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NCI CANCERLIT® Search: Chronic Myelogenous Leukemia - May 2002
National Cancer Institute®
Last Modified: May 1, 2002
Table of Contents
1
UI - 11765724
AU - Anonymous
TI -
Imatinib mesylate.
SO - Am J Health Syst Pharm 2001 Dec 1;58(23):2241-2
2
UI - 11960331
AU - Holyoake TL; Jiang X; Drummond MW; Eaves AC; Eaves CJ
TI -
Elucidating critical mechanisms of deregulated stem cell turnover in the
chronic phase of chronic myeloid leukemia.
SO - Leukemia 2002 Apr;16(4):549-58
AD - Departments of Medicine and Hematology, Glasgow Royal Infirmary,
Glasgow, UK.
Chronic myeloid leukemia (CML) has been studied intensively for many
years; yet its treatment remains problematic and its biology remains
elusive. In chronic phase, the leukemic clone appears to be maintained
by a small number of BCR-ABL-positive hematopoietic stem cells that
differentiate normally and amplify slowly. In contrast, as these cells
enter the intermediate stages of lineage restriction, their progeny are
selectively expanded and generate an enlarged pool of neoplastic
progenitors. Recent analyses of purified subsets of primitive CML cells
have provided a coherent explanation for this dichotomous behavior of
BCR-ABL-positive stem and progenitor cells based on the discovery of an
unusual autocrine IL-3/G-CSF mechanism activated in them. This only
partially counteracts in vivosignals that maintain normal stem cells in
a quiescent state but, when active in CML stem cells, promotes their
differentiation in favor of their self-renewal. In more differentiated
CML progenitors, the same mechanism has a more potent mitogenic effect
which is then extinguished when the cells enter the terminal stages of
differentiation. Thus, further expansion of the clone is limited until
inevitably additional mutations are acquired that further distort or
override the regulatory mechanisms still operative in the chronic phase.
3
UI - 11960334
AU - Blagosklonny MV
TI -
STI-571 must select for drug-resistant cells but 'no cell breathes fire
out of its nostrils like a dragon'.
SO - Leukemia 2002 Apr;16(4):570-2
AD - Medicine Branch, National Cancer Institute, NIH, Bethesda, MD 20892,
USA.
Seemingly disappointing, the Bcr-Abl kinase inhibitor STI-571 shares an
'unfortunate' characteristic with conventional cancer drugs: the
development of drug resistance. I argue that the resistance must develop
even faster to STI-571 than to conventional drugs, because STI-571 is so
effective. This is predictable, but is it inevitable? And how do
mechanisms of resistance in relapse depend on a degree of remission. In
addition to mutation rate and number of tumor cells, one additional
factor determines relapse vs. 'extinction' of the leukemia cell
population.
4
UI - 11960335
AU - Maloisel F; Guerci A; Guyotat D; Ifrah N; Michallet M; Reiffers J;
TI -
Tertain G; Blanc M; Bauduer F; Briere J; Abgrall JF; Pegourie-Bandelier
B; Solary E; Cambier N; Coso D; Vilque JP; Delain M; Harousseau JL;
Rousselot P; Belhadj K; Morice P; Attal J; Chabin M; Chastang C; Guilhot
J; Guilhot F; France Intergroupe des Leucemies Myeloides Chroniques
Results of a phase II trial of a combination of oral cytarabine
ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic
myelogenous leukemia patients in chronic phase.
SO - Leukemia 2002 Apr;16(4):573-80
AD - Division of Hematology, University Hospital of Strasbourg, France.
Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which
is resistant to systemic deamination after oral administration.
Following initial studies indicating significant anti-tumour activity of
YNK01 a phase II trial was initiated in order to assess the tolerability
and efficacy of a combination of this agent with interferon alpha-2b
(IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98).
The treatment was subdivided into cycles consisting of 4 weeks of
continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and
then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At
the end of each cycle the dose of YNK01 was adjusted according to the
blood count observed during the previous 4 weeks. The median time from
diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5
months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a
complete hematological response. At 24 weeks, of 98 patients, two
achieved a complete cytogenetic response, 14 a partial response (16%
major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response;
19 patients were not evaluable for cytogenetic response. During the
trial, 20 patients progressed to accelerated (6) or blastic phases (14).
The median time to progression was 15 months (range 2-38 months). At 3
years the overall survival was 79% (95% CI, 70-88). Although the
complete hematological response rate compared favorably with the 40%
response rate previously obtained with the subcutaneous formulation of
Ara-c, the cytogenetic response rate was less than expected. Most of the
patients experienced side-effects and all permanently stopped YNK01.
Although the combination seems attractive the initial dose of 600 mg per
day is probably too high and should be reconsidered in further trials.
5
UI - 11960336
AU - Schlenk RF; Hartmann F; Hensel M; Jung W; Weber-Nordt R; Gabler A; Haas
TI -
R; Ho AD; Trumper L; Dohner H
Less intense conditioning with fludarabine, cyclophosphamide, idarubicin
and etoposide (FCIE) followed by allogeneic unselected peripheral blood
stem cell transplantation in elderly patients with leukemia.
SO - Leukemia 2002 Apr;16(4):581-6
AD - Department of Internal Medicine III, University of Ulm, Ulm, Germany.
The objective of this study was to assess toxicity and feasibility of
achieving engraftment of allogeneic blood progenitor cells following
nonmyeloablative conditioning according to the FCIE protocol
(fludarabine 25 mg/m(2)/day, days -7 to -3; cyclophosphamide 200
mg/m(2)/day, days -7 to -3; idarubicin 12 mg/m(2)/day, days -7 to -5;
etoposide 250 mg/m(2)/day, days -4 to -3) in elderly patients with
leukemia. Eleven patients were included in the study: six patients with
acute myeloid leukemia (AML) in complete remission (CR); three patients
with refractory or relapsed AML; one patient with chronic myeloid
leukemia; one patient with acute lymphoblastic leukemia. The median age
of the patients was 62 years. All patients received blood progenitor
cells from an HLA-identical sibling with 8.8 x 10(6) CD34(+) cells/kg
(median; range 4.7 to 26.2 x 10(6)/kg) and 5.5 x 10(8) CD3(+)cells/kg
(median; range 4.5 to 7.9 x 10(8)/kg). Graft-versus-host disease (GVHD)
prophylaxis consisted of cyclosporine and three courses of methotrexate.
The median duration of white blood cell counts <1 x 10(9)/l was 17 days
and of platelet counts <50 x 10(9)/l 20 days. In two patients acute GVHD
grade I occurred. Nine of 10 patients analyzed developed mixed
chimerism. Of seven patients transplanted in CR, three remained in CR 19
to 31 months after transplantation. Three patients with refractory
leukemia did not achieve CR, while the patient with relapsed AML
achieved a 3rd CR. After a median follow-up time of 22 months, chronic
GVHD was mild and limited. The data from this pilot study in elderly
patients with leukemia show that the combination of primarily
immunosuppressive (FC) and antileukemic (IE) drugs for nonmyeloablative
conditioning has moderate nonhematological toxicity and allows
engraftment of allogeneic blood progenitor cells.
6
UI - 11960345
AU - Manabe A; Okamura J; Yumura-Yagi K; Akiyama Y; Sako M; Uchiyama H;
TI -
Kojima S; Koike K; Saito T; Nakahata T; MDS Committee of the Japanese
Society of Pediatric Hematology
Allogeneic hematopoietic stem cell transplantation for 27 children with
juvenile myelomonocytic leukemia diagnosed based on the criteria of the
International JMML Working Group.
SO - Leukemia 2002 Apr;16(4):645-9
AD - Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Prognostic factors of juvenile myelomonocytic leukemia (JMML) have not
been clarified because of its very low incidence and inaccuracy in the
diagnosis. The purpose of this study was to evaluate children with JMML
given an allogeneic hematopoietic stem cell transplantation (SCT) and
the role of different variables potentially influencing outcome in a
nationwide survey in Japan based on the newly proposed criteria by the
International JMML Working Group. The study patients were 27 children
who underwent SCT among 55 JMML patients retrospectively collected in
the survey. The source of grafts was HLA-identical siblings in 12 cases,
HLA-matched unrelated individuals in 10 and others in five. Total body
irradiation was used in 18 cases. Event-free and overall survival (OS)
at 4 years after SCT were 54.2 +/- 11.2% (s.e.) and 57.9 +/- 11.0%
(s.e.), respectively. Six patients died of relapse and three of
complications. Patients with abnormal karyotypes showed a significantly
lower OS than those with normal karyotypes (P < 0.001). Patients below 1
year of age showed a significantly higher OS than those of 1 year of age
or more (P = 0.02). Patients with grade 0-1 acute graft-versus-host
disease (GVHD) or chronic GVHD had a more favorable OS than those
without them, although they were not statistically significant (P >
0.05). Other variables studied were not associated with OS. A
multivariate analysis of these factors yielded the abnormal karyotype as
the only significant risk factor for lower OS (risk ratio: 11.0; 95% CI:
2.7-45.1).
7
UI - 11960353
AU - Ferry-Dumazet H; Mamani-Matsuda M; Dupouy M; Belloc F; Thiolat D; Marit
TI -
G; Arock M; Reiffers J; Mossalayi MD
Nitric oxide induces the apoptosis of human BCR-ABL-positive myeloid
leukemia cells: evidence for the chelation of intracellular iron.
SO - Leukemia 2002 Apr;16(4):708-15
AD - Bone Marrow Transplantation, CNRS UMR5540 and EA482, Bordeaux-2
University, Bordeaux, France.
Anti-leukemia activity of human macrophages involves the generation of
nitric oxide (NO) derivatives. However, leukemic transformation may
involve mechanisms that rescue cells from NO-mediated apoptosis. In the
present work, we analyzed the effects of exogenous NO on the
proliferation of BCR-ABL(+) chronic myelogenous leukemia (CML) cells. As
normal leukocytes, the proliferation of leukemia cells was inhibited by
SNAP (S-nitroso-N-acetyl-penicillamine), GEA (Oxatriazolium
amino-chloride), and SIN-1 (Morpholino-sydnonimine), whereas SNP (sodium
nitroprusside) had no effect on leukemia cell growth. SIN-1 induced
higher anti-proliferation activity in BCR-ABL(+) cells, compared to
normal hemopoietic cells. Inhibition of leukemia cell proliferation
correlated with increased apoptosis and DEVDase activity. The
simultaneous addition of exogenous iron reversed NO-mediated inhibition
of cell growth, caspase activation and apoptosis in all BCR-ABL(+) cells
tested. The quantification of intracellular iron levels in leukemia
cells indicated that NO induced an early, dose-dependent decrease in
ferric iron levels. Accordingly, elevation of intracellular iron
protected leukemia cells from NO-mediated apoptosis. Together, the
present work reveals the presence of an iron-dependant mechanism for
leukemia cell rescue from NO-induced growth inhibition and apoptosis.
8
UI - 11920164
AU - Landolfo S; Guarini A; Riera L; Gariglio M; Gribaudo G; Cignetti A;
TI -
Cordone I; Montefusco E; Mandelli F; Foa R
Chronic myeloid leukemia cells resistant to interferon-alpha lack STAT1
expression.
SO - Hematol J 2000;1(1):7-14
AD - Centro CNR di Immunogenetica ed Oncologia Sperimentale, University of
Torino, Torino, Italy.
INTRODUCTION: Interferon-alpha (IFN) plays a role in the management of
different neoplasias, particularly those of hematological origin. The
mechanisms of action of IFN are still poorly understood and the
individual response is unpredictable. In the present study, the pattern
of intracellular gene expression following in vitro and in vivo exposure
of chronic myeloid leukemia (CML) cells to IFN was evaluated and
correlated with the response to in vivo treatment with IFN. MATERIALS
AND METHODS: CML patients in different phases of the disease were
studied. The pattern of expression of two IFN-inducible proteins
involved in IFN-mediated biological activities, the p91 and p84 proteins
(STAT1alpha and STAT1beta), components of the IFN-stimulated gene factor
3 (ISGF3) complex and the enzyme 2'-5' oligoadenylate synthetase (2'-5'
OASE) were investigated by Western blot in peripheral blood mononuclear
cells stimulated or not in vitro by IFN. RESULTS AND CONCLUSIONS: In 6/9
patients evaluated before starting treatment, STAT1 was expressed either
constitutively or after in vitro stimulation by IFN. In three cases,
STAT1 remained negative even after in vitro activation. The pattern of
protein expression correlated with the subsequent hematological response
to prolonged in vivo IFN administration: the presence of STAT1 being
associated with the clinical response to IFN and the absence and
non-inducibility of STAT1 with resistance to IFN. This was further
substantiated by studies carried out in ten patients analyzed at the
time of a documented clinico-hematological response or resistance to the
in vivo administration of IFN. Finally, in order to establish whether
the pattern of response to IFN treatment could be predicted at
diagnosis, cells cyropreserved at diagnosis from patients with a
documented complete response, confirmed also by cytogenetic negativity,
or resistance, were studied. While complete responders proved STAT1
positive, none of the four resistant cases ever expressed STAT1. The
expression of 2'-5' OASE did not correlate with the clinical response to
IFN. This study documents the pivotal role of STAT1 in the in vitro and
in vivo responses of CML cells to IFN. The constitutive or induced
presence or absence of STAT1 shows a predictive correlation with the
response or resistance to treatment with IFN and could be utilized to
identify, at diagnosis, resistant patients who may be spared an
expensive and unnecessary prolonged IFN administration.
9
UI - 11792418
AU - Hashimoto S; Toba K; Tsuchiyama J; Abe T; Yano T; Momoi A; Okazuka K;
TI -
Kanazawa N; Takahashi M; Aizawa Y
CD56+, NKp46+ cell line (MZ93) expressing T-cell and myeloid antigens.
SO - Leuk Res 2002 Mar;26(3):289-95
AD - First Department of Internal Medicine, School of Medicine, Niigata
University, Asahimachi-dori 1, Niigata City 951-8520, Japan.
The MZ93 cell line, established from a patient with CML, expressed CD4,
CD7, CD13, CD25, CD33, CD34, CD56 and NKp46. The additional karyotype
abnormality of the Ph-positive leukemia cells in vivo, 6p+, was also
observed in MZ93. The early passages of MZ93 expressed CD3 in the
cytoplasm, but the late passages did not. The cells did not express
mature NK-markers as expected. The messenger RNAs of CD2 and NKp46 were
detected and those of CD3varepsilon and CD3zeta were absent in the
cells. Therefore, the cell line has the immunophenotype likely to NK
and/or T cell precursor.
10
UI - 11965836
AU - Sarasombath P; Sumida K; Kaku DA
TI -
Parkinsonism associated with interferon alpha therapy for chronic
myelogenous leukemia.
SO - Hawaii Med J 2002 Mar;61(3):48, 57
AD - UH School of Medicine, 1356 Lusitana St., 7th Fl., Honolulu, HI 96813,
USA. spichaya@hotmail.com
A 79 year-old man was treated with Interferon alpha for chronic
myelogenous leukemia and developed severe parkinsonism that resolved
after Interferon alpha was stopped. Carbidopa-levodopa was associated
with early improvement, but discontinuation did not result in worsening
of the parkinsonism.
11
UI - 11968584
AU - Tothova E
TI -
[New views on the treatment of chronic myelocytic leukemia. Literature
review]
SO - Vnitr Lek 2002 Mar;48(3):230-3
AD - Klinika hematologie LF UPJS a FNsP, Kosice, Slovenska republika.
The expansion of knowledge of molecular biology and pathophysiology of
chronic myeloid leukaemia (CML) indicate a new therapeutic approaches of
the disease. Besides less toxic nonmyeloablative regimes of allogenEic
transplantation and the introduction of modified interpherone regimes
attracts our interest therapy more specific, aimed to a primary reason
of a disease, BCR/ABL gene, and its products, that are responsible for
leukaemic transformation. The paper is a summary of experimental, as
well as first clinical experiences with application of
thyrosinkinase-inhibitors, farnesyl-transferase-inhibitors and
vaccination therapy of CML. Even thought is allogeneic transplantation
the only curative therapy of CML, first clinical experiences with
thyrosinkinase inhibitors show, that these are the medicaments that can
become in a near future its important alternative.
12
UI - 11425449
AU - Mohr B; Bornhauser M; Platzbecker U; Freiberg-Richter J; Naumann R;
TI -
Prange-Krex G; Mohm J; Kroschinsky F; Ehninger G; Thiede C
Problems with interphase fluorescence in situ hybridization in detecting
BCR/ABL-positive cells in some patients using a novel technique with
extra signals.
SO - Cancer Genet Cytogenet 2001 Jun;127(2):111-7
AD - Medizinische Klinik und Poliklinik I, Universitatsklinikum Carl Gustav
Carus, Fetscherstrasse 74, 01307 Dresden, Germany.
Interphase fluorescence in situ hybridization (I-FISH) is frequently
used to monitor the response to therapy in various hematological
malignancies. We performed a comparison of I-FISH, metaphase FISH
(C-FISH), conventional cytogenetics, spectral karyotyping (SKY) and PCR
for the detection of the t(9;22) and the BCR/ABL rearrangement in 32
patients with chronic myelogenous leukemia (CML). FISH was done using a
novel commercial probe set (VYSIS LSI BCR/ABL ES), which is designed to
reduce the rate of false-positive results by marking the
argininosuccinate synthetase (ASS) gene and thus providing an extra
signal on chromosome 9. Our data indicate, that a substantial number of
BCR/ABL-positive patients (n=5 patients, 3 with Ph, 2 with masked Ph)
present negative results using this probe set in I-FISH analyses,
because they did not fulfill the scoring criteria. In fact, the ASS
region, which usually remains on 9q in Ph+ CML, appears to be lost or
translocated. Due to these results we recommend that the initial
diagnosis as well as the follow-up of patients with Ph+ leukemias should
not be based on a single technique but should integrate results of
cytogenetics and molecular biology.
13
UI - 11759071
AU - Muller L; Provenzani C; Pawelec G
TI -
Generation of chronic myelogenous leukemia-specific T cells in
cytokine-modified autologous mixed lymphocyte/tumor cell cultures.
SO - J Immunother 2001 Nov-Dec;24(6):482-92
AD - Section for Transplantation Immunology, Second Department of Internal
Medicine, University of Tubingen Medical School, Germany.
ludmila.mueller@uni-tuebingen.de
Chronic myelogenous leukemia (CML) may be amenable to cell-based
adoptive immunotherapy, as suggested by the graft-versus-leukemia effect
of bone marrow transplantation and the therapeutic benefit of donor
leukocyte infusions. Specific adoptive immunotherapy without bone marrow
transplantation might be more effective and less cost-intensive.
Professional antigen-presenting cells, the dendritic cells, from
patients with CML are derived from the malignant clone and may stimulate
antileukemia T-cell responses. Autologous T cells may also be able to
recognize tumor antigens on CML cells directly. Here, the authors show
that CD4 and CD8 T-cell responses to autologous CML cells can be
generated in vitro rapidly and effectively by performing modified
autologous mixed lymphocyte/tumor cell cultures (MLTC) in serum-free
medium in the presence of cytokines known to support dendritic cell
differentiation. MLTC-sensitized T cells secreted large amounts of the
type 1 cytokine interferon-gamma, as well as interleukin (IL)-2.
However, they also secreted a variety of other cytokines, including the
type 2-subtype cytokine IL-13 but not the classic type 2 cytokines IL-4,
IL-5, and IL-10. Monoclonal populations of CML-specific CD4 cells could
be derived from these lines in limited numbers but showed markedly
enhanced reactivity. This suggests that CML-specific T cells are
relatively rare in these autologous MTLC-derived sensitized populations,
but that their isolation and propagation would yield much more potent
antitumor effector cells for use in adoptive immunotherapy without the
need for bone marrow transplantation.
14
UI - 11932803
AU - Nackley J 2nd; Barthel J; Coppola D
TI -
Upper gastrointestinal bleeding from leukemic gastric implants.
SO - Endoscopy 2002 Apr;34(4):354
AD - Moffitt Cancer Center, University of South Florida, Tampa, Florida
33612, USA. barthejs@moffit.usf.edu
15
UI - 11996791
AU - Tong CR; Hong B; Qiu JY; Chen Z; Lu DP
TI -
Significance of cytogenetic and fluorescence in situ hybridization
analysis in evaluating antichronic myeloid leukemia efficacy of
different immune effector cells.
SO - Cancer Genet Cytogenet 2002 Apr 1;134(1):21-4
AD - Cellular Therapy Center, Institute of Hematology, People's Hospital,
Peking University, No. 11 South Street, Xi-Zhi-Men, 100044 Beijing, P.
R. China. phcet@public3.bta.net.com
We report on the antileukemia effect of interleukin 2 (IL2) on different
immune cells from 22 patients with chronic myeloid leukemia (CML). Bone
marrow cells from these patients were first cultured in modified
long-term bone marrow culture medium for several days, then separately
cultured with lymphokine activated killer cells (LAK), cytokine-induced
killer cells (CIK), and dendritic cell cocultured CIK (DC-CIK) for
another 1-2 days. They were then detected for presence of the
Philadelphia chromosome (Ph) by cytogenetic analysis and fluorescence in
situ hybridization (FISH). The percentage of Ph-chromosome-positive
cells in the bone marrow mononuclear cells after culturing with CIK and
DC-CIK was significantly lower than that after culturing with IL2 or
LAK. Our results demonstrate that cytogenetics and FISH are useful
techniques for the evaluation of the anti-CML effect of immune cells and
that CIK or DC-CIK can be appropriate candidates for adoptive immune
cell therapy in vivo or for leukemia cell purging ex vivo.
16
UI - 11996803
AU - Yamamoto K; Nagata K; Kida A; Hamaguchi H
TI -
Acquired gain of an X chromosome as the sole abnormality in the blast
crisis of chronic neutrophilic leukemia.
SO - Cancer Genet Cytogenet 2002 Apr 1;134(1):84-7
AD - Department of Hematology, Musashino Red Cross Hospital, 1-26-1
Kyonan-cho, Musashino, Tokyo 180-8610, Japan.
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative
disorder characterized by sustained neutrophilic leukocytosis and
absence of the Philadelphia chromosome. Most patients with CNL have
normal karyotypes, and no specific cytogenetic abnormality has been
identified. We report here a patient with CNL that evolved to myeloid
blast crisis. A 73-year-old man was admitted to the hospital because of
marked leukocytosis (leukocyte count 112.5 x 10(9)/L with 91% segmented
neutrophils) and massive hepatosplenomegaly that was diagnosed as CNL
with a normal karyotype. After treatment with hydroxyurea for 7 months,
the disease progressed to a blast crisis. Bone marrow showed myeloid
hyperplasia with 21% myeloblasts, 15% promyelocytes, and marked
dysplastic changes of neutrophils. Blastic cells were positive for CD10,
CD13, CD14, CD33, CD34, and HLA-DR. Chromosome analysis of the bone
marrow cells showed 46,XY,+X in all 20 metaphase spreads. We reviewed 15
cases of CNL terminating in the blast crisis and confirmed that all
cases transformed into myeloid crises and had poor prognoses.
Furthermore, to our knowledge, this is the first case showing the
acquired gain of an extra X chromosome as a sole abnormality in CNL. The
gain of an extra X chromosome may play an important role in the
progression from chronic phase to the blast crisis of CNL.
17
UI - 11861264
AU - Baccarani M; Rosti G; de Vivo A; Bonifazi F; Russo D; Martinelli G;
TI -
Testoni N; Amabile M; Fiacchini M; Montefusco E; Saglio G; Tura S;
Italian Cooperative Study Group on Myeloid Leukemia
A randomized study of interferon-alpha versus interferon-alpha and
low-dose arabinosyl cytosine in chronic myeloid leukemia.
SO - Blood 2002 Mar 1;99(5):1527-35
AD - L. and A. Seragnoli Institute of Hematology and Medical Oncology, S.
Orsola Hospital, University of Bologna, Italy. baccarani@med.unibo.it
Interferon-alpha (IFN-alpha) has significantly prolonged survival in
chronic myeloid leukemia (CML), but some patients do not respond and
many responses are not durable. To improve the results, IFN-alpha has
been combined with other treatments, but so far only the association
with low-dose arabinosyl cytosine (LDAC) has been shown to increase the
response rate and to prolong survival. Here are reported the results of
a study of 538 Philadelphia chromosome-positive CML patients who were
assigned at random to treatment with IFN-alpha 2a alone or in
combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6)
IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of
each month of treatment. The efficacy endpoints were a complete
hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC
arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response
(MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival
(5-year survival, 68% versus 65%; P =.77). Treatment did not affect
overall survival within different prognostic risk groups: low,
intermediate, or high. Also the duration of MCgR was identical. The
results of this study confirm the results of a similar French study only
for the response rate, not for survival, suggesting that the
relationship between cytogenetic response and survival may be extremely
variable and that a meta-analysis of these and other studies of
IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of
the role of LDAC in the treatment of CML.
18
UI - 11861294
AU - Schultheis B; Carapeti-Marootian M; Hochhaus A; Weisser A; Goldman JM;
TI -
Melo JV
Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia:
possible inadequacy of a negative feedback mechanism.
SO - Blood 2002 Mar 1;99(5):1766-75
AD - Department of Haematology, Faculty of Medicine, Imperial College of
Science, Technology and Medicine, London, United Kingdom.
Constitutive activation of the BCR-ABL tyrosine kinase is fundamental to
the pathogenesis of chronic myeloid leukemia (CML). STI571 inhibits this
activity and modulates the transcription of several genes. It was shown
by differential display that the suppressor of cytokine signaling-2
(SOCS-2) gene was down-regulated by STI571 treatment in 14 of 16
BCR-ABL-positive cell lines and in 2 BCR-ABL-transfected murine lines,
but not in BCR-ABL-negative counterparts. The effect was maximal at 2
hours and persisted for at least 24 hours after exposure to 1 microM
STI571, whereas SOCS-1 and SOCS-3 expression were unaffected. Baseline
levels of SOCS-2 were significantly higher in BCR-ABL-positive as
compared with BCR-ABL-negative cell lines. It was similar in leukocytes
and CD34(+) cells from healthy persons (n = 44) and patients with CML in
chronic phase (CP; n = 60) but significantly increased in patients with
CML in blast crisis (BC; n = 20) (P <.0001). Mononuclear cells (MNCs)
from 3 of 4 patients with CML in BC showed a 2-fold to 12-fold
down-regulation of SOCS-2 levels on in vitro exposure to STI571;
moreover, a 2-fold to 11-fold decrease in SOCS-2 was observed in MNCs
from 7 of 8 patients with CML in BC who responded to treatment with
STI571. Refractoriness to STI571 or relapse after initial response was
accompanied by augmentation of SOCS-2 expression. Ectopic overexpression
of SOCS-2 in 32Dp210 cells slowed growth, inhibited clonogenicity, and
increased their motility and sensitivity to STI571. Overall, the results
suggest that SOCS-2 is a component of a negative feedback mechanism; it
is induced by Bcr-Abl but cannot reverse its overall growth-promoting
effects in blastic transformation.
19
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UI - 11916528
AU - Bruserud O; Gjertsen BT; Ulvestad E
TI -
Expression of Fc(epsilon)-receptors by human acute myelogenous leukemia
(AML) blasts: studies of high- and low- (CD23) affinity receptor
expression and the effects of IgE-mediated receptor ligation on
functional AML blast characteristics.
SO - Leuk Res 2002 May;26(5):515-21
AD - Division for Hematology, Medical Department, The Gade Institute,
Haukeland University Hospital, University of Bergen, N-5021 Bergen,
Norway. oystein.bruserud@haukeland.no
Acute myelogenous leukemia (AML) blasts derived from 20 patients were
examined for expression of high- (Fc(epsilon)RI) and low-affinity
(Fc(epsilon)RII, CD23) IgE Fc(epsilon)-receptors. Fc(epsilon)RI
expression was not detected for any patient. In contrast, expression of
CD23 (at least 15% of the blasts stained positive) was detected for 6
out of the 20 patients. Acute lymphoblastic leukemia (ALL) blasts
derived from 12 patients did not express CD23 (<1% positive cells for
all patients). The functional effects of Fc(epsilon)R-receptor ligation
were also examined for 20 patients, including the five patients with
highest CD23 expression (30-55% positive cells) and five patients with
verified low CD23 expression (
UI - 11836601
AU - Liu TC; Lin SF; Chen TP; Chang JG
TI -
Polymorphism analysis of CYP3A5 in myeloid leukemia.
SO - Oncol Rep 2002 Mar-Apr;9(2):327-9
AD - Division of Hematology-Oncology, Department of Internal Medicine,
Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
The human cytochrome P450 (CYP) metabolizes more than 100 structurally
diverse exogenous and endogenous molecules. The CYP3A5 is a major P450
enzyme in the liver and represents 50% of the total hepatic CYP3A
content in people expressing CYP3A5. The single nucleotide polymorphisms
in CYP3A5*3 and CYP3A5*6 that resulted in the absence of CYP3A5 from
tissues were noted in some people. Polymorphisms of potential relevance
to leukemia and myelodysplastic syndrome (MDS) have been described for
various CYP. The bone marrow and/or peripheral blood from 188 acute
myeloid leukemia (AML) patients, 101 chronic myeloid leukemia (CML), 40
MDS, and 270 normal controls were analyzed by a PCR-RFLP assay to
evaluate the association of the CYP3A5 polymorphisms with myeloid
leukemia. Our data showed that 15/188 (8%), 8/101 (7.9%), and 3/40
(7.5%) of the patients (i.e., 188 AML, 101 CML, 40 MDS) were
CYP3A5*1/*1; 88/188 (46.8%), 47/101 (46.5%), and 20/40 (50%) were
CYP3A5*1/*3; and 85/188 (45.2%), 46/101 (45.5%), and 17/40 (42.5%)
carried the CYP3A5*3/*3 genotype, respectively. CYP3A5*6 was not found
in any of the patients' specimens. Similar frequencies of CYP3A5*3 were
observed in the leukemic patients and normal controls. Consequently, the
finding suggests that the CYP3A5 polymorphism was not associated with
the risk of myeloid leukemia.
UI - 11847518
AU - Ribeiro EM; Rodriguez JM; Coser VM; Sotero MG; Fonseca Neto JM; Pasquini
TI -
R; Cavalli IJ
Microsatellite instability and cytogenetic survey in myeloid leukemias.
SO - Braz J Med Biol Res 2002 Feb;35(2):153-9
AD - Departamento de Genetica, Universidade Federal do Parana, Curitiba, PR,
Brasil. eribeiro@bio.ufpr.br
Microsatellites are short tandem repeat sequences dispersed throughout
the genome. Their instability at multiple genetic loci may result from
mismatch repair errors and it occurs in hereditary nonpolyposis
colorectal cancer. This instability is also found in many sporadic
cancers. In order to evaluate the importance of this process in myeloid
leukemias, we studied five loci in different chromosomes of 43 patients,
22 with chronic myelocytic leukemia (CML) in the chronic phase, 7 with
CML in blast crisis, and 14 with acute myeloid leukemia (AML), by
comparing leukemic DNA extracted from bone marrow and constitutional DNA
obtained from buccal epithelial cells. Only one of the 43 patients
(2.1%), with relapsed AML, showed an alteration in the allele length at
a single locus. Cytogenetic analysis was performed in order to improve
the characterization of leukemic subtypes and to determine if specific
chromosome aberrations were associated with the presence of
microsatellite instability. Several chromosome aberrations were
observed, most of them detected at diagnosis and during follow-up of the
patients, according to current literature. These findings suggest that
microsatellite instability is an infrequent genetic event in myeloid
leukemias, adding support to the current view that the mechanisms of
genomic instability in solid tumors differ from those observed in
leukemias, where specific chromosome aberrations seem to play a major
role.
UI - 11769961
AU - Druker BJ
TI -
ST1571: a paradigm for clinical trials of molecularly targeted agents.
SO - Biomed Pharmacother 2001 Nov;55(9-10):529-30
AD - Division of Hematology and Medical Oncology, Oregon Health Sciences
University, Portland 97201, USA.
UI - 11858124
AU - Petukhov VI; Strozha IL; Bondare DK
TI -
[Chronic myeloid leukemia: current pathogenetic aspects and new
therapeutic approaches (a foreign literature review)]
SO - Ter Arkh 2001;73(12):96-101
UI - 11869959
AU - Piccinini L; Arigliano V; Artusi T
TI -
Blast crisis merely lymph nodal of chronic myeloid leukemia.
SO - Haematologica 2002 Mar;87(3):EIM09
AD - Divisione di Oncologia, Dipartmento di Scienze mediche Oncologiche e
Radiologiche Policlinico, Via del Pozzo 71, 41100 Modena, Italy.
piccinini@unimo.it
UI - 11869961
AU - Ruiz-Arguelles GJ
TI -
What is the dose of STI-571 needed to induce a molecular remission in
chronic myeloid leukemia?
SO - Haematologica 2002 Mar;87(3):ELT15
UI - 11877262
AU - Talpaz M; Silver RT; Druker BJ; Goldman JM; Gambacorti-Passerini C;
TI -
Guilhot F; Schiffer CA; Fischer T; Deininger MW; Lennard AL; Hochhaus A;
Ottmann OG; Gratwohl A; Baccarani M; Stone R; Tura S; Mahon FX;
Fernandes-Reese S; Gathmann I; Capdeville R; Kantarjian HM; Sawyers CL
Imatinib induces durable hematologic and cytogenetic responses in
patients with accelerated phase chronic myeloid leukemia: results of a
phase 2 study.
SO - Blood 2002 Mar 15;99(6):1928-37
AD - M. D. Anderson Cancer Center, Houston, Texas, USA.
mtalpaz@mail.mdanderson.org
Chronic myelogenous leukemia (CML) is caused by expression of the
BCR-ABL tyrosine kinase oncogene, the product of the t(9;22)
Philadelphia translocation. Patients with CML in accelerated phase have
rapidly progressive disease and are characteristically unresponsive to
existing therapies. Imatinib (formerly STI571) is a rationally
developed, orally administered inhibitor of the Bcr-Abl kinase. A total
of 235 CML patients were enrolled in this study, of whom 181 had a
confirmed diagnosis of accelerated phase. Patients were treated with
imatinib at 400 or 600 mg/d and were evaluated for hematologic and
cytogenetic response, time to progression, survival, and toxicity.
Imatinib induced hematologic response in 82% of patients and sustained
hematologic responses lasting at least 4 weeks in 69% (complete in 34%).
The rate of major cytogenetic response was 24% (complete in 17%).
Estimated 12-month progression-free and overall survival rates were 59%
and 74%, respectively. Nonhematologic toxicity was usually mild or
moderate, and hematologic toxicity was manageable. In comparison to 400
mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28%
compared to 16%), longer duration of response (79% compared to 57% at 12
months), time to disease progression (67% compared to 44% at 12 months),
and overall survival (78% compared to 65% at 12 months), with no
clinically relevant increase in toxicity. Orally administered imatinib
is an effective and well-tolerated treatment for patients with CML in
accelerated phase. A daily dose of 600 mg is more effective than 400 mg,
with similar toxicity.
UI - 11877268
AU - Weisdorf DJ; Anasetti C; Antin JH; Kernan NA; Kollman C; Snyder D;
TI -
Petersdorf E; Nelson G; McGlave P
Allogeneic bone marrow transplantation for chronic myelogenous leukemia:
comparative analysis of unrelated versus matched sibling donor
transplantation.
SO - Blood 2002 Mar 15;99(6):1971-7
AD - University of Minnesota--Mayo Mail Code 480, 420 Delaware Street SE,
Minneapolis, MN 55455, USA. weisd001@tc.umn.edu
Allogeneic bone marrow transplantation (BMT) offers the only curative
therapy for chronic myelogenous leukemia. We compared prospectively
collected results of 2464 unrelated donor (URD) transplantations with
450 HLA-identical, matched sibling donor (MSD) transplantations
performed at collaborating National Marrow Donor Program institutions. A
total of 63% of URDs were matched at HLA-A, -B, and at -DRB1 alleles;
all MSDs were genotypically identical at major histocompatibility loci.
URD recipients were younger (median 36 vs 39, P =.001) than MSDs and
underwent BMT later after diagnosis (median 17 [0-325 months] vs 7
[1-118 months], P =.001) and less often in chronic phase (CP) (67% vs
82%, P =.001). Multivariate analysis demonstrated a significantly
increased risk of graft failure and acute graft versus host disease
after URD BMT. The risk of hematologic relapse was low after either
matched URD or MSD transplantations. We observed significantly though
modestly poorer survival and disease-free survival (DFS) after URD
transplantations. However, for those undergoing transplantation during
CP within 1 year from diagnosis, 5-year DFS was similar or only slightly
inferior after matched URD versus MSD transplantation (age < 30: URD 61%
+/- 8% vs MSD 68% +/- 15%, P =.18; 30-40: URD 57% +/- 9% vs MSD 67% +/-
10%, P =.05; > 40: URD 46% +/- 9% vs MSD 57% +/- 9%, P =.02). Delay from
diagnosis to BMT in CP patients led to substantially poorer 5-year DFS
after matched URD than MSD BMT (CP 1-2 years: URD 39% +/- 6% vs MSD 63%
+/- 12%; beyond 2 years: URD 33% +/- 7% vs MSD 50% +/- 20%). Outcome of
matched URD BMT for early CP chronic myelogenous leukemia yields
survival and DFS approaching that of MSD transplantation. However, delay
may compromise URD outcomes to a greater extent. Improvements in URD and
MSD transplantation are still needed, and results of newer,
nontransplantation therapies should be evaluated against the established
curative potential of URD and MSD marrow transplantation.
UI - 11877286
AU - Baron F; Turhan AG; Giron-Michel J; Azzarone B; Bentires-Alj M; Bours V;
TI -
Bourhis JH; Chouaib S; Caignard A
Leukemic target susceptibility to natural killer cytotoxicity:
relationship with BCR-ABL expression.
SO - Blood 2002 Mar 15;99(6):2107-13
AD - INSERM 487, Laboratoire de therapie cellulaire, Institut Gustave Roussy,
39 rue Camille Desmoulins, F-94805 Villejuif, France.
Chronic myeloid leukemia is a clonal myeloproliferative expansion of
transformed primitive hematopoietic progenitor cells characterized by
high-level expression of BCR-ABL chimeric gene, which induces growth
factor independence. However, the influence of BCR-ABL expression on
cell-mediated cytotoxicity is poorly understood. In the present study,
we asked whether BCR-ABL expression interferes with leukemic target
sensitivity to natural killer (NK) cell cytolysis. Our approach was
based on the use of 2 BCR-ABL transfectants of the pluripotent
hematopoietic cell line UT-7 expressing low (UT-7/E8, UT-7/G6) and high
(UT-7/9) levels of BCR-ABL. As effector cells, we used CD56(bright),
CD16-, CD2- NK cells differentiated in vitro from CD34 cord blood
progenitors. We demonstrated that BCR-ABL transfectants UT-7/9 were
lysed by NK cells with a higher efficiency than parental and low
UT-7/E8.1 and UT-7/G6 transfectants. This enhanced susceptibility to
lysis correlated with an increase in expression of intercellular
adhesion molecule 1 (ICAM-1) by target cells. Treatment of UT-7/9 cells
by STI571 (a specific inhibitor of the abl kinase) resulted in a
decrease in NK susceptibility to lysis and ICAM-1 down-regulation in
target cells. Furthermore, the constitutive activation of nuclear
factor-kappaB (NF-kappaB) detected in BCR-ABL transfectant UT-7/9, was
significantly attenuated when cells were treated by STI571.
Interestingly, inhibition of NF-kappaB activation by BAY11-67082 (a
specific NF-kappaB inhibitor) resulted in down-regulation of ICAM-1
expression and a subsequent decrease in NK-induced killing of UT-7/9
transfectants. Our results show that oncogenic transformation by BCR-ABL
may increase susceptibility of leukemic progenitors to NK cell
cytotoxicity by a mechanism involving overexpression of ICAM-1 as a
consequence of NF-kappaB activation.
UI - 11877311
AU - Verstovsek S; Kantarjian H; Manshouri T; Cortes J; Giles FJ; Rogers A;
TI -
Albitar M
Prognostic significance of cellular vascular endothelial growth factor
expression in chronic phase chronic myeloid leukemia.
SO - Blood 2002 Mar 15;99(6):2265-7
AD - Department of Leukemia and Hematopathology, The University of Texas M D
Anderson Cancer Center, 1515 Holcombe Boulevard, Box 72, Houston, TX
77030, USA.
The impact of elevated vascular endothelial growth factor (VEGF)
expression on the course of chronic myeloid leukemia (CML) is unknown.
By radioimmunoassay, we measured pretreatment cellular VEGF protein in
bone marrow samples from 184 (148 chronic and 36 accelerated/blastic
phases) CML patients and found the levels to be 1.6-fold higher than in
31 normal control bone marrow samples (P =.000 01). No significant
differences were found in VEGF levels by different phases of CML (P
=.1). VEGF levels correlated with older age (P =.01) and higher platelet
count (P =.0003), but also with smaller spleen size (P =.004), lower
white blood cell count (P =.0006), and lower percentage of peripheral
blasts (P =.04). With the use of Cox proportional hazard model and VEGF
levels as a continuous variable, high VEGF levels correlated with
shorter survival of patients in chronic CML (P =.008). Multivariate
analysis showed that VEGF was not independent of the synthesis stage (P
=.09). These data suggest that VEGF plays a role in the biology of CML
and that VEGF inhibitors should be investigated in CML.
UI - 11990309
AU - Sharathkumar A; Thornley I; Saunders EF; Calderwood S; Freedman MH;
TI -
Doyle J
Allogeneic bone marrow transplantation in children with chronic
myelogenous leukemia.
SO - J Pediatr Hematol Oncol 2002 Mar-Apr;24(3):215-9
AD - The Hospital for Sick Children, University of Toronto, Ontario, Canada.
PURPOSE: To determine the outcome of children undergoing allogeneic bone
marrow transplantation for chronic myelogenous leukemia (CML) at the
authors' institution. PATIENTS AND METHODS: Between 1985 and 1999, 18
allogeneic bone marrow transplantations were performed in 17 patients
with CML at the Hospital for Sick Children in Toronto. Median age at
diagnosis was 9.5 years (range 3-17). Fourteen patients had disease in
the first chronic phase, one had disease in the second chronic phase,
and two had disease in the accelerated phase. Preparative regimens
varied, with radiation-based protocols used in eight patients. Thirteen
donors were related (11 matched, 2 mismatched); four were unrelated (2
matched, 2 mismatched). Patients received T-cell-replete bone marrow a
median of 7.5 months (range 2.2-22) from diagnosis. A median of 3.0 x
10(8)/kg nucleated cells was infused (range 1.6-6.7). Graft-versus-host
disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in
13 children. cyclosporine in three, and methotrexate in one. RESULTS:
Primary graft failure occurred in one patient. Grade 2 acute GVHD or
more developed in 11 of the 17 children (64%; grade 2 in 4, grade 3 in
7). Chronic GVHD occurred in 6 of the 16 patients at risk (37.5%; 5
extensive, 1 localized). No patient experienced overt or cytogenetic
relapse. There were two deaths (12%): one from acute GVHD and
cytomegalovirus pneumonia and the other from chronic GVHD. Probability
of 5-year event-free survival was 87 +/- 9%. CONCLUSIONS: These results
strongly support the practice of allotransplantation in children with
CML, even in the setting of advanced disease and histoincompatibility.
Efforts should be aimed at reducing the transplantation-related death
rate.
UI - 11870247
AU - Savage DG; Antman KH
TI -
Imatinib mesylate--a new oral targeted therapy.
SO - N Engl J Med 2002 Feb 28;346(9):683-93
AD - Herbert Irving Comprehensive Cancer Center, Columbia University College
of Physicians and Surgeons, New York, NY, USA.
UI - 11981005
AU - Kiss TL; Abdolell M; Jamal N; Minden MD; Lipton JH; Messner HA
TI -
Long-term medical outcomes and quality-of-life assessment of patients
with chronic myeloid leukemia followed at least 10 years after
allogeneic bone marrow transplantation.
SO - J Clin Oncol 2002 May 1;20(9):2334-43
AD - Bone Marrow Transplant Service, Department of Medical Oncology and
Hematology, Princess Margaret Hospital/University Health Network,
Toronto, Ontario, Canada. thomas.kiss@uhn.on.ca
PURPOSE: Benchmark analysis of patients with chronic myeloid leukemia
(CML) alive for more than 10 years after allogeneic bone marrow
transplantation (BMT) including data on disease status, bone marrow
reserve, long-term complications, and quality of life (QOL). PATIENTS
AND METHODS: Eighty-nine patients (46 in first chronic phase, 43 in
advanced phase) received an allogeneic BMT for CML during the study
period. Medical outcomes and QOL of patients were analyzed
retrospectively. RESULTS: Twenty-eight (31.5%) of 89 patients were alive
at 10 years and included in this analysis. Thirteen (46.4%) of 28
long-term survivors never relapsed. Fifteen patients relapsed between
0.5 and 16 years after transplantation. Ten patients showed a
hematologic relapse and received salvage treatment. Five patients showed
transient low levels of BCR-ABL-positive cells by Southern blot with no
subseq
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