliminary results in a small group of
patients suggest that CM programme has limited value in pre-treated
patients with CML BP. However, this regimen may be used as palliation in
the end stage of disease.
28
UI - 21468568
AU - Kiratli H; Irkec M
TI -
Presumed interferon-associated bilateral macular arterial branch
obstruction.
SO - Eye 2000 Dec;14(Pt 6):920-2
29
UI - 21314603
AU - McDonald HR
TI -
Diagnostic and therapeutic challenges.
SO - Retina 2001;21(3):256-9
30
UI - 21424592
AU - Kilian PH; Skrzypek S; Becker N; Havemann K
TI -
Exposure to armament wastes and leukemia: a case-control study within a
cluster of AML and CML in Germany.
SO - Leuk Res 2001 Oct;25(10):839-45
AD - Department of Haematology, Marburg University Medical Center,
Baldingerstrasse, 35033, Marburg, Germany.
An unusually high incidence of acute myeloid leukemia (AML) and chronic
myeloid leukemia (CML) concentrated in a specific locality of a region
in Germany motivated a descriptive incidence study in that region which
showed a near 10-fold increased risk of CML among males but not among
females (Kolb G, Becker N, Scheller S, Zugmaier G, Pralle H, Wahrendorf
J, Havemann K. Increased risk of acute myelogenous leukemia (AML) and
chronic myelogenous leukemia (CML) in a County of Hesse, Germany, Soc
Prev Med 1993;38:190-195). Since a serious environmental contamination
of areas in this locality with armament wastes containing
toluene-derivatives has been known for a long time, the hypothesis arose
that TNT production and the related severe contamination of soil and
water might be responsible for the observed higher risk. We carried out
a case-control study within the cluster to test this hypothesis.
Overall, the results do not confirm the hypothesis. There is an
indication of a relationship of an increased odds ratio with the
exposure for a small group of persons who lived at a particular site in
one of the two communities involved during the peak phase of TNT
production during the 1940s. However, this finding is spurious and
cannot explain the large majority of cases which occurred in that area
in the 1980s. At the moment, no other explanation can be given for the
increased risk of leukemias in that area.
31
UI - 21424597
AU - Kabutomori O; Kanakura Y; Iwatani Y
TI -
Increase in platelet-large cell ratio in chronic myeloid leukemia.
SO - Leuk Res 2001 Oct;25(10):873
AD - Central Laboratory for Clinical Investigation, Osaka University
Hospital, 2-15 Yamada-oka, Suita, 565-0871, Osaka, Japan.
32
UI - 21456614
AU - Dufva IH; Birgens H
TI -
[New target-aimed molecular cancer treatment of chronic myeloid leukemia
and gastrointestinal stromal tumor]
SO - Ugeskr Laeger 2001 Aug 27;163(35):4759-60
AD - Medicinsk haematologisk afdeling, Amtssygehuset i Herlev.
33
UI - 21466755
AU - Reiter A; Hochhaus A; Berger U; Kuhn C; Hehlmann R
TI -
AraC-based pharmacotherapy of chronic myeloid leukaemia.
SO - Expert Opin Pharmacother 2001 Jul;2(7):1129-35
AD - III. Medizinische Universitatsklinik, Klinikum Mannheim, Fakultat fur
Klinische Medizin der Universtat Heidelberg, Germany.
andreas.reiter@med3.ma.uni-heidelberg.de
In interferon-alpha (IFN) treated chronic phase chronic myeloid
leukaemia (CML) patients, survival depends on individual risk profile
and achievement of a complete haematological response (CHR) and a major
cytogenetic response (MCR) (< 35% Philadelphia-chromosome-positive
metaphases). The highest cytogenetic response rates have been achieved
with the combination of IFN and low-dose sc. AraC (10 mg daily to 10-20
mg/m2 for 10-14 days/month). Whether the higher cytogenetic response
rates are also associated with a significant improvement of survival
still remains controversial. The different results obtained from large
randomised and observational trials may be due to the numbers of
patients enrolled, distribution of risk profiles and the treatment
schedule, which is influenced greatly by the haematological and
gastrointestinal toxicity of AraC. An oral formulation (YNK01), which is
lipophilic and resistant to deamination, is currently under
investigation. Clinically, it has similar activity, but toxicity leads
to discontinuation of treatment in a considerable proportion of
patients. The clinical benefits may therefore be outweighed by the
dose-limiting toxicity for both application forms. Combinations with
other drugs, e.g., STI571 or homoharringtonine, have shown promising
early results in vitro and in vivo.
34
UI - 20357830
AU - Modol JM; Riu F
TI -
[Prolonged fever in a 78-year-old woman with chronic myelocytic
leukemia]
SO - Med Clin (Barc) 2000 May 6;114(17):669-77
AD - Servicio de Medicina Interna, Hospital Universitari Germans Trias i
Pujol, Badalona, Barcelona.
35
UI - 94101255
AU - Anonymous
TI -
Bedside story.
SO - Camb Q Healthc Ethics 1992 Fall;1(4):409-10
36
UI - 21406202
AU - Shteper PJ; Ben-Yehuda D
TI -
Molecular evolution of chronic myeloid leukaemia.
SO - Semin Cancer Biol 2001 Aug;11(4):313-23
AD - Department of Haematology, Hadassah University Hospital, Ein-Karem,
P.O.B. 12000, Jerusalem 91120, Israel.
Chronic myeloid leukaemia (CML) is a clonal disorder of the pluripotent
haematopoietic stem cell. The typical triphasic course of CML starts
with the premalignant chronic phase initiated by BCR-ABL hybrid oncogene
formation. Secondary genetic and epigenetic aberrations accompany the
progression to the accelerated phase and fatal blastic crisis. Properly
timed bone marrow transplantation in eligible patients can result in
durable remissions or cure. Both of these states are often accompanied
by a long-term persistence of quiescent leukaemic cells. Accordingly, a
"functional cure" (i.e. tumour dormancy induction), rather than complete
eradication of the malignant cells, is an adequate therapeutical goal.
The level of the residual BCR-ABL-positive clones should be monitored
and salvage treatment initiated whenever these quiescent leukaemic cells
exit their dormant state. Copyright 2001 Academic Press.
37
UI - 21416550
AU - Doi S; Edamura S; Akasaka H; Kawamura M; Arima N; Nasu K
TI -
[Complete cytogenetic response to interferon-alpha in a patient with
chronic myelogenous leukemia undergoing hemodialysis]
SO - Rinsho Ketsueki 2001 Jul;42(7):549-53
AD - Osaka Red Cross Hospital, Internal Medicine.
We describe a complete cytogenetic response to interferon-alpha in a
patient with chronic myelogenous leukemia undergoing chronic
hemodialysis. Although IFN-alpha therapy has been applied to patients
with chronic hepatitis C receiving hemodialysis, the pharmacokinetics of
IFN-alpha in patients with poor renal function still remain unclear. In
the present patient, the serum IFN-alpha concentration remained high
even 48 hours after injection (42.9 IU/ml), and IFN-alpha was almost
completely removed by hemodialysis (< 6 UI/ml). The patient was treated
with IFN-alpha (3 x 10(6) IU, three times a week), and cytogenetic
disappearance (0%) of the Ph-positive clone was confirmed 31 months
after the start of therapy. Recombinant human erythropoietin (Epo) was
used to treat anemia due to renal failure and IFN-alpha therapy. The
anemia was controllable with Epo, and no adverse effect was observed.
38
UI - 21433708
AU - Brouard MC; Prins C; Mach-Pascual S; Saurat JH
TI -
Acute generalized exanthematous pustulosis associated with STI571 in a
patient with chronic myeloid leukemia.
SO - Dermatology 2001;203(1):57-9
AD - Department of Dermatology, University Hospital, Geneva, Switzerland.
mcvpb@hotmail.com
The tyrosine kinase inhibitor STI571 is a novel promising class of
anticancer drugs. We report a case of cutaneous adverse reactions to
STI571 in a young woman with blast crisis of chronic myeloid leukemia.
She had first typical acute generalized exanthematous pustulosis
mimicking mercury rash and then urticarial eruption. We suggest that
cell pathways mediated by some tyrosine kinases might be involved in the
pathogenesis of these skin eruptions. Copyright 2001 S. Karger AG, Basel
39
UI - 21433715
AU - Granel B; Serratrice J; Bouabdallah R; Pache X; Weiller-Merli C; Swiader
TI -
L; Aquaron R; Disdier P; Nordmann Y; Weiller PJ
Atypical porphyria cutanea tarda in a patient with chronic myelogenous
leukemia.
SO - Dermatology 2001;203(1):82-3
40
UI - 21469302
AU - Neylon A; O'Brien S
TI -
Improving the management of chronic myeloid leukaemia.
SO - Hosp Med 2001 Sep;62(9):553-5
AD - University of Newcastle, Royal Victoria Infirmary, Newcastle NE1 4LP.
Until recently the therapeutic options available to patients diagnosed
with chronic myeloid leukaemia hinged on their suitability for
allogeneic bone marrow transplantation. With the advent of new agents
targeting the specific molecular pathways involved in the disease, drug
therapies may have an increasingly important role in improving outcome.
41
UI - 21460452
AU - Verweij J; Judson I; van Oosterom A
TI -
STI571: a magic bullet?
SO - Eur J Cancer 2001 Oct;37(15):1816-9
AD - Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den
Hoed Kliniek) and University Hospital, Rotterdam, The Netherlands.
verweij@onch.azr.nl
42
UI - 21485489
AU - Mahon FX
TI -
[Chronic myeloid leukemia and tyrosine kinase inhibitors]
SO - Rev Med Interne 2001 Sep;22(9):894-9
AD - Laboratoire de greffe de moelle, universite Victor-Segalen, UMR CNRS
5540, 146, rue Leo-Saignat, 33076 Bordeaux, France.
Francois-Xavier.Mahon@umr5540.u-bordeaux2.fr
INTRODUCTION: Chronic myeloid leukemia is a myeloproliferative disorder
clinically characterised by a triphasic course: after a chronic phase
over a median time of 4 years, patients developed an accelerated phase,
then a blastic phase, resulting in the patient's death with 3 to 6
months. PURPOSE: During the last past years, progress have been made in
the understanding of the molecular mechanism responsible of leukemic
growth. This has also provided support for a therapeutic improvement
with the appearance of treatment such as tyrosine kinase inhibitors
which specifically target the oncoprotein inside the leukemic cells.
CONCLUSION: These treatments, such as STI571 or Glivec, are at present
in clinical trials, and could be the medicines for the future. Thus,
chronic myeloid leukemia is also a model for the development of the new
therapeutic drugs.
43
UI - 21519936
AU - Jeanteur P
TI -
[STI571: the resistance organizes!]
SO - Bull Cancer 2001 Sep;88(9):819
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