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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4116-4124
Double Induction Strategy for Acute Myeloid Leukemia: The Effect of
High-Dose Cytarabine With Mitoxantrone Instead of Standard-Dose
Cytarabine With Daunorubicin and 6-Thioguanine: A Randomized Trial
by the German AML Cooperative Group
By
Thomas Büchner,
Wolfgang Hiddemann,
Bernhard Wörmann,
Helmut Löffler,
Winfried Gassmann,
Torsten Haferlach,
Christa Fonatsch,
Detlef Haase,
Claudia Schoch,
Dieter Hossfeld,
Eva Lengfelder,
Carlo Aul,
Axel Heyll,
Georg Maschmeyer,
Wolf-Dieter Ludwig,
Maria-Cristina Sauerland, and
Achim Heinecke
From the Departments of Hematology/Oncology and of Biostatistics,
University of Münster, Münster, Germany; the Department of
Hematology/Oncology, University of Göttingen, Göttingen,
Germany; the Department of Hematology/Oncology, University of Kiel,
Kiel, Germany; the Department of Hematology/Oncology, University of
Hamburg, Hamburg, Germany; the Department of Hematology/Oncology,
University of Düsseldorf, Düsseldorf, Germany; the
Department of Cell Biology, University of Vienna, Vienna, Austria; the
Department of Hematology/Oncology Mannheim, University of Heidelberg,
Heidelberg, Germany; and the Department of Hematology/Oncology,
Robert-Rössle Medical Center, Humboldt University, Berlin,
Germany.
 |
ABSTRACT |
Early intensification of chemotherapy with high-dose cytarabine
either in the postremission or remission induction phase has recently
been shown to improve long-term relapse-free survival (RFS) in patients
with acute myeloid leukemia (AML). Comparable results have been
produced with the double induction strategy. The present trial
evaluated the contribution of high-dose versus standard-dose cytarabine
to this strategy. Between March 1985 and November 1992, 725 eligible
patients 16 to 60 years of age with newly diagnosed primary AML entered
the trial. Before treatment started, patients were randomized between
two versions of double induction: 2 courses of standard-dose cytarabine
(ara-C) with daunorubicin and 6-thioguanine (TAD) were compared with 1 course of TAD followed by high-dose cytarabine (3 g/m2
every 12 hours for 6 times) with mitoxantrone (HAM). Second courses started on day 21 before remission criteria were reached, regardless of
the presence or absence of blast cells in the bone marrow. Patients in
remission received consolidation by TAD and monthly maintenance with
reduced TAD courses for 3 years. The complete remission (CR) rate in
the TAD-TAD compared with the TAD-HAM arm was 65% versus 71% (not
significant [NS]), and the early and hypoplastic death rate was 18%
versus 14% (NS). The corresponding RFS after 5 years was 29% versus
35% (NS). An explorative analysis identified a subgroup of 286 patients with a poor prognosis representing 39% of the entire
population; they included patients with more than 40% residual blasts
in the day-16 bone marrow, patients with unfavorable karyotype, and
those with high levels of serum lactate dehydrogenase. Their CR rate
was 65% versus 49% (p = .004) in favor of TAD-HAM and was
associated with a superior event-free survival (median, 7 v 3 months; 5 years, 17% v 12%; P = .012) and overall
survival (median, 13 v 8 months; 5 years, 24% v 18%; P = .009). This suggests that the incorporation of high-dose
cytarabine with mitoxantrone may contribute a specific benefit to
poor-risk patients that, however, requires further substantiation.
Double induction, followed by consolidation and maintenance, proved a safe and effective strategy and a new way of delivering early intensification treatment for AML.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
RESULTS OF LARGE scale therapeutic trials
in acute myeloid leukemia (AML) reported during the 1980s and 1990s
have shown a gradual improvement in the results of chemotherapy. During this period of time, an increasing majority of patients have achieved complete remission (CR)1-6 and the proportion of patients
remaining in permanent remission (still a minority) has also
improved.1-3,5,7,8 When remission induction had reached
some standard dose levels,1 further increase in the
remission rate appeared associated with progress in supportive care
rather than intensification in antileukemic treatment.
However, in contrast with remission rates, chemotherapy dose effects
have been found in the duration of remissions and relapse-free survival
(RFS). This was first shown for the effect of prolonged myelosuppressive maintenance treatment after 1 course of consolidation at standard induction doses. Patients assigned to maintenance had a
markedly improved RFS compared with patients assigned to consolidation
alone.2 Similarly, dose effects could be demonstrated for
the immediate postremission phase, in that 4 courses of cytarabine at
either 3 g/m2 or 400 mg/m2 or 100 mg/m2 resulted in a dose-dependent RFS.5
Furthermore, it has been demonstrated that, after 4 courses of
induction/consolidation chemotherapy, the addition of myeloablative
chemotherapy plus total body irradiation and autologous bone marrow
transplantation substantially improved RFS when compared with no
further treatment.9 More recently, it has been shown that
the dosage of cytarabine, even when included from the beginning of the
induction treatment, clearly affected RFS,8,10 with a
probability of 41% at 5 years when cytarabine, at a dose of 3 g/m2, was incorporated in the protocol.8 The
present trial now addressed the question of the dose effect of
induction treatment by comparing a regimen containing high-dose
cytarabine with a regimen containing the drug at a standard dose, both
included in the second courses of double induction. The response
nonadapted double induction strategy provides an ideal basis for the
comparison of dose effects, because the amount of induction treatment
depends only on the randomization and not on an individualized number of induction courses. Although little is known of which subtypes of AML
may benefit from intensification strategies, the curative impact of
postremission high-dose cytarabine appeared to be restricted to
favorable and intermediate karyotype abnormalities in one
study.11 The effect of intensification of induction therapy
on the outcome in special prognostic groups has been analyzed
exploratively in this trial.
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MATERIALS AND METHODS |
Patients.
Patients 16 to 60 years of age with AML according to the
French-American-British (FAB) classification12,13 who had
never received antileukemic therapy were eligible. In common with other comparable trials5,6,8 and to optimize homogeneity,
patients with a history of myelodysplasia or other antecedent
hematologic disorder or who had previous exposure to cytotoxic drugs or
radiotherapy were excluded, as were patients with pre-existing
non-leukemia-related liver disease or renal or heart failure. Written
informed consent was obtained before a patient entered the study.
Study design.
Before treatment started, all patients were randomized, by a phone call
to the statistical center, between one of the two induction therapy
arms. All patients then received the first induction course, consisting
of 100 mg/m2 cytarabine by continuous intravenous infusion
daily on days 1 and 2 and subsequently by infusion over 30 minutes
every 12 hours on days 3 through 8; 60 mg/m2 daunorubicin
by 30 minutes of intravenous infusion on days 3, 4, and 5; and
6-thioguanine 100 mg/m2 orally every 12 hours on days 3 through 9 (TAD).14 On day 16 of therapy, the bone marrow
was examined for the percentage of blast cells. On day 21, all patients
received a second induction course (double induction). According to the
randomization, the second course was either 3 g/m2
cytarabine by 3 hours of intravenous infusion every 12 hours on days 1 through 3 with 10 mg/m2 mitoxantrone by 30 minutes of
intravenous infusion on days 3, 4, and 5 (HAM)15 or a
repetition of the first TAD induction course. If after the second
course the bone marrow contained  5% blasts or similar features
reappeared in weekly bone marrow sampling, the patient was treated off
study. Patients who went into CR received a consolidation course of
TAD. After consolidation, maintenance treatment was administered to all
patients and consisted of monthly courses of 100 mg/m2
cytarabine by subcutaneous injection every 12 hours for 5 days, with a
second drug being administered in rotation, including 45 mg/m2 daunorubicin by 30 minutes of intravenous infusion on
days 3 and 4 (course 1), 100 mg/m2 6-thioguanine orally
every 12 hours on days 1 through 5 (course 2), 1 g/m2
cyclophosphamide intravenous injection on day 3 (course 3), or again
6-thioguanine (course 4) and restarting with daunorubicin (course 5).
If absolute neutrophil counts decreased to less than 500/µL and/or
platelets to less than 20,000/µL after 2 sequential courses, the
doses of all antileukemic drugs were reduced to 50%, permanently.
Using this policy it was found that from the third maintenance course,
the vast majority of patients required adjustment and continued at 50%
of full dosage. Maintenance treatment continued until the patient was 3 years in remission.2 As an alternative to maintenance
chemotherapy, allogeneic bone marrow transplantation in first remission
was offered to all patients up to 50 years of age who had a
histocompatible sibling.
Evaluation.
Patients underwent full physical examinations and assessment of blood
counts and liver and renal function tests before each maintenance
course. Bone marrow examinations were performed before alternating
maintenance courses and every 3 months after the end of maintenance,
unless earlier bone marrow examinations were indicated by peripheral
blood changes inconsistent with CR.
Criteria for response.
A CR was defined by a bone marrow with normal hematopoieses of all cell
lines, less than 5% blast cells, and a peripheral blood with at least
1,500 neutrophils and 100,000 platelets/µL. Therapeutic failures were
classified as persistent leukemia, death less than 7 days after
completion of the first induction therapy course (early death) and
death during treatment-induced bone marrow hypoplasia, irrespective of
the time after chemotherapy (hypoplastic death). Relapse was defined as
reinfiltration of the bone marrow by 25% or more leukemic
blasts5 or a proven leukemic infiltration at any other
site. Relapse-free interval was measured from the achievement of CR
until relapse and RFS from CR until relapse or death in remission.
Survival was recorded from randomization until death. Event-free
survival was recorded from randomization until nonachievement of
remission, relapse, or death. Analyses considering day-16
bone marrow blasts began from the date when this marrow was collected.
Patients receiving bone marrow transplantation were censored at the
time of transplantation.
Cytogenetics.
Cytogenetic examination was performed on pretreatment bone marrow
specimens. Chromosome analysis was performed after short-term cultures
using standard protocols for G- or R-banding techniques. Karyotype
changes were interpreted according to the 1995 ISCN nomenclature.16 All cytogenetic results were centrally
reviewed by the study reference laboratory.
Statistical analysis.
The primary objective of the study was the randomized comparison of the
two versions of double induction TAD-TAD and TAD-HAM with respect to
event-free survival. The size of the study was based on power
calculations. The type I error was fixed at  = .05 and the median
event-free survival was expected to be at least 7 months. Patient
accrual should last at least 3 years. The participating centers
expected about 100 randomizations per year. The follow up period was
set at a minimum of 2 years. Thus, the study had a power of about 0.8 to detect a minimum difference of 3 months in median event-free survival.
After the target number of 300 patients had been exceeded, it was
decided to extend this number substantially. The main reason for this
decision was the increasing availability of cytogenetics for the study
and the new evidence on the impact of the karyotype on patients'
outcome. Thus, further substantiation of the role of cytogenetic
changes was incorporated as an objective of the trial.
Comparison of the rates of CR and failures was evaluated by Pearson's
 2 test. Distributions of time to event variables were
estimated by the Kaplan-Meier method,17 and comparisons
were based on the log-rank-test.18 All P values
reported are two-sided. Potential prognostic factors were tested by
multiple regression analysis using logistic regression for response to
induction treatment and Cox proportional hazard model19 for
RFS and overall survival. Randomization was stratified by center, which
was ignored in the statistical analyses. There was no further stratification.
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RESULTS |
Patient population.
Between March 1985 and November 1992, a total of 788 patients from 45 participating institutions entered the trial. Sixty-three patients were
excluded according to protocol criteria, including medical
contraindications to intensive chemotherapy in 46 patients, missing
consent of 10 patients, and protocol violation, mainly through
nonrandomized treatment, in 7 patients. A total of 725 patients were
eligible and randomized. Patient numbers evaluable according to the
treatment groups are shown in Fig 1.
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| Fig 1.
Flow diagram showing evaluable patient numbers according
to treatment arms and numbers of patients receiving the assigned
treatment.
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Patient characteristics.
Table 1 shows the pretreatment
characteristics of patients in the two randomized arms. Cytogenetics of
the bone marrow cells were obtained from 47% of all patients.
Karyotypes classified as favorable included translocations t(15;17),
t(8;21), and inversion 16, whereas deletions and losses of chromosomes
5 and 7, abnormalities involving 11q23, and complex karyotype with
three or more numerical or structural abnormalities were considered
unfavorable. This karyotype classification was similar to that used in
other large multicenter series.11,20
Drug delivery.
Double induction with both courses was administered to 665 of the
entire 725 patients (91%), with 322 patients (89%) in the TAD-TAD arm
and 340 patients (93%) in the TAD-HAM arm. On 37 and 51 occasions, in
the TAD-TAD and TAD-HAM sequence, respectively, second courses were
postponed to the postremission period as additional consolidation
courses, following protocol guidelines to avoid excessive toxicity.
Thus, 79% of the patients in both arms received double induction as
was planned to be administered before CR criteria were
achieved. The remaining 63 (9%) patients only received 1 induction course due to early death (8%) or contraindications. Among
the 494 patients going into CR (234 in the TAD-TAD arm and 260 in the
TAD-HAM arm), 186 and 212 patients, respectively, went on to
consolidation. The reasons for not receiving consolidation in the
TAD-TAD arm and in the TAD-HAM arm were early relapse in 10 and 4 patients, respectively; early death in remission in 1 patient in each
group; toxicity in induction treatment in 17 and 28 patients,
respectively; refusal of consolidation by 10 and 7 patients,
respectively; and planned allogeneic bone marrow transplantation in 10 and 8 patients, respectively. Maintenance treatment was started in 147 patients in the TAD-TAD arm and in 171 patients in the TAD-HAM arm. The
reasons for not administering maintenance were death in remission in 3 and 8 patients, respectively; toxicity in consolidation in 7 and 8 patients, respectively; refusal of maintenance by 11 and 4 patients,
respectively; relapse in 9 and 7 patients, respectively; and planned
allogeneic bone marrow transplantation in 9 and 14 patients,
respectively. Twenty-three and 28 patients went to allogeneic bone
marrow transplantation, respectively: 10 and 8 of them without and 9 and 14 after having received consolidation. Another 4 and 6 patients
went to transplantation after having received maintenance courses. For
patient assignment and flow, see Fig 1.
Therapeutic outcome by treatment.
The essential data on patients' outcome are listed in
Table 2 for the total population and for
the two randomized treatment arms. The median observation time for
survival and remaining in remission is 6 years. Kaplan Meier life table
plots for all randomized patients are shown for overall survival in
Fig 2 and for RFS and mortality in
remission in Fig 3. Among the 360 and 365 patients assigned to TAD-TAD and TAD-HAM double induction,
respectively, 228 and 218 have died. Among the 234 and 260 patients
going into remission, respectively, 131 and 127 relapsed and another 9 and 24 patients died in remission.
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| Fig 2.
Overall survival from randomization for all patients
entering the trial in the two randomized treatment arms. Tick marks
indicate patients alive and patients censored at the time of allogeneic
bone marrow transplantation.
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| Fig 3.
RFS from achievement of remission and mortality in
remission for the two randomized treatment arms. Tick marks indicate
patients alive and in remission and patients censored at the time of
allogeneic bone marrow transplantation.
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Toxicity.
Toxicity and adverse events during the period of induction and
consolidation treatment were classified in the two arms according to
the World Health Organization criteria and are listed for grades 3 and
4 in Table 3. No significant difference was
found for any kind of adverse events. Myelotoxicity was measured by the
recovery time of blood neutrophils and platelets from the end of the
second induction course until 500/µL absolute neutrophils and
100,000/µL platelets. Median time to recovery for those who recovered
was 16 days (range, 15 to 17 days) in the TAD-TAD arm and 20 days (range, 19 to 21 days) in the TAD-HAM arm (P = .0001). Nineteen percent of patients in the TAD-TAD arm and 16.5% in
the TAD-HAM arm did not fulfill criteria of recovery.
Prognostic factors.
The multiple regression analysis of potential prognostic factors
predictive for achieving CR included initial white blood cell count
(WBC), lactate dehydrogenase (LDH) in serum, karyotype, and FAB subtype. Independent prognostic factors were FAB-M4Eo (odds
ratio, 2.62; 95% confidence interval [CI], 1.21 to
5.67) and unfavorable karyotype (odds ratio, 0.47; 95% CI, 0.26 to
0.87). In addition to these potential prognostic factors, the
percentage of residual bone marrow blasts on day 16 of treatment was
also analyzed for its impact on RFS and overall survival. Factors found to be independently predictive are listed in Table
4. LDH values have been available in the great majority of patients in
this trial. Homogeneity testing did not detect any disparity at the 5%
level between the centers. To define a poor prognostic group according
to LDH, we selected patients with greater than 700 U/L, representing the upper quartile of the population, with the cut-off point being approximately 3 times the upper limit of normal.
Although karyotype was available from only 47% of the patients,
availability did not cause differences in the results between
patients or centers. Patients in whom karyotype was missing showed
average results for response and long-term outcome.
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Table 4.
Prognostic Factors Predicting Duration of RFS and
Overall Survival as Resulting From Multiple Regression Analysis
Using Cox and Regression
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The impact of poor prognostic factors such as a high LDH (>700 U/L),
unfavorable karyotype, or day-16 bone marrow blasts greater than 40%
on overall survival is shown in Fig 4. Similar effects were seen on event-free survival (P = . 0001), survival of
responders (P = .0096), and relapse-free interval
(P = .0004). Of the 286 patients representing the
poor prognostic group, 140 were poor risk for LDH alone, 81 for day-16
blasts alone, 26 for karyotype alone, 20 for both LDH and blasts, 7 for
LDH and karyotype, 9 for blasts and karyotype, and 3 for all three
features.
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| Fig 4.
Overall survival from randomization of all eligible and
evaluable patients in three risk groups according to initial LDH,
unfavorable karyotype, and day-16 bone marrow blasts. "Other
patients" include the rest of the patients whose risk is not defined
by the criteria listed above. Tick marks indicate patients alive and
patients censored at the time of allogeneic bone marrow
tranplantation.
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Outcome by treatment in prognostic groups.
Table 5 shows the therapeutic outcome between the two
treatment arms in patients exhibiting poor-risk features such as a high
LDH, an unfavorable karyotype, or a high percentage of day 16-bone
marrow blasts compared with patients having none of the three criteria
and with the rest of the patients whose risk remained undefined by
these criteria. Within the poor-risk patients, there were no
differences between the two treatment arms in the distribution of FAB
types or in the mean age, WBC counts, LDH, and day-16 blasts, respectively. Overall survival by treatment arm is shown in
Fig 5 for poor risk according to LDH or karyotype or day
16 blasts. In keeping with the entire group of patients with poor
prognosis, high-dose cytarabine in double induction was also superior
for each of the single poor-risk features. Thus, in the high LDH
population, a superior remission rate (P = .031), event-free
survival (P = .036), and overall survival (P = .036)
was achieved and again in those with an unfavorable karyotype
(P = .011, .053, and .090, respectively) and (at least for the
remission rate; P = .028) in the day-16 blasts greater than
40% subgroup.
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| Fig 5.
Overall survival from randomization in the two randomized
treatment arms for all patients entering the trial and showing poor
risk according to LDH, karyotype, or day-16 bone marrow blasts. Tick
marks indicate patients alive and patients censored at the time of
allogeneic bone marrow transplantation.
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DISCUSSION |
In the present trial, starting in March 1985, the German AML
Cooperative Group investigated the effects of intensification of
induction treatment in patients 16 to 60 years of age. Intensification was approached in two ways: (1) by the introduction of double induction
and (2) by the incorporation of high-dose cytarabine into induction
treatment. Double induction is a strategy of very early intensification
by starting a second induction course on day 21 of treatment
irrespective of the presence or absence of residual leukemic blasts in
the bone marrow after the first induction course. One of the two aims
of this strategy was to administer a second course immediately to
patients who would not have attained CR with 1 course alone. The second
aim is to administer additional antileukemic treatment to patients who
would not receive a second induction course if the normal convention
for the majority of patients was followed. The enhanced cytotoxic
activity provided by the second course aims at further reducing minimal
residual disease to improve the long-term outcome of patients. At the
start of the second course on day 21, CR by any criteria has not yet been reached. Thus, the routine second course becomes a part of induction treatment by definition. In contrast to conventional induction therapy,5,6,8,10,21,22 in which decisions on
additional induction courses are made individually, double induction
introduces a more standardized approach that achieves greater
homogeneity in the quantity of induction treatment. Thus, double
induction provides a basis for the second approach, namely the
incorporation of high-dose cytarabine into induction treatment as a
component of the second course by randomization.
Double induction in the present trial proved a useful and safe strategy
for the study population of patients up to 60 years of age. It was
found helpful that the decision about a second induction course was not
individualized and that extensions of the risk period by postponement
of this decision were largely avoided. This may explain why the
combined early and hypoplastic death rate of 16%, which includes death
in hypoplasia as late as 100 days from the start of double induction,
remains similar to the 13%5 and 15%8 values
obtained in recent reports from non-double induction regimens.
However, in comparing treatment-related mortality, some differences in
the definitions cannot be excluded; other publications may not even be
comparable, because different definitions are used or data are
lacking.6,10,21,22 As far as response is concerned, the
68% CRs from double induction compares with the highest values of
71%5 and 72%8 and even with younger populations in which 66%,6 58%,10 and
70%22 CR rates have been reported using similar criteria.
Because double induction fulfilled safety and efficacy standards in the
remission induction phase, the question arises as to how this kind of
very early intensification affected the long-term outcome of patients.
In its original form, only using standard-dose cytarabine, double
induction followed by standard consolidation and maintenance can be
compared with the historical control of the preceding trial of the AML
Cooperative Group, in which the same chemotherapy courses were used in
a non-double induction fashion.2 With a median of 23 versus 14 months and 29% versus 22% at 5 years (P = .091),
the RFS shows a tendency in favor of double induction. This finding has
to be interpreted with caution, because improvements in supportive care
may have contributed to the improved results, although they should have
affected response rates rather than long-term outcome.
The contribution of high-dose cytarabine to the double induction effect
has been investigated in the present trial by randomization for the
second induction course between standard-dose cytarabine with
daunorubicin and 6-thioguanine (TAD) or high-dose cytarabine with
mitoxantrone (HAM). High-dose cytarabine, as in HAM adminstered in the
present trial at 3 g/m2 twice daily on 3 days, has also
been used recently for the intensification of postremission
treatment.5 High-dose cytarabine in this dose range
previously had been found successful in refractory
AML.23-27 A single drug salvage effect had also been shown
for mitoxantrone.28-30 These experiences led to the
combination of high-dose cytarabine with mitoxantrone in the HAM
regimen that, by its special timing, also uses a conditioning effect of
cytarabine on subsequently administered anthracyclines.31
The HAM regimen proved highly effective by inducing 53%
CR in patients with refractory AML by rigid criteria.15
When incorporated into first-line induction therapy as the second
course, HAM provides two new components: (1) high-dose cytarabine at a
dosage 12.9 times as high as the standard-dose cytarabine included in
the preceding TAD induction course, which represents an intensification
that potentially overcomes cellular resistance to standard-dose
cytarabine32-34; and (2) mitoxantrone as a
non-cross-resistant drug replacing the daunorubicin administered in
the first course.
Potentiation of the antileukemic effect by HAM was not confirmed in the
present trial for the entire target group of patients randomized.
Whereas the CR rate was insignificantly higher in the HAM arm than in
the standard-dose arm (71% v 65%), the long-term outcome was
almost identical in the two arms. When applying explorative subgroup
analyses, HAM appeared superior by producing significantly higher
remission rates in special poor-risk groups such as patients with more
than 40% residual blasts on day 16, patients with unfavorable karyotype, and patients with highly elevated LDH. In the entire group
of 286 patients with poor-risk disease, TAD-HAM double induction resulted in 65% CR versus 49% in the TAD-TAD arm (P = .004).
This also extended to a superior overall survival (P = .009) and event-free survival (P = .012). These data are
in contrast to two other reports on subgroup analyses in which the
curative effects of postremission high-dose cytarabine
chemotherapy11 and of autologous bone marrow transplantation9 were associated with favorable and not
with unfavorable karyotypes.9,11 The different timing of
intensification between the induction phase of this trial and the
postremission phase of others9,11 may partly account for
the conflicting results. Furthermore, the endpoints were
different; we have shown significant improvement in
response, survival, and event-free survival in contrast to RFS in the
other studies.9,11 Our data therefore suggest that a
patient with poor prognostic criteria may have an improved outlook
after very early intensification treatment.
An unfavorable karyotype and a highly elevated LDH in serum were the
two most important independent poor prognostic factors in present
trial. In common with other comparable trials, unfavorable karyotypes
included losses or deletions of chromosomes 5 or 7, abnormalities
involving 11q23, or complex karyotypes.11,20 LDH, which is
considered as an index of the extent of the disease and cell
turnover,35 was found to be the strongest
laboratory parameter, predicting the length of response in AML in a
large series35 and, more recently, also predicting survival
of patients with aggressive non-Hodgkin's lymphoma.36 The
present trial therefore provides the first evidence that high-dose
cytarabine with mitoxantrone in induction treatment may overcome, in
part, cellular resistance in a high-risk group of patients that
represents about 40% of all patients.
The intensification by HAM resulted in a prolongation in the median
recovery time of neutrophils and platelets by 4 days (P = .0001) but did not increase the early and hypoplastic death rate
(14% HAM v 18% TAD). Likewise, a delayed mortality from HAM is not seen in the event-free survival, RFS, and overall survival. Thus, the increased myelotoxicity of HAM may also increase the antileukemic cytotoxicity without increasing the therapeutic risk.
Patients assigned to high-dose cytarabine and mitoxantrone and
evaluated on an intention to treat basis have a probability of RFS at 5 years, for the 260 patients in the HAM arm, of 35%. This compares with
41% for 106 patients in the high-dose cytarabine induction treatment
arm of the Australian study8 and with 43% for 156 patients5 and 35% for 117 patients22 in the
high-dose cytarabine postremission arms of the CALGB5 and
Intergroup22 studies, respectively, with the latter two
studies excluding patients from randomization in remission. Double
induction including HAM followed by standard consolidation and
maintenance thus contributed one of the most favorable long-term
results in AML.
Thus, double induction has been established by the present trial to be
a new way of delivering very early intensification. The results are
comparable with leading recent reports of high-dose cytarabine in
postremission5 and induction8 treatment. As suggested by explorative subgroup analyses, the incorporation of
high-dose cytarabine with mitoxantrone as the second course in a double
induction strategy may add to its effects in patients with unfavorable
disease biology where it appeared to improve response and survival.
Substantiation of this effect in a separate prospective study is
clearly warranted.
| |
ACKNOWLEDGMENT |
The authors are indebted to Dr Wolfgang Köpcke (University of
Münster, Münster, Germany) for his biostatistical advice and to Dr John Rees (University of Cambridge, Cambridge,
UK) for his critical review of this report. We thank
Sandra Cebulla for assistance in the preparation of the manuscript. We
are grateful to the clinicians who entered their patients into this
trial. The following institutions participated: Hospital Moabit Berlin (K.P. Hellriegel, H. Fülle); Municipal Hospital Neukölln
Berlin (A. Grüneisen); St. Hedwig Hospital Berlin (C. Boewer);
University Hospital Benjamin Franklin Berlin (E. Thiel, M. Notter);
University Hospital Charité Berlin (A. Trittin); University
Hospital Charlottenburg Berlin (H. Baurmann, R. Zimmermann); University
Hospital Robert-Rössle Berlin (G. Maschmeyer, W.-D. Ludwig);
Municipal Hospital St. Jürgen-Strasse Bremen (H. Rasche, A. Peyn); University Hospital Cologne (V. Diehl, B. Lathan); St. Johannes
Hospital Dortmund (H. Pielken, B. Pahnke); Municipal Hospital
Düren (J. Karow); University Hospital Düsseldorf (C. Aul,
A. Heyll); St. Johannes Hospital Duisburg (R. Donhuijsen-Ant. C. Schadeck-Gressel); University Hospital Erlangen (J.R. Kalden); St.
Antonius Hospital Eschweiler (R. Fuchs, A. Thomalla); University Hospital, Department of Hematology Essen (H.J. König, B. Ottinger); University Hospital, Tumor Research Essen (R. Becher, M.R.
Nowrousian); Evangelian Hospital Essen-Werden (W. Heit, C. Tirier);
Municipal Hospital Flensburg (L. Nowicki); University Hospital
Göttingen (W. Hiddemann, B. Wörmann, D. Haase, C. Schoch);
Municipal Hospital Hagen (H. Eimermacher); General Hospital Altona
Hamburg (K. Mainzer, D. Braumann); St. George Hospital Hamburg (R. Kuse); University Hospital Hamburg (D.K. Hossfeld); Evangelian Hospital
Hamm (L. Balleisen); District Hospital Herford (U. Schmitz-Hübner, G. Just); St. Bernward Hospital Hildesheim (D. Urbanitz, D. Bartholomäus); Municipal Hospital Kaiserslautern (A. Leimer, B. Völler); Municipal Hospital Karlsruhe (J. Fischer);
University Hospital Kiel (H. Löffler, W. Gassmann, T. Haferlach);
Municipal Hospital Krefeld (K. Becker, M. Planker); University Hospital
Lübeck (I. Dörges); Municipal Hospital South Lübeck
(H. Bartels); University Hospital Lübeck (A. Harms); Municipal
Hospital Ludwigshafen (M. Uppenkamp, M. Baldus); University Hospital
Mainz (C. Huber); University Hospital Mannheim (R. Hehlmann, E. Lengfelder); Maria-Hilf-Hospital Mönchengladbach (H.W. Reis,
B. Trenn); Technical University Hospital Munich (A. Reichle);
University Clinic Munich (B. Emmerich, R. Dengler, B. Schlag); University Hospital Münster (T. Büchner);
Department of Biostatistics, University of Münster (A. Heinecke, M.C. Sauerland); St. Josef-Hospital Potsdam (A. Rupprecht); Johanniter-Hospital Rheinhausen-Duisburg (K. Ziegert,
A. Lang); Department of Cell Biology, University of Vienna, Austria (C. Fonatsch); Municipal Hospital Wiesbaden (H.G. Fuhr); St.
Willehad-Hospital Wilhelmshaven (W. Augener); and
Heinrich-Braun-Hospital Zwickau (G. Schott, S. Sommer)
| |
FOOTNOTES |
Submitted May 27, 1998; accepted February 16, 1999.
Supported by Grant No. 01ZP8701 of German Federal Minister for Research
and Technology.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Thomas Büchner, MD, University
Medical Center, Department of Medicine, Hematology/Oncology,
Albert-Schweitzer-Str. 33, D-48129 Münster, Germany.
| |
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TOP
ABSTRACT
INTRODUCTION