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NCI CANCERLIT® Search: Therapy of Acute Myeloid Leukemia - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
1
UI - 11818666
AU - Douer D
TI -
Advances in the treatment of relapsed acute promyelocytic leukemia.
SO - Acta Haematol 2002;107(1):1-17
AD - Division of Hematology, Keck School of Medicine, USC/Norris Cancer
Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
douer-d@mikey.hsc.usc.edu
The presence of the characteristic fusion transcript gene, promyelocytic
leukemia-retinoic acid receptor-alpha (PML-RARalpha), provided
hematologists with a rationale for the use of all-trans retinoic acid
(ATRA) for differentiation therapy for acute promyelocytic leukemia
(APL). Multiple studies have established that combination of ATRA and
chemotherapy in newly diagnosed patients has increased the cure rate to
70% from 35% in patients treated with chemotherapy alone. However, still
about 30% of the patients relapse and are often resistant to ATRA
retreatment. Consequently, a number of novel agents that include several
differentiation agents and monoclonal antibodies have been studied to
provide improved outcomes for patients with APL who have relapsed. In
particular, arsenic trioxide has shown great promise for the induction,
consolidation, and maintenance of complete remission in relapsed
patients with APL. The unique mechanisms of action by which arsenic
trioxide exerts its effects are complementary to those of ATRA,
potentially allowing for combination therapies with additive or even
synergistic results. Within this context autologous or allogeneic bone
marrow transplantations are also considered in second or subsequent
relapse, especially after arsenic trioxide-induced complete remission in
relapsing patients. Furthermore, molecular monitoring for the
PML-RARalpha fusion protein permits prompt intervention for early
molecular relapse of APL before clinical relapse, ultimately improving
chances of prolonged remission. Copyright 2002 S. Karger AG, Basel
2
UI - 11868364
AU - Yata K; Yamada O; Iwato K; Kyo T; Otsuki T; Nakanishi H; Suetsugu Y;
TI -
Mikami M; Wada H; Yawata Y; Sugihara T
[Acute myelogenous leukemia associated with severe esophageal stricture
after chemotherapy]
SO - Rinsho Ketsueki 2002 Jan;43(1):41-3
AD - Division of Hematology, Department of Medicine, Kawasaki Medical School.
A 41-year-old woman with relapsed acute myelogenous leukemia was treated
twice with idarubicin hydrochloride and cytarabine. She developed a
6-cm-long stricture in the lower esophagus 12 days after re-induction
therapy. Although she had preceding candida infection, it is suspected
that her stricture was caused by mucosal damage due to chemotherapeutic
agents. This case suggests that the possibility of esophageal stricture
should be considered in patients with swallowing disturbance after
intensive chemotherapy.
3
UI - 11781652
AU - Tack DK; Letendre L; Kamath PS; Tefferi A
TI -
Development of hepatic veno-occlusive disease after Mylotarg infusion
for relapsed acute myeloid leukemia.
SO - Bone Marrow Transplant 2001 Nov;28(9):895-7
AD - Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN
55905, USA.
Mylotarg (gemtuzumab zogamicin) is a conjugated monoclonal antibody that
has recently become available for use in patients with relapsing or
refractory acute myeloid leukemia. Reversible hepatotoxicity is common
after administration. We describe the first report of hepatic
veno-occlusive disease (HVOD) developing after Mylotarg infusion in a
patient who underwent hematopoietic stem cell transplantation 8 months
earlier. Certain antineoplastic agents have been implicated as a cause
of HVOD, but the disease is most commonly seen within 30 days after
hematopoietic stem cell transplantation. The possible association
between Mylotarg infusion and HVOD is discussed.
4
UI - 11930925
AU - Anonymous
TI -
Arsenic-based therapy benefits leukemia patients.
SO - FDA Consum 2001 Jan-Feb;35(1):4
5
UI - 11842488
AU - White C
TI -
Painful lesions in a pancytopenic patient.
SO - Clin J Oncol Nurs 2002 Jan-Feb;6(1):47-9, 51
AD - Loyola University Medical Center, Foster McGaw Hospital, in Maywood, IL,
USA. cwhite@lumc.edu
6
UI - 11921269
AU - Rowley JD; Olney HJ
TI -
International workshop on the relationship of prior therapy to balanced
chromosome aberrations in therapy-related myelodysplastic syndromes and
acute leukemia: overview report.
SO - Genes Chromosomes Cancer 2002 Apr;33(4):331-45
AD - Department of Medicine, University of Chicago, Chicago, Illinois, USA.
jrowley@medicine.bsd.uchicago.edu
7
UI - 10578153
AU - Burt RK; Drobyski WR; Traynor AE; Link CJ Jr
TI -
Herpes simplex thymidine kinase (HStk) transgenic donor lymphocytes.
SO - Bone Marrow Transplant 1999 Nov;24(10):1043-51
AD - Northwestern University School of Medicine, Robert H Lurie Cancer
Center, Chicago, IL, USA.
Patients with recurrent leukemia after an allogeneic hematopoietic stem
cell transplant may be treated with donor lymphocyte infusions (DLI).
The transfusion of lymphocytes from the original hematopoietic stem cell
donor induces remission in approximately one third of relapsed AML cases
and 80% of relapsed CML. DLI may be complicated by delayed and sometimes
lethal graft-versus-host disease (GVHD). In an attempt to avoid this
complication, several centers have initiated DLI trials in which the
infused lymphocytes carry a suicide gene, herpes simplex thymidine
kinase (HStk), which confers sensitivity to ganciclovir (GCV). In the
event of severe GVHD, administration of GCV should terminate or
ameliorate GVHD.
8
UI - 11410481
AU - Bross PF; Beitz J; Chen G; Chen XH; Duffy E; Kieffer L; Roy S; Sridhara
TI -
R; Rahman A; Williams G; Pazdur R
Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid
leukemia.
SO - Clin Cancer Res 2001 Jun;7(6):1490-6
AD - Division of Oncology Drug Products, Center for Drug Evaluation and
Research, Food and Drug Administration, Rockville, Maryland 20852, USA.
brossp@cder.fda.gov
PURPOSE: Gemtuzumab ozogamicin (Mylotarg; Wyeth Laboratories,
Philadelphia, PA) consists of a semisynthetic derivative of
calicheamicin, a cytotoxic antibiotic linked to a recombinant monoclonal
antibody directed against the CD33 antigen present on leukemic
myeloblasts in most patients with acute myeloid leukemia (AML). In this
study, we review the preclinical and clinical profiles of this
immunoconjugate and the regulatory review that led to marketing approval
by the United States Food and Drug Administration. EXPERIMENTAL DESIGN:
From the literature and manufacturer's data, we review the activity,
tolerability, and pharmacokinetics of gemtuzumab ozogamicin in
preclinical and Phase I studies and its activity, efficacy, and side
effects in three Phase 2 trials of 142 patients with relapsed AML.
RESULTS: In Phase I studies, the major toxicity was myelosuppression,
especially neutropenia and thrombocytopenia, resulting from the
expression of CD33 on myeloid progenitor cells. The Phase 2 dose was 9
mg/m(2) infused i.v. over 4 h, repeated on day 14. A minority of
patients experienced acute infusion-related symptoms, usually transient
and occasionally requiring hospitalization. The complete response (CR)
rate with full recovery of hematopoiesis was 16%. A subset of patients
[CRs with incomplete platelet recovery (CRps)] was identified with blast
clearance and neutrophil recovery but incomplete platelet recovery. The
duration of responses of CRps appeared to be similar to those of the
CRs, although the numbers were small. The question of the equivalence of
these response groups was a central issue in the review of this new drug
application (NDA). After considerable discussion, the Oncology Drugs
Advisory Committee recommended allowing inclusion of CRps resulting in
an overall response rate in the Phase 2 studies of 30%. In the subgroup
of patients over 60 years of age, the overall response rate was 26%.
Response duration was difficult to establish because of the high
prevalence of postremission therapies. Tolerability and ease of
administration may be improved compared with conventional chemotherapy,
except for hepatotoxicity, with 31% of patients exhibiting abnormal
liver enzymes. One patient died of liver failure in the Phase 2 trials.
CONCLUSIONS: Marketing approval of gemtuzumab ozogamicin was granted on
May 17, 2000 by the United States Food and Drug Administration under the
Accelerated Approval regulations. Gemtuzumab ozogamicin is indicated for
the treatment of patients with CD33 positive AML in first relapse who
are 60 years of age or older and who are not considered candidates for
cytotoxic chemotherapy. The approved dose was 9 mg/m(2) i.v. over 4 h
and repeated in 14 days. Completion of the ongoing studies of gemtuzumab
ozogamicin in relapsed AML and initiation of randomized clinical trials
comparing the effects of gemtuzumab ozogamicin in combination with
conventional induction chemotherapy to conventional chemotherapy alone
on survival are mandated to confirm clinical benefit under the
accelerated approval Subpart H regulations. Postmarketing reports of
fatal anaphylaxis, adult respiratory distress syndrome (ARDS), and
hepatotoxicity, especially venoocclusive disease (VOD) in patients
treated with gemtuzumab ozogamicin, with and without associated
hematopoietic stem cell transplantation (HSCT), have required labeling
revisions and the initiation of a registration surveillance program.
Tumor lysis and ARDS have been reported in patients with leukocytes
above 30,000/ml treated with gemtuzumab ozogamicin; therefore, the
reduction of leukocyte counts to below 30,000/ml is recommended prior to
treatment. Patients should be carefully monitored for acute
hypersensitivity, hypoxia, and delayed hepatotoxicity following
treatment with gemtuzumab ozogamicin.
9
UI - 11852722
AU - Simpson JK; Rosenzweig MQ
TI -
Treatment considerations for the elderly person with cancer.
SO - AACN Clin Issues 2002 Feb;13(1):43-60
AD - University of Pittsburgh, Graduate School of Public Health, Women's
Health Office, 516 Parran Hall, 130 DeSoto Street, Pittsburgh, PA 15261,
USA. jsimp@stargate.net
In an aging population, the number of patients with cancer continues to
rise. Little research has focused on the treatment of cancer in the
elderly. Therefore, the treatment for various cancers differs across the
healthcare system. A uniform approach in assessing the elderly person
with cancer is lacking. This article describes two case studies in the
elderly population, focusing on two common cancers: acute myelogenous
leukemia and breast cancer. Common side effects of treatment and
determinants of treatment options are discussed. It is important that
the elderly receive appropriate screening, early detection, treatment,
and management of comorbidities.
10
UI - 11898239
AU - Treish IM
TI -
Targeting leukemia cells with gemtuzumab ozogamicin.
SO - Cancer Pract 2000 Sep-Oct;8(5):254-7
AD - Department of Pharmacy, University of North Carolina Hospitals, Chapel
Hill, North Carolina, USA.
11
UI - 11823950
AU - Reinhardt D; Thiele C; Creutzig U; AML-BFM-Studiengruppe
TI -
[Neuropsychological sequelae in children with AML treated with or
without prophylactic CNS-irradiation]
SO - Klin Padiatr 2002 Jan-Feb;214(1):22-9
AD - Padiatrische Hamatologie/Onkologie, Westfalischen-Wilhelms Universitat,
Munster. dreinh@uni-muenster.de
BACKGROUND: In study AML-BFM 87 the relapse rate was lower in patients
receiving cranial irradiation (CRT). However, CRT has always been
associated with adverse cognitive side effects. Therefore, the impact of
CRT on neuropsychological function in children with AML was
retrospectively evaluated. PATIENTS: We tested 53 children (30 boys, 23
girls) treated according to the AML-BFM-87 protocol (median age at
diagnosis: 8.5 years, range 0.3 - 17.5; median time since diagnosis: 5.7
yrs, 3.8 - 10.7 yrs). To avoid any bias from additional therapy
elements, patients with relapse or initial CNS involvement and
transplanted patients were excluded (n=32). Our cohort was
representative of the total group of 104 long term survivors of study
AML-BFM 87. CNS prophylaxis consisted of ARA-C i.th., high dose ARA-C i.
v. and either no CRT (n=15) or CRT (n=38) at a dose of 12 - 18 Gy
depending on age. METHODS: Neuropsychological function was evaluated by
psychological tests of attention and concentration (test d2 by
Brickenkamp) and an intelligence test (Progressive Matrices by Raven).
In addition, patients and their parents were interviewed about the
occurrence of learning problems, subjective deficits in concentration
and physical impairment. RESULTS: In the total group, no significant
differences were seen between irradiated and non-irradiated patients
regarding the psychological tests. However, the irradiated patients
scored below the non-irradiated control group in test "d2"
(concentration: 41st vs. 59th percentile). In the interview, irradiated
patients tended to report more learning problems (lp) (10/36 vs. 1/14;
p=0.15) and subjective deficits in concentration (con). In irradiated
girls (con: 6/15 vs. 0/8; p=0.06; lp: 5/15 vs. 0/8; p=0.12) and younger
patients (0 - 5 years at diagnosis; con: 7/12 vs. 2/9; p=0.18; lp 3/10
vs. 1/9; p=0.18) this trend was even more pronounced. CONCLUSION:
Children with AML and CRT had no significant intellectual impairment in
standardized tests when compared to non-irradiated patients. However,
more irradiated patients reported learning problems and subjective
concentration deficits.
12
UI - 11836177
AU - Martinez-Chamorro C; Martinez E; Gil-Fernandez JJ; Alonso A; Escudero A;
TI -
Fernandez-Ranada JM
ATRA-induced myositis in induction therapy of acute promyelocytic
leukemia.
SO - Haematologica 2002 Feb;87(2):ECR08
AD - C/ General Oraa, 3-1, 28006- Madrid SPAIN. m-chamorro@navegalia.com
13
UI - 11836180
AU - Spedini P
TI -
Retinoic acid syndrome: a case of massive lung consolidation.
SO - Haematologica 2002 Feb;87(2):EIM06
AD - Divisione di Medicina II, Sezione di Ematologia, Istituti Ospitalieri di
Cremona, Italy.
14
UI - 11836189
AU - Breccia M; Cimino G; Alimena G; De Carolis S; Lo Coco F; Mandelli F
TI -
AIDA treatment for high-risk acute promyelocytic leukemia in a pregnant
woman at 21 weeks of gestation.
SO - Haematologica 2002 Feb;87(2):ELT12
AD - Dept. of Human Biotechnology and Hematology of the University La
Sapienza of Roma, Via Benevento 6, 00161 Roma, Italy.
mbreccia@hotmail.com
15
UI - 11907794
AU - Astudillo L; Loche F; Reynish W; Rigal-Huguet F; Lamant L; Pris J
TI -
Sweet's syndrome associated with retinoic acid syndrome in a patient
with promyelocytic leukemia.
SO - Ann Hematol 2002 Feb;81(2):111-4
AD - Department of Haematology, University Hospital, Toulouse, France.
leoastu@club-internet.fr
We report a case of Sweet's syndrome associated with retinoic acid
syndrome in a patient with acute promyelocytic leukemia treated with
all- trans retinoic acid (ATRA). Sweet's syndrome appeared on day 6 of
ATRA therapy for promyelocytic leukemia. It was associated with a mild
retinoic acid syndrome, an inflammatory syndrome occurring in 25% of
patients treated with ATRA and characterized by features of capillary
leakage with systemic inflammatory signs. The ATRA therapy was
discontinued for 11 days and treatment with corticosteroids improved the
systemic and cutaneous signs. Only 11 cases of Sweet's syndrome
associated with ATRA have been previously reported in the literature,
involving only the skin in eight cases, the skin and muscles in two
cases, and the lung, kidney, fascia, and muscles in one case. Sweet's
syndrome was followed by retinoic acid syndrome in one of these cases.
The previously reported cases are reviewed, and the mechanisms of
Sweet's and retinoic acid syndromes and the link between them are
discussed.
16
UI - 11896112
AU - Furman WL; Stewart CF; Kirstein M; Kepner JL; Bernstein ML; Kung F;
TI -
Vietti TJ; Steuber CP; Becton DL; Baruchel S; Pratt C
Protracted intermittent schedule of topotecan in children with
refractory acute leukemia: a pediatric oncology group study.
SO - J Clin Oncol 2002 Mar 15;20(6):1617-24
AD - Department of Hematology-Oncology, St Jude Children's Research Hospital,
Memphis, TN, USA. wayne.furman@stjude.edu
PURPOSE: To determine dose-limiting toxicity (DLT) and maximum-tolerated
dose (MTD) of a protracted, intermittent schedule of daily 30-minute
infusions of topotecan (TPT) for up to 12 consecutive days, every 3
weeks, in children with refractory leukemia. PATIENTS AND METHODS:
Forty-nine children were enrolled onto this phase I trial (24 with acute
nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic
leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m(2)/d for
5 days and 2.4 mg/m(2)/d from 7 days to the same dose for 9 and 12 days
in cohorts of three to six patients when no DLT was identified. TPT
pharmacokinetics were studied in 33 children once or twice (first and
last doses in patients who received TPT for > 7 days). RESULTS: Seventy
assessable courses of TPT were administered to 49 children who had
refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and
the MTD was 2.4 mg/m(2)/d for 9 days in this group of heavily pretreated
children. In 33 patients, the median TPT lactone clearance after the
first dose was 19.2 L/h/m(2) (range, 9.4 to 45.9 L/h/m(2)) and did not
change during the course. There were significant responses (one complete
response [CR] and four partial responses [PR] in patients with ANLL and
one CR and two PRs in patients with ALL), and all but one were at
dosages of TPT given for at least 9 days. CONCLUSION: The MTD was 2.4
mg/m(2)/d for 9 days. Further testing is warranted of TPT's schedule
dependence in children with leukemia.
17
UI - 11930660
AU - Chen Z; Wang Y; Wang W; Gong J; Xue Y
TI -
All-trans retinoic acid as a single agent induces complete remission in
a patient with acute leukemia of M2a subtype.
SO - Chin Med J (Engl) 2002 Jan;115(1):58-61
AD - First Affiliated Hospital, Suzhou University, Jiangsu Institute of
Hematology, Suzhou 215006, China. szchenzx@263.net
OBJECTIVE: To present a special case with the karyotype and molecular
marker of acute myeloid leukemia (AML)-M2 who was induced to complete
remission by all-trans retinoic acid (ATRA) alone. METHODS: A recently
hospitalized young female patient with acute leukemia was initially
diagnosed as M3 subtype based on morphological French-American-British
(FAB) classification. Karyotype analysis using standard G and R banding
techniques and RT-PCR were applied to further define the diagnosis.
After primarily cultured bone marrow cells from the iliac aspiration
were tested for in vitro induced differentiation, the patient was
treated with oral all-trans retinoic acid alone, 60 mg per day until
complete remission was achieved. Peripheral blood and bone marrow
changes were monitored over the whole treatment course. RESULTS: The
characteristic chromosomal aberration for M3, the t(15;17) reciprocal
translocation, was not found while a t(8;21) translocation was verified.
Furthermore, an amplified product of the AML-1/ETO fusion gene instead
of the PML/RAR alpha fusion gene was detected by RT-PCR and the
diagnosis was corrected from M3 to M2. Primary cultured bone marrow
cells can be fully induced to terminal differentiation after 4 days
exposure to ATRA. A hematological complete remission was achieved after
40 days treatment with ATRA as a single therapeutic agent, suggesting an
alternative pathway mediating ATRA-induced myeloid differentiation.
CONCLUSION: A leukemia patient with a subtype other than M3, such as M2
in this case, may also be induced to complete remission by the mechanism
of ATRA-induced terminal differentiation. This implies that there may be
a pathway other than PML/RAR alpha fusion gene product which mediates
ATRA-induced myeloid maturation in leukemia cells.
18
UI - 11267978
AU - Hsu CP; Yang CC; Yang SD
TI -
Suppression of proline-directed protein kinase F(A) systemically
inhibits the growth of human acute leukemia cells.
SO - Int J Cancer 2001 Mar 1;91(5):650-53
AD - Department of Life Science, National Tsing Hua University, Hsinchu,
Taiwan, R.O.C.
Initial studies revealed that proline-directed protein kinase F(A) (PDPK
F(A)) was overexpressed in various cancerous tissues relative to normal
controls. However, the functional role of overexpressed PDPK F(A) in
cancer remains to be established. In this report, we explore the
potential role of PDPK F(A) in leukemia cell growth by investigating the
effects of partial inhibition of this kinase on human acute
promyelocytic leukemia (HL-60) and acute lymphoblastic leukemia (Jurkat)
cells. Cloning of PDPK F(A) cDNA and its recombinant antisense
expression vector and antibody were successfully developed. Several
stable antisense clones of HL-60 and Jurkat cells were subcloned, which
expressed a low level of PDPK F(A) when compared with the
control-transfected clone in immunoblot analysis. Moreover, these
antisense clones potently inhibited cell growth, clonogenic growth in
soft agar and serum-independent growth. The results taken together
demonstrate that suppression of PDPK F(A) is able to interfere with the
growth of HL-60 and Jurkat cells, suggesting an essential role of this
PDPK in human acute leukemia cell growth. Copyright 2001 Wiley-Liss,
Inc.
19
UI - 11368378
AU - Larson RA
TI -
New agents for induction and postremission therapy of acute myeloid
leukemia.
SO - Leukemia 2001 Apr;15(4):675-6
AD - University of Chicago, IL 60637, USA.
20
UI - 11371621
AU - Pendino F; Flexor M; Delhommeau F; Buet D; Lanotte M; Segal-Bendirdjian
TI -
E
Retinoids down-regulate telomerase and telomere length in a pathway
distinct from leukemia cell differentiation.
SO - Proc Natl Acad Sci U S A 2001 Jun 5;98(12):6662-7
AD - Institut National de la Sante et de la Recherche Medicale U496, Centre
G. Hayem, Hopital Saint-Louis, 1, Avenue Claude Vellefaux, 75010 Paris,
France.
Human telomerase, a cellular reverse transcriptase (hTERT), is a nuclear
ribonucleoprotein enzyme complex that catalyzes the synthesis and
extension of telomeric DNA. This enzyme is specifically activated in
most malignant tumors but is usually inactive in normal somatic cells,
suggesting that telomerase plays an important role in cellular
immortalization and tumorigenesis. Terminal maturation of tumor cells
has been associated with the repression of telomerase activity. Using
maturation-sensitive and -resistant NB4 cell lines, we analyzed the
pattern of telomerase expression during the therapeutic treatment of
acute promyelocytic leukemia (APL) by retinoids. Two pathways leading to
the down-regulation of hTERT and telomerase activity were identified.
The first pathway results in a rapid down-regulation of telomerase that
is associated with retinoic acid receptor (RAR)-dependent maturation of
NB4 cells. Furthermore, during NB4 cell maturation, obtained
independently of RAR by retinoic X receptor (RXR)-specific agonists
(rexinoids), no change in telomerase activity was observed, suggesting
that hTERT regulation requires a specific signaling and occurs
autonomously. A second pathway of hTERT regulation, identified in the
RAR-responsive, maturation-resistant NB4-R1 cell line, results in a
down-regulation of telomerase that develops slowly during two weeks of
all-trans retinoic acid (ATRA) treatment. This pathway leads to telomere
shortening, growth arrest, and cell death, all events that are overcome
by ectopic expression of hTERT. These findings demonstrate a clear and
full dissociation between the process of tumor cell maturation and the
regulation of hTERT mRNA expression and telomerase activity by
retinoids. We propose telomerase expression as an efficient and
selective target of retinoids in the therapy of tumors.
21
UI - 11911247
AU - Faderl S; Estrov Z; Kantarjian H M; Harris D; Van Q; Fokt I; Przewloka
TI -
T; Godlewski C; Woynarowski J M; Priebe W
WP744, a novel anthracycline with enhanced proapoptotic and antileukemic
activity.
SO - Anticancer Res 2001 Nov-Dec;21(6A):3777-84
AD - The University of Texas M. D. Anderson Cancer Center, Houston 77030,
USA.
BACKGROUND: MDR1 or MRP1 drug resistance mechanisms seriously limit the
efficacy of anthracyclines such as doxorubicin, in the treatment of
acute myeloid leukemia (AML). Our studies indicated that reducing
basicity, increasing steric hindrance at C-4', and/or lipophilicity may
help circumvent P-glycoprotein (P-gp)-mediated anthracycline efflux and
thus increase drug retention in MDR-positive cells. From a series of
4'-substituted analogs, 4'-O-benzylated doxorubicin (WP744) was selected
for a comparison with the classic anthracycline doxorubicin for their
cytotoxic and pro-apoptotic properties. WP744 retains cytotoxic activity
against P-gp and MRP-positive cells. METHODS AND RESULTS: In three AML
cell lines (K562, KBM-3, and OCIM2) WP744 was markedly more potent (IC50
values of 0.18, <0.05, and <0.05 microg/ml, respectively) than
doxorubicin (IC50 values of >0.5, 0.07, and 0.09 microg/ml,
respectively). Likewise, WP744 inhibited the colony formation by AML-CFU
cells from fresh bone marrow of three AML patients more strongly than
doxorubicin. Cell growth inhibition by WP744 is accompanied by apoptosis
induction as shown by TUNEL assay in OCIM2 cells. WP744-induced
apoptosis appears to be mediated by caspase-3 as apoptotic changes were
abrogated in the presence of the caspase 3 inhibitor Z-DEVD-FMK.
Accordingly, caspase 3 activity was elevated in the lysates from
drug-treated cells. WP744 induced also cleavage of apoptotic marker
poly(ADP-ribose)polymerase (PARP). Finally, WP744 at 0.05 microM and
greater was a potent inducer of apoptosis (by quantitative DNA
fragmentation) in cultured human acute lymphoblastic leukemia (ALL) CEM
cells, compared to 0.5 microM doxorubicin needed for a similar effect.
CONCLUSION: The novel anthracycline WP744 was found to be an
antileukemic agent with proapoptotic activity superior to that of
doxorubicin.
22
UI - 11902306
AU - Huang F S; Zwerdling T; Stern L E; Ballard E T; Warner B W
TI -
Renal cell carcinoma as a secondary malignancy after treatment of acute
promyelocytic leukemia.
SO - J Pediatr Hematol Oncol 2001 Dec;23(9):609-11
AD - Division of Hematology/Oncology, Children's Hospital Medical Center,
Cincinnati, Ohio 45229-3039, USA.
Numerous children have been treated successfully for cancer and are
surviving into adulthood. As this population has aged, an increasing
number of secondary malignancies has emerged. Renal cell carcinoma (RCC)
is a rare tumor in childhood and has not been documented previously to
occur after treatment of acute promyelocytic leukemia (APL). This report
describes the clinical course of APL treated in a child in whom RCC
subsequently developed during adolescence approximately 5 years after
therapy.
23
UI - 11237056
AU - Creutzig U; Ritter J; Zimmermann M; Hermann J; Gadner H; Sawatzki DB;
TI -
Niemeyer CM; Schwabe D; Selle B; Boos J; Kuhl J; Feldges A
Idarubicin improves blast cell clearance during induction therapy in
children with AML: results of study AML-BFM 93. AML-BFM Study Group.
SO - Leukemia 2001 Mar;15(3):348-54
AD - University Children's Hospital, Department of Hematology/Oncology,
Munster, Germany.
In the randomized trial AML-BFM 93 we compared 60 mg/m2/day daunorubicin
with 12 mg/m2/day idarubicin for 3 days each, combined with cytarabine
and etoposide during induction. Results showed a significant better
blast cell reduction in the bone marrow on day 15 in patients of the
idarubicin arm (25 of 144 = 17% of patients with > or = 5% blasts
compared to 46 of 149 = 31% of patients after daunorubicin, Pchi2 =
0.01). This was, however, mainly seen in high risk patients treated with
idarubicin (19% vs 38%, Pchi2 = 0.007). Cardiotoxicity, WHO grade 1-3
shortening fraction reduction after induction occurred in 6% patients in
both arms. Bone marrow toxicity differed slightly with a median recovery
time of neutrophils >500/microl of 25 days (daunorubicin) compared to 27
days (idarubicin), P = 0.05. In the total group of patients
probabilities of 5 years event-free survival and disease-free survival
were similar for patients treated with daunorubicin or idarubicin (49%
+/- 4% vs 55% +/- 4% and 57% +/- 4% vs 64% +/- 4%, P logrank 0.29 and
0.15, respectively). However, in patients presenting with more than 5%
blasts on day 15 there was a trend for a better outcome after treatment
with idarubicin (P logrank 0.06). Together with the early effect seen
for high risk patients these results indicate a better efficacy of
idarubicin than of daunorubicin during induction with a similar rate of
toxicity.
24
UI - 11843281
AU - Mikoshiba M; Ohashi K; Takei N; Okuyama Y; Maeda Y; Hiruma K; Akiyama H;
TI -
Fukuhara O; Takeshita A; Sakamaki H
Successful unrelated bone marrow transplantation after arsenic trioxide
treatment in a patient with relapsed acute promyelocytic leukemia.
SO - Int J Hematol 2002 Jan;75(1):104-6
25
UI - 11823363
AU - Greaves M
TI -
Childhood leukaemia.
SO - BMJ 2002 Feb 2;324(7332):283-7
AD - Leukaemia Research Fund Centre, Institute of Cancer Research, Chester
Beatty Laboratories, London SW3 6JB. m.greaves@icr.ac.uk
26
UI - 11830487
AU - Zhou DC; Kim SH; Ding W; Schultz C; Warrell RP Jr; Gallagher RE
TI -
Frequent mutations in the ligand-binding domain of PML-RARalpha after
multiple relapses of acute promyelocytic leukemia: analysis for
functional relationship to response to all-trans retinoic acid and
histone deacetylase inhibitors in vitro and in vivo.
SO - Blood 2002 Feb 15;99(4):1356-63
AD - Department of Oncology, Montefiore Medical Center, Albert Einstein
Cancer Center, Bronx, NY 10467, USA.
This study identified missense mutations in the ligand binding domain of
the oncoprotein PML-RARalpha in 5 of 8 patients with acute promyelocytic
leukemia (APL) with 2 or more relapses and 2 or more previous courses of
all-trans retinoic acid (RA)-containing therapy. Four mutations were
novel (Lys207Asn, Gly289Arg, Arg294Trp, and Pro407Ser), whereas one had
been previously identified (Arg272Gln; normal RARalpha1 codon
assignment). Five patients were treated with repeat RA plus
phenylbutyrate (PB), a histone deacetylase inhibitor, and one patient
experienced a prolonged clinical remission. Of the 5 RA + PB-treated
patients, 4 had PML-RARalpha mutations. The Gly289Arg mutation in the
clinical responder produced the most defective PML-RARalpha function in
the presence of RA with or without sodium butyrate (NaB) or trichostatin
A. Relapse APL cells from this patient failed to differentiate in
response to RA but partially differentiated in response to NaB alone,
which was augmented by RA. In contrast, NaB alone had no differentiation
effect on APL cells from another mutant case (Pro407Ser) but enhanced
differentiation induced by RA. These results indicate that PML-RARalpha
mutations occurred with high frequency after multiple RA treatment
relapses, indicate that the functional potential of PML-RARalpha was not
correlated with clinical response to RA + PB treatment, and suggest that
the response to RA + PB therapy in one patient was related to the
ability of PB to circumvent the blocked RA-regulated gene response
pathway.
27
UI - 11783227
AU - Hu X; Ma L; Hu N
TI -
[Ailing No. I in treating 62 cases of acute promyelocytic leukemia]
SO - Zhongguo Zhong Xi Yi Jie He Za Zhi 1999 Aug;19(8):473-6
AD - Xiyuan Hospital, China Academy of TCM, Beijing, China.
OBJECTIVE: To obtain further knowledge on the effect, mechanism and
toxic side-effect of Ailing No. I (AL), a preparation of As2O3, in
treating acute promyelocytic leukemia (APL). METHODS: AL was used in
induction and consolidation treatment of 62 cases of APL, the effect of
treatment and the changes of clinical symptoms, peripheral blood and
bone marrow pictures, T-lymphocyte subset, and immunofunctions of
patients after treatment were observed. RESULTS: Twenty-seven cases out
of the 31 patients who received induction treatment got complete
remission (CR), the CR rate being 87.1%. Of the 31 cases who received
consolidation treatment, the longest remission period was 37 months, and
7 cases relapsed within one month to 2 years. Peripheral white blood
cell count raised after one week but lowered after 4 weeks of induction
treatment, but in receiving consolidation treatment, it started to lower
after one week and raised after 4 weeks of treatment. No obvious change
on hemoglobin level was observed. Platelet count significantly increased
after treatment. The treatment showed no obvious inhibition on bone
marrow. The T-lymphocyte subsets and immunoglobulin level were changed
insignificantly after treatment. Various side-effects were shown
clinically, particularly those digestive tract involved symptoms were
prominent, and liver damage was shown in a certain degree. CONCLUSION:
AL has good and protracted effect in treating APL with high CR rate, the
mechanism may be related with its cytotoxicity and action of
differentiation induction.
28
UI - 11899326
AU - Sorokin P
TI -
Mylotarg approved for patients with CD33+ acute myeloid leukemia.
SO - Clin J Oncol Nurs 2000 Nov-Dec;4(6):279-80
Acute myeloid leukemia (AML) is the most common adult leukemia and has
historically been treated with intensive multiagent chemotherapy. In May
2000, the U.S. Food and Drug Administration approved a new agent,
gemtuzumab ozogamicin (Mylotarg) to treat patients who are 60 years and
older in first relapse with CD33+ AML and not considered candidates for
chemotherapy. Gemtuzumab is an antibody-targeted agent that binds
specifically to the CD33 antigen that is found on the surface of more
than 80% of patients with AML. The agent is administered via i.v. over
two hours, and premedication with acetaminophen and diphenhydramine is
recommended. Side effects include fever, chills, neutropenia and
thrombocytopenia, and asymptomatic hypotension. Clinical remissions have
been observed with gemtuzumab, and additional trials with this new agent
currently are being conducted.
29
UI - 11951090
AU - Aquino VM
TI -
Acute myelogenous leukemia.
SO - Curr Probl Pediatr Adolesc Health Care 2002 Feb;32(2):50-8
AD - Department of Pediatrics, University of Texas Southwestern Medical
Center at Dallas, Dallas, Texas, USA.
30
UI - 11953850
AU - Perrillat F; Clavel J; Auclerc MF; Baruchel A; Leverger G; Nelken B;
TI -
Philippe N; Schaison G; Sommelet D; Vilmer E; Hemon D
Day-care, early common infections and childhood acute leukaemia: a
multicentre French case-control study.
SO - Br J Cancer 2002 Apr 8;86(7):1064-9
AD - Institut National de la Sante et de la Recherche Medicale, Inserm U170,
16 avenue Paul Vaillant Couturier, 94807 Villejuif, France.
We conducted a case-control study to investigate the role of early
infections in the aetiology of childhood acute leukaemias. The study
included 280 incident cases (240 acute lymphoblastic leukaemia and 40
acute non-lymphoblastic leukaemia) and 288 hospital controls, frequency
matched by age, gender, hospital, catchment area of the hospital and
ethnic origin. Data were obtained from standardised face-to-face
interviews of the mothers. The interviews included questions on early
common infections, day-care attendance, breast-feeding, birth order and
infantile diseases. Odds ratios were estimated using an unconditional
regression model including the stratification variables, parental
socio-economic status and perinatal characteristics. Birth order was not
associated with childhood leukaemia (acute lymphoblastic or acute
non-lymphoblastic). A statistically-significant inverse association was
observed between childhood leukaemia and day-care attendance (odds
ratio=0.6, 95% Confidence Interval=(0.4-1.0)), repeated early common
infections (> or = 4 per year before age two, odds ratio=0.6 (0.4-1.0)),
surgical procedures for ear-nose-throat infections before age two (odds
ratio=0.5 (0.2-1.0)) and prolonged breast-feeding (> or = 6 months, odds
ratio=0.5 (0.2-1.0)). In the multivariate model including day-care
attendance, early common infections and breast-feeding, results
concerning breast-feeding remained unchanged. A statistically
significant interaction between day-care attendance and repeated early
common infections was observed. When the interaction was taken into
account, the simple effects of day-care and early common infections
disappeared (odds ratio=1.1 (0.5-2.3) and odds ratio=0.8 (0.5-1.3),
respectively) while the joint effect of day-care attendance and early
common infections was negatively associated with childhood leukaemia
(odds ratio=0.3 (0.1-0.8)). All the above associations were observed
both for acute lymphoblastic leukaemia and acute non-lymphoblastic
leukaemia. Our results support Greaves' hypothesis, even though they are
not specific of common leukaemia.
31
UI - 11879303
AU - Lam MS; Ignoffo RJ
TI -
Arsenic trioxide for the treatment of acute promyelocytic leukemia.
SO - Cancer Pract 2001 May-Jun;9(3):155-7
AD - School of Clinical Pharmacy, University of California, San Francisco,
California, USA.
32
UI - 11879277
AU - Alfiere M; Syombathy V
TI -
The challenge of providing culturally competent cancer care.
SO - Cancer Pract 2001 Mar-Apr;9(2):62-3
AD - Medical Oncology Inpatient Unit, Yale New Haven Hospital, New Haven,
Connecticut, USA.
33
UI - 11926186
AU - Loeb DM; Arceci RJ
TI -
Treatment and outcome of infants with acute myeloid leukemia.
SO - Blood 2002 Apr 1;99(7):2626-7
34
UI - 11882366
AU - Sora F; Antinori A; Piccirillo N; De Luca A; Chiusolo P; Cingolani A;
TI -
Laurenti L; Rutella S; Ortona L; Leone G; Sica S
Highly active antiretroviral therapy and allogeneic CD34(+) peripheral
blood progenitor cells transplantation in an HIV/HCV coinfected patient
with acute myeloid leukemia.
SO - Exp Hematol 2002 Mar;30(3):279-84
AD - Istituto di Ematologia, Universita Cattolica Sacro Cuore, Rome, Italy.
OBJECTIVE: To evaluate the safety, feasibility, and efficacy of
allogeneic stem cell transplantation (SCT) for acute myelogenous
leukemia (AML) in a young female coinfected by HIV and HCV undergoing
highly active antiretroviral therapy (HAART). PATIENTS AND METHODS: A
33-year-old female HIV(+), HCV(+) in complete remission after standard
chemotherapy was submitted to CD34(+) selected allogeneic
transplantation from her HLA-identical HIV(-) brother after
myeloablative regimen. HAART was started before transplantation,
achieving a reduction of HIV load to undetectable levels. GVHD
prophylaxis was carried out with cyclosporine A alone. RESULTS: The
patient achieved prompt and durable engraftment with acute GVHD grade II
easily managed with steroids; CMV prophylaxis was prolonged, no
clinically relevant infectious complications developed early after
transplantation and during follow-up. HIV viremia was controlled by
HAART although medication adherence was reduced early after
transplantation and required drug adjustment. There was a gradual
recovery of immune cells with normal CD4-cell count 39 months after
engraftment, a significantly higher level than before transplantation.
At 39 months post-transplantation follow-up the patient is alive and in
continuous complete remission with undetectable levels of plasma HIV RNA
on HAART. CONCLUSION: The introduction of HAART has recently changed the
paradigm of AIDS, allowing the control of HIV replication, the reduction
of opportunistic infections, and the overall improvement of survival.
One may therefore reconsider the current exclusion of patients with AIDS
and a concomitant lethal malignancy from programs of high-dose
chemotherapy and stem cell transplantation, as suggested by this report.
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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