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NCI CANCERLIT® Search: Therapy of Acute Lymphocytic Leukemia - May 2002
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Table of Contents
1
UI - 11960336
AU - Schlenk RF; Hartmann F; Hensel M; Jung W; Weber-Nordt R; Gabler A; Haas
TI -
R; Ho AD; Trumper L; Dohner H
Less intense conditioning with fludarabine, cyclophosphamide, idarubicin
and etoposide (FCIE) followed by allogeneic unselected peripheral blood
stem cell transplantation in elderly patients with leukemia.
SO - Leukemia 2002 Apr;16(4):581-6
AD - Department of Internal Medicine III, University of Ulm, Ulm, Germany.
The objective of this study was to assess toxicity and feasibility of
achieving engraftment of allogeneic blood progenitor cells following
nonmyeloablative conditioning according to the FCIE protocol
(fludarabine 25 mg/m(2)/day, days -7 to -3; cyclophosphamide 200
mg/m(2)/day, days -7 to -3; idarubicin 12 mg/m(2)/day, days -7 to -5;
etoposide 250 mg/m(2)/day, days -4 to -3) in elderly patients with
leukemia. Eleven patients were included in the study: six patients with
acute myeloid leukemia (AML) in complete remission (CR); three patients
with refractory or relapsed AML; one patient with chronic myeloid
leukemia; one patient with acute lymphoblastic leukemia. The median age
of the patients was 62 years. All patients received blood progenitor
cells from an HLA-identical sibling with 8.8 x 10(6) CD34(+) cells/kg
(median; range 4.7 to 26.2 x 10(6)/kg) and 5.5 x 10(8) CD3(+)cells/kg
(median; range 4.5 to 7.9 x 10(8)/kg). Graft-versus-host disease (GVHD)
prophylaxis consisted of cyclosporine and three courses of methotrexate.
The median duration of white blood cell counts <1 x 10(9)/l was 17 days
and of platelet counts <50 x 10(9)/l 20 days. In two patients acute GVHD
grade I occurred. Nine of 10 patients analyzed developed mixed
chimerism. Of seven patients transplanted in CR, three remained in CR 19
to 31 months after transplantation. Three patients with refractory
leukemia did not achieve CR, while the patient with relapsed AML
achieved a 3rd CR. After a median follow-up time of 22 months, chronic
GVHD was mild and limited. The data from this pilot study in elderly
patients with leukemia show that the combination of primarily
immunosuppressive (FC) and antileukemic (IE) drugs for nonmyeloablative
conditioning has moderate nonhematological toxicity and allows
engraftment of allogeneic blood progenitor cells.
2
UI - 11904731
AU - Pospisilova D; Borovickova J; Polouckova A; Spisek R; Sediva A; Hrusak
TI -
O; Stary J; Bartunkova J
Generation of functional dendritic cells for potential use in the
treatment of acute lymphoblastic leukemia.
SO - Cancer Immunol Immunother 2002 Apr;51(2):72-8
AD - Institute of Immunology, Charles University, Second Medical Faculty and
Faculty Hospital Motol, V Uvalu 84, 150-06 Prague 5, Czech Republic.
Immunotherapy of malignant diseases mediated by dendritic cells (DC)
pulsed with tumor antigens ex vivo is a promising new tool in the
individual treatment of malignant diseases. The present study focuses on
the problem of how to optimize in vitro culture conditions and induce
the maturation of DC with the capacity to induce antitumor immunity
toward leukemic cells. DC were generated from peripheral mononuclear
cells by co-cultivation with granulocyte/macrophage-colony stimulating
factor (GM-CSF) and interleukin-4 (IL-4). Tumor antigens were added for
2 h after 7 days in culture. Irradiated leukemic blasts, blast lysate,
apoptotic cells from the Jurkat cell line (T ALL) and their lysate were
used in various concentrations for antigen pulsing. Harvested DC were
phenotyped by flow cytometry, and viability was assessed using trypan
blue exclusion (Annexin test). After the cells had been pulsed with
tumor antigens and co-cultured with autologous lymphocytes, the
production of interferon-gamma (IFN-gamma) and IL-12 was analyzed, and
lymphocyte proliferative response and cytotoxicity against the target
tumor cell line were assessed. The cultivation of monocytes under the
described conditions led to the expression of surface markers typical of
DC (i.e. CD83, CD86, HLA-DR, CD11c and CD40). Pulsation by antigens from
leukemic cells further increased the cell populations expressing these
markers. Antigen pulsation decreased the viability of generated DC
depending on the increase in concentration of tumor antigens. Pulsed
DC-lymphocyte interaction increased the proliferative response of
lymphocytes and IFN-gamma production depending on the type of tumor
antigens used for pulsation. The highest proliferative response was
detected with DC pulsed with Jurkat cell-line lysate. Similarly to the
proliferation assay, cytotoxic testing showed the highest efficiency of
DC pulsed with Jurkat cell-line lysate in killing the target malignant
cells. Our results show that an appropriate antigen concentration used
for DC pulsing is one of the crucial factors in an effective treatment
strategy, as high concentrations of tumor antigens induce apoptosis of
DC, thereby rendering them non-functional. Under optimal conditions,
pulsation by lysate from leukemic blasts induced the maturation of DC
and led to an increase in the proliferation of autologous lymphocytes,
to the production of Th1-cytokines and to the induction of cytotoxicity
toward the leukemic cell line. These results are encouraging for the
possible application of pulsed DC in the therapy of acute lymphoblastic
leukemia.
3
UI - 11792421
AU - Broome HE; Yu AL; Diccianni M; Camitta BM; Monia BP; Dean NM
TI -
Inhibition of Bcl-xL expression sensitizes T-cell acute lymphoblastic
leukemia cells to chemotherapeutic drugs.
SO - Leuk Res 2002 Mar;26(3):311-6
AD - University of California, San Diego Medical Center, 200 West Arbor
Drive, Mail Code 8320, San Diego, CA 92103, USA. ebroome@ucsd.edu
We have examined the effects of antisense oligonucleotides to bcl-x on
the survival and chemosensitivity of CEM cells, a T-acute lymphoblastic
leukemia (T-ALL) cell line. Also, we have measured the levels of Bcl-2,
Bcl-x, and Bax in 20 cases of T-ALL. By 18 h after the bcl-x antisense
treatment, CEM cells showed over a 75% reduction in the levels of Bcl-xL
protein and over 30% decreased viable cell counts compared with cells
treated with the control oligonucleotide. The combination of bcl-x
antisense plus either dexamethasone or doxorubicin showed either strong
synergistic or additive killing of CEM cells, respectively. These
findings indicate that bcl-x antisense has cytotoxic activity and
increases chemotherapy-induced cell death in CEM cells, a model for
T-ALL.
4
UI - 11908926
AU - Ronghe M; Burke GA; Lowis SP; Estlin EJ
TI -
Remission induction therapy for childhood acute lymphoblastic leukaemia:
clinical and cellular pharmacology of vincristine, corticosteroids,
L-asparaginase and anthracyclines.
SO - Cancer Treat Rev 2001 Dec;27(6):327-37
AD - Department of Paediatric Oncology, Royal Hospital for Sick Children, St
Michael's Hill, Bristol, UK.
Remission induction therapy with vincristine, a corticosteroid,
L-asparaginase and an anthracycline has been the mainstay of the initial
phase of treatment for childhood acute lymphoblastic leukaemia (ALL) for
the past 25 years. The speed and depth of the early response to
remission induction therapy has become an important determinant of the
intensity of subsequent therapy in many protocols worldwide. Moreover,
the detection of significant levels of minimal residual disease at the
end of remission induction may have an important bearing on subsequent
outcome. Although these clinical observations may reflect, in part, the
inherent sensitivity of lymphoblasts to remission induction therapy, the
pharmacology of these agents in relation to childhood ALL may also play
an important part in early response to therapy. In-vitro studies of
human leukaemia cell lines indicate that both the extracellular fluid
concentration and duration of exposure to vincristine and anthracyclines
are important determinants of cytotoxicity. For L-asparaginase and
corticosteroids, the cellular and molecular pharmacological determinants
of chemosensitivity have been partially characterized, but further work
is needed in this area. The clinical pharmacology of vincristine and
L-asparaginase have been well characterized in relation to childhood
ALL, and considerable interpatient pharmacokinetic variability exists
for these drugs. For corticosteroids and anthracyclines, pharmacology
studies are needed in order to fully characterize and understand the
factors influencing interpatient pharmacokinetic variability for these
agents in relation to childhood ALL. Whereas the relationship between
the clinical pharmacology, and potentially important pharmacodynamic
effects such as asparagine depletion, has been well characterized for
therapy with L-asparaginase, similar studies have yet to be performed
for the other drugs that form the mainstay of remission induction
therapy for childhood ALL. Therefore, further studies are required to
investigate the relative importance of the clinical and cellular
pharmacology of vincristine, corticosteroids, L-asparaginase and
anthracyclines in the speed and depth of response to remission induction
therapy for childhood ALL. Where these have been studied,
interindividual differences in the clinical and cellular pharmacology of
anticancer agents have been shown to be important determinants of the
long-term disease-free survival for children with ALL. Copyright 2002,
Elsevier Science Ltd. All rights reserved.
5
UI - 11908927
AU - Estlin EJ; Yule SM; Lowis SP
TI -
Consolidation therapy for childhood acute lymphoblastic leukaemia:
clinical and cellular pharmacology of cytosine arabinoside,
epipodophyllotoxins and cyclophosphamide.
SO - Cancer Treat Rev 2001 Dec;27(6):339-50
AD - Department of Paediatric Oncology, Royal Manchester Children's Hospital,
Pendlebury, Manchester M27 4HA, UK. eestlin@mch.srht.nwest.nhs.uk
The intensification of post-remission induction therapy has been shown
to improve the relapse-free survival for childhood acute lymphoblastic
leukaemia (ALL), and is now a standard component of the treatment of
childhood acute lymphoblastic leukaemia. For cytosine arabinoside
(ara-C), methotrexate, vincristine and corticosteroids, in-vitro studies
indicate that the extracellular drug concentration and exposure time are
important determinants of cytotoxicity for human leukaemia cell lines.
For L-asparaginase, epipodopyllotoxins and cyclophosphamide, there have
been few studies of the relationship between cellular pharmacology and
cytotoxicity in relation to ALL. The clinical and cellular pharmacology
of methotrexate and cytosine arabinoside have been studied in relation
to childhood ALL in vivo. For these drugs, there is evidence to suggest
that maintenance of plasma concentrations that are biochemically optimal
is necessary to maximize anti-leukaemic effects. For cytosine
arabinoside in particular, optimal extracellular fluid concentrations
are not likely to be achieved or maintained by bolus or short-duration
i.v. infusions. A potentially important example of this may be served by
the success of antimetabolite-based intrathecal chemotherapy for
CNS-directed treatment of childhood ALL. Intrathecal administration of
both methotrexate and cytosine arabinoside results in prolonged
leukaemic cell exposure to cytotoxic concentrations of the drug. For
vincristine, anthracyclines and asparaginase, the actual dose intensity
received by children during consolidation therapy may be important, and
there is considerable interpatient variation in the pharmacokinetics of
cyclophosphamide and teniposide in the therapy of childhood cancers. The
importance of this relationship to childhood ALL is not known. The
pharmacological and cellular pharmacological studies performed at St
Jude Children's Research Hospital (Memphis, TN, USA) have allowed
investigation of the relationships between the clinical and cellular
pharmacology of methotrexate and prognosis, and have supported the
individualization of consolidation therapy with this drug. Cytosine
arabinoside has been less well studied in relation to childhood ALL,
although evidence exists to suggest that the administration of
conventional-dose bolus or infusion schedules may not be optimal in
terms of the antileukaemic efficacy of this antimetabolite. For
L-asparaginase, ongoing studies may allow the relationship between dose
and schedule of administration to be related to pharmacodynamic measures
such as asparagine depletion and prognosis. Therefore, through knowledge
of clinical and cellular pharmacological properties, it may be possible
to optimize the consolidation phase of therapy for childhood ALL,
without disrupting the fundamental principles by which the overall
treatment is administered. This may be particularly important for
children with disease that has inherent or acquired resistance to
therapy. Copyright 2002, Elsevier Science Ltd. All rights reserved.
6
UI - 11908928
AU - Estlin EJ
TI -
Continuing therapy for childhood acute lymphoblastic leukaemia: clinical
and cellular pharmacology of methotrexate, 6-mercaptopurine and
6-thioguanine.
SO - Cancer Treat Rev 2001 Dec;27(6):351-63
AD - Department of Paediatric Oncology, Royal Manchester Children's Hospital,
Pendlebury, Manchester M27 4HA, UK. eestlin@mch.srht.nwest.nhs.uk
Across the world, therapy with 6-mercaptopurine (6-MP) and methotrexate
(MTX) forms the basis of the continuing therapy of childhood acute
lymphoblastic leukaemia (ALL). In this review, the pharmacological
determinants of the sensitivity of human leukaemia cell lines and
lymphoblasts derived from children with ALL will be discussed. In
addition, clinical pharmacological studies of 6-MP and MTX in relation
to the continuing therapy with childhood ALL will be reviewed. For 6-MP
in vitro, prolonged exposure times to relatively high extracellular drug
concentrations are necessary for cytotoxicity, and these concentrations
are much higher than those achieved during continuing therapy for
childhood ALL. For MTX, plasma concentrations are achieved during
continuing therapy that would be cytotoxic to human leukaemia cells
during prolonged exposures in vitro. For both MTX and 6-MP, wide inter-
and intrapatient variation in plasma pharmacokinetic parameters has been
described. For 6-MP and MTX, cellular pharmacological studies have been
largely restricted to erythrocytes as a surrogate of the possible
effects in leukaemic blasts. Although measures of the pharmacology of
6-MP and MTX in erythrocytes has been related to prognosis in many
studies, 6-MP systemic exposure and the dose intensity of 6-MP and MTX
actually received by children during this phase of therapy seems to be
the most important determinant of efficacy. Further studies will be
needed to determine the importance of pharmacokinetic variability during
continuing therapy as a determinant of outcome for children with ALL. In
this respect, minimal residual disease status during this phase of
treatment may prove to be a useful pharmacodynamic endpoint. Copyright
2002, Elsevier Science Ltd. All rights reserved.
7
UI - 11759074
AU - Dinndorf P; Krailo M; Liu-Mares W; Frierdich S; Sondel P; Reaman G
TI -
Phase I trial of anti-B4-blocked ricin in pediatric patients with
leukemia and lymphoma.
SO - J Immunother 2001 Nov-Dec;24(6):511-6
AD - Children's National Medical Center, Washington DC, USA.
Monoclonal antibodies, specific for antigens expressed on lymphoid
malignancies, which have been conjugated to toxins such as ricin, hold
promise in the therapy of childhood leukemia and lymphoma.
Anti-B4-blocked ricin (anti-B4-bR) is such an agent, and a phase I study
of this agent was conducted in children with relapsed or refractory
B-lineage leukemia and lymphoma. Anti-B4-bR was given as two 7-day
continuous infusions separated by 7 days. Twenty patients were enrolled
and 19 received the drug. Two dosage levels (30 and 40 microg/kg per
day) were evaluated. Forty micrograms per kilogram per day was the
maximally tolerated dose. Dose-limiting toxicity was capillary leak
syndrome. Grade 3 reversible elevation in transaminases was also
encountered. Human antimouse antibodies or human antiricin antibodies
were detected in five patients. No complete remissions or partial
remissions were seen.
8
UI - 11902549
AU - Pui C H; Campana D; Evans W E
TI -
Childhood acute lymphoblastic leukaemia--current status and future
perspectives.
SO - Lancet Oncol 2001 Oct;2(10):597-607
AD - Leukaemia/Lymphoma Division, Fahad Nassar Al-Rashid Chair of Leukaemia
Research at St Jude Children's Research Hospital, Memphis, TN 38105,
USA. ching-hon.pui@stjude.org
The current cure rate of 80% in childhood acute lymphoblastic leukaemia
attests to the effectiveness of risk-directed therapy developed through
well-designed clinical trials. In the past decade there have been
remarkable advances in the definition of the molecular abnormalities
involved in leukaemogenesis and drug resistance. These advances have led
to the development of promising new therapeutic strategies, including
agents targeted to the molecular lesions that cause leukaemia. The
importance of host pharmacogenetics has also been recognised. Thus,
genetic polymorphisms of certain enzymes have been linked with host
susceptibility to the development of de novo leukaemia or
therapy-related second cancers. Furthermore, recognition of inherited
differences in the metabolism of antileukaemic agents has provided
rational selection criteria for optimal drug dosages and scheduling.
Treatment response assessed by measurements of submicroscopic leukaemia
(minimal residual disease) has emerged as a powerful and independent
prognostic indicator for gauging the intensity of therapy. Ultimately,
treatment based on biological features of leukaemic cells, host
genetics, and the amount of residual disease should improve cure rates
further.
9
UI - 11699212
AU - Sakatani T; Shimazaki C; Hirai H; Okano A; Hatsuse M; Okamoto A;
TI -
Takahashi R; Ashihara E; Inaba T; Yokota H; Nakahara K; Hirai H;
Nakagawa M
Early relapse after high-dose chemotherapy rescued by tumor-free
autologous peripheral blood stem cells in acute lymphoblastic leukemia:
importance of monitoring for WT1-mRNA quantitatively.
SO - Leuk Lymphoma 2001 Jun;42(1-2):225-9
AD - Second Department of Medicine, Kyoto Prefectural University of Medicine,
Kamigyo-ku, Kyoto, 602-8566, Japan.
A 24-year-old woman who suffered from ALL with MLL gene rearrangement
received high-dose chemotherapy followed by autologous PBSC
transplantation during complete remission (CR). Reverse
transcriptase-polymerase chain reaction (RT-PCR) used to detect MLL/LTG4
chimeric mRNA showed no minimal residual disease (MRD) in the graft or
bone marrow at the transplantation. However, the leukemia relapsed four
months after transplantation. Retrospective analysis of quantitative
measurement of Wilms tumor gene (WT-1) mRNA showed an increased level in
the bone marrow although it was within the normal range. These
observations suggest that careful monitoring of MRD by quantitative
measurement of WT-1 mRNA in addition to disease-specific chimeric mRNA
is required to predict relapse.
10
UI - 11861307
AU - Hofmann WK; Jones LC; Lemp NA; de Vos S; Gschaidmeier H; Hoelzer D;
TI -
Ottmann OG; Koeffler HP
Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase
inhibitor STI571 has a unique BCR-ABL gene mutation.
SO - Blood 2002 Mar 1;99(5):1860-2
AD - Division of Hematology/Oncology, Cedars Sinai Research Institute, UCLA
School of Medicine, Los Angeles, California 90048, USA.
w.k.hofmann@em.uni-frankfurt.de
The tyrosine kinase inhibitor STI571 is a promising agent for the
treatment of advanced Philadelphia chromosome positive (Ph(+)) acute
lymphoblastic leukemia (ALL), but resistance develops rapidly in most
patients after an initial response. To identify mechanisms of resistance
to STI571, 30 complementary DNAs (including 9 matched samples) obtained
from the bone marrow of individuals with Ph(+) ALL were analyzed by
direct sequencing of a 714-base pair region of ABL encoding for the
adenosine triphosphate (ATP)-binding site and the kinase activation
loop. A single point mutation was found at nucleotide 1127 (GI6382056)
resulting in Glu255Lys. This mutation occurred in 6 of 9 patients (67%)
following their treatment with STI571 but not in the samples from
patients before beginning treatment with STI571. Glu255Lys is within the
motif important for forming the pocket of the ATP-binding site in ABL
and it is highly conserved across species. In conclusion, Ph(+) ALL
samples resistant to STI571 have a unique mutation Glu255Lys of BCR-ABL.
11
UI - 11916520
AU - Sotomayor EM; Piantadosi S; Miller CB; Karp JE; Jones RJ; Rowley SD;
TI -
Kaufmann SH; Braine H; Burke PJ; Gore SD
Long-term follow-up of intensive ara-C-based chemotherapy followed by
bone marrow transplantation for adult acute lymphoblastic leukemia:
impact of induction Ara-C dose and post-remission therapy.
SO - Leuk Res 2002 May;26(5):461-71
AD - The Johns Hopkins Oncology Center, 1650 Orleans Street, Baltimore, MD
21231-1000, USA.
We report single institution outcome of brief, intensive ara-C-based
chemotherapy using bone marrow transplantation as primary
intensification for untreated adult patients with acute lymphoblastic
leukemia (ALL). Overall disease-free and overall survival were inferior
to those reported with prolonged chemotherapy modeled on pediatric
protocols. Survival and disease-free survival were superior for patients
receiving allogeneic BMT compared with chemopurged autologous transplant
or maintenance chemotherapy (patients ineligible for or declining BMT).
In multivariate analysis, non-L2-FAB, higher ara-C dose, absence of CNS
disease, non-Ph1+ karyotype, allogeneic BMT, T cell phenotype, and
younger age were associated with improved disease-free survival.
Autologous BMT was not superior to chemotherapy, and appears unlikely to
provide adequate curative treatment for most adult ALL patients if not
followed by maintenance.
12
UI - 11916521
AU - Gokbuget N; Hoelzer D
TI -
The role of high-dose cytarabine in induction therapy for adult ALL.
SO - Leuk Res 2002 May;26(5):473-6
AD - University of Frankfurt, Medical Clinic III, Theodor Stern Kai 7, 60590
Frankfurt, Germany. goekbuget@em.uni-frankfurt.de
13
UI - 11916527
AU - Lam V; Findley HW; Reed JC; Freedman MH; Goldenberg GJ
TI -
Comparison of DR5 and Fas expression levels relative to the
chemosensitivity of acute lymphoblastic leukemia cell lines.
SO - Leuk Res 2002 May;26(5):503-13
AD - Department of Pharmacology, Interdepartmental Division of Oncology,
University of Toronto, Ont., Canada.
The relationship between p53 gene status and the expression of DR5 and
Fas was evaluated as a function of sensitivity of 11 acute lymphoblastic
leukemia cell lines to adriamycin, etoposide, vincristine, methotrexate
and dexamethasone. There was up to a 37-fold increase in expression of
DR5 following treatment with ADR or VP-16 only in cells with wt p53. A
direct correlation was observed between enhanced DR5 expression and
sensitivity to ADR and VP-16. There was no induction of DR5 following
treatment with VCR, MTX or DEX. There was up to a 51-fold increase in
the median level of expression of Fas following treatment with ADR and
VP-16, and unlike DR5 this occurred in cells with either wild-type or
mutant p53. Nevertheless, a direct correlation was observed between Fas
expression and drug-sensitivity. Conversely, there was only a two-fold
increase in expression of Fas after exposure to VCR, MTX and DEX. These
findings suggest that DR5 mediates sensitivity to ADR and VP-16 in a
p53-dependent manner, whereas, Fas appears to mediate sensitivity to
these two drugs independent of p53 status. DR5 and Fas do not appear to
play a major role as determinants of chemosensitivity to VCR, MTX and
DEX.
14
UI - 11397469
AU - Holstein SA; Hohl RJ
TI -
Interaction of cytosine arabinoside and lovastatin in human leukemia
cells.
SO - Leuk Res 2001 Aug;25(8):651-60
AD - Department of Pharmacology, University of Iowa, Iowa City, IA 52242,
USA.
Cytosine arabinoside (ara-C) is widely used for the treatment of
leukemias and displays significant toxicities. Lovastatin, an HMG-CoA
reductase inhibitor, is extensively used to treat hypercholesterolemia.
To determine whether lovastatin could augment ara-C's activity we have
examined their effects in the human erythroleukemia K562 cell line and
the ara-C resistant ARAC8D cell line. A synergistic interaction between
the two drugs was found. We have demonstrated that the interaction does
not occur at the level of RAS but may involve lovastatin's effect of
downregulating MAPK activity and preventing ara-C-induced MAPK
activation. These studies represent the first description of a
potentially beneficial interaction between lovastatin and ara-C that
could be applied to the treatment of human leukemia.
15
UI - 10599724
AU - Nysom K; Holm K; Michaelsen KF; Hertz H; Muller J; Molgaard C
TI -
Degree of fatness after treatment for acute lymphoblastic leukemia in
childhood.
SO - J Clin Endocrinol Metab 1999 Dec;84(12):4591-6
AD - Section of Pediatric Hematology and Oncology, The Juliane Marie Center,
Rigshospitalet, Copenhagen, Denmark. nysom@dadlnet.dk]
Excessive fatness is considered a frequent late complication of
treatment for childhood acute lymphoblastic leukemia. Most previous
studies, however, were based on body mass index (BMI) rather than more
direct fat mass measurements. We studied 95 survivors of childhood acute
lymphoblastic leukemia a median of 11 yr (range, 3-23 yr) after
diagnosis. BMI values at diagnosis, at cessation of therapy, yearly
thereafter for up to 10 yr, and at follow-up were compared with French
reference values. Whole body percent fat was measured at follow-up by
dual energy x-ray absorptiometry and compared with data from 463 local
controls. Adjusted for sex and age, the mean BMI increased significantly
during therapy and remained largely unchanged thereafter. At follow-up,
BMI did not differ significantly between patients and local controls. On
the other hand, the whole body percent fat was significantly increased
(mean observed/predicted value, 21.8/19.0%; P < 0.0002). Twenty-five
patients (26%) had a percent fat above the 90th percentile of the
reference values, which indicates excessive fatness. Adjusted for sex
and age, a higher percent fat was related to cranial irradiation or GH
insufficiency, but not to sex, the cumulative doses of anthracyclines or
corticosteroids, or the type of corticosteroid used. BMI was a poor
measure of body fatness.
16
UI - 11877270
AU - Avramis VI; Sencer S; Periclou AP; Sather H; Bostrom BC; Cohen LJ;
TI -
Ettinger AG; Ettinger LJ; Franklin J; Gaynon PS; Hilden JM; Lange B;
Majlessipour F; Mathew P; Needle M; Neglia J; Reaman G; Holcenberg JS
A randomized comparison of native Escherichia coli asparaginase and
polyethylene glycol conjugated asparaginase for treatment of children
with newly diagnosed standard-risk acute lymphoblastic leukemia: a
Children's Cancer Group study.
SO - Blood 2002 Mar 15;99(6):1986-94
AD - Children's Hospital, Los Angeles, CA, USA. vavramis@chla.usc.edu
For this study, 118 children with standard-risk acute lymphoblastic
leukemia (ALL) were given randomized assignments to receive native or
pegylated Escherichia coli asparaginase as part of induction and 2
delayed intensification phases. Patients treated with pegaspargase had
more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow
aspirates and more prolonged asparaginase activity than those treated
with native asparaginase. In the first delayed intensification phase,
26% of native asparaginase patients had high-titer antibodies, whereas
2% of pegaspargase patients had those levels. High-titer antibodies were
associated with low asparaginase activity in the native arm, but not in
the pegaspargase arm. Adverse events, infections, and hospitalization
were similar between arms. Event-free survival at 3 years was 82%. A
population pharmacodynamic model using the nonlinear mixed effects model
(NONMEM) program was developed that closely fit the measured enzyme
activity and asparagine concentrations. Half-lives of asparaginase were
5.5 days and 26 hours for pegaspargase and native asparaginase,
respectively. There was correlation between asparaginase enzymatic
activity and depletion of asparagine or glutamine in serum. In
cerebrospinal fluid asparagine, depletion was similar with both enzyme
preparations. Intensive pegaspargase for newly diagnosed ALL should be
tested further in a larger population.
17
UI - 11877272
AU - Woolfrey AE; Anasetti C; Storer B; Doney K; Milner LA; Sievers EL;
TI -
Carpenter P; Martin P; Petersdorf E; Appelbaum FR; Hansen JA; Sanders JE
Factors associated with outcome after unrelated marrow transplantation
for treatment of acute lymphoblastic leukemia in children.
SO - Blood 2002 Mar 15;99(6):2002-8
AD - Pediatric Transplantation, Fred Hutchinson Cancer Research Center, 1100
Fairview Ave N, Seattle, WA 98109-1024, USA. awoolfre@fhcrc.org
Acute lymphoblastic leukemia (ALL) is the most common indication for
transplantation of marrow from unrelated donors in children. We analyzed
results of this procedure in children with ALL treated according to a
standard protocol to determine risk factors for outcome. From January
1987 to 1999, 88 consecutively seen patients with ALL who were younger
than 18 years received a marrow transplant from an HLA-matched (n = 56)
or partly matched (n = 32) unrelated donor during first complete
remission (CR1; n = 10), second remission (CR2; n = 34), third remission
(CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide
and fractionated total-body irradiation as conditioning treatment and
were given methotrexate and cyclosporine for graft-versus-host disease
(GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS)
according to phase of disease were 70% for CR1, 46% for CR2, 20% for
CR3, and 9% for relapse (P <.0001). Three-year cumulative relapse rates
were 10%, 33%, 20%, and 50%, respectively, and 3-year cumulative rates
of death not due to relapse were 20%, 22%, 60%, and 41%, respectively,
for patients with CR1, CR2, CR3, and relapse. Grades III to IV acute
GVHD occurred in 43% of patients given HLA-matched transplants and in
59% given partly matched transplants (P =.10); clinical extensive
chronic GVHD occurred in 32% and 38%, respectively (P =.23). LFS rates
were lower in patients with advanced disease (P <.0001), age 10 years or
older (P =.002), or short duration of CR1 (P =.007). Thus, in addition
to phase of disease, age and duration of CR1 were predictors of outcome
after unrelated-donor transplantation for treatment of ALL in children.
Outcome was particularly favorable in younger patients with early phases
of the disease.
18
UI - 11990301
AU - Gaynon PS
TI -
From where do clinical trials come?
SO - J Pediatr Hematol Oncol 2002 Mar-Apr;24(3):172-4
AD - Childrens Hospital Los Angeles, University of Southern California, USA.
19
UI - 11990303
AU - Ogden AK; Pollock BH; Bernstein ML; Camitta B; Buchanan GR
TI -
Intermediate-dose methotrexate and intravenous 6-mercaptopurine
chemotherapy for children with acute lymphoblastic leukemia who did not
respond to initial induction therapy.
SO - J Pediatr Hematol Oncol 2002 Mar-Apr;24(3):182-7
AD - Pharmacia Corporation, Peapack, New Jersey, USA.
PURPOSE: To determine the complete remission rate of children with acute
lymphoblastic leukemia (ALL) who were not induced into remission by
initial therapy, when subsequently treated with intermediate-dose
methotrexate and intravenous 6-mercaptopurine. PATIENTS AND METHODS:
Children with B-precursor ALL who did not achieve initial remission
after 4 or 6 weeks of standard three- or four-drug induction
chemotherapy were entered on study. Therapy consisted of three doses at
weekly intervals of methotrexate 1,000 mg/m2 over 24 hours followed by
6-mercaptopurine 1,000 mg/m2 over 8 hours 20 minutes. Patients achieving
a partial remission could receive two additional weekly courses of
methotrexate and 6-mercaptopurine. Initially, patients received weekly
intrathecal chemotherapy, but the study was amended to include
intrathecal therapy only at week 1. RESULTS: Nineteen patients were
entered on study. All were evaluable for toxicity and response. There
were seven complete remissions, four partial remissions, six patients
with no response, and two children with progressive disease, for an
overall complete remission rate of 37%. One patient was removed from the
study after the second course of methotrexate and 6-mercaptopurine
because of renal failure. Two patients had neurologic toxicity resulting
in a study amendment. No patients subsequently experienced neurologic
toxicity. CONCLUSIONS: Intermediate-dose intravenous methotrexate and
intravenous 6-mercaptopurine can induce remission in some patients with
ALL who experience initial induction failure. Features predicting
complete remission, however, could not be identified.
20
UI - 11878573
AU - Felice MS; Zubizarreta PA; Alfaro EM; 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.
21
UI - 11878575
AU - Porea TJ; Dreyer ZE; Bricker JT; Mahoney DH Jr
TI -
Evaluation of left ventricular function in asymptomatic children about
to undergo anthracycline-based chemotherapy for acute leukemia: an
outcome study.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):420-3
AD - Division of Pediatric Hematology-Oncology, Texas Children's Hospital,
Baylor College of Medicine, Houston, USA.
BACKGROUND: Cardiac toxicity is a well-recognized potential complication
of anthracycline use. Children treated with anthracyclines undergo
several cardiac screening procedures before therapy, but the usefulness
of these pretherapy cardiac studies has never been evaluated. The
authors examined whether induction chemotherapy in patients with
high-risk acute lymphoblastic leukemia (ALL) was altered based on a
pretherapy left ventricular shortening fraction (SF). PATIENTS AND
METHODS: Medical records of 134 children registered on treatment
protocols of the Pediatric Oncology Group for high-risk B-precursor and
T-cell ALL between 1987 and 1998 were reviewed. Demographic information
consisting of age at diagnosis, sex, and past cardiac history was
collected, as were the results of all echocardiographic evaluations for
SF and actions taken based on these evaluations. The outcome measured
was whether any changes were made in induction therapy based on initial
SF. In addition, secondary SF results obtained at the cumulative
anthracycline dose range of 90 to 150 mg/m2 were studied to determine
whether modifications of future chemotherapy were made after this
limited exposure. RESULTS: Three of 128 children (2.3%) without a
previous cardiac history had an initial SF on their pretherapy
echocardiogram that prompted additional evaluation but no change in
therapy. A secondary analysis of SF in 85 children who completed
anthracycline doses of 90 to 150 mg/m2 was performed. There were three
(3.5%) with abnormal study results who were evaluated further. Again, no
changes were made in the anthracycline doses based on these findings. No
cardiac dysfunction occurred among these six patients during later
follow-up. CONCLUSIONS: In the absence of a previous cardiac history or
signs and symptoms or cardiac disease, pretherapy evaluation of left
ventricular function may not be indicated in children about to undergo
anthracycline-based treatment of acute leukemia. The timing of
initiation of cardiac evaluation remains unclear, but these results
suggest that even at a cumulative dose of 90 to 150 mg/m2, studies to
determine left ventricular function do not yield data sufficient to
warrant a change in the clinical management of these patients.
22
UI - 11878576
AU - Oeffinger KC; Buchanan GR; Eshelman DA; Denke MA; Andrews TC; Germak JA;
TI -
Tomlinson GE; Snell LE; Foster BM
Cardiovascular risk factors in young adult survivors of childhood acute
lymphoblastic leukemia.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):424-30
AD - Department of Family Practice and Community Medicine, The University of
Texas Southwestern Medical Center at Dallas, 75390-9067, USA.
kevin.oeffinger@email.swmed.edu
PURPOSE: To assess cardiovascular risk factors (CVRF) in young adult
survivors of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND
METHODS: Twenty-six subjects (median age, 20.9 years; median interval
since completion of therapy, 13.3 years) were evaluated. Ten
participants had received cranial irradiation (CRT), whereas 16 had
received only chemotherapy. Primary outcome measures included body mass
index (BMI), blood pressure, fasting lipoprotein, glucose, and insulin
levels. Secondary measures included insulin-like growth factor-1 (IGF-1)
and IGF binding protein-3 levels, physical activity index, a 7-day
dietary recall, tobacco product use, and measurement of the intima-media
thickness (IMT) of the common carotid artery. RESULTS: Sixty-two percent
(16/26) of participants had at least one CVRF potentially related to
their cancer treatment (obesity, dyslipidemia, increased blood pressure,
or insulin resistance), with 30% (7/26) having more than two CVRF.
Thirty-one percent (8/26) of subjects were obese (BMI > or = 30).
Subjects who were treated with CRT (BMI, 30.4 +/- 6.7) had an increased
BMI (P = 0.039) in comparison with those who received only chemotherapy
(BMI, 25.4 +/- 5.1). Triglyceride and very low-density lipoprotein C
levels were significantly higher in those treated with CRT (P = 0.027
and 0.022, respectively). The IGF-1 was inversely correlated with IMT
(total group, -0.514, P = 0.009; females only, -0.729, P = 0.003).
CONCLUSIONS: Young adult survivors of childhood ALL, especially those
treated with CRT, are at risk for obesity and dyslipidemia, insulin
resistance, hypertension, and cardiovascular disease. Further
investigation of these risks is warranted.
23
UI - 11876615
AU - Yahya HI; Al-Allawi NA; Mattar Y
TI -
Acute Lympoblastic Leukaemia in seventy Iraqi adults: clinical and
haematological findings and outcome of therapy.
SO - Indian J Cancer 2000 Jun-Sep;37(2-3):85-90
AD - Dept of Medicine, College of Medicine, University of Baghdad and its
teaching Hospitals, Iraq.
Studies on acute Leukaemia from developing and Asian countries are
scarce, and generally reflect poorer outcomes of therapy compared to
their Western counterparts. This study was undertaken to address the
latter issue in Iraqi adults with Acute Lymphoblastic Leukaemia (ALL).
It included seventy unselected Iraqi adults (aged 14-60years), diagnosed
as ALL in Baghdad Teaching Hospital, Baghdad, during the period between
included patients were generally comparable with those reported from the
West, except for the lower median age. The patients were scheduled to
receive a modified intensive chemotherapy protocol, and had an overall
complete remission rate of 84.3%, and all overall median survival of 24
months. Nineteen patients were still alive in complete remission after a
median follow-up of 67 months, and the estimated five year disease free
survival was 27.2%. The above finding compare favourably with Western
studies and are among the more favourable reports from Asian countries.
The study also includes a discussion of the problems facing
haematologists in the management of ALL in this part of the world.
24
UI - 11918540
AU - Lee S; Kim DW; Kim YJ; Park YH; Min CK; Lee JW; Min WS; Kim CC
TI -
Influence of karyotype on outcome of allogeneic bone marrow
transplantation for adults with precursor B-lineage acute lymphoblastic
leukaemia in first or second remission.
SO - Br J Haematol 2002 Apr;117(1):109-18
AD - Catholic Hemopoietic Stem Cell Transplantation Center, College of
Medicine, The Catholic University of Korea, Seoul, Korea.
The prognostic relevance of karyotype has been established in adult
acute lymphoblastic leukaemia (ALL) patients treated with chemotherapy
but not definitively evaluated in an allogeneic bone marrow
transplantation (BMT) setting. To determine the factors affecting the
outcome of allogeneic BMT for adults with precursor B-lineage ALL in
first or second complete remission (CR), a total of 41 consecutive
patients with a successful karyotype were enrolled in this study. There
were 21 men and 20 women with a median age of 27 (15-43) years. The
distribution of French-American-British (FAB) subtypes was as follows:
L1 (n = 26), L2 (n = 15). Unfavourable karyotypes (n = 12) were defined
as Ph+ or t(4;11). Disease status at the time of transplant was first CR
(n = 35) or second CR (n = 6). With a median follow-up of 36 months, the
3-year probabilities of relapse and disease-free survival (DFS) were
36.3 +/- 8.4% and 57.3 +/- 8.4% respectively. Potential variables
predicting worse relapse and DFS were FAB subtype (L2), extramedullary
involvement, pre-BMT status (second CR), unfavourable karyotype and type
of graft-versus-host disease (GVHD). Further multivariate analysis
showed that karyotype and pre-BMT status were independently associated
with relapse and DFS. In addition, chronic GVHD was found to be
significantly associated with a lower relapse rate.
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