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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Centre for Children's Cancer and Blood
Disorders, Sydney Children's Hospital, Randwick; Royal Children's
Hospital, Parkville, Melbourne; Children's Hospital at Westmead,
Sydney; Royal Children's Hospital, Brisbane; Women's and Children's
Hospital, Adelaide, Australia; and Starship Children's Hospital,
Auckland, New Zealand.
Despite improvements in the treatment of acute myeloid leukemia
(AML), approximately 50% of children die of the disease. Clinical trials in adult patients with AML indicate that idarubicin may have
superior efficacy when compared to daunorubicin in the
remission-induction phases of chemotherapy. We conducted consecutive
clinical trials in children with newly diagnosed AML in which
daunorubicin (group 1, n = 102) or idarubicin (group 2, n = 160)
was used during the remission-induction (RI) and the early
consolidation phases of chemotherapy. Idarubicin was given at a dose of
either 10 mg/m2 (group 2A, n = 106) or 12 mg/m2 (group 2B, n = 53). A high rate of RI was achieved
for all groups (95% group 1, 90% group 2A, 94% group 2B). There were
no significant differences in 5-year event-free survival (EFS) or in
overall survival (OS) when the 3 groups were compared (group 1: EFS
50%, OS 56%; group 2A: EFS 50%, OS 60%; group 2B: EFS 34%, OS
50%). RI deaths resulting from treatment toxicity were low Reported survival figures for childhood acute
myeloid leukemia (AML) range from 31% to 60%, and the proportion of
patients achieving complete remission (CR) ranges from 61% to
91%.1-9 Debate continues regarding the best
chemotherapeutic agents to use in remission induction. Most of the
large collaborative pediatric AML studies have used different
remission-induction regimens, which perhaps explains the wide
variability in remission-induction rates. The most widely used
combination of chemotherapy for remission induction is anthracycline
and cytarabine, often in combination with etoposide or
thioguanine.10 Daunorubicin has been shown to be superior
to doxorubicin in the treatment of pediatric AML, and it has a more
favorable toxicity profile.11 Several large randomized
studies have compared different combinations of induction agents. For
example, the Paediatric Oncology Group, in a randomized study, compared
the use of vincristine, cytarabine, and dexamethasone (VADx) with
daunorubicin, cytarabine, and thioguanine (DAT) for remission
induction. A significantly higher complete remission (CR) rate using
DAT over VADx was found (82% vs 61%).4 Similarly, a
randomized comparison of DAT versus daunorubicin, cytarabine, and
etoposide (ADE) in the United Kingdom Medical Research Council 10th AML Trial showed no difference in the remission-induction rate Evidence from adult AML collaborative clinical trials showing that
idarubicin may be superior to daunorubicin and to have improved CR
rates, higher overall survival (OS) rates, and a similar toxicity
profile prompted a review of the use of idarubicin in pediatric
patients.12-14 Limited data are published on the efficacy of idarubicin as a remission-induction agent in the treatment of AML in
children.15,16 For this reason, the Australian and New
Zealand Children's Cancer Study Group (ANZCCSG) undertook consecutive
single-arm studies comparing daunorubicin with idarubicin for
remission-induction and early consolidation chemotherapy.
Patients and study design
Treatment
For patients in groups 1 and 2, end-consolidative therapy consisted of
bone marrow transplantation (BMT). For patients with an HLA-identical
sibling, allogeneic-matched sibling BMT conditioned with busulphan and
cyclophosphamide (BU/CY) was recommended. Busulphan was given at a dose
of 16 mg/kg and cyclophosphamide at a dose of 120 mg/kg. Patients
without an HLA-identical sibling received an autograft either with
Percoll-gradient-separated marrow after melphalan (180 mg/m2) conditioning or with BU/CY. A pilot study, reported
previously, indicated that autologous BMT, using melphalan conditioning
and Percoll-gradient cell separation, improved survival rates in
childhood AML.17
For patients in group 2 with acute promyelocytic leukemia (FAB M3),
all-trans retinoic acid (ATRA) was commenced on day 1 at a
dose of 25 mg/m2 and continued daily until CR was achieved.
Prednisone was also commenced in these patients on day 1 and continued
for 14 to 21 days. Patients with AML and WBC counts greater than
10 × 109/L at diagnosis or whose WBC counts rose more
than 4 × 109/L over the first 48 hours of ATRA were also
started on chemotherapy according to the protocol on days 1 to 3. FAB
M3 patients in group 1 were treated with chemotherapy as detailed in
Figure 1, with no ATRA. All patients with FAB M3, regardless of patient
group, underwent BMT as end-consolidation therapy.
Supportive care
Statistical methods Observed differences in proportions were tested for statistical significance using the appropriate 2 statistic. For
small sample sizes, the Fisher exact test was used. Kaplan-Meier curves
were constructed for survival data and were compared using log-rank
testing. Data for all surviving patients was censored as of June 2000. First CR was defined as normocellular bone marrow containing less than
5% blast cells. Remission failure was classified as the result of
induction death or failure to remit. Overall survival (OS) was defined
as the time from entry to death or to end of study observation period,
if alive. EFS represented time from diagnosis to first event (relapse,
death, failure to remit). For BMT patients, disease-free survival (DFS) is the time from CR to first event (either relapse or death in remission). Cytogenetic risk groups were classified as at good, standard, or poor risk, in keeping with recent published
data.3,19 Good risk was defined as balanced translocation
between chromosomes 8 and 21 and between 15 and 17, inversion of
chromosome 16, and FAB type M3. Poor cytogenetic risk was defined as
monosomy of chromosome 5 or 7, deletions and abnormalities of the
long arm of chromosome 5 or 3, or complex cytogenetic rearrangements
with 4 or more abnormalities. Standard cytogenetic risk included all other patients.
Patient characteristics Of the 113 group 1 patients, 102 were available for evaluation. Eleven patients registered in group 1 were excluded from analysis 4 patients died before treatment was given, and 7 patients were registered in the study but did not receive protocol treatment. Of the
167 group 2 patients, 160 were available for evaluation. Seven patients
were excluded from analysis4 died before any treatment was given, and
3 were registered at diagnosis but did not receive protocol treatment.
Overall, 262 patients were available for comparison. Median follow-up
for survivors was 103 months (range, 49-161 months) for group 1 patients and 42 months (range, 12-85 months) for group 2 patients.
Potential prognostic factors previously reported in the literature,
including age, WBC count, FAB morphological classification, and
cytogenetics at diagnosis, were examined for any confounding effect on
OS. Clinical and laboratory characteristics comparing group 1 (daunorubicin) with group 2 (idarubicin) and group 2A (10 mg/m2 idarubicin) with group 2B (12 mg/m2
idarubicin) are shown in Table 1. Groups
were well matched, and there were no major differences between them in
terms of age, median WBC count at diagnosis, presence or absence of CNS
disease at diagnosis, FAB morphological subclass, and cytogenetic risk groups. Five-year OS rates for each group based on potential prognostic factors are shown in Table 2.
Remission induction Higher remission-induction rates than many previously reported studies were achieved in this study95.1% for group 1 (n = 102) and 91.2% for group 2 (n = 160;
P = .11).4-7 When group 2 patients
are considered in terms of the dose of idarubicin they received, there
was no statistical difference in achievement of remission, with 90.6%
of patients receiving 10 mg/m2 idarubicin (group 2A,
n = 106) achieving CR compared to 94.3% receiving 12 mg/m2 (group 2B, n = 53; P = .41). There
were 2 (2%) deaths during induction in group 1 compared with 8 (5%)
deaths in group 2 (P = .21). In group 1, 1 patient died of
neutropenic colitis after course 1, and 1 died as a result of
hemorrhage during course 2. In group 2, 3 patients died after course 1, 4 after or during course 2, and 1 during treatment with ATRA (before
chemotherapy). Five of the 8 deaths were caused by overwhelming sepsis,
and the remaining 3 resulted from hemorrhage.
The median interval between course 1 and 2 was similar for groups
1 and 2 and for the different idarubicin dose groups in the group 2 patients. The dose of Ara-C received, based on the results of day 14 BMA results, was also similar between treatment groups (Table
3). The 5-year EFS rate for patients
receiving 12 g/m2 of Ara-C for course 2 (48%, n = 203)
was not significantly different from that for patients receiving 30 g/m2 of Ara-C (38%, n = 43; P = .22). There
were no significant differences in 5-year EFS rates for patients whose
day 14 bone marrow examination showed a good (less than 10% blasts)
response to course 1 and who were then given the lower dose of Ara-C at
day 21 (48%, n = 188), compared with patients who had a poor (more
than 10% blasts) response to course 1 and who received the higher dose
of Ara-C at day 14 (49%, n = 56).
Toxicity graded according to the Children's Cancer Group toxicity and
complications criteria following remission-induction chemotherapy
(courses 1 and 2) is shown in Table 4.
Gastrointestinal (GI), renal toxicity, and pulmonary toxicity (grades
3-4) were seen significantly more frequently in those receiving
idarubicin during remission induction. Twenty-five percent of patients
receiving idarubicin experienced grades 3 to 4 gastrointestinal
toxicity compared with 4.9% of patient's receiving daunorubicin
(P < .01). Significantly more GI toxicity (grades 3-4)
was noted in patients receiving the higher dosage of idarubicin, with
43% of group 2B patients (12 mg/m2 idarubicin) compared
with 16% of group 2A (10 mg/m2 idarubicin)
(P < .01) experiencing toxicity. Both renal and pulmonary toxicity was noted more frequently in patients receiving idarubicin (4.4% and 9.4% respectively) compared with patients receiving daunorubicin during remission induction (0% and 3% respectively; P = .03, P = .04). Unlike GI toxicity,
patients receiving the higher dose of idarubicin did not experience
more renal or pulmonary toxicity. Documented infections, conversely,
were seen less frequently during remission induction in the idarubicin
group than in those receiving daunorubicin (P = .02).
Despite this, however, the toxicity death rate was higher in group 2 patients than in group 1 patients (5% vs 2%, respectively;
P = .23).
Four patients in group 1 were withdrawn from the study at the discretion of the treating physician after the commencement of remission-induction chemotherapy. One patient was withdrawn after course 1 for severe esophagitis and peptic ulcer disease. One patient, who did not achieve remission, was withdrawn after course 2 and subsequently died of disease progression. One patient, who achieved CR, was withdrawn after course 3 because of cardiac toxicity. The remaining group 1 patient withdrawn from the study also achieved CR and was withdrawn after course 3. Additional nonprotocol chemotherapy agents were used for courses 4 to 6 in this patient. One patient in group 2 was removed from the study after induction therapy and was treated with nonprotocol agents after not achieving CR. Data on all 5 patients removed from the study are included from study entry to the point of study withdrawal, where this is considered to be an event. Overall survival, event-free survival, and relapse before bone marrow transplantation The OS rate for group 1 patients was 56%; it was 55% for group 2 patients (P = .58) (Figure 2A). There was a trend for superior OS rates for patients receiving the lower dosage of idarubicinOS 60%
for group 2A (10 mg/m2) compared with 50% for group 2B
patients (12 mg/m2) (P = .48). Similarly, the
EFS rate was better in patients receiving the lower dose of
idarubicin50% for patients receiving 10 mg/m2 idarubicin
compared with 34% for patients receiving 12 mg/m2
(P = .24). When group 2 patients are considered together,
the EFS rate (41%) was lower than that of patients receiving
daunorubicin (group 1, EFS 50%; P = .13) (Figure
2B).
OS rates for cytogenetic risk groups are shown in Table 2. As expected, patients with good risk cytogenetic abnormalities did better in both groups than patients with standard or poor risk cytogenetic features. OS was better than expected for the small number of patients with FAB M7 who have traditionally had a poor outcome; the OS rate for group 1 was 100% (n = 3), and for group 2A it was 71% (n = 7). Patients with FAB M3 had an OS rate of 75% for group 1 and 72% for group 2. Because this is a group of patients known to have superior survival and therefore possibly increased OS results for the group as a whole, data were reanalyzed without the inclusion of FAB M3 patients. No significant difference was noted; the OS rate was 55% for all patients, including FAB M3 patients (n = 262), compared with 52% (n = 231) for all patients, excluding those with FAB M3. Group 2 patients with FAB M5 subclass had superior OS with 10 mg/m2 idarubicin (group 2A) than patients receiving 12 mg/m2 (group 2B; OS 52% vs 23%, respectively; P = .02). Fourteen (15%) group 1 patients who achieved CR had relapses before BMT. Nine of these patients went on to have a BMT in second remission. One patient did not achieve a second remission and underwent transplantation during first relapse. Thirteen of the 14 group 1 patients who did not undergo transplantation during the first CR because of relapse died of disease progression. Twenty (14%) patients in group 2 who achieved CR had relapses before BMT. Eleven of these patients underwent BMT in second remission; 4 remain alive and free of disease at the time of censoring. Nine relapsed patients in group 2 died of disease progression without achieving a second CR or without undergoing BMT. Of the patients in group 2 who had relapses before transplantation, 13 had received 10 mg/m2 idarubicin compared with 7 who had received 12 mg/m2. This represented 12% of group 2A (10 mg/m2) and 13% of group 2B patients (12 mg/m2). Another 11 patients in group 2 who achieved CR did not progress to BMT. Three of these patients had granulocytic sarcomas without bone marrow involvement and received chemotherapy alone. Two patients in group 2 died in CR1 before BMT. Three patients did not proceed to BMT because of chronic lung disease, including 1 patient with persistent fungal infection, and 3 patients did not proceed because of parental or physician preference. Two patients in group 1 also refused BMT in CR1. Bone marrow transplantation Time from diagnosis to BMT was similar for both groups: a median of 6 months for group 1 (range, 4-9 months) and 5 months (range, 3-8 months) for group 2. Five-year DFS and OS rates for patients whose treatment included BMT are shown in Table 5 and Figure 3.
Sixteen patients in group 1 and 19 in group 2 underwent matched allogeneic BMT in CR 1 (33 matched-sibling, 1 matched-related cord blood, and 1 matched-unrelated BMT). Five-year DFS rates were 76% for group 1 and 73% for group 2B (12 mg/m2) and 53% for group 2A (10 mg/m2). With small numbers of patients in each group, however, this difference was not statically significant (group 1 vs group 2A, P = .22; group 1 vs group 2B, P = .85; group 2A vs group 2B, P = .44). The incidence of clinically significant (more than grade 2) graft-versus-host disease was not different between group 1 and group 2 (12% group 1, 25% group 2; P = .34). There were 3 deaths within the first 3 months of allogeneic BMT. Despite a difference in the 5-year DFS rates of allogeneic BMT recipients (69%, n = 35) and autologous BMT recipients (52%, n = 156), the difference was not statistically significant (P = .12; Table 5). Overall survival rates at 5 years, from time of diagnosis, were 79% for patients undergoing allogeneic BMT and 63% for patients undergoing autologous BMT (P = .23). A total of 156 autologous BMTs were performed: 62 in group 1, 62 in group 2A, and 32 in group 2B. Patients in group 1 and group 2A had superior DFS rates than group 2B patients (Figure 3B; group 1 vs group 2A, P = .50; group 1 vs group 2B, P = .10; group 2A vs group 2B, P = .35). Autografts were conditioned using either high-dose melphalan with Percoll gradient separation or with BU/CY. Ninety-eight melphalan autografts were performed; 26 in group 1, 61 in group 2A, and 11 in group 2B. DFS overall for all melphalan autografts was 56%, and there were no transplantation-related deaths. DFS was better for group 1 (daunorubicin) patients than for group 2A and group 2B patients (group 1 vs group 2, P = .10; group 2A vs group 2B, P = .83). Of the 72 melphalan autografts performed in group 2, 65 grafts were also Percoll gradient separated, whereas all group 1 melphalan autografts were Percoll gradient separated. Thirty-four patients had relapses following melphalan autograft. Of these, 12 went on to have allogeneic BMT, and 7 (58%) were alive at the time of data censoring. Forty-eight patients received autograft conditioned with BU/CY, 33 in group 1 and 15 in group 2, giving a combined 5-year DFS rate of 52% (Figure 3B). DFS rates for patients receiving daunorubicin (group 1) were similar to those for patients receiving idarubicin (group 2; 50% vs 47%, respectively). Most group 2 patients receiving BU/CY had received idarubicin at a dose of 12 mg/m2 (n = 14; DFS, 43%), and only 1 patient received idarubicin at 10 mg/m2 (n = 1; DFS, 100%). Twenty-two patients receiving a BU/CY autograft had relapses following BMT, and only one of these patients survived in second remission following a second allogeneic BMT. Ten patients received alternative conditioning regimens, mostly using BU/CY with melphalan (n = 6). When these 10 patients are taken together, there is no significant difference in 5-year DFS compared with patients conditioned with melphalan or BU/CY (P = .46, P = .57, respectively). Comparisons of outcomes for patients conditioned with melphalan
compared with BU/CY are shown for different morphological subtype, age,
presence of central nervous system disease, and cytogenetics for all
patients who received autografts (Tables 6 and 7).
With the exception of group 1 patients between 6 and 10 years of age,
who had higher DFS rates after receiving autografts conditioned with
melphalan than after receiving autografts conditioned with BU/CY
(P = .04), no significant difference in DFS was noted in
conditioning regimens (Table 5).
Anthracyclines have been used for many years in the treatment of AML. Murine models have shown that idarubicin is more potent against leukemic cells and less cardiotoxic than daunorubicin.19 When compared with daunorubicin, idarubicin has more rapid cellular uptake, longer intracellular transit time, and an active metabolite, 13-hydroxyidarubicin, with a long half-life.19 Multiple randomized studies and a recent metaanalysis of adult patients with AML have shown that idarubicin has superior efficacy than daunorubicin, particularly in achieving remission induction.14,20-23 In contrast to current findings in adults, there is a paucity of information regarding the efficacy of idarubicin in the initial treatment of childhood AML. A recently published randomized trial showed that idarubicin used in remission induction resulted in a greater reduction in AML blast cell count in the bone marrow of patients on day 15 than in patients receiving daunorubicin in remission induction.15 However, the reduction in marrow blast count did not provide an overall benefit in terms of survival rates.15 In our study we showed no benefit for idarubicin compared with daunorubicin for remission induction, EFS rates, or OS rates at 5 years. Furthermore, there was a trend for patients who received daunorubicin in remission induction to have higher DFS rates following either allogeneic or autologous BMT than the idarubicin group. Creutzig et al15 found that idarubicin when used for remission induction in childhood AML was associated with more bone marrow toxicity, with a greater number of days to neutrophil recovery, than patients treated with daunorubicin. We have shown in our study that greater renal, gastrointestinal, and pulmonary toxicity occurred in patients receiving idarubicin during remission induction. Gastrointestinal toxicity in our patient group was dose related and entailed significantly more toxicity in patients receiving the higher dosage of idarubicin. This may reflect different pharmacokinetic parameters in pediatric patients than those used in previously published studies in adults. No difference in acute cardiotoxicity was noted in our study, but long-term follow-up is needed to establish any evidence of benefit that idarubicin may provide in that regard. Recent large collaborative group studies have reported remission-induction rates in childhood AML varying from 61% to 91%.2-5,8,24 Our results are superior to these reports, with remission-induction rates reaching 95% and 91% for patients receiving daunorubicin and idarubicin, respectively. Moreover, toxicity-related death rates in the remission-induction phase of chemotherapy in our study were low compared with those in other studies.2 When group 1 and 2 patients are combined, 79% of patients undergoing allogeneic BMT and 63% of patients undergoing autograft remain alive at 5 years. This compares favorably with larger published series.1,3,5 We used an algorithm for course 2, which stratified some patients to higher dose Ara-C if the day 14 bone marrow response demonstrated more than 10% blasts. This approach might have improved the prognosis of patients who responded poorly to course 1, but it will have to be formally assessed in a randomized trial. Although several studies in adults with AML have demonstrated that high-dose Ara-C (3 g/m2) can induce remission in patients who have not responded to conventional-dose Ara-C (100 mg/m2), a randomized comparison of different dosing levels of high-dose Ara-C has not been performed.26 In patients who underwent autologous BMT, we have shown that conditioning with melphalan alone is safe, with no BMT-related deaths and with survival rates equal to those achieved with BU/CY. Furthermore, if relapse occurred following melphalan autografting, significantly more patients benefited from further chemotherapy or allogeneic BMT than from autograft conditioned with BU/CY. In patients who underwent autograft, best results were achieved in patients who received daunorubicin for remission-induction therapy followed by autograft and melphalan. Overall survival was 20% lower for patients receiving a melphalan autograft following idarubicin for remission induction. The reason for this is unclear but may be related to greater systemic toxicity and lower dose intensity experienced by patients taking idarubicin. Allogeneic sibling BMT for childhood AML has now been shown to achieve the best survival results in most published randomized trials, with many studies showing statistically significant differences.1,8,25,27-29 Our results are consistent with this finding; however, statistical significance was not achieved, possibly because of the small numbers of allogeneic transplantations performed. Furthermore, for patients without an HLA-matched sibling donor, we have shown that autologous BMT achieved results exceeding reported outcomes with intensive chemotherapy alone. Consistent with other studies, our results have shown superior results for patients with favorable cytogenetic abnormalities. Patients in our studies, regardless of cytogenetic risk group, underwent allogeneic BMT if a matched sibling donor was available. Future studies examining reduction of therapy in this group with good prognosis, possibly without the need for transplantation, may be warranted. As other authors have highlighted, definitive conclusions may be difficult to make, even in large published series, because of small numbers of patients with specific cytogenetic abnormalities.30 Two FAB morphological groups are worthy of further mention. First, the 10 patients in our series with acute megakaryoblastic leukemia (AMKL) FAB M7 had an excellent outcome, with OS rates of 100% for group 1 patients and 71% for group 2 patients. A recently published single-institution study of 29 children with de novo AMKL reported an estimated 2-year EFS rate of 14%, with an advantage for those undergoing allogeneic BMT (EFS, 26%) compared with those receiving chemotherapy alone (EFS, 0%).31 Of the 10 patients in our series, 5 underwent autograft and 5 underwent allogeneic transplantation. Although our data involve small numbers of AMKL patients, an argument can be made that, in absence of a timely available allogeneic match, autologous transplantation may be superior to intensive chemotherapy as consolidation therapy in this subclass of patients. The second FAB subclass of patients worthy of discussion is the group with acute promyelocytic leukemia (FAB M3). ATRA was available for group 2 patients only because our group 1 patients were enrolled before 1992. Recent reports indicate superior survival rates in M3 patients with ATRA containing chemotherapy protocols, without the need for BMT.32 Furthermore, in our series of M3 patients, there was no survival advantage for patients in group 2 compared with group 1, possibly indicating that any benefit gained from the administration of ATRA is reduced by the toxicity associated with aggressive induction therapy and BMT. Consistent with other studies, our data confirm that the major cause of mortality in childhood AML is recurrence of disease. Improvements in remission-induction rates, decreased treatment-related toxicity, and improved outcomes with allogeneic sibling transplantation have contributed to higher survival rates. Nevertheless, further improvements are needed. Unlike AML trials in adults, our results do not support an advantage of idarubicin over daunorubicin in the treatment of pediatric AML in terms of remission induction or overall survival rates. In addition, we found greater toxicity with idarubicin than with daunorubicin.
We thank the patients, parents and families, nursing staff, hospital medical staff, and data managers at each of the participating institutions. Particular thanks go to Genevieve Daly (Senior Paediatric Oncology Pharmacist) and Brigitte Richmond (Data Manager).
Submitted October 31, 2001; accepted June 3, 2002.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Glenn M. Marshall, Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, High St, Randwick, 2031, Sydney, Australia; e-mail: g.marshall{at}unsw.edu.au.
1.
Woods WG, Neudorf S, Gold S, et al.
A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission.
Blood.
2001;97:56-62
2.
Woods WG, Kobrinsky N, Buckley JD, et al.
Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group.
Blood.
1996;87:4979-4989
3.
Hann IM, Stevens RF, Goldstone AH, et al.
Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukemia Working Parties of the Medical Research Council.
Blood.
1997;89:2311-2318 4. Steuber CP, Civin C, Krischer J, et al. A comparison of induction and maintenance therapy for acute nonlymphocytic leukemia in childhood: results of a Pediatric Oncology Group study. J Clin Oncol. 1991;9:247-258[Abstract].
5.
Ravindranath Y, Yeager AM, Chang MN, et al.
Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood: Pediatric Oncology Group.
N Engl J Med.
1996;334:1428-1434 6. Buckley JD, Chard RL, Baehner RL, et al. Improvement in outcome for children with acute nonlymphocytic leukemia: a report from the Children's Cancer Study Group. Cancer. 1989;63:1457-1465[CrossRef][Medline] [Order article via Infotrieve]. 7. Hurwitz CA, Mounce KG, Grier HE. Treatment of patients with acute myelogenous leukemia: review of clinical trials of the past decade. J Pediatr Hematol Oncol. 1995;17:185-197[Medline] [Order article via Infotrieve]. 8. Nesbit ME, Buckley JD, Feig SA, et al. Chemotherapy for induction of remission of childhood acute myeloid leukemia followed by marrow transplantation or multiagent chemotherapy: a report from the Children's Cancer Group. J Clin Oncol. 1994;12:127-135[Abstract]. 9. Lie SO, Jonmundsson G, Mellander L, Siimes MA, Yssing M, Gustafsson G. A population-based study of 272 children with acute myeloid leukemia treated on two consecutive protocols with different intensity: best outcome in girls, infants, and children with Down's syndrome. Nordic Society of Paediatric Haematology and Oncology (NOPHO). Br J Haematol. 1996;94:82-88[CrossRef][Medline] [Order article via Infotrieve]. 10. Weinstein H. Acute myeloid leukemia. In: Pui CH, ed. Childhood Leukemias. Cambridge United Kingdom: Cambridge University Press; 1999:322-335. 11. Buckley JD, Lampkin BC, Nesbit ME, et al. Remission-induction in children with acute nonlymphocytic leukemia using cytosine arabinoside and doxorubicin or daunorubicin: a report from the Children's Cancer Study Group. Med Pediatr Oncol. 1989;17:382-390[Medline] [Order article via Infotrieve].
12.
Berman E, Heller G, Santorsa J, et al.
Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia.
Blood.
1991;77:1666-1674
13.
Wiernik PH, Banks PL, Case DC Jr, et al.
Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia.
Blood.
1992;79:313-319 14. A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukemia: AML Collaborative Group. Br J Haematol. 1998;103:100-109[CrossRef][Medline] [Order article via Infotrieve]. 15. Creutzig U, Ritter J, Zimmermann M, et al. Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia. 2001;15:348-354[CrossRef][Medline] [Order article via Infotrieve]. 16. Sackmann-Muriel F, Fernandez-Barbieri MA, Santarelli MT, et al. Results of treatment with an intensive combination induction regimen containing idarubicin in children with acute myeloblastic leukemia: preliminary report of the Argentine Group for Treatment of Acute Leukemia. Semin Oncol. 1993;20(suppl 8):34-38[Medline] [Order article via Infotrieve].
17.
Tiedemann K, Waters KD, Tauro GP, Tucker D, Ekert H.
Results of intensive therapy in childhood acute myeloid leukemia, incorporating high-dose melphalan and autologous bone marrow transplantation in first complete remission.
Blood.
1993;82:3730-3738
18.
Shaw PJ, Bergin ME, Burgess MA, et al.
Childhood acute myeloid leukemia: outcome in a single center using chemotherapy and consolidation with busulfan/cyclophosphamide for bone marrow transplantation.
J Clin Oncol.
1994;12:2138-2145
19.
Webb DK, Harrison G, Stevens RF, Gibson BG, Hann IM, Wheatley K.
Relationship between age at diagnosis, clinical features and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia.
Blood.
2001;98:1714-1720 20. Carella AM, Berman E, Maraone MP, Ganzina F. Idarubicin in the treatment of acute leukemias: an overview of preclinical and clinical studies. Haematologica. 1990;75:159-169[Medline] [Order article via Infotrieve].
21.
Berman E, Heller G, Santorsa J, et al.
Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia.
Blood.
1991;77:1666-1674 22. Reiffers J, Huguet F, Stoppa AM, et al. A prospective randomized trial of idarubicin vs daunorubicin in combination chemotherapy for acute myelogenous leukemia of the age group 55 to 75. Leukemia. 1996;10:389-395[Medline] [Order article via Infotrieve]. 23. Vogler WR, Velez-Garcia E, Weiner RS, et al. A phase 2I trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol. 1992;10:1103-1111[Abstract].
24.
Wiernik PH, Banks PL, Case DC, et al.
Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia.
Blood.
1992;79:313-319
25.
Amadori S, Testi AM, Arico M, et al.
Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia: the Associazione Italiana Ematologia ed Oncologia Pediatrica Cooperative Group.
J Clin Oncol.
1993;11:1046-1054 26. Cole N, Gibson BE. High-dose cytosine arabinoside in the treatment of acute myeloid leukemia. Blood Rev. 1997;11:39-45[CrossRef][Medline] [Order article via Infotrieve]. 27. Dahl GV, Kalwinsky DK, Mirro J Jr, et al. Allogeneic bone marrow transplantation in a program of intensive sequential chemotherapy for children and young adults with acute nonlymphocytic leukemia in first remission. J Clin Oncol. 1990;8:295-303[Abstract]. 28. Stevens RF, Hann IM, Wheatley K, Gray RG. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial: MRC Childhood Leukemia Working Party. Br J Haematol. 1998;101:130-140[CrossRef][Medline] [Order article via Infotrieve].
29.
Michel G, Gluckman E, Esperou-Bourdeau H, et al.
Allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: impact of conditioning regimen without total-body irradiation 30. Woods WG, Lange BJ, Smith FO, Alonzo TA. A comparison of allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy in pediatric acute myeloid leukemia [letter]. Blood. 2001;97:3674. 31. Athale UH, Razzouk BI, Raimondi SC, et al. Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience. Blood. 2001;97:3722-3732.
32.
Fenaux P, Chastang C, Chevret S, et al.
A randomized comparison of all-trans retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia: the European APL Group.
Blood.
1999;94:1192-1200
© 2002 by The American Society of Hematology.
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  J. J. Ortega, L. Madero, G. Martin, A. Verdeguer, P. Garcia, R. Parody, J. Fuster, A. Molines, A. Novo, G. Deben, et al. Treatment With All-Trans Retinoic Acid and Anthracycline Monochemotherapy for Children With Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group J. Clin. Oncol., October 20, 2005; 23(30): 7632 - 7640. [Abstract] [Full Text] [PDF]
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 I. Tamm, S. Richter, D. Oltersdorf, U. Creutzig, J. Harbott, F. Scholz, L. Karawajew, W.-D. Ludwig, and C. Wuchter High Expression Levels of X-Linked Inhibitor of Apoptosis Protein and Survivin Correlate with Poor Overall Survival in Childhood de Novo Acute Myeloid Leukemia Clin. Cancer Res., June 1, 2004; 10(11): 3737 - 3744. [Abstract] [Full Text] [PDF]
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B. J. Lange, P. Dinndorf, F. O. Smith, C. Arndt, D. Barnard, S. Feig, J. Feusner, N. Seibel, M. Weiman, R. Aplenc, et al. Pilot Study of Idarubicin-Based Intensive-Timing Induction Therapy for Children With Previously Untreated Acute Myeloid Leukemia: Children's Cancer Group Study 2941 J. Clin. Oncol., January 1, 2004; 22(1): 150 - 156. [Abstract] [Full Text] [PDF]
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 C.-H. Pui, M. Schrappe, R. C. Ribeiro, and C. M. Niemeyer Childhood and Adolescent Lymphoid and Myeloid Leukemia Hematology, January 1, 2004; 2004(1): 118 - 145. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
