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NCI CANCERLIT® Search: Chronic Myelogenous Leukemia - October 2002
National Cancer Institute®
Last Modified: October 1, 2002
- Longitudinal monitoring of immune reconstitution by CDR3 size spectratyping after T-cell-depleted allogeneic bone marrow transplant
- Identification of T-cell clones showing expansion associated with graft-vs-leukemia effect on chronic myelogenous leukemia in vivo and in
- Expression of KL-6 antigen on leukemia cells of a patient with chronic myelocytic leukemia in blastic phase.
- Multicolor COBRA-FISH analysis of chronic myeloid leukemia reveals novel cryptic balanced translocations during disease progression.
- Acute suprachoroidal haemorrhage with acute angle closure glaucoma as a presenting sign of chronic myelomonocytic leukemia.
- [Effect of estrogen on the blast transformation of lymphocytes and interleukin-2 production in lupus erythematosus]
- Mobilization of Philadelphia-negative peripheral blood mononuclear cells in chronic myeloid leukaemia using hydroxyurea and G-CSF (filgrastim).
- ICE, mini-ICE or high-dose hydroxyurea to mobilize Philadelphia (Ph1)-negative PBPC in chronic myelogenous leukaemia.
- Immature leukemic CD34+CXCR4+ cells from CML patients have lower integrin-dependent migration and adhesion in response to the chemokine
- Resolution of psoriasis following allogeneic bone marrow transplantation for chronic myelogenous leukemia: case report and review of the
- Myelodysplastic and myeloproliferative syndromes associated with giant cell arteritis and polymyalgia rheumatica: a coincidental coexistence or
- Contact with fibronectin enhances preservation of normal but not chronic myelogenous leukemia primitive hematopoietic progenitors.
- Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous
- [Expression of beta 2 integrins and L-selectin on CML cells after treatment with IFN-alpha and allo-bone marrow transplantation]
- Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia.
- [Detection of BCR-ABL gene sequences using RT-PCR in patients with leukemia in the IX region. Chile]
- Systemic sclerosis after interferon-alfa therapy for myeloproliferative disorders.
- Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis.
- Autologous peripheral blood stem cell transplantation for chronic myelocytic leukaemia, using unmanipulated grafts.
- Normal and leukaemic haematopoiesis in bone marrow and peripheral blood of patients with chronic myeloid leukaemia.
- Autologous peripheral blood haematopoietic stem cell transplantation for chronic myelogenous leukaemia.
- Management of the chronic leukemias: special considerations in the elderly patient. Part III rarer chronic myeloid leukemias.
- Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia.
- Relationship of the BCR gene breakpoint and the type of BCR/ABL transcript to clinical course, prognostic indexes and survival in
- Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase.
Table of Contents
1
UI - 10845939
AU - Verfuerth S; Peggs K; Vyas P; Barnett L; O'Reilly RJ; Mackinnon S
TI -
Longitudinal monitoring of immune reconstitution by CDR3 size
spectratyping after T-cell-depleted allogeneic bone marrow transplant
and the effect of donor lymphocyte infusions on T-cell repertoire.
SO - Blood 2000 Jun 15;95(12):3990-5
AD - Department of Haematology, University College London, London, United
Kingdom.
Delayed immune reconstitution after allogeneic bone marrow
transplantation (BMT) with associated infection is a major cause of
morbidity and mortality. We used third complementarity region (CDR3)
size spectratyping as a tool for monitoring T-cell repertoire
reconstitution in 19 patients over a median time of 40 months after
T-cell-depleted allogeneic BMT for chronic myeloid leukemia (CML).
Furthermore, the effect of donor lymphocyte infusions (DLI) for the
treatment of relapse in 18 of the 19 patients was analyzed. All BMT
recipients had irregular spectratypes in the first 3- to -6 months after
transplant. These evolved to more normal patterns by 12 months after
transplant and continued to improve thereafter. In approximately a third
of the patients, it took 2 to 3 years for all spectratypes to normalize,
whereas in the other two thirds, some abnormal spectratypes persisted
even after several years. In 9 patients, there was no immediate change
in the CDR3 size profiles after DLI. In 3 patients, spectratypes
improved slightly after DLI, whereas in 6 patients, spectratypes became
more restricted and irregular. Overall, T-cell spectratypes in BMT
patients were characterized by instability over time and in patients
with graft-versus-host disease (GVHD), this was even more exaggerated.
Several factors, such as pre-BMT conditioning, T-cell depletion of the
donor marrow, loss of thymic function in adults, exposure to infectious
agents, GVHD, and immunosuppressive treatment, are likely contributors
to the delay in T-cell-repertoire reconstitution. (Blood.
2000;95:3990-3995)
2
UI - 11301187
AU - Kondo Y; Shiobara S; Nakao S
TI -
Identification of T-cell clones showing expansion associated with
graft-vs-leukemia effect on chronic myelogenous leukemia in vivo and in
vitro.
SO - Exp Hematol 2001 Apr;29(4):471-6
AD - Third Department of Medicine, Kanazawa University School of Medicine,
13-1 Takaramachi, Kanazawa, Ishikawa, Japan 920-8641.
Although the graft-vs-leukemia (GVL) effect induced by donor leukocyte
infusion (DLI) is thought to be mediated by T cells, their features, as
well as target molecules, remain unknown. To characterize T cells that
mediate the GVL effect on chronic myelogenous leukemia (CML), we studied
T-cell repertoire in peripheral blood (PB) of two patients treated with
DLI for relapsed CML after allogeneic bone marrow
transplantation.Peripheral blood mononuclear cells (PBMCs) were obtained
at 2-week intervals following DLI and examined for the presence of
antigen-driven T-cell proliferation using complementarity-determining
region (CDR) 3 size spectratyping of T-cell receptor beta chain
subfamilies.Both patients exhibited transient proliferation of a limited
number of T cells at a certain point in time (day 132 for patient 1 and
day 75 for patient 2) after DLI in association with a decrease in the
proportion of Philadelphia chromosome (Ph)-positive cells. In patient 2,
who showed expansion of a BV16(+) T cell in PB, expansion of BV16(+) T
cells with a similar CDR3 motif containing QDR to that of PB was
demonstrated in the bone marrow (BM) sampled on day 33 and in the buccal
mucosal tissue, showing chronic graft-vs-host disease (GVHD) on day 138
after DLI. When PBMCs obtained from patient 2 in remission were cultured
with cryopreserved CML cells for 2 weeks, proliferation of a BV16(+) T
cell with a CDR3 motif of QIR was induced in vitro.These findings
indicate that transient proliferation of a limited number of T cells
detected in PB 3-5 months after DLI probably reflects the GVL response
against CML cells and may serve as a marker for the appearance of the
GVL effect induced by DLI.
3
UI - 11583030
AU - Takubo T; Fujino H; Hino M; Yamane T; Ohta K; Koh KR; Kumura T;
TI -
Hashimoto S; Nakao T; Nakamae H; Aoyama Y; Nishiki S; Kinoshita Y;
Kamitani T; Tatsumi N; Hojo S; Fujita J
Expression of KL-6 antigen on leukemia cells of a patient with chronic
myelocytic leukemia in blastic phase.
SO - Haematologia (Budap) 2001;31(2):173-6
AD - Department of Clinical and Laboratory Medicine, Osaka City University
Medical School, Osaka, Japan. m3542254@med.osaka-cu.ac.jp
4
UI - 12203776
AU - Barbouti A; Johansson B; Hoglund M; Mauritzson N; Strombeck B; Nilsson
TI -
PG; Tanke HJ; Hagemeijer A; Mitelman F; Fioretos T
Multicolor COBRA-FISH analysis of chronic myeloid leukemia reveals novel
cryptic balanced translocations during disease progression.
SO - Genes Chromosomes Cancer 2002 Oct;35(2):127-37
AD - Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
Aikaterini.Barmpouti@klingen.lu.se
During the initial indolent chronic phase of chronic myeloid leukemia
(CML), the t(9;22)(q34;q11), resulting in the Philadelphia chromosome
(Ph), is usually the sole cytogenetic anomaly, but as the disease
progresses into the accelerated phase (AP), and eventually into
aggressive blast crisis (BC), secondary aberrations, mainly unbalanced
changes such as +8, i(17q), and +Ph, are frequent. To date, molecular
genetic studies of CML BC have mainly focused on alterations of
well-known tumor-suppressor genes (e.g., TP53, CDKN2A, and RB1) and
oncogenes (e.g., RAS and MYC), whereas limited knowledge is available
about the molecular genetic correlates of the unbalanced chromosomal
abnormalities. Balanced secondary changes are rare in CML AP/BC, but it
is not known whether cryptic chromosomal translocations, generating
fusion genes, may be responsible for disease progression in a subgroup
of CML. To address this issue, we used multicolor combined binary ratio
fluorescence in situ hybridization (FISH), which allows the simultaneous
visualization of all 24 chromosomes in different colors, verified by
locus-specific FISH in a series of 33 CML cases. Two cryptic balanced
translocations, t(7;17)(q32-34;q23) and t(7;17)(p15;q23), were found in
two of the five cases showing the t(9;22) as the only cytogenetic
change. Using several BAC clones, the breakpoints at 17q23 in both cases
were mapped within a 350-kb region. In the case with the 7p15
breakpoint, a BAC clone containing the HOXA gene cluster displayed a
split signal, suggesting a possible creation of a fusion gene involving
a member of the HOXA family. Furthermore, one case with a partially
cryptic t(9;11)(p21-22;q23) and an MLL rearrangement as well as a
previously unreported t(3;10)(p22;p12-13) were identified. Altogether, a
refined karyotypic description was achieved in 12 (36%) of the 33
investigated cases, illustrating the value of using multicolor FISH for
identifying pathogenetically important aberrations in CML AP/BC.
Copyright 2002 Wiley-Liss, Inc.
5
UI - 12194088
AU - Shaikh A; Parulekar M; James B
TI -
Acute suprachoroidal haemorrhage with acute angle closure glaucoma as a
presenting sign of chronic myelomonocytic leukemia.
SO - Eye 2002 Sep;16(5):651-3
6
UI - 1584598
AU - Pozsonyi T; Jakab L; Jakab L; Onody K; Cseh K; Kalabay L
TI -
[Effect of estrogen on the blast transformation of lymphocytes and
interleukin-2 production in lupus erythematosus]
SO - Orv Hetil 1992 May 10;133(19):1167-71
AD - Semmelweis Orvostudomanyi Egyetem III., Budapest.
The mitogenic response of peripheral lymphocytes was investigated in 12
patients with systemic lupus erythematosus and in healthy female
volunteers who were on 11 and without 9 contraceptive pills. The effect
of estrogen (ethinyl-estradiol 10(-5)-10(-6)-10(-7)M) was studied on
Phytohaemagglutinin and Pokeweed mitogen induced blastogenic
transformation and interleukin-2 production of peripheral lymphocytes in
vitro. We observed a significantly depressed Phytohaemagglutinin induced
lymphoblastic transformation both in patients and women taking oral
contraceptive in presence of 10(-5)M estrogen as compared to normal
controls. However there was no significant alteration neither in the
response of lymphocyte nor in the production of interleukin-2 using of
Pokeweed mitogen. The stimulataneous inhibition of the interleukin-2
production proved to be moderate. Marked significant correlation (r
greater than = 0.8) vas detected between lymphoblastic transformation
and interleukin-2 production in healthy females. Correlation coefficient
measured in females taking oral contraceptive (r less than = 0.64) and
patients with systemic lupus erythematosus (r less than = 0.34) suggest
that in these groups the inhibition of lymphoblastic transformation is
due to the inhibition effect of estrogen on the interleukin-2
production.
7
UI - 8703818
AU - Johnson RJ; Owen RG; Child JA; Morgan GJ; Barnard DL; Dickinson H;
TI -
Ricketts S; Rawstron A; Evans P; Woodhead V; Major K; Robinson F; Smith
GM
Mobilization of Philadelphia-negative peripheral blood mononuclear cells
in chronic myeloid leukaemia using hydroxyurea and G-CSF (filgrastim).
SO - Br J Haematol 1996 Jun;93(4):863-8
AD - General Infirmary at Leeds.
A relatively simple and non-toxic out-patient-based regimen for the
mobilization of Philadelphia-negative (Ph-ve) mononuclear cells in
chronic myeloid leukaemia (CML) was evaluated in 10 patients, nine in
stable chronic phase and one in accelerated phase. They received oral
hydroxyurea at a mean dose of 3.5 g/m2 daily for 7 d, followed by 300
micrograms of G-CSF daily until the last day of harvesting. In the nine
chronic-phase patients the mean number of days from the end of
hydroxyurea to the commencement of harvesting was 14.5 (range 10-18).
The patient in accelerated phase recovered and was harvested after 6 d.
The mean number of aphereses performed was 3.4. Adequate numbers of stem
cells were obtained in 9/10 patients judged by our usual criteria.
Side-effects were mild in comparison to published intravenous schedules.
No patients lost their hair. Five (50%) patients required admission with
neutropenic fever which responded to antibiotics in all cases. Four
(40%) patients developed a transient rash and four (40%) experienced
mild oral mucostis. This level of toxicity enabled half of the patients
to be treated entirely on an out-patient basis. The harvest products
were analysed for cells belonging to the leukaemic clone by conventional
cytogenetics, FISH and PCR. All were PCR positive. The mean Ph
positivities by cytogenetics and FISH were comparable at 18.1% and 15%
respectively. Half the patients had > 98% normal metaphases. We conclude
that this approach is comparable in efficacy to published intravenous
regimens and significantly less toxic. It can be safely used at
diagnosis before interferon therapy commences.
8
UI - 8857964
AU - Carella AM; Frassoni F
TI -
ICE, mini-ICE or high-dose hydroxyurea to mobilize Philadelphia
(Ph1)-negative PBPC in chronic myelogenous leukaemia.
SO - Br J Haematol 1996 Oct;95(1):213-5
9
UI - 12004084
AU - Peled A; Hardan I; Trakhtenbrot L; Gur E; Magid M; Darash-Yahana M;
TI -
Cohen N; Grabovsky V; Franitza S; Kollet O; Lider O; Alon R; Rechavi G;
Lapidot T
Immature leukemic CD34+CXCR4+ cells from CML patients have lower
integrin-dependent migration and adhesion in response to the chemokine
SDF-1.
SO - Stem Cells 2002;20(3):259-66
AD - Hadassah University Hospital, Gene Therapy Institutem, Jerusalem,
Israel. peled@hadassah.org.il
Chronic myelogenous leukemia (CML), a malignant myeloproliferative
disorder originating from a pluripotent stem cell expressing the bcr-abl
oncogene, is characterized by abnormal release of the expanded,
malignant stem cell clone from the bone marrow (BM) into the
circulation. Moreover, immature CD34+ CML cells have lower adhesion to
stromal cells and fibronectin as well as lower engraftment potential in
severe combined immunedeficient (SCID) and nonobese diabetic (NOD)/SCID
mice than normal CD34+ cells. We report in this study that leukemic
Philadelphia chromosome-positive (Ph+)CD34+ cells from newly diagnosed
CML patients that express the chemokine receptor CXCR4 migrate in
response to stromal-derived factor-1 (SDF-1). However, normal
Ph-CD34+CXCR4+ cells derived from the same patient have significantly
higher migration levels toward SDF-1. In contrast to their transwell
migration potential, the SDF-1-mediated integrin-dependent polarization
and migration of the Ph+CD34+CXCR4+ cells through extracellular
matrix-like gels were significantly lower than for normal cells.
Concomitantly, binding of these cells to vascular cell adhesion
molecule-1 or fibronectin, in the presence of SDF-1, was also
substantially lower. These findings suggest a major role for
SDF-1-mediated, integrin-dependent BM retention of Ph+CD34+ cells.
10
UI - 12221673
AU - Kanamori H; Tanaka M; Kawaguchi H; Yamaji S; Fujimaki K; Tomita N;
TI -
Fujisawa S; Ishigatsubo Y
Resolution of psoriasis following allogeneic bone marrow transplantation
for chronic myelogenous leukemia: case report and review of the
literature.
SO - Am J Hematol 2002 Sep;71(1):41-4
AD - First Department of Internal Medicine, Yokohama City University School
of Medicine, Yokohama, Japan. heiwak@med.yokohama-cu.ac.jp
We describe a case of a 49-year-old man with chronic myelogenous
leukemia (CML) whose coincidental psoriasis resolved following
allogeneic bone marrow transplantation (BMT). The patient had suffered
from psoriasis for 20 years and was treated with corticosteroid
ointment. He was diagnosed as having CML in 1998, and his psoriasis
BMT from an HLA-identical sister after undergoing a conditioning regimen
involving busulfan, cytosine arabinoside, and cyclophosphamide.
Prophylaxis of acute graft-versus-host disease was done using short-term
methotrexate and cyclosporin A. His psoriasis improved immediately and
disappeared completely on day 70 after BMT. For 2.5 years, his CML
remains in remission and he is free of psoriasis without undergoing
immunosuppressive therapy. This case suggests the potential benefits of
the treatment of immune-mediated diseases with allogeneic BMT. Copyright
2002 Wiley-Liss, Inc.
11
UI - 12189460
AU - Espinosa G; Font J; Munoz-Rodriguez FJ; Cervera R; Ingelmo M
TI -
Myelodysplastic and myeloproliferative syndromes associated with giant
cell arteritis and polymyalgia rheumatica: a coincidental coexistence or
a causal relationship?
SO - Clin Rheumatol 2002 Aug;21(4):309-13
AD - Service of Autoimmune Diseases, Institut Clinic d'Infeccions i
Immunologia, Institut d'Investigacions Biomediques August Pi i Sunyer
(IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain.
A variety of systemic autoimmune disorders have been reported in
patients with myelodysplastic and myeloproliferative syndromes. A
possible association with polymyalgia rheumatica and giant cell
arteritis has also been recognised. We report another case of
polymyalgia rheumatica and one of giant cell arteritis associated with a
myelodysplastic syndrome and the two first cases of giant cell arteritis
associated with essential thrombocytaemia and chronic myelomonocytic
leukaemia, respectively. It seems that there is a relationship between
these entities, but the nature of this association is still unknown.
12
UI - 11937267
AU - Bhatia R; Williams AD; Munthe HA
TI -
Contact with fibronectin enhances preservation of normal but not chronic
myelogenous leukemia primitive hematopoietic progenitors.
SO - Exp Hematol 2002 Apr;30(4):324-32
AD - Division of Hematology and Bone Marrow Transplantation, City of Hope
National Medical Center, 1500 E Duarte Road, Duarte, CA 91010, USA.
rbhatia@coh.org
OBJECTIVE: Coculture with stromal cells enhances preservation and
self-renewal of primitive progenitor potential in hematopoietic cells
during ex vivo culture with growth factors (GF). However, the respective
roles of growth factors, stromal contact, and extracellular matrix (ECM)
ligands in this effect are not clear. Here we investigated the role of
direct contact with stroma and the ECM protein fibronectin (FN) in these
effects, and investigated whether abnormal integrin receptor function in
chronic myelogenous leukemia (CML) progenitors was associated with
perturbation in these responses. METHODS: Normal bone marrow CD34+ cells
were cultured in GF-containing medium with or without contact with
stromal layers, glutaraldehyde-fixed stromal layers (stroma-contact), or
integrin-binding FN fragments for 7 days. Progeny cells were assayed for
primitive progenitors in week-6 long-term culture-initiating cell
(LTC-IC) and week-10 extended LTC-IC (ELTC-IC) assays. RESULTS:
Increased LTC-IC and ELTC-IC preservation was seen following coculture
with stroma, and was also observed after culture in contact with fixed
stromal layers and FN. Both alpha4beta1 and alpha5beta1-integrin binding
FN fragments enhanced LTC-IC preservation. Analysis of single CD34+CD38-
cells showed that coculture with FN resulted in significantly reduced
cell division, but enhanced retention of LTC-IC capacity in divided
cells. FN also increased LTC-IC frequency in undivided cells. CML
progenitors demonstrate deficient integrin-mediated adhesion, migration,
and signaling. Coculture of CML CD34+ cells with stroma and FN failed to
enhance LTC-IC preservation. CONCLUSION: We conclude that beta1
integrin-FN interactions enhance normal primitive progenitor
preservation with or without cell division, and that these mechanisms
are impaired in CML primitive progenitors.
13
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.
14
UI - 11235567
AU - Tong X; Luo S; Hong W
TI -
[Expression of beta 2 integrins and L-selectin on CML cells after
treatment with IFN-alpha and allo-bone marrow transplantation]
SO - Zhonghua Zhong Liu Za Zhi 2000 Nov;22(6):474-6
AD - Department of Hematology, First Affiliated Hospital of Sun Yat-sen
University of Medical Sciences, Guangzhou 510080, China.
OBJECTIVE: To study the expression of L-selectin, Mac-1, LFA-1 on CML
progenitor cells in relation to CML progression and therapeutic effect.
METHODS: The expression of adhesion molecules (LFA-1, Mac-1, L-selectin)
on bone marrow CD34+ cells from 34 CML patients were analyzed by
three-color flow cytometry. RESULTS: The mean percentage of expression
of L-selectin, and LFA-1 on CD34+ CD38-(-)+ cells from untreated CML
patients was significantly lower than that from normal controls. Among 8
CML patients treated with IFN-alpha, the expression of L-selectin and
LFA-1 on CD34+ CD38- cell (37.6 +/- 5.3%, 42.1 +/- 13.1%) was comparable
to that from normal controls (38.2 +/- 9.4%, 48.2 +/- 12.2%). L-selectin
expression in CD34+ CD38- cells from CML patients was inversely
correlated with the percentage of Ph'(+) cells. In 2 CML patients
treated with allo-bone marrow transplantation, the expression rate of
L-selectin, IFA-1 and Mac-1 on CD38+ CD38- cells was comparable to that
from normal controls. CONCLUSION: The data suggest that decreased
expression of L-selectin and LFA-1 in CML CD34+ cells reflects one of
the features of malignant CML progenitors. IFN-alpha and allo-BMT
restore the expression of Mac-1, L-selectin and LFA-1 to normal on CML
CD34+ cells.
15
UI - 12006504
AU - Cohen MH; Williams G; Johnson JR; Duan J; Gobburu J; Rahman A; Benson K;
TI -
Leighton J; Kim SK; Wood R; Rothmann M; Chen G; U KM; Staten AM; Pazdur
R
Approval summary for imatinib mesylate capsules in the treatment of
chronic myelogenous leukemia.
SO - Clin Cancer Res 2002 May;8(5):935-42
AD - Division Oncology Drug Products, Center for Drug Evaluation and
Research, Food and Drug Administration, Rockville, Maryland 20857, USA.
cohenm@cder.fda.gov
PURPOSE: Chronic myelogenous leukemia (CML) results from the breakpoint
cluster region-Abl fusion gene product, a tyrosine kinase involved in
cell division and apoptosis. Imatinib, an orally administered inhibitor
of the breakpoint cluster region-Abl tyrosine kinase, is capable of
blocking proliferation and inducing apoptosis in CML cell lines. In this
report, we describe the preclinical profile of imatinib and the data
submitted in the New Drug Application that led to its marketing
approval. EXPERIMENTAL DESIGN: Chemistry manufacturing and controls,
animal toxicology, and biopharmaceutical data are described. Results of
Phase I and Phase II clinical studies in patients with CML in blast
crisis (CML-BC), in accelerated phase (CML-AP), and in chronic phase
disease-resistant or intolerant to IFN-alpha (CML-CP) are summarized.
The basis for marketing approval and postmarketing commitments by the
pharmaceutical company are discussed. RESULTS: Toxicology studies in the
rat, dog, and monkey show the hematological, renal, and hepatobiliary
toxicity of imatinib. Pharmacokinetic studies in patients with CML
demonstrate 98% imatinib bioavailability. The elimination half-lives of
the parent drug and the major active metabolite, CGP74588, from plasma
are approximately 18 and 40 h, respectively. Approximately 81% of the
drug is eliminated in 7 days, 68% in the feces and 13% in the urine.
Cytochrome P-450 3A4 is the main enzyme responsible for imatinib
metabolism. Phase I and II clinical studies were conducted. The Phase I
study, in 83 CML patients, evaluated oral imatinib doses from 25 to 1000
mg/day. Dose-limiting toxicity was not observed. The three Phase II
studies, in CML-CP, CML-AP, and CML-BC, enrolled 1027 patients. CML-CP
patients received 400 mg/day imatinib, whereas CML-AP and CML-BC
patients generally received 600 mg/day imatinib. Primary study endpoints
were cytogenetic response rate (CML-CP) and hematological response rate
(CML-AP and CML-BC). The cytogenetic response rate for CML-CP patients
was 49%. The hematological response rate of CML-AP and CML-BC patients
was 63 and 26%, respectively. The most common imatinib adverse events
were nausea, vomiting, myalgia, edema, and diarrhea. Elevated liver
enzymes and/or bilirubin were reported in 27 patients (2.6%).
CONCLUSIONS: On May 10, 2001, imatinib mesylate (Gleevec, formerly known
as STI-571 and Glivec), manufactured and distributed by Novartis
Pharmaceuticals, East Hanover, NJ, was approved by the United States
Food and Drug Administration for the treatment of CML in three clinical
settings: CML-BC, CML-AP, and CML-CP. This report summarizes the Food
and Drug Administration's review of the New Drug Application.
16
UI - 12194684
AU - Artigas CG; Melo A; Roa JC; Paez E; Vittini C; Arriagada M; Gonzalez L;
TI -
Pflaumer E; Roa I
[Detection of BCR-ABL gene sequences using RT-PCR in patients with
leukemia in the IX region. Chile]
SO - Rev Med Chil 2002 Jun;130(6):623-30
AD - Departamento Medicina Interna, Facultad de Medicina, Universidad de La
Frontera, Casilla 54-D, Temuco-Chile. cgartiga@ufro.cl
BACKGROUND: The BCR-ABL fusion gene is the molecular expression of the
Philadelphia chromosome. This cytogenetic aberration is the most
frequent alteration found in leukemias, which is produced by the
translocation t(9;22). Two different fusion proteins are produced
depending on the break point (210 kD and 190 kD). The detection of this
gene has both diagnostic and prognostic importance, associated with poor
prognosis in acute lymphoblastic leukemia (ALL). AIM: To detect BCR-ABL
gene sequences in patients with leukemia from the IX Region of Chile.
MATERIAL AND METHODS: We studied 58 patients: 5 chronic myeloid leukemia
(CML), 35 ALL, 15 acute myeloid leukemia (AML) and 3 biphenotypic
leukemia. The gene sequences were detected using reverse transcriptase
polymerase chain reaction (RT-PCR). RESULTS: BRC-ABL gene sequences were
positive in all patients with CML, 2 of 35 ALL (one child and one
adult). The remaining patients were negative. We found p210 and p190
co-expression in 2 CML and 1 ALL. CONCLUSIONS: Our results are in
agreement with other reports. The detection of these and other genetic
alterations will allow us to have invaluable diagnostic and prognostic
information from our patients with leukemia.
17
UI - 12174121
AU - Beretta L; Caronni M; Vanoli M; Scorza R
TI -
Systemic sclerosis after interferon-alfa therapy for myeloproliferative
disorders.
SO - Br J Dermatol 2002 Aug;147(2):385-6
18
UI - 12357373
AU - Ohyashiki K; Kuriyama Y; Nakajima A; Tauchi T; Ito Y; Miyazawa H; Kimura
TI -
Y; Serizawa H; Ebihara Y
Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia
demonstrated focal necrosis resembling acute viral hepatitis.
SO - Leukemia 2002 Oct;16(10):2160-1
19
UI - 11000992
AU - Pigneux A; Mahon FX; Reiffers J
TI -
Autologous peripheral blood stem cell transplantation for chronic
myelocytic leukaemia, using unmanipulated grafts.
SO - Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):193-8
AD - Service d'Hematologie, Hopital du Haut Leveque, Bordeaux, France.
In chronic myeloid leukaemia (CML) allogeneic stem cell transplantation
can be proposed to a minority of patients who are both less than 50
years of age and have an HLA-identical donor. Recombinant
alpha-interferon induces cytogenetic responses (and prolongation of
survival) in only 25-40% of patients. Thus, alternative treatments need
to be proposed. When performed in chronic phase with unmodified stem
cells, autologous stem cell transplantation is followed by cytogenetic
responses in about 40% of cases, and some data suggest that these
responder patients could have a prolongation of survival. This now needs
to be demonstrated prospectively. If so, further studies could be
performed in order to define the best source of stem cells (purged or
unpurged) to be used.
20
UI - 11000993
AU - Frassoni F; Podesta M; Piaggio G
TI -
Normal and leukaemic haematopoiesis in bone marrow and peripheral blood
of patients with chronic myeloid leukaemia.
SO - Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):199-208
AD - Dipartimento di Ematologia, Divisione Ematologia II, Ospedale San
Martino, Genoa, Italy.
In the majority of newly diagnosed patients with chronic myeloid
leukaemia (CML), the bone marrow contains consistent numbers of normal
Ph-negative surrogate stem cells (LTC-IC) which seem to decline rapidly
with time. This is confirmed by mobilization studies showing that early
after diagnosis is the optimal time to collect Ph-negative progenitor to
be utilized for restoring Ph-negative haematopoiesis. In the marrow of
the majority of CML patients at diagnosis Ph-positive LTC-IC are found
at a lower frequency than Ph-negative LTC-IC and, unexpectedly, they do
not show a tendency to increase with time as long as patients remain in
chronic phase. Therefore, the decline of normal haematopoiesis does not
seem related to a parallel increase in Ph-positive stem cells.
21
UI - 11000994
AU - Carella AM; Cavaliere M; Lerma E; Corsetti MT
TI -
Autologous peripheral blood haematopoietic stem cell transplantation for
chronic myelogenous leukaemia.
SO - Baillieres Best Pract Res Clin Haematol 1999 Mar-Jun;12(1-2):209-17
AD - Haematology and ABMT Unit, Azienda Ospedaliera e Cliniche, Universitarie
Convenzionate, Ospedale San Martino, Genoa, Italy.
In these last four decades there has been extraordinary progress in our
understanding of the biology of, and therapeutic approach to, chronic
myelogenous leukaemia (CML). During these decades new observations
arising from studies of the biological behaviour of diploid and
leukaemic stem cells and, recently, from clinical investigations have
received the most attention. From a clinical point of view, allografting
is still the only procedure which is able to cure CML. For patients
without HLA-compatible donors, current therapeutic options include
conventional chemotherapy (hydroxyurea), interferon-alpha (IFN-alpha)
and autografting. While IFN-alpha (+/- low-dose ARA-C) must be
considered the first-line therapy, autografting, according to our
approach, or other procedures, raises the question of an ideal
sequential strategy in the management of CML patients (diploid stem cell
mobilization, autografting, IFN-alpha). Because it seems that the
diploid haematopoietic reservoir declines with time, it may be desirable
to mobilize and collect diploid stem cells in order to store them as
soon as diagnosis is possible when the WBC count has been controlled by
hydroxyurea.
22
UI - 12171771
AU - Spiers AS
TI -
Management of the chronic leukemias: special considerations in the
elderly patient. Part III rarer chronic myeloid leukemias.
SO - Hematology 2002 Feb;7(1):1-8
AD - Department of Haematology, John Radcliffe Hospital, Oxford, UK.
The manifestations, diagnosis and management of the rarer chronic
myeloid leukemias are reviewed, with special attention to problems that
affect elderly patients. The spectrum of disorders includes atypical
myeloproliferative syndrome, so-called Ph-negative CGL, chronic
myelomonocytic leukemia, and leukemias characterized by chronic
proliferation of neutrophil, eosinophil, or basophil leukocytes. These
latter are sometimes difficult to differentiate from chronic nonleukemic
proliferations of the index cells. Termination in an acute myeloid
leukaemia that is usually refractory to treatment may occur in any of
the above disorders but is not a constant event.
23
UI - 12365015
AU - Onida F; Ball G; Kantarjian HM; Smith TL; Glassman A; Albitar M;
TI -
Scappini B; Rios MB; Keating MJ; Beran M
Characteristics and outcome of patients with Philadelphia chromosome
negative, bcr/abl negative chronic myelogenous leukemia.
SO - Cancer 2002 Oct 15;95(8):1673-84
AD - Department of Leukemia, The University of Texas M. D. Anderson Cancer
Center, Houston, Texas 77030, USA.
BACKGROUND: Up to 5% of patients with chronic myelogenous leukemia (CML)
do not have the Philadelphia (Ph) translocation t(9;22)(q34;q11) or a
bcr/abl molecular rearrangement. Although the diagnostic criteria of
this entity are still under debate, there is general agreement that
patients with Ph negative, bcr/abl negative CML have a severe clinical
course that is not affected significantly by current treatment options.
METHODS: A population of 76 patients with bcr/abl negative CML who had
received minimal or no previous therapy was characterized carefully with
the intent of investigating clinical and hematologic variables and their
association with survival by univariate, correlation, and multivariate
analyses. A group of 73 patients with Ph negative CML who were not
tested for the bcr/abl rearrangement (bcr/abl unknown) was analyzed
separately and used for extension of the analysis. RESULTS: In the
bcr/abl negative patient population, the median overall survival was 24
months. At the time of the analysis, 38 patients (50%) had died, and
blastic transformation preceded death in 31%. Chromosomal abnormalities
were found in 30% of the 76 patients, with trisomy 8 the most common
abnormality. Complex chromosomal abnormalities were rare, and monosomy 7
was not observed. Survival was not affected significantly by treatment.
Multivariate analysis identified older age (> 65 years), anemia
(hemoglobin < 10 g/dL), and severe leukocytosis (white blood cells > 50
x 10(9)/L) as variables with independent prognostic significance for
poor survival. A prognostic scoring system stratified patients into a
low-risk group (53%) and a high-risk group (47%), with median survivals
of 38 months and 9 months, respectively. CONCLUSIONS: Bcr/abl negative
CML is a distinct clinical entity associated with very poor prognosis.
Two risk categories are identifiable using a simple scoring system based
on age, hemoglobin level, and leukocyte number. Copyright 2002 American
Cancer Society.
24
UI - 12011769
AU - Prejzner W
TI -
Relationship of the BCR gene breakpoint and the type of BCR/ABL
transcript to clinical course, prognostic indexes and survival in
patients with chronic myeloid leukemia.
SO - Med Sci Monit 2002 May;8(5):BR193-7
AD - Department of Hematology, Medical University of Gdansk, Poland.
BACKGROUND: Chronic myeloid leukemia is characterized by the presence of
the Philadelphia chromosome. At the molecular level a fusion of part of
the ABL and BCR genes is observed. The breakpoint locations in the BCR
gene fall between exons b2a2 or b3a2 (5' and 3', respectively).
Depending on the BCR gene breakpoint two types of mRNA are created.
Differences in the types of transcripts and/or the breakpoint site may
have an influence on the clinical course of the disease. This prompted
the present author to separate subtypes of chronic myeloid leukemia on
the molecular level. MATERIAL/METHODS: 71 patients diagnosed with
chronic myeloid leukemia in the chronic phase were enrolled in the
study. In 61 patients the type of BCR/ABL transcript was determined, and
in 27 patients BCR breakpoints were established. Possible correlations
between the clinical course, prognostic indexes, survival and the type
of transcript and breakpoint were examined. RESULTS: No correlation
between the clinical course, prognostic index, or survival was observed
in patients with 5' and 3' breakpoints. The patients with b3a2
transcript experienced longer survival than the patients expressing b2a2
transcript. However, no significant differences were observed in the
duration of the chronic phase between the two groups. CONCLUSIONS: The
type of BCR gene breakpoint seems to have no prognostic value in
patients with chronic myeloid leukemia. The longer survival of patients
expressing the b3a2 transcript may be caused by the less aggressive
course of the accelerated or blastic phase.
25
UI - 12296996
AU - Shim MJ; Kim HJ; Yang SJ; Lee IS; Choi HI; Kim T
TI -
Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562
cells: possible involvement of p38 MAP kinase.
SO - J Biochem Mol Biol 2002 Jul 31;35(4):377-83
AD - Department of Biomedical Laboratory Science, College of Health Science,
Yonsei University, Wonju 220-710, Korea. Kimtu@dragon.yonsei.ac.kr
Arsenic trioxide (As(2)O(3)) was recently demonstrated to be an
effective inducer of apoptosis in patients with relapsed acute
promyelocytic leukemia (APL) as well as in patients with APL in whom
all-trans-retinoic acid and conventional chemotherapy failed. Chronic
myelogenous leukemia cells are highly resistant to chemotherapeutic
drugs. To determine if As(2)O(3) might be useful for the treatment of
chronic myelogenous leukemia, we examined the ability of As(2)O(3) to
induce apoptosis in K562 cells. In vitro cytotoxicity of As(2)O(3) was
evaluated in K562 cells by a MTT assay; the IC(50) value for As(2)O(3)
was determined to be 10 microM. When analyzed by agarose gel
electrophoresis, the DNA fragments became evident after incubation of
the cells with 20 microM As(2)O(3) for 24 h. We also found morphological
changes and chromatin condensation of the cells undergoing apoptosis.
Activation of caspase-3 was observed 6 h after treatment with 20 microM
As(2)O(3) by a Western blot analysis. Next, we examined the MAP
kinase-signaling pathway of As(2)O(3)-induced apoptosis in K562 cells.
As(2)O(3) at 10 microM strongly induced the activation of p38 and JNK
1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580,
a specific inhibitor of p38, inhibited As(2)O(3) induced apoptotic cell
death. These results suggest that As(2)O(3) is able to induce the
apoptotic activity in K562 cells, and its apoptotic mechanism may be
associated with the activation of p38.
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