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NCI CANCERLIT® Search: Therapy of Acute Myeloid Leukemia - March 2002
National Cancer Institute®
Last Modified: March 1, 2002
Table of Contents
1
UI - 11820331
AU - Naoe T
TI -
Mechanism-based therapy for leukemia: a lesson from ATRA therapy.
SO - Nagoya J Med Sci 2001 Nov;64(3-4):103-8
AD - Department of Infectious Diseases, Nagoya University Graduate School of
Medicine, Japan. tnaoe@med.nagoya-u.ac.jp
In the past two decades, there has been a tremendous increase in our
understanding of the molecular mechanism of human leukemias. Leukemias
are now recognized as a deregulated state of cell proliferation,
differentiation and apoptosis, which is induced by gene alterations,
including chromosomal translocations. Many of the mechanisms are
potentially exploited as new targets for drug development. All-trans
retinoic acid therapy for acute promyelocytic leukemia, which was
initially developed as a differentiation therapy in an experienced-based
manner, is currently known to be the first successful
oncoprotein-directed therapy. Basic and clinical research into
ATRA-resistance provides new directions for acute myeloid leukemia
therapy. Anti-leukemia therapy will continue to lead the field of
chemotherapy in the coming decades.
2
UI - 11806982
AU - Latagliata R; Petti MC; Fenu S; Mancini M; Spiriti MA; Breccia M;
TI -
Brunetti GA; Avvisati G; Lo Coco F; Mandelli F
Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in
patients treated for acute promyelocytic leukemia: an emerging problem.
SO - Blood 2002 Feb 1;99(3):822-4
AD - Department of Human Biotechnologies and Hematology, University La
Sapienza of Rome, Cattedra di Ematologia, Via Benevento 6-00161, Rome,
Italy. rob.lati@libero.it
The use of all-trans retinoic acid (ATRA) in combination with
chemotherapy has markedly improved the prognosis for patients with acute
promyelocytic leukemia (APL); the higher complete remission (CR) and
survival rates now reported in this disease almost approach those
obtained for other highly curable hematologic malignancies. Of 77
patients with APL who were consecutively treated at a single institution
and who achieved CR after induction and consolidation therapy, 5 (6.5%)
acquired therapy-related myelodysplasia (tMDS), acute myelogenous
leukemia (AML), or both (tMDS-AML). Of these, 3 of 46 (6.5%) patients
received front-line chemotherapy with or without ATRA and acquired
tMDS-AML while in first remission of APL. Two underwent repeated
chemotherapy cycles with ATRA because of APL relapse and acquired
tMDS-AML while in the second or third remission of APL. In 2 patients,
clinical and biologic characteristics of tMDS-AML were as expected for
postalkylating forms (long latency, MDS phase preceding AML, karyotypic
aberrations involving chromosomes 5 or 7), even though one of them had
not previously received alkylating drugs. Three of the 5 patients died
shortly after tMDS-AML diagnosis, one is alive with tMDS, and one is
alive and in CR after allogeneic bone marrow transplantation. The
occurrence of tMDS-AML after successful therapy for APL is an emerging
problem. The availability of prognostic score systems at initial
diagnosis and monitoring of residual disease by polymerase chain
reaction might allow better tailoring of treatment intensity in APL to
spare unnecessary toxicity and to minimize the risk for tMDS-AML in
patients who are presumably cured.
3
UI - 11841402
AU - Usuki K; Urabe A; Masaoka T; Ohno R; Mizoguchi H; Hamajima N; Miyazaki
TI -
T; Niitsu Y; Yoshida Y; Miura A; Shibata A; Abe T; Miura Y; Ikeda Y;
Nomura T; Nagao T; Saitou H; Shirakawa S; Ohkuma M; Matsuda T; Nakamura
T; Horiuchi A; Kuramoto A; Kimura I; Irino S; Niho Y; Takatsuki K;
Tomonaga M; Uchino H; Takaku F; Gran AML Study Group
Efficacy of granulocyte colony-stimulating factor in the treatment of
acute myelogenous leukaemia: a multicentre randomized study.
SO - Br J Haematol 2002 Jan;116(1):103-12
AD - Division of Hematology, NTT Kanto Medical Center, Tokyo, Japan.
To investigate the efficacy and safety of granulocyte colony-stimulating
factor (G-CSF) in patients with acute myelogenous leukaemia, a
leukaemia were randomized to G-CSF or control groups after remission
induction therapy. The G-CSF group received G-CSF (Filgrastim) from 48 h
after the completing chemotherapy until the absolute neutrophil count
exceeded 1.5 x 10(9)/l. The control group did not receive G-CSF unless
severe infection occurred. There were 245 evaluable patients (120 and
125 in the G-CSF and control groups respectively). The complete
remission rate was similar in the G-CSF and control groups (80.8% versus
76.8%), as was the 5-year probability of disease-free survival (34.5%
versus 33.6%) and overall survival (42.7% versus 35.6%). Neutrophil
recovery was significantly faster in the G-CSF group than in the control
group (12 d versus 18 d, P = 0.0001). The median duration of febrile
neutropenia was significantly shorter in the G-CSF group than in the
control group (3 d versus 4 d, P = 0.0001). In conclusion, prophylactic
administration of G-CSF after remission induction therapy for acute
myelogenous leukaemia is safe and useful even in patients without
infection on completing chemotherapy.
4
UI - 11858371
AU - Tunc B; Oner AF; Hicsonmez G
TI -
The effect of short-course high-dose methylprednisolone on peripheral
blood CD34+ progenitor cells of children with acute leukemia during
remission induction therapy.
SO - Turk J Pediatr 2002 Jan-Mar;44(1):1-4
AD - Department of Pediatrics, Suleyman Demirel University Faculty of
Medicine, Isparta, Turkey.
This study was undertaken to determine the effect of short-course
high-dose methylprednisolone (HDMP) treatment on peripheral blood (PB)
CD34+ progenitor cells during remission induction treatment in 11
children with newly diagnosed acute leukemia (7 with ALL, 4 with AML)
whose bone marrow (BM) cells expressed fewer than 5% CD34 at the time of
diagnosis. All children who had no infection were given HDMP as a single
daily oral dose of 30 mg/kg for the first four days of induction
therapy. The number of CD34+ progenitor cells were determined by flow
cytometry before and after four days of HDMP treatment. While the number
of PB blast cells significantly decreased after only a four-day course
of HDMP treatment, the number of PB CD34+ progenitor cells increased in
all patients. In addition, after four days of HDMP treatment
polymorphonuclear leukocytes (PMN) and mononuclear cells (MNC) increased
significantly (p < 0.05). We suggest that the potential beneficial
effects of HDMP in the induction treatment of acute leukemia may occur
partly by the stimulation of PB CD34+ hematopoietic progenitor cells in
a short period of time.
5
UI - 11535988
AU - Nabhan C; Mehta J; Tallman MS
TI -
The role of bone marrow transplantation in acute promyelocytic leukemia.
SO - Bone Marrow Transplant 2001 Aug;28(3):219-26
AD - Division of Hematology-Oncology, Department of Medicine, Northwestern
University Medical School, Robert H Lurie Comprehensive Cancer Center,
Chicago, IL 60611, USA.
Acute promyelocytic leukemia (APL) is characterized by a specific gene
rearrangement and the generation of the PML-RARalpha fusion transcript
which results from a translocation between chromosomes 15 and 17.
Targeted therapy with all-trans retinoic acid (ATRA) and
anthracycline-based chemotherapy results in an apparent cure in 70-80%
of patients. Both allogeneic (ALLO) and autologous (AUTO) hematopoietic
stem cell transplantation (HSCT) are effective in acute myeloid leukemia
(AML), but their role in APL is not clear given the excellent outcome
with ATRA and chemotherapy. Several retrospective studies have analyzed
the outcome of patients undergoing AUTO or ALLO-HSCT in first (CR1) or
second (CR2) complete remission. Most of these studies have shown
significant transplant-related mortality (TRM) with ALLO-HSCT, but a
reduction in relapse rate compared with AUTO-HSCT. The high TRM with
ALLO-HSCT and the excellent outcome with ATRA and chemotherapy do not
justify recommending this procedure for the majority of patients in CR1.
The role of AUTO-HSCT in CR1 also is unclear. A small subset of patients
at high risk of relapse, possibly identifiable by a high white blood
cell count at presentation may benefit from HSCT. Most patients with
relapsed disease achieve CR2 with ATRA, arsenic trioxide, or combination
therapy. However, it is not known if these responses are sustained or if
consolidation with HSCT has a place in this setting. The outcome of
AUTO-HSCT in CR2 using stem cells that are negative for PML-RARalpha is
excellent. It is unclear whether ALLO-HSCT from an HLA-identical sibling
is superior to AUTO-HSCT with PML-RARalpha-negative cells in CR2 since
the former would be associated with graft-versus-leukemia effects and
the latter with lower TRM. Alternatively, arsenic trioxide or
re-treatment with ATRA, followed by intensive chemotherapy may also be
effective. A randomized prospective clinical trial, or a retrospective
analysis of the available data would be useful in answering this
critical question.
6
UI - 11803362
AU - Trisolini R; Bandini G; Stanzani M; Chilosi M; Cancellieri A; Boaron M;
TI -
Poletti V
Morphologic changes leading to bronchiolitis obliterans in a patient
with delayed non-infectious lung disease after allogeneic bone marrow
transplantation.
SO - Bone Marrow Transplant 2001 Dec;28(12):1167-70
AD - Department of Thoracic Diseases, Maggiore Hospital, Largo Nigrisoli 2,
40100 Bologna, Italy.
A 37-year-old man developed delayed non-infectious lung disease after
undergoing bone marrow transplantation (BMT) for acute myeloid
leukaemia. Over a 15-month period, the progression of morphologic
changes from cellular interstitial pneumonia to bronchiolitis obliterans
organizing pneumonia and cicatricial bronchiolitis obliterans was
documented. Pulmonary function tests, high-resolution CT,
bronchoalveolar lavage, lung biopsy and extensive microbiological
studies were used as diagnostic tools either at onset and during the
follow-up. This represents the first reported case in which a
model--supported by longitudinal biopsy results--for the evolution of
histologic lesions toward bronchiolitis obliterans after BMT is
suggested; therapeutic implications are discussed.
7
UI - 10673689
AU - Seo S; Kami M; Honda H; Kashima T; Matsumura T; Moriya A; Machida U;
TI -
Kanda Y; Chiba S; Hirai H
Extramedullary relapse in the so-called 'sanctuary' sites for
chemotherapy after donor lymphocyte infusion.
SO - Bone Marrow Transplant 2000 Jan;25(2):226-7
8
UI - 11418363
AU - Anonymous
TI -
Spanish contributions to management of acute promyelocytic leukemia.
SO - Haematologica 2001 Jun;86(6):561-2
9
UI - 11817489
AU - Anonymous
TI -
Respiratory distress following transfusion.
SO - Oncol Nurs Forum 2002 Jan-Feb;29(1):23-4
10
UI - 11706877
AU - Milligan DW
TI -
The diagnosis and management of acute myeloid leukaemia.
SO - Clin Med 2001 Sep-Oct;1(5):358-61
AD - Birmingham Heartlands Hospital. d.w.milligan@bham.ac.uk
Significant advances have been made in the management of AML in younger
patients in the last 20 years, and it is easier to identify individual
risk groups and stratify treatment accordingly. Results remain
discouraging in the elderly, except for the minority with favourable
risk factors, and new approaches are needed for most of these patients.
11
UI - 11890109
AU - Wang ZY
TI -
Mechanism of action of all-trans retinoic acid and arsenic trioxide in
the treatment of acute promyelocytic leukemia.
SO - Gan To Kagaku Ryoho 2002 Feb;29 Suppl 1():214-8
AD - Shanghai Institute of Hematology, Rui-jin Hospital, Shanghai Second
Medical University, Shanghai 200025, China.
Treatment of APL with ATRA or As2O3 alone or in combination with
chemotherapy yields a complete remission as high as 85%-95%, but their
mechanisms of action remain unclear. The mechanisms of action underlying
ATRA treatment are (1) relocalization of the PML restoration of normal
structure of nuclear bodies and degradation of PML-RAR alpha protein via
caspase-mediated cleavage and proteosome-dependent degradation; (2)
conversion of PML-RAR alpha from a transcription repressor (CoR) to a
transcription activator (CoA) under therapeutic concentration of ATRA
(3) coordinated genes expression induced by ATRA resulting in an elegant
and intricate cellular program for the commitment to differentiation.
169 genes were modulated to express, with 100 genes up-regulated and 69
down-regulated. As2O3 exerts its action by dual dose-dependent manner.
At higher concentration (1-2 microns/l), it induces apoptosis of the
leukemic cells associated with disruption of mitochondrial membrane
potential, elevation of caspase-3 and other caspases activity and
decline of Bcl-2 expression. At lower concentration (0.1-0.5 micron/l),
it triggers differentiation with elevation of CD11b expression
accompanied by morphologically partial differentiation. At both
concentrations, As2O3 causes degradation of PML-RAR alpha protein
implicated probably in its mechanisms of action.
12
UI - 11860447
AU - Mishra SK; Melinkeri SR; Dabadghao S
TI -
Benign thymic hyperplasia after chemotherapy for acute myeloid leukemia.
SO - Eur J Haematol 2001 Oct;67(4):252-4
AD - Department of Immunology, Sanjay Gandhi Postgraduate Institute of
Medical Sciences, Lucknow, India.
Thymic hyperplasia can occur after cytotoxic therapy for various
malignancies. The possible cause could be rebound enlargement after
initial atrophy caused by these drugs. During the treatment of
hematological malignancies this could be a cause of great concern. We
report here a case of thymic hyperplasia after chemotherapy for acute
myeloid leukemia. Awareness of this unusual side-effect may prevent
needless investigation and therapy.
13
UI - 11841431
AU - Fassas A; Buffels R; Anagnostopoulos A; Gacos E; Vadikolia C; Haloudis
TI -
P; Kaloyannidis P
Safety and early efficacy assessment of liposomal daunorubicin
(DaunoXome) in adults with refractory or relapsed acute myeloblastic
leukaemia: a phase I-II study.
SO - Br J Haematol 2002 Feb;116(2):308-15
AD - Department of Haematology, George Papanicolaou General Hospital, Exokhi,
Thessaloniki, Greece. hempap@otenet.gr
We have conducted a phase I/II trial to determine the maximum tolerated
dose, early safety and efficacy of single-agent liposomal daunorubicin
in relapsed or refractory acute myeloid leukaemia (AML). Successive
cohorts of six patients received escalated doses of 75, 100, 125 or 150
mg/m2 of DaunoXome for three consecutive days. Responding patients
received a further consolidation cycle of DaunoXome at a dose identical
to the one inducing complete or partial remission at the various dose
levels. Twenty-eight patients with a median age of 50.5 years were
enrolled. A maximum tolerated dose was determined at 150 mg/m2. Twelve
patients received the second cycle. DaunoXome was well tolerated at all
administered levels; dose-limiting toxicities included nausea and
vomiting, mucositis and two episodes of cardiotoxicity resulting in the
death of two patients. The overall response rate was 46% with a median
duration of response of 180 d and a median duration of survival of 208
d. Ten patients demonstrated a complete response following cycle 1, and
a further four entered partial response with the first cycle (marrow
blasts between 5% and 10%). Of these, three attained complete response
with the second cycle (total complete response 13/28). Our results
indicate that DaunoXome at a dose of 150 mg/m2 displays acceptable
toxicity in a 3-d regimen followed by a 3-d consolidation course at 100
mg/m2/d. At this dose schedule, interestingly high remission rates were
achieved, justifying further evaluation of DaunoXome for the treatment
of relapsed or refractory AML patients.
14
UI - 11757771
AU - Hirayama Y; Koyama R; Nagai T; Ohta H; Kondo A; Ishikawa K; Ishitani K;
TI -
Matsunaga T; Sakamaki S; Niitsu Y
Successful treatment of a case of relapsed acute promyelocytic leukemia
with arsenic trioxide.
SO - Intern Med 2001 Nov;40(11):1136-9
AD - Hokkaido Prefectural Sapporo Kitano Hospital.
We report a patient with an initial relapse of acute promyelocytic
leukemia (APL) who achieved a second complete remission (CR) after
treatment with arsenic trioxide. The patient, a 66-year-old woman
diagnosed as having relapsed APL, received arsenic trioxide
intravenously at a dose of 10 mg/day. At day 36, the patient achieved a
second CR. The side effects were slight neuralgia and mild skin
erythematous changes, which improved following cessation of the drug.
Although arsenic trioxide may be effective for relapsed APL, it should
be used with caution because of various complications.
15
UI - 11821446
AU - Gandhi V; Plunkett W; Du M; Ayres M; Estey EH
TI -
Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies
during a phase I trial in relapsed acute myelogenous leukemia.
SO - J Clin Oncol 2002 Feb 1;20(3):665-73
AD - Department of Experimental Therapeutics, University of Texas M.D.
Anderson Cancer Center, Houston, TX 77030, USA. vgandhi@mdanderson.org
PURPOSE: To determine the maximum tolerated duration of infusions at the
fixed gemcitabine dose rate of 10 mg/m(2)/min and to analyze the
pharmacodynamic actions in leukemia blasts during gemcitabine therapy.
PATIENTS AND METHODS: The study was conducted in a phase I trial by
escalating the duration of gemcitabine infusion at a fixed-dose rate of
10 mg/m(2)/min. Patients with relapsed or refractory acute myelogenous
leukemia (AML) received gemcitabine for 8.0 (n = 3), 10.0 (n = 3), 12.5
(n = 8), 15.5 (n = 3), or 18.0 hours (n = 2). Pharmacokinetic and
pharmacodynamic investigations were undertaken in circulating AML
blasts. RESULTS: Gemcitabine was infused for up to 18 hours at the
fixed-dose rate. Four patients had grade 3 toxicities at longer infusion
schedules. One patient had a partial remission; two others had a
reduction in blasts and concomitant rise in neutrophils. Gemcitabine
triphosphate was detectable in AML cells even at 1 hour after the start
of infusion in eight patients. The concentration ranged from 130 to 900
micromol/L at the end of the infusion. Consistently, there was a rapid
decline in DNA synthesis, which remained suppressed at 85% to 95% during
and for at least 10 hours after the end of the infusion. Compared with
levels in cells measured before therapy, at 8 hours after the start of
the infusion, there was a decline in the cellular purine deoxynucleotide
pools. CONCLUSION: At the fixed-dose rate of 10 mg/m(2)/min, gemcitabine
could be administered for longer than 12 hours without untoward
toxicity. The favorable toxicity profile and pharmacokinetic and
pharmacodynamic features warrant combination with DNA-damaging agents.
16
UI - 11721417
AU - Song Y; Wang G; Wan D
TI -
[Successful treatment of AML by HLA-compatible sibling umbilical cord
blood stem cell transplantation--the first case report in China]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Aug;20(8):399-401
AD - First Affiliated Hospital, Henan Medical University, Zhengzhou 450052.
OBJECTIVE: To apply umbilical cord blood stem cell transplantation
(UCBSCT) to the treatment of hematological malignancies, and to observe
the persistent hematopoietic reconstitution, graft-versus-host disease
(GVHD) and transplantation-related complications. METHODS: An
11-year-old patient with acute myeloid leukemia in complete remission
(CR) received UCBSCT from a HLA-compatible sibling. The conditioning
regimen was BU/CY (busulfan 4 mg.kg-1.d-1 x 4, cyclophosphamide 60
mg.kg-1.d-1 x 2). CsA was given for prophylaxis of acute GVHD. The
patient received 0.35 x 10(8) nucleated cells/kg, including 1.82 x 10(4)
CFU-GM/kg and 2.04 x 10(5) CD34+ cells/kg. RESULTS: The recipient showed
hematopoietic reconstitution on day 14 post-transplantation; ANC > 1.0 x
10(9)/L on day 21; DNA fingerprinting showed engraftment on day 60, the
blood type of the patient changed from O group to B group. In the
follow-up of 330 days, the patient was in good condition without acute
or chronic GVHD. CONCLUSION: It is the first case reported in China that
have succeeded in the treatment of acute myeloid leukemia by allogeneic
UCBSCT.
17
UI - 11721423
AU - Wu B; Sun J; Meng F
TI -
[Allogeneic peripheral stem cell transplantation (PBSCT) for
hematological malignancies]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Aug;20(8):420-3
AD - Nanfang Hospital, First Military Medical University, Guangzhou 510515.
OBJECTIVE: To evaluate the efficacy of allo-PBSCT in hematological
malignancies. METHODS: Sixteen patients with hematological malignancies
were treated by allo-PBSCT, started from march 1997. Five of them were
ALL (CR1 4, CR2 1), 2 ANLL (CR1), 8 CML(CP 5, AP 3), and one NHL(PR).
The median age was 33(18-49) years. Conditioning regimen was TBI 9-10 Gy
+ CTX 120 mg/kg, or TBI 10 Gy + CTX 120 mg/kg + Vp16 500 mg. A
combination of cyclosporine and methotrexate was administered to prevent
acute GVHD. All donors received G-CSF 5 micrograms.kg-1.d-1 for 5 to 6
days. One or three leukapheresis procedures were performed by CS 3000
plus blood cell separator to collect a median mononuclear cells of 9 x
10(8)/kg recipient weight [range(5.79-13.7) x 10(8)/kg], including a
median CD34+ cells 13.9 x 10(6)/kg [range(5.69-49.00) x 10(6)/kg].
RESULTS: All patients were engrafted and hematopoietic reconstitution
was rapid: neutrophils achieving 0.5 x 10(9)/L on day 12 (range, 10-15),
platelets > 30 x 10(9)/L on day 13 (range, 8-24). More than grade II
aGVHD occurred in 3(18.7%), and localized cGVHD in 3 patients. Leukemia
relapse occurred in one patients. The median follow-up duration was 13
months. Eleven patients were alive in disease-free situation.
CONCLUSION: Allo-PBSCT can rapidly reconstitute hematopoiesis with
incidences of aGVHD and cGVHD not more than that in BMT.
The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.
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