Table of Contents
1
UI - 11526594
AU - Sawyers CL
TI -
Implications of signal transduction inhibition for the treatment of
chronic myeloid leukemia.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):1-2
AD - Department of Medicine, Division of Hematology and Oncology, Molecular
Biology Institute, University of California Los Angeles School of
Medicine, Los Angeles, CA 90095, USA.
2
UI - 11526597
AU - Sawyers CL
TI -
Molecular studies in chronic myeloid leukemia patients treated with
tyrosine kinase inhibitors.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):15-21
AD - Department of Medicine, Division of Hematology and Oncology, Molecular
Biology Institute, University of California Los Angeles School of
Medicine, Los Angeles, CA 90095, USA.
The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis
Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) blocks the
constitutively activated Bcr-Abl tyrosine kinase that is characteristic
of chronic myeloid leukemia (CML). Molecular analysis for the presence
of residual Bcr-Abl-positive cells in patients with a cytogenetic
response following treatment with imatinib mesylate reveals that some
patients have undetectable disease using quantitative
reverse-transcriptase polymerase chain reaction (RT-PCR) assays capable
of detecting 1 in 10(5) Philadelphia chromosome-positive (Ph(+)) cells.
To examine whether the leukemia is still Bcr-Abl-dependent in patients
who have responded to imatinib mesylate but have relapsed, a
quantitative assay that directly measures enzymatic activity of Bcr-Abl
toward one of its major signaling substrates has been developed. This
assay allows monitoring both of the imatinib mesylate sensitivity of
patient cells in vitro, and of the endogenous inhibition of Bcr-Abl
kinase activity during imatinib mesylate treatment and relapse. Studies
show that imatinib mesylate resistance is associated with restored
activation of the Bcr-Abl signal transduction pathway in the majority of
cases, indicating that Bcr-Abl remains a valid target for therapeutic
intervention. Understanding resistance mechanisms of Ph(+) leukemia to
imatinib mesylate will allow design of therapies to overcome such
barriers to efficacy. Copyright 2001 by W.B. Saunders Company.
3
UI - 11526598
AU - Talpaz M
TI -
Interferon-alfa-based treatment of chronic myeloid leukemia and
implications of signal transduction inhibition.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):22-7
AD - Division of Medicine, Department of Bioimmunotherapy, M.D. Anderson
Cancer Center, Houston, TX 77030, USA.
The cytokine interferon-alfa (IFN-alpha) has substantial activity in
chronic myeloid leukemia (CML) and is the nontransplant standard of care
for chronic-phase disease. When used as front-line therapy, IFN-alpha
induces a state of tumor dormancy and delays progression to advanced
phase. Unfortunately, IFN-alpha is associated with substantial toxicity
at therapeutic doses. The introduction of pegylated IFN-alpha
(PEG-IFN-alpha), a modified form of the protein that permits weekly
administration, may alleviate some of the problems observed with
IFN-alpha. Combination regimens of IFN-alpha with other drugs such as
cytarabine (Ara-C) appear to enhance efficacy and are currently under
investigation. The tyrosine kinase inhibitor imatinib mesylate (Gleevec,
Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) also
is efficacious in chronic-phase CML, with a low toxicity profile.
However, its potential to cure CML remains unknown even though it
achieves frequent cytogenetic responses. To enhance treatment outcome, a
combination of IFN-alpha and imatinib mesylate therapies is proposed.
Low-dose IFN-alpha may be given after imatinib mesylate-induced
remission as a specific immune stimulant to consolidate the remission.
Recent data showing a possible additive effect of imatinib mesylate and
IFN-alpha suggest that concurrent use of these agents may also be more
effective than single use, particularly in advanced stages of CML where
imatinib mesylate has activity but resistance develops. Copyright 2001
by W.B. Saunders Company.
4
UI - 11526599
AU - Goldman J
TI -
Implications of imatinib mesylate for hematopoietic stem cell
transplantation.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):28-34
AD - Department of Haematology, Imperial College School of Medicine,
Hammersmith Hospital, London, UK.
The ability of allogeneic bone marrow or blood stem cell transplantation
(SCT) to induce long-term remission or cure of chronic myeloid leukemia
(CML) is well established. However, the use of this treatment is limited
by the availability of suitable human leukocyte antigen (HLA) identical
siblings or matched unrelated donors (MUD). As a consequence only a
relatively small proportion of CML patients are eligible for a
transplant, and of these not all are cured. The preliminary results of
trials using the new Bcr-Abl kinase inhibitor imatinib mesylate
(formerly CGP57-148B, STI571, Gleevec) to treat CML are very
encouraging. However, a number of important questions cannot yet be
answered: Can imatinib mesylate induce durable molecular remissions? Can
the drug prolong survival in comparison with other nontransplant
treatments? and, can it actually cure CML patients? Until answers to
these questions are available, SCT and use of interferon-alfa
(IFN-alpha) alone or in combination (perhaps with imatinib mesylate)
must remain major therapeutic options. I summarize here the advantages
and disadvantages associated with currently available therapy. I review
three different approaches to initial treatment of the CML patient
diagnosed in chronic phase, and make a tentative recommendation for one
of these options. It is likely that the situation will alter
considerably in the foreseeable future. Copyright 2001 by W.B. Saunders
Company.
5
UI - 11526600
AU - Appelbaum FR
TI -
Perspectives on the future of chronic myeloid leukemia treatment.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):35-42
AD - Fred Hutchinson Cancer Research Center, University of Washington School
of Medicine, Seattle, WA 98109-1024, USA.
Chronic myeloid leukemia (CML) is probably the best understood human
malignancy at the molecular level, but among the hardest to explain to
patients concerning appropriate treatment options. At present, we do not
know the long-term outcome of promising new therapies such as the
tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis
Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) and
nonmyeloablative transplants. There is also no reliable way to predict
which patients will respond to a particular therapy. The development of
methods to predict therapeutic response will be of major benefit to
patients, and the newly emerging science of gene array analysis may
provide such a tool. In this context, given the proven likelihood of
cure with allogeneic transplantation and the negative effects of delay,
in Seattle we continue to suggest transplantation as the initial form of
therapy for patients below age 55 years with matched sibling donors. For
patients without matched donors below the age of 40, we would suggest an
unrelated donor search and only proceed directly to transplant for those
with allele-level matches. For younger patients without matches and
those aged 40 to 55, an initial trial of imatinib mesylate might be
preferred. For patients over age 55 with CML, initial therapy with
imatinib mesylate, possibly an interferon-containing regimen or
nonmyeloablative allogeneic transplantation may be considered. Copyright
2001 by W.B. Saunders Company.
6
UI - 11526596
AU - Druker B
TI -
Signal transduction inhibition: results from phase I clinical trials in
chronic myeloid leukemia.
SO - Semin Hematol 2001 Jul;38(3 Suppl 8):9-14
AD - Department of Medicine, Division of Hematology and Medical Oncology,
Oregon Health and Science University, Portland, OR 97201, USA.
The tyrosine kinase inhibitor, imatinib mesylate (Gleevec, Novartis
Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) showed
significant antileukemic activity with minimal toxicity in preclinical
studies. Based on these data, a phase I clinical trial was conducted in
patients with chronic myeloid leukemia (CML) who failed other treatment
options. Once therapeutic doses were attained, 53 of 54 patients (98%)
in the chronic phase achieved hematologic remissions. With prolonged
therapy of 2 to 5 months duration, a growing percentage of patients
achieved cytogenetic responses. Imatinib mesylate also has activity as a
single agent in CML blast crisis and in patients with Ph(+) acute
lymphocytic leukemia (ALL). Although responses tend not to be durable,
20% of patients with myeloid blast crisis are in continuous remission
for periods up to 1 year. Ongoing clinical studies are directed at
optimizing the use of imatinib mesylate. Copyright 2001 by W.B. Saunders
Company.
7
UI - 11843818
AU - Bhatia R; Munthe HA; Forman SJ
TI -
Abnormal growth factor modulation of beta1-integrin-mediated adhesion in
chronic myelogenous leukaemia haematopoietic progenitors.
SO - Br J Haematol 2001 Dec;115(4):845-53
AD - Division of Hematology and Bone Marrow Transplantation, City of Hope
National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
rbhatia@coh.org
Abnormal progenitor circulation and extramedullary haematopoiesis are
characteristic features of chronic myelogenous leukaemia (CML). Growth
factor (GF) and beta1-integrin interactions play an important role in
regulation of progenitor trafficking to and from the marrow space. CML
progenitors demonstrate abnormal beta1-integrin-mediated adhesion to
fibronectin (FN). In the present study we investigated whether GF
modulation of beta1-integrin-mediated adhesion and migration was altered
in CML progenitors. Culture with low concentrations of GF enhanced
normal progenitor adhesion to FN compared with no GF, but failed to
enhance CML progenitor adhesion to FN. Similarly, high concentrations of
selected GF rapidly enhanced beta1-integrin-mediated adhesion of normal
progenitors to FN through a phosphotidylinositol-3 (PI-3)
kinase-dependent mechanism, but failed to increase CML progenitor
adhesion. Exposure to a BCR-ABL tyrosine kinase inhibitor restored GF
modulation of CML progenitor adhesion. CML colony-forming cells (CFC)
demonstrated increased migration across FN-coated transwells compared
with normal CFC in the absence of GF. The addition of stem cell factor
resulted in enhanced migration of CML and normal CFC on FN. In
conclusion, GF stimulation failed to enhance integrin-mediated adhesion
but enhanced migration in CML progenitors on FN. BCR-ABL induced
abnormalities in GF-integrin interactions could contribute to abnormal
circulation and microenvironmental localization of CML progenitors.
8
UI - 11806985
AU - Onida F; Kantarjian HM; Smith TL; Ball G; Keating MJ; Estey EH; Glassman
TI -
AB; Albitar M; Kwari MI; Beran M
Prognostic factors and scoring systems in chronic myelomonocytic
leukemia: a retrospective analysis of 213 patients.
SO - Blood 2002 Feb 1;99(3):840-9
AD - Department of Leukemia, The University of Texas M. D. Anderson Cancer
Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy
characterized by wide heterogeneity of clinical presentation and course.
CMML shares myelodysplastic characteristics with features of
myeloproliferative disorders. No treatment has proven effective in
modifying the natural course of the disease. To improve the prognostic
assessment of clinical outcome, the associations of patient and disease
characteristics with survival times of 213 patients with CMML was
investigated retrospectively. Median survival was 12 months. Univariate
analysis identified low hemoglobin level; low platelet count; high white
blood cell, monocyte, and lymphocyte counts; presence of circulating
immature myeloid cells, high percentage of marrow blasts, low percentage
of marrow erythroid cells, abnormal cytogenetics, and high levels of
serum lactate dehydrogenase and beta(2)-microglobulin as characteristics
associated with shorter survival. Hemoglobin level below 120 g/L (12
g/dL), presence of circulating immature myeloid cells, absolute
lymphocyte count above 2.5 x 10(9)/L, and marrow blasts 10% or more were
independently associated with shorter survival by multivariate analysis
and were used to generate a prognostic score. The model identified 4
subgroups of patients with median survival of 24, 15, 8, and 5 months
for low, intermediate-1, intermediate-2, and high risk, respectively.
Researchers could not confer objective evidence suggesting that
arbitrary divisions of CMML by white blood cell counts into "dysplastic"
and "proliferative" categories reflect clinical entities differing in
the risk of acute leukemia development, although a trend of shorter
survival in patients with leukocytosis was observed. The prognostic
model was compared with 6 previously published scoring systems for
myelodysplastic syndrome/CMML. The reported results should provide an
improved assessment of prognosis in CMML.
9
UI - 11841395
AU - Reilly JT
TI -
Chronic neutrophilic leukaemia: a distinct clinical entity?
SO - Br J Haematol 2002 Jan;116(1):10-8
AD - Molecular Haematology Unit, Division of Molecular and Genetic Medicine,
Royal Hallamshire Hospital, Sheffield, UK. j.t.reilly@sheffield.ac.uk
10
UI - 11841409
AU - Voskaridou E; Terpos E; Komninaka V; Eftyhiadis E; Mantzourani M;
TI -
Loukopoulos D
Chronic myeloid leukaemia with marked thrombocytosis in a patient with
thalassaemia major: complete haematological remission under the
combination of hydroxyurea and anagrelide.
SO - Br J Haematol 2002 Jan;116(1):155-7
AD - Unit of Thalassaemia, Laikon General Hospital, Athens, Greece.
dloukop@otenet.gr
The co-existence of thalassaemia major and chronic myeloid leukaemia
(CML) is a very rare event. We report a 32-year-old man with
thalassaemia major whose progressively increasing leukocytosis and
thrombocytosis led to the diagnosis of CML confirmed by the
characteristic t(9;22)(q34;q11) chromosomal translocation and the
bcr-abl (b3a2) DNA fusion. The patient was treated with hydroxyurea and
anagrelide. This combination resulted in the satisfactory control of
both the white blood cell and platelet counts, which has continued over
the past 14 months with no major side-effects, albeit with no molecular
response. The administration of hydroxyurea was also associated with a
significant HbF increase.
11
UI - 11841411
AU - Marley SB; Davidson RJ; Goldman JM; Gordon MY
TI -
Effects of combinations of therapeutic agents on the proliferation of
progenitor cells in chronic myeloid leukaemia.
SO - Br J Haematol 2002 Jan;116(1):162-5
AD - Leukaemia Research Fund Centre for Adult Leukaemia, Department of
Haematology, Imperial College School of Medicine, London, UK.
s.marley@ic.ac.uk
Combination of STI571, a tyrosine kinase inhibitor, with other drugs may
be beneficial in the treatment of chronic myeloid leukaemia (CML). We
measured the effects of STI571, AG490, farnesyltransferase inhibitor
(FTI), interferon alpha (IFN-alpha), cytosine arabinoside (Ara-C) and
all-trans retinoic acid (ATRA), singly and in combination, on clonogenic
leukaemic cell proliferation. STI571, IFN-alpha and ATRA each reduced
proliferation by 50-60%; AG490, FTI and Ara-C had less effect. Comparing
the observed and expected (i.e. additive) effects of drug combinations
showed STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA were additive;
STI571 + IFN-alpha, IFN-alpha + Ara-C and STI571 + AG490 + FTI were less
than additive. Thus, STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA
may be better combination therapies for CML than STI571 + IFN-alpha,
IFN-alpha + Ara-C or STI571 + AG490 + FTI.
12
UI - 11841417
AU - Pigneux A; Tanguy ML; Michallet M; Jouet JP; Kuentz M; Vernant JP;
TI -
Milpied N; Ifrah N; Cahn JY; Gratecos N; Reman O; Cure H; Caillot D;
Witz F; Pillier-Loriette C; Tron P; Reiffers J; Societe Francaise de
Greffe de Moelle
Prior treatment with alpha interferon does not adversely affect the
outcome of allogeneic transplantation for chronic myeloid leukaemia.
SO - Br J Haematol 2002 Jan;116(1):193-201
AD - Service d'Hematologie, Hopital du Haut Leveque, CHU Bordeaux, Pessac,
France.
The timing of transplantation in chronic myeloid leukaemia is still
debated and previous treatment with interferon (IFN) alpha has been
reported to be deleterious. We have analysed the outcome of 438
allogeneic transplants performed between 1984 and 1995 and reported to
the Societe Francaise de Greffe de Moelle (SFGM) registry. One hundred
and two patients (group I) received IFN for more than 6 weeks (median =
9 months) before transplant. Their outcome was compared with 336 other
patients (group II) not pretreated with IFN. There were no significant
differences between the groups for engraftment and chronic
graft-versus-host disease (GVHD) incidence. However, other significant
differences included the incidence of acute GVHD > or = 2 at 3 months
which was higher in group I (65 +/- 10%) than in group II (38 +/- 5%; P
= 0.01). Moreover, disease-free survival (DFS) and overall survival (OS)
at 5 years were significantly shorter for group I than for group II (33
+/- 10% vs. 41 +/- 6%; P = 0.005)(95% CI) and (41 +/- 10% vs. 55 +/- 6%;
P = 0.002)(95% CI) respectively. After adjustment for patient and
transplant covariables in a multivariate analysis, prior IFN was not
found to adversely affect transplant outcome.
13
UI - 11848092
AU - Keung YK; Pettenati M; Hurd DD; Powell BL; Buss DH
TI -
Allogenic marrow grafts from unrelated donors with congenital
pericentric inversion of chromosome 9.
SO - Br J Haematol 2002 Jan;116(1):237-8
14
UI - 11865642
AU - Uehara E; Uesugi T; Tasaka T; Matsuhashi Y; Tamura T; Kuwajima M; Nagai
TI -
M
[Reversible cardiomyopathy secondary to interferon-alpha in chronic
myelogenous leukemia]
SO - Gan To Kagaku Ryoho 2002 Feb;29(2):317-21
AD - Division of Internal Medicine, Kagawa Prefectural Central Hospital.
Interferon-alpha (IFN-alpha) has been accepted as an effective agent in
the treatment of chronic myelogenous leukemias (CML). Cardiac toxicity
of IFN-alpha has rarely been reported in cases of CML. A 62-year-old
woman with a two-year history of chronic myelogenous leukemia who had
been treated with IFN-alpha (10 million U/3 days/week) given
subcutaneously with oral hydroxycarbamide 500 mg, presented with chest
pain, dyspnea and subconsciousness. Chest X-ray revealed cardiomegaly
and congestion, and ultrasonography showed diffuse hypokinesis of the
heart with decreased left ventricular ejection fraction (LVEF) 34%. She
was diagnosed cardiomyopathy caused by IFN-alpha administration. She was
treated with furosemide, dobutamine hydrochloride, milrinone and
carperitide. The administration of IFN-alpha was terminated. LVEF was
improved to 50% within one month from the onset of events, and the
patient was discharged. We discuss herein the cardiomyopathy caused by
IFN-alpha in CML.
15
UI - 11870241
AU - Kantarjian H; Sawyers C; Hochhaus A; Guilhot F; Schiffer C;
TI -
Gambacorti-Passerini C; Niederwieser D; Resta D; Capdeville R; Zoellner
U; Talpaz M; Druker B; The International STI571 CML Study Group
Hematologic and cytogenetic responses to imatinib mesylate in chronic
myelogenous leukemia.
SO - N Engl J Med 2002 Feb 28;346(9):645-52
AD - M.D. Anderson Cancer Center, Houston, TX 77030, USA.
hkantarj@mdanderson.org
BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL
tyrosine kinase, the product of the Philadelphia chromosome. Imatinib
mesylate, formerly STI571, is a selective inhibitor of this kinase.
METHODS: A total of 532 patients with late--chronic-phase CML in whom
previous therapy with interferon alfa had failed were treated with 400
mg of oral imatinib daily. Patients were evaluated for cytogenetic and
hematologic responses. Time to progression, survival, and toxic effects
were also evaluated. RESULTS: Imatinib induced major cytogenetic
responses in 60 percent of the 454 patients with confirmed chronic-phase
CML and complete hematologic responses in 95 percent. After a median
follow-up of 18 months, CML had not progressed to the accelerated or
blast phases in an estimated 89 percent of patients, and 95 percent of
the patients were alive. Grade 3 or 4 nonhematologic toxic effects were
infrequent, and hematologic toxic effects were manageable. Only 2
percent of patients discontinued treatment because of drug-related
adverse events, and no treatment-related deaths occurred. CONCLUSIONS:
Imatinib induced high rates of cytogenetic and hematologic responses in
patients with chronic-phase CML in whom previous interferon therapy had
failed.
16
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.
17
UI - 11642601
AU - Claxton DF; McMannis J; Champlin R; Choudhury A
TI -
Therapeutic potential of leukemia-derived dendritic cells: preclinical
and clinical progress.
SO - Crit Rev Immunol 2001;21(1-3):147-55
AD - Division of Hematology/Oncology, Milton S. Hershey Medical Center,
Hershey, PA 17033, USA. dclaxton@psu.edu
Human leukemia-derived dendritic cells show potential as tools for
therapy. Leukemic cells of patients with chronic myelogenous leukemia
(CML), acute myelogenous leukemia (AML), and chronic myelomonocytic
leukemia (CMML) will all undergo substantial differentiation toward
dendritic cells (DC) and may be used to drive autologous T cells to
acquire anti-leukemic cytotoxicity. This article describes the use of
these human leukemia-derived dendritic cells for stimulation of
allogeneic donor lymphocytes and presents a clinical trial of autologous
CML DC-stimulated lymphocytes.
18
UI - 11803360
AU - Mohty M; Faucher C; Gaugler B; Vey N; Sainty D; Arnoulet C; Mozziconacci
TI -
MJ; Isnardon D; Gastaut JA; Maraninchi D; Olive D; Blaise D
Large granular lymphocytes (LGL) following non-myeloablative allogeneic
bone marrow transplantation: a case report.
SO - Bone Marrow Transplant 2001 Dec;28(12):1157-60
AD - Laboratoire d'Immunologie des Tumeurs, Institut Paoli-Calmettes,
Universite de la Mediterranee, Marseille, France.
We report here the first case of large granular lymphocytes (LGL)
expansion following non-myeloablative allo-BMT for chronic myeloid
leukemia. We characterized the morphologic, phenotypic and functional
features of the LGL subset amplified in vivo 14 months after allo-BMT.
Our results indicate that LGL can mediate in vitro a cytolytic activity
on tumor cells. In vivo, the timing of the LGL expansion was associated
with a sustained complete molecular remission. These observations
suggest that LGL are a subset with the properties of effector
lymphocytes which may contribute to the graft-versus-tumor effect.
19
UI - 11808163
AU - Matsuo T; Tomonaga M
TI -
[Chronic myeloid leukemia]
SO - Nippon Rinsho 2001 Nov;59 Suppl 7():529-36
AD - Blood Transfusion Service, Nagasaki University Hospital.
20
UI - 11872078
AU - Stentoft J; Pallisgaard N; Kjeldsen E; Holm MS; Nielsen JL; Hokland P
TI -
Kinetics of BCR-ABL fusion transcript levels in chronic myeloid leukemia
patients treated with STI571 measured by quantitative real-time
polymerase chain reaction.
SO - Eur J Haematol 2001 Nov-Dec;67(5-6):302-8
AD - Department of Hematology, Arhus University Hospital, Arhus, Denmark.
The activated tyrosine kinase, which arises as a result of the balanced
t(9,22) translocation in chronic myeloid leukemia (CML), is thought to
be essential for the development of the leukemic phenotype. Recently,
designer drugs have been introduced which specifically inhibit such
specific kinases. Among these, STI571 (Glivec) has entered clinical
trials and shown promising activities in chronic phase (CP), accelerated
phase (AP) and blast crisis (BC) as evidenced by significant
hematological and cytogenetic responses in CML patients. To evaluate the
effect of STI571 at the molecular level we have employed quantitative
real-time PCR (RQ-PCR) to measure the amount of BCR-ABL fusion
transcript in a series of 19 patients treated with STI571, either in
CP(11) or in (AP)(8) of the disease for 3--9 months (median 6 months).
Employing this method, which is able to detect at least one BCR-ABL+
cell in 500,000, in serial blood and bone marrow specimens we found
decreases in transcript levels in 10/11 CP patients, but only in 1/8 of
the AP patients. When present such decreases were gradual and became
evident only after 3 months of STI571 treatment, and their kinetics in
blood closely mirrored those seen in parallel marrow samples. Moreover,
decreases were between 10- and 100-fold in 11/13 patients, with only two
patients reaching residual disease levels below 10(-2) (a 900-fold
decrease). Thus, no patient reached PCR negativity. We conclude that the
RQ-PCR method is a highly suitable tool for following the effect of
STI571 in CML and that further validation of the method, performed in a
prospective manner, will contribute significantly to the elucidation of
the proper role of STI571 in CML.
21
UI - 11872080
AU - Patel M; Ezzat W; Pauw KL; Lowsky R
TI -
Bronchiolitis obliterans organizing pneumonia in a patient with chronic
myelogenous leukemia developing after initiation of interferon and
cytosine arabinoside.
SO - Eur J Haematol 2001 Nov-Dec;67(5-6):318-21
AD - Department of Medical Oncology, Saskatoon Cancer Centre, Saskatoon,
Saskatchewan, Canada.
A 59-yr-old man developed fevers, shortness of breath, persistent cough
and weight loss, shortly after initiation of therapy with
interferon-alpha 2a and cytosine arabinoside for treatment of chronic
myelogenous leukemia. Radiologic pulmonary infiltrates and lung tissue
biopsy were consistent with bronchiolitis obliterans organizing
pneumonia (BOOP). After discontinuation of the chemotherapeutic drugs,
the pneumonic symptoms and chest roentgenogram infiltrates resolved.
This report suggests that treatment with interferon-alpha, in
combination with cytosine arabinoside, may produce the rare complication
of BOOP.
22
UI - 10578166
AU - Machida U; Kami M; Kanda Y; Takeuchi K; Akahane M; Yamaguchi I; Kakiuchi
TI -
C; Takeda N; Tanaka Y; Chiba S; Honda H; Hirai H
Aspergillus tracheobronchitis after allogeneic bone marrow
transplantation.
SO - Bone Marrow Transplant 1999 Nov;24(10):1145-9
AD - The Department of Hematology and Oncology, Faculty of Medicine,
University of Tokyo, Tokyo, Japan.
We describe a patient who developed Aspergillus tracheobronchitis after
BMT. She complained of progressive dyspnea on day +165 and her
respiratory function deteriorated rapidly. Although neither early chest
X-rays nor CT scans were negative, bronchoscopy revealed formation of a
pseudomembrane around the bronchial walls. Based upon pathological and
microbiological examinations, she was diagnosed as having invasive
Aspergillus tracheobronchitis. Retrospectively analyzed, the Aspergillus
circulating antigen detection tests became positive before clinical
symptoms developed, and may be beneficial for early diagnosis of
Aspergillus tracheobronchitis. This form of aspergillosis should be
regarded as one of the serious complications after BMT.
23
UI - 11603003
AU - Benthin M; Dallmann I; Atzpodien J
TI -
13cis- and all-trans retinoic acid have antiproliferative effects on CML
cells and render IFN alpha antiproliferative potency after combined
treatment in vitro.
SO - Cancer Biother Radiopharm 2001 Aug;16(4):323-31
AD - Medizinische Hochschule Hannover, Germany.
The treatment of CML with IFN alpha is limited due to resistance against
this substance. Recent studies with different cells than chronic
myelogenous leukemic cells revealed a synergistic effect of a combined
use of Retinoids (RA) and IFN alpha. The purpose of the study was to
detect possible interactions of IFN alpha and RA in CML considering also
the effect of the BCR-ABL gene-product. Therefore, we investigated three
CML cell lines in their proliferation after incubation with IFN alpha
and Retinoids alone and in combination. We measured low susceptibility
to IFN alpha but a marked influence of the Retinoids. In combination,
the growth inhibition was enhanced potentially in response to an
increased efficacy of IFN alpha. Even solely, ineffective concentrations
of both substances lead to decreased proliferation.
24
UI - 11852815
AU - Wajs J; Zabielski S; Trawinski J
TI -
[Neoplastic skin infiltration in chronic myelomonocytic leukemia]
SO - Pol Merkuriusz Lek 2001 Nov;11(65):427-9
AD - Klinika Chorob Wewnetrznych i Hematologii z Osrodkiem Transplantacji
Szpiku, Warszawa.
Chronic myelomonocytic leukemia has been associated with various
nonspecific cutaneous manifestations. Rarely has the leucaemia been
reported to directly affect the skin. We present a case of 53-year old
man with CMML who showed neoplastic cutaneous lesions. The occurrence of
these lesions may be the presenting feature of the disease or may herald
its progression to acute leukemia. Early diagnosis have therapeutic and
prognostic significance.
25
UI - 11706876
AU - Stark G; O'Brien SG
TI -
An update on chronic myeloid leukaemia.
SO - Clin Med 2001 Sep-Oct;1(5):354-7
AD - School of Clinical Science, Department of Haematology University of
Newcastle, Newcastle upon Tyne, UK.
The therapy of CML is clearly 'work in progress' Although long-term
follow-up data for patients treated with STI571 are not yet available,
preliminary results are encouraging. STI571 is likely to be licensed in
late 2001/early 2002 and will certainly find a place in the treatment of
CML. Current therapeutic considerations are summarised in Fig 2. At all
stages of treatment it is vital that the patient is fully aware of
treatment options, their risks and benefits. In some cases there is
little evidence to suggest that one treatment option is better than
another; in these situations, treatment is likely to depend on a
patient's individual circumstances and preferences.
26
UI - 11845064
AU - Denizon N; Beraud JJ; Mourad G; Blanc P; Bureau JP; Navarro M;
TI -
Lavabre-Bertrand T
[Hemolitic uremic syndrome with hypertransaminasemia following treatment
by interferon for chronic myeloid leukemia]
SO - Gastroenterol Clin Biol 2001 Nov;25(11):1039-40
27
UI - 11523404
AU - Stromskaia TP; Rybalkina EIu; Turkina AG; Zabotina TN; Logacheva NP;
TI -
Zakharova ES; Mechetner EB; Baryshnikov AIu; Khoroshko ND; Stavrovskaia
AA
[Functional activity and expression of P-glycoprotein in chronic myeloid
leukemia]
SO - Ter Arkh 2001;73(7):20-5
AIM: To evaluate the prognostic significance of P-glycoprotein (Pgp) in
chronic myeloid leukemia (CML). MATERIALS AND METHODS: Functional
activity (rhodamine 123 test) and expression of Pgp (binding of UIC2
monoclonal antibodies by cells) were evaluated by flow cytofluorometry.
A total of 141 samples of peripheral blood from 121 patients with
various stages of CML were examined. RESULTS: The number of patients
whose cells express functionally active Pgp increases during the blast
crisis (BC) in comparison with the chronic phase (CP). Repeated testing
of patients with BC and CP showed that Pgp-expressing cells can
disappear from the peripheral blood of patients despite the treatment by
Pgp preparations and substrates. However the number of cases with
expression and functional activity of Pgp increases in the course of BC.
Several patients in whom functionally active Pgp was not detected during
diagnosis of BC had longer BC phase than patients with the active
protein. CONCLUSION: These data suggest that active Pgp contributes to
CML BC (presumably to patient's response to therapy) but this
contribution is not decisive.
28
UI - 11523405
AU - Vinogradova OA; Savchenko VG; Neverova AL; Diachenko LV; Domracheva EV;
TI -
Liubimova LS; Mendeleeva LP
[Study of the time course of mixed chimerism by fluorescent in situ
hybridization in patients with chronic myeloid leukemia after allogenic
transplantation of bone marrow]
SO - Ter Arkh 2001;73(7):26-34
AIM: To determine the type of chimerism in patients with chronic myeloid
leukemia (CML) in various periods after allogenic transplantation of
bone marrow (TBM) and its association with subsequent relapse. MATERIALS
AND METHODS: Ten patients were examined after allogenic TBM, which was
performed during the chronic phase of CML in 9 patients and during
acceleration phase in 1. Two patients received therapy with donor
lymphocytes during relapse after transplantation. Time course of
chimerism and minimum residual illness was studied by standard
cytogenetic methods, fluorescent in situ hybridization (FISH) with DNA
probes to centromer sites of X and Y chromosomes and BCR and ABL genes.
The studies were carried out 30, 60, 90, 180 days, 9 months, 1 year, and
then every 6 months after transplantation. RESULTS: Mixed chimerism was
observed in all patients during 9 months after TBM. The count of host
cells was 0.1-5.8% in 8 patients; later the count of autologous cells
was less than 1% in 5 patients, and in 3 patients complete donor
chimerism was observed. Clinical hematological remission was stable in
these patients. Relapses of leukemia with 40 and 83.1% host cells
occurred in 2 patients 13 and 23 months after transplantation,
respectively. Donor lymphocytes were transfused in order to induce the
graft versus host effect, and in patient No. 2 restoration of donor
hemopoiesis was attained. CONCLUSION: Highly sensitive FISH method with
DNA probe to centromer sites of X and Y chromosomes detects early
relapse of the disease and demonstrates the time course of donor
hemopoiesis recovery after transfusion of donor lymphocytes. The data
indicate that 9 months after transplantation molecular cytogenetic
studies should be carried out more often (once a month), particularly in
patients with poor prognosis, for earlier detection of the relapse and
beginning of immunotherapy.
29
UI - 11683803
AU - Subudhi CP; Adedeji A; Kaufmann ME; Lucas GS; Kerr JR
TI -
Fatal Roseomonas gilardii bacteremia in a patient with refractory blast
crisis of chronic myeloid leukemia.
SO - Clin Microbiol Infect 2001 Oct;7(10):573-5
30
UI - 11878573
AU - Felice M S; Zubizarreta P A; Alfaro E M; Sackmann-Muriel F
TI -
Childhood acute lymphoblastic leukemia: prognostic value of initial
peripheral blast count in good responders to prednisone.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):411-5
AD - Hematology/Oncology Department, Hospital de Pediatria SAMIC Prof. Dr.
Juan P. Garrahan, Buenos Aires, Argentina. mfelice@dd.com.ar
PURPOSE: To assess the value of initial peripheral blast count in
patients with acute lymphoblastic leukemia (ALL) and prednisone good
1995, 403 consecutive patients with newly diagnosed ALL were enrolled in
the authors' protocol 1-ALL90-BFM/HPG. Prednisone good response was
defined as a blast count of less than 1,000/microL and a prednisone poor
response (PPR) as a blast count of at least 1,000/microL, both in
peripheral smears, after 7 days of oral prednisone (60 mg/m2 per day)
and one intrathecal dose of methotrexate. In the PGR group, patients
were divided into two subgroups: patients who had less than 1,000
blasts/microL at diagnosis and those with at least 1,000 blasts/microL
at diagnosis. RESULTS: Three-hundred thirty-seven patients (90%) had PGR
and 37 had (10%) PPR. At 5-year follow-up, event-free survival estimates
were 67 +/- 3.8% and 38 +/- 8% for PGR and PPR, respectively (P =
0.0001). In the PGR group, 114 patients (34%) had an initial blast count
of less than 1,000/microL and 223 (66%) had an initial blast count of at
least 1,000/microL. The authors compared the clinical and laboratory
characteristics of these subgroups at diagnosis and outcome and detected
significant differences in white cell count, incidence of T
immunophenotype, and presence of mediastinal or spleen enlargement.
However, there were no differences in response to induction treatment,
death in complete remission, relapses, or event-free survival
probability. CONCLUSIONS: In the PGR group, regardless of the initial
blast count, both subgroups had the same outcome. The PGR group with an
initial blast count of at least 1,000/microL had significantly higher
white cell counts. T markers, and mediastinal or spleen enlargement at
diagnosis. Response to prednisone is a practical, inexpensive, and good
prognostic factor in childhood ALL.
31
UI - 11693465
AU - Lyseng-Williamson K; Jarvis B
TI -
Imatinib.
SO - Drugs 2001;61(12):1765-74; discussion 1775-6
AD - Adis International Limited, Mairangi Bay, Auckland, New Zealand.
demail@adis.co.nz
Imatinib inhibits the BCR-ABL tyrosine kinase created by the
Philadelphia chromosome (Ph+) in chronic myeloid leukaemia (CML).
Complete haematological responses were achieved in 88% of patients and
major cytogenetic responses were detected in 49% of patients with
chronic phase CML treated with oral imatinib 400 mg/day in a multicentre
noncomparative study of 532 patients. Administration of oral imatinib
400 or 600 mg/day to 235 patients with accelerated phase CML in a
multicentre noncomparative study resulted in haematological responses in
63% of patients and major cytogenetic responses in 21% of patients. 26%
of the 260 patients with blast crisis CML receiving imatinib 400 or 600
mg/day in a multicentre noncomparative trial sustained a haematological
response and 13.5% of patients had a major cytogenetic response.
Imatinib 400 or 600 mg/day orally achieved ahaematological response in
19 of 32 patients with Ph+ acute lymphoblastic leukaemia in a pilot
study. Clinical improvement was demonstrated in 89% of 36 patients with
gastrointestinal stromal tumours unresponsive to standard chemotherapy
during treatment with 400 or 600 mg/day oral imatinib in a
noncomparative phase II trial. Adverse events were frequent in clinical
trials of imatinib but most events were mild or moderate in severity.
Serious adverse events reported include severe fluid retention,
cytopenias and hepatotoxicity.
32
UI - 11766235
AU - Egyed M; Mihalyfalvi Z; Kollar B; Rumi G; Keller E; Vass J; Fekete S
TI -
[Effect of retinoic acid on the cytogenetic remission in the first
chronic phase of chronic myeloid leukemia treated with interferon]
SO - Orv Hetil 2001 Nov 4;142(44):2421-5
AD - Belgyogyaszati Osztaly, Kaposi Mor Megyei Korhaz, Kaposvar.
egyedmiklos@yahoo.com
Cytogenetic responses of 11 chronic myeloid leukemic (CML) patients
during the first chronic phase, treated with the combination of
all-trans retinoic acid (ATRA) + interferon (IFN) were compared to 9
other CML patients of phase one, treated with interferon monotherapy.
Metaphase and interphase cytogenetics and a semiquantitative polymerase
chain reaction (PCR) were used to evaluate the cytogenetic responses.
Two of the 11 patients in the ATRA + interferon treated group were
withdrawn, one of them because of interferon intolerance, and the other
because of compliance failure. Among the 9 ATRA + interferon treated
patients 6 major cytogenetic responses could be detected and 3 of them
were complete. Of the 9 patients treated with IFN monotherapy only 2
major cytogenetic responses could be registered. No severe adverse
effects were observed. The first results suggest that the ATRA +
interferon combination may be superior in achieving cytogenetic
remission in the first chronic phase of CML.
33
UI - 11855148
AU - Xu L; Guo N; Huang X
TI -
[Effect of interferon-alpha on the prognosis of bone marrow
transplantation in chronic myeloid leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 2001 Nov;22(11):589-91
AD - Institute of Hematology, People's Hospital, Beijing University, Beijing
100044, China.
OBJECTIVE: To investigate whether prior interferon alfa (IFN-alpha)
treatment affects the outcome of allogeneic bone marrow transplantation.
METHODS: The outcome of 85 patients with chronic myelogenous leukemia
(CML) in first chronic phase received transplants from an HLA-identical
sibling donor was analyzed. Of the 85 patients, 30 did not receive
IFN-alpha, whereas 30, 15 and 10 patients received IFN-alpha 3 x 10(6)
units 3-4 times per week for < 6, 6-12 and > 12 months before transplant
combined with hydroxyurea and/or HA regimen (H: Harringtonine; A: Ara-C)
respectively. RESULTS: Pretransplant IFN-alpha therapy for > or = 6
months was associated with an increased risk of severe (grade III-IV)
acute graft-versus-host disease (GVHD) (P < 0.01) as compared to that in
< 6 months or no IFN-alpha therapy. No influence of pretransplant
IFN-alpha treatment on engraft, cGVHD, VOD, relapse and TRM
(transplant-related mortality) was found. Survival rate of IFN-alpha
therapy < 6 months group (90.0%) was higher than that of no IFN-alpha
group (68.9%) or > 12 months group(60.0%) (P < 0.05). CONCLUSION: It was
found that there was a trend towards an improved survival in the
IFN-alpha < 6 months group. Pretransplant IFN-alpha therapy for > or = 6
months was associated with an increased risk of severe aGVHD.
34
UI - 11879900
AU - Gratwohl A; Baldomero H; Urbano-Ispizua A
TI -
Transplantation in chronic myeloid leukaemia.
SO - Lancet 2002 Feb 23;359(9307):712-3
35
UI - 11831065
AU - Deininger M; Niederwieser D
TI -
[Molecular therapy of chronic myeloid leukemia--a new era in the
treatment of malignant diseases]
SO - Med Klin 2002 Jan 15;97 Suppl 1():1
36
UI - 11831068
AU - Fischer T
TI -
[Results up to now of administration of STI-571 (Glivec) in recurrence
after allogenic and autologous stem cell transplantation in chronic
myeloid leukemia]
SO - Med Klin 2002 Jan 15;97 Suppl 1():22-7
AD - III. Medizinische Klinik und Poliklinik, Hamatologie und Onkologie,
Johannes-Gutenberg-Universitat Mainz.
t.fischer@3-med.klinik.uni-mainz.de
BACKGROUND: Gleevec (STI-571) is s selective inhibitor of the bcr/abl
tyrosine kinase. Recent phase I and phase II studies in patients with
bcr/abl positive CML and ALL showed a low rate of grade III/IV toxicity
and good clinical efficacy. This report describes the preliminary
results in patients relapsing post autologous or allogeneic peripheral
blood stem cell transplantation. The focus of this analysis will include
toxicity, feasibility and clinical efficacy. THERAPY AND RESULTS: 18 of
18 patients with cytogenetic and/or hematologic relapse in chronic phase
CML post autologous stem cell transplantation achieved a complete
hematologic remission upon therapy with Gleevec. The cytogenetic
response rate was 75% with a complete cytogenetic response rate of 50%.
After allogeneic stem cell transplantation, patients in cytogenetic or
hematologic relapse also experienced high hematologic and cytogenetic
response rates upon therapy with Gleevec. In these patients, Gleevec was
shown to induce mixed chimerism. Overall, Gleevec was well tolerated
after autologous and allogeneic stem cell transplantation. Most common
side effects were mild to moderate gastrointestinal discomfort and
edema. No symptoms of chronic extensive or > grade I acute GvHD could be
observed. Hematologic toxicity was dependent on stage of disease. Grade
III/IV granulocytopenia and/or thrombopenia could be observed in 50% of
patients with transformed phases of CML. Management of these patients
required frequent controls of peripheral blood counts and transfusion of
blood products. CONCLUSION: These results show a new approach in
treatment of patients with Philadelphia-chromosome-positive leukemia
relapsing post autologous or allogeneic stem cell transplantation.
Gleevec is able to induce mixed chimerism without induction of severe
GvHD. The data suggest that early start of STI-571 therapy in
MRD-positive patients is a promising approach. Recently, a multicenter
phase II study to evaluate the toxicity and efficacy of Gleevec in CML
patients with minimal residual disease post allogeneic transplantation
was started.
37
UI - 11831070
AU - Hochhaus A; Berger U; Reiter A; Lahaye T; Kreil S; Hehlmann R
TI -
[Drug therapy of chronic myeloid leukemia]
SO - Med K
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