1
Comparison of high-dose cytarabine and timed-sequential chemotherapy as
consolidation for younger adults with AML in first remission: the ALFA-9802 study
Xavier Thomas 1, Mohamed Elhamri 1, Emmanuel Raffoux 2, Aline Renneville 3, Cécile
Pautas 4, Stéphane de Botton 5, Thierry de Revel 6, Oumedaly Reman 7, Christine Terré 8,
Claude Gardin 9, Youcef Chelghoum 1, Nicolas Boissel 2, Bruno Quesnel 3, Yosr Hicheri 4,
Jean-Henri Bourhis 5, Pierre Fenaux 9, Claude Preudhomme 3, Mauricette Michallet 1, Sylvie
Castaigne 8, Hervé Dombret 2.
From the Departments of Hematology, 1 Hôpital Edouard Herriot, Lyon, France; 2 Hôpital
Saint-Louis, Paris, France; 3 Hôpital Claude Huriez, Lille, France; 4 Hôpital Henri Mondor,
Créteil, France; 5 Institut Gustave Roussy, Villejuif, France; 6 Hôpital des Armées Percy,
Clamart, France; 7 Hôpital Georges Clémenceau, Caen, France; 8 Hôpital André Mignot,
Versailles, France; 9 Hôpital Avicenne, Bobigny, France.
Corresponding author: Xavier Thomas, Department of Hematology, Hôpital Edouard
Herriot, Hospices Civils de Lyon, 69437 Lyon Cedex 03, France; phone: (33)472117395;
fax: (33)472117404; e-mail: [email protected].
Running head: A randomized consolidation therapy of HDAraC vs TSC for AML
Keywords: acute myeloid leukemia, consolidation, prognosis, timed-sequential
chemotherapy, high-dose cytarabine.
Blood First Edition Paper, prepublished online June 20, 2011; DOI 10.1182/blood-2011-04-349258
Copyright © 2011 American Society of Hematology
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Abstract
To assess the value of administering timed-sequential chemotherapy (TSC) (two therapeutic
sequences separated by a four-day interval-free chemotherapy) or high-dose cytarabine
(HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients
aged 15 to 50 years were enrolled in the prospective randomized Acute Leukemia French
Association-9802 trial. Complete remission was achieved in 89%. Two hundred and thirty
seven patients were then randomized to either TSC consolidation (120 patients) or HDAraC
consolidation cycles (117 patients). Overall, there was no significant difference between the
two consolidation arms (5-year event-free survival (EFS): 41% for HDAraC vs 35% for TSC),
or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal
AML (CN-AML) NPM1+ or CEBPA+ and FLT3-ITD− had the same outcome as those with
favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend
was in favor of HDAraC. However, the difference became significant when considering
intermediate cytogenetics (5-year EFS: 49% vs 29%; p = 0.02), especially CN-AML (5-year
EFS: 48% vs 31%; p = 0.04), which was related to lower relapse rate and less toxicity. This
study demonstrates that TSC did not produce any benefit when used as consolidation therapy
in younger adult as compared to HDAraC. This trial is registered at www.clinicaltrials.gov as
no. NCT00880243.
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Introduction
The optimal treatment of acute myeloid leukemia (AML) in younger adults remains to be
defined. A recent trend in leukemia treatment has been the use of increasingly myelotoxic
induction and postremission therapy; however, optimal doses and schedulings remain
uncertain. Long-term analysis of the Acute Leukemia French Association (ALFA)-9000 trial
was recently published.1 In this trial, the best results were observed in younger adults who
received one course of timed-sequential chemotherapy (TSC), consisting of two sequences of
chemotherapy separated by a four-day interval-free as induction therapy, followed by another
course of TSC as consolidation. The rational was based on the observation that after initial
intensive therapy, leukemic cells can be recruited synchronously into the cell cycle, and may
then be more susceptible to killing by cytotoxic agents. During the same period of time, the
Cancer and Leukemia Group B (CALGB) conducted a study to evaluate the role of high-dose
cytarabine (HDAraC) as consolidation treatment after successful induction treatment with
daunorubicin and conventional-dose cytarabine.2 This study demonstrated a benefit for
cytarabine dose escalation in consolidation for younger adults. Later, this beneficial effect
was restricted to patients with core binding factor (CBF) AML 3-5 and, to a lesser extent, to
patients with cytogenetically normal AML (CN-AML). 6
Determining the best consolidation chemotherapy remains an important concern in the
treatment of younger adults with AML, particularly for patients with intermediate or
unfavorable cytogenetics for whom no identical donor can be identified before post-remission
therapy. One issue is whether intensive TSC is more effective than successive cycles of
consolidation containing HDAraC. In order to clarify this question, the ALFA Group
conducted a study in which all newly diagnosed younger adult AML patients received
identical induction consisting of a TSC with daunorubicin, mitoxantrone, and cytarabine.
After achieving complete remission (CR), patients having no allogeneic stem cell
transplantation (SCT) requirement or possibility were then randomized to receive either a
second course of TSC (ALFA-9000 like) or 4 courses of HDAraC followed by maintenance
therapy (CALGB-like).
Patients and methods
Patients
The ALFA-9802 trial was conducted in 16 French centers between April 1999 and October
2006. Eligibility criteria included: a diagnosis of de novo AML (except for cases of acute
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promyelocytic leukemia), an age of between 15 and 50 years inclusive, and an absence of
irreversible major organ failure [World Health Organization (WHO) grade ≥ 3]. 7 Diagnosis
was morphologically proven according to the French-American-British (FAB) classification.
8-10 The study protocol was approved by the Human Ethics Committee of each participating
institution prior to the start of enrollment at each center and was conducted in accordance with
the Declaration of Helsinki. All patients gave written informed consent prior to registration on
the study. This trial was registered at www.clinicaltrials.gov as no. NCT00880243.
Treatment design
All patients received induction chemotherapy consisting of a TSC that includes a first
sequence combining daunorubicin (80 mg/m2/day IV on days 1 – 3) and cytarabine (500
mg/m2/day continuous IV infusion over the same period). The second sequence, administered
after a 4-day free interval, consisted of mitoxantrone (12 mg/m2/day, IV on days 8 and 9) and
cytarabine (500 mg/m2/12h bolus IV infusion on days 8 – 10). The initial 259 patients
registered on the study were included in the granulocyte-macrophage colony-stimulating
factor (GM-CSF) trial and randomized at registration to receive GM-CSF or no GM-CSF
during chemotherapy as previously reported. 11 All subsequent registered patients did not
receive hematopoietic growth factors. A mandatory bone marrow aspirate was performed at
the time of bone marrow recovery or at day 35 after the start of chemotherapy to assess
response. Complete remission was defined by the Standard National Cancer Institute (NCI). 12
If residual leukemia was present, a second cycle of induction therapy was permitted,
depending on the medical condition of the patient. This salvage chemotherapy consisted of
cytarabine (3 g/m2/12h IV on days 1, 3, 5, 7) and amsacrine (100 mg/m2/day IV on days 1 –
3). Patients failing to achieve a CR after salvage therapy were taken off study. Allogeneic
SCT was performed after CR achievement if a suitable donor was available in the presence of
at least one risk factor: initial leukocytosis > 100 x 109/l (except for patients with
chromosome 16 abnormality), unfavorable cytogenetics, intermediate cytogenetics in patients
aged ≤ 35 years, absence of response to initial induction chemotherapy, presence of one
mixed-lineage leukemia (MLL) gene translocation, and fms-like tyrosine kinase-3 internal
duplications (FLT3-ITD) (after October 2002). The other patients achieving CR were
randomly assigned to consolidation courses consisting of either a TSC (P2 arm) or CALGB-
like post-remission chemotherapy (P1 arm). TSC (P2 arm) was similar to that of the ALFA-
9000 trial in which the first sequence combines mitoxantrone (12 mg/m2/day on days 1 – 3) and
cytarabine (500 mg/m2/day continuous IV infusion over the same period), and the second
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sequence combines etoposide (200 mg/m2/day IV on days 8 – 10) and cytarabine (500
mg/m2/day continuous IV infusion on days 8 – 10). 1 In contrast, CALGB-like post-remission
chemotherapy (P1 arm) included 4 cycles of HDAraC (cytarabine, 3 g/m2/12h IV on days 1, 3
and 5) followed by 4 additional maintenance courses (daunorubicin, 45 mg/m2 IV on day 1,
and cytarabine, 100 mg/m2/12h SC on days 1 – 5) 2 (Figure 1). Because of several reports
showing an improved outcome with regimens that include HDAraC, 3,4 patients with t(8;21)
were retrieved from the second randomization after November 2000 and systematically
received the CALGB-like consolidation treatment.
Risk classification
Cytogenetic studies on pretreatment bone marrow samples were performed at diagnosis using
standard banding techniques and classification according to the International System of
Human Cytogenetic Nomenclature. 13 Karyotype abnormalities that involve CBF leukemias
[t(16;16)(p13;q22), inv(16)(p13;q22), or t(8;21)(q22;q22)] with or without other cytogenetic
abnormalities were considered favorable cytogenetics. Monosomies or deletions of
chromosomes 5 and 7, abnormalities of the long arm of chromosome 3, 11q23 abnormalities,
or complex cytogenetic abnormalities (defined as at least three unrelated cytogenetic clones)
were considered unfavorable risk factors. Other cytogenetic abnormalities and CN-AML were
designated intermediate risk factors. Intermediate-risk cytogenetics was further subdivided
into a favorable intermediate-risk group [CN-AML with nucleophosmin (NPM1) or
CCAAT/enhancer-binding protein-α (CEBPA) mutations and no FLT3-ITD (NPM1+ or
CEBPA+ wt FLT3-ITD)] and a poor intermediate-risk group (other patients), as previously
described. 14 No cytogenetic data were available from 40 patients (not performed in 8 cases
and failure in 33 cases).
Response criteria
Response was evaluated at the time of cell recovery and confirmed again just before the onset
of the first consolidation course. Standard National Cancer Institute (NCI) criteria were used
to define CR. 12 Patients alive after induction or induction and salvage, but not reaching CR
criteria, were considered as patients with resistant disease. Induction deaths were defined as
deaths occurring between the onset of induction chemotherapy and evaluation of induction or
induction/salvage chemotherapy.
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Statistical analysis
For the whole cohort, EFS was calculated from the date of registration, with CR achievement
failures, deaths during induction or in first CR, and relapses included as events. EFS after
consolidation randomization was calculated from the date of randomization, with deaths and
relapses included as events. OS following consolidation randomization was calculated from
the date of randomization to the date of death of any cause. The data was censored at the
earlier of the date of last contact and the date of closeout when applicable. The primary end
point was EFS. Tolerance and OS defined secondary end points. A third objective was to
assess the relationship between risk classification and outcome.
Toxicity and adverse events were classified according to the WHO criteria. 7 Time to recovery
from cytopenia was defined as the number of days from the first day that leukocytes,
granulocytes, and platelets were < 1 x 109/l, < 0.5 x 109/l, and < 50 x 109/l (or < 100 x 109/l)
until cell recovery, respectively, for 2 consecutive days. Assessment of comparability of
characteristics for the randomized groups was evaluated by the Pearson χ2 test and the
Wilcoxon rank sum test for categoric and continuous variables, respectively. All tests were
two sided with statistical significance set at 0.05. Statistical analyses were performed on an
intention-to-treat basis. Relapse was defined as a recurrence of leukemia after a first CR. EFS
and OS distributions were estimated by the method of Kaplan and Meier. All comparisons
were performed by the log-rank test. The Cox’s proportional hazards model was used to
obtain the estimate and the 95% CI of the hazard ratio of one category vs another. Analyses
used a disjunctive coding allowing a one-to-one comparison with an a priori defined
reference category. The Wald test has been used to determine the prognostic significance. The
Mantel-Haenszel test for trend and chi-squared tests were used to test for differences in
cytogenetic and risk groups data by consolidation arm. Interaction test between the first
randomization (GM-CSF trial) 11 and the consolidation randomization was introduced into the
Cox model for testing a difference of effect of post-remission therapy in the GM-CSF group
and the no GM-CSF group for the initial 259 patients registered in the study. All
computations were made using the BMDP software (BMDP Statistical Software, Los
Angeles, CA).
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Results
A total of 473 patients entered the study. Six patients were withdrawn (2 patients with past
history of cancer, 1 patient with chronic myeloid leukemia in blastic phase, 2 patients
retrieved their consent, and 1 patient treated according to another schedule due to physician
decision). Data from 8 patients were not received or incomplete at time of analysis. Thus, we
report on 459 eligible patients. Surviving patients were censored on mid-2009. Patients lost to
follow-up were censored at the date they were last known to be alive. Median follow-up of the
entire cohort was 5 years (95% CI, 4.7 – 5.2 years).
Overall results
Complete remission was achieved in 408 of the 459 eligible patients (89%; 95% CI, 86% -
92%), with 380 receiving one induction course and 28 requiring salvage therapy. Twenty-
three patients died (5%) during induction course, and two during salvage therapy. Twenty-six
patients (6%) had persistent leukemia, 16 of whom were taken off study after one course of
induction and 10 after 2 courses. The median EFS and OS for the 459 adults were 16.2
months (95% CI, 14.6 – 20.8 months) and 41.9 months (95% CI, 30.7 – 67.4 months) with 5-
year EFS and OS of 38% (Figure 2A) and 46%, respectively. The risk classification described
above was confirmed (Figure 2B).
Outcome of consolidation therapy
Of the 408 patients achieving CR, 237 patients (58%) were randomized to consolidation: 120
received a TSC (P2 arm) similar to that of the ALFA-9000 trial, and 117 received a CALGB-
like post-remission chemotherapy (P1 arm) including 4 cycles of HDAraC (Figure 1).
Seventy-one patients with a HLA-identical sibling donor identified during induction therapy
were not eligible for randomization and received allogeneic SCT. Reasons the remaining 100
potentially eligible patients who achieved CR were not randomized include: toxicity of
induction or salvage therapy (39 patients), early relapse (7 patients), investigator decision (22
patients), patient’s refusal (8 patients), and systematic assignment to the HDAraC
consolidation schedule for patients with t(8;21) AML after November 2000 (24 patients).
Despite randomization inclusion criteria, 29 patients, who were randomized to consolidation
(11 in the P2 arm and 17 in the P1 arm, representing 11% of the randomized cohort) and for
whom an identical donor was later identified, were subsequently allografted (by local
investigator decision) but kept in the intention-to-treat based analysis (Figure 1).
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The remainder of the report will be based on the 237 eligible randomized patients.
On-study patient details are shown in Table 1. The median time to commencement of
consolidation therapy was 57 days following commencement of induction therapy for P1 arm
(range, 39 – 112 days) and 53 days for P2 arm (range, 34 – 146 days). Evolution after
randomization is summarized in Figure 1. By the time of study closeout, 124 patients had
relapsed (52%) (60 in the P1 arm and 64 in the P2 arm with median time to relapse of 10.7
months and 9.9 months, respectively) and 25 patients had died in CR (11 in the P1 arm and 14
in the P2 arm). The median EFS was 23.3 months (95% CI, 15.7 – 45 months) for the P1 arm
and 13.7 months (95% CI, 11.3 – 22.5 months) for the P2 arm with 5-year EFS of 41% and
35%, respectively (p = 0.24) (Figure 3). The median OS was 62.9 months for the P1 arm and
55.6 months for the P2 arm with 5-year OS of 50% and 48%, respectively (p = 0.82). Overall,
there was no significant difference between the two consolidation arms in terms of cumulative
incidence of relapse and treatment-related mortality (TRM). Interaction with the GM-CSF
trial for the previous comparisons was not significant, indicating a similar effect for GM-CSF
and no GM-CSF subgroups.
Toxicity of consolidation therapy
Detailed information on the toxicity of consolidation chemotherapy arms is given in Table 2.
P2 arm (TSC) was more toxic than P1 arm (HDAraC). Intensive P2 arm appeared less well
tolerated than P1 arm cycles with respect of nonhematologic toxicities. P2 arm was associated
with significant increases for severe diarrhea (WHO grade ≥ 3) (24% for TSC vs 3%
maximum for HDAraC cycles), severe nausea/vomiting (26% vs 5% maximum), and
mucositis (26% vs 3% maximum). Severe infections (WHO grade ≥ 3) were also more
frequent for patients receiving the P2 arm (39% vs 19% maximum). In addition, severe
cardiac and/or pulmonary side effects were essentially observed in the P2 arm.
Regarding hematologic toxicity, the median duration of neutropenia less than 0.5 x 109/L was
37 days for patients receiving P2 arm, and did not exceed 15 days at each course for patients
receiving the P1 arm consolidation cycles. Similarly, platelet count recovery to 50 x 109/L
was 47 days with the P2 arm compared with 24 days for each P1 arm cycles. However,
patients following the P1 arm received more transfusions overall than those following the P2
arm due to cycle repetition.
Results according to risk stratification
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Among patients following consolidation randomization, 71 patients were stratified to the
favorable risk group (including 31 patients with CBF leukemias and 40 patients with
favorable intermediate-risk AML), and 146 to the poor risk group (103 patients with poor
intermediate-risk AML and 43 patients with unfavorable cytogenetics). Twenty patients
remained unclassified because of unknown cytogenetics (2 not performed; 18 failures).
Results are given in Table 3. Both groups showed better results for the P1 arm compared with
the P2 arm: In the favorable risk group, the 5-year EFS was 67% and 50% for the P1 arm and
the P2 arm, respectively (p = 0.1); however, in the poor risk group, the 5-year EFS was 31%
and 21% for the P1 arm and the P2 arm, respectively (p = 0.13).
No significant differences were noted between the two arms in patients with favorable
cytogenetics and in those with unfavorable cytogenetics. A significant advantage of HDAraC
over TSC was only observed among patients with intermediate cytogenetics with median EFS
at 31.4 months and 5-year EFS of 49% in the P1 arm versus median EFS at 13.4 months and
5-year EFS of 29% in the P2 arm (p = 0.02) (Figure 4A). This was mainly due to a benefit of
HDAraC consolidations in patients with CN-AML (Figure 4B), which involve patients from
the favorable intermediate-risk group and those from the poor intermediate-risk group. In
patients with CN-AML, the median EFS was 29.6 months with 5-year EFS of 48% in the P1
arm versus 13.7 months and 31% in the P2 arm (p = 0.04). In both cases (intermediate
cytogenetics and CN-AML), the advantage for HDAraC was related to lower relapse
incidence (p = 0.02 and p = 0.01, respectively) and lower TRM (p = 0.02 and p = 0.01,
respectively). Although there were few patients in each arms (12 in P1 and 7 in P2), HDAraC
appeared significantly better than TSC for patients with MLL abnormalities (p = 0.03) (Table
3).
Discussion
Relapse prevention may be achieved by optimizing post-remission therapy. This randomized
study was designed to test the hypothesis that intensive TSC can produce greater leukemic
cytoreduction and, therefore, superior long-term EFS than sequential cycles of HDAraC. The
rational for the study was based on previously published observations from our group
showing TSC as an efficient consolidation therapy after a first TSC as induction treatment. 1
We therefore assessed whether consolidation TSC improves the long-term outcome of
younger adults with AML as compared to sequential courses of chemotherapy containing
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HDAraC, which showed a significant benefit for consolidation chemotherapy as compared to
conventional-dose treatment. 2 After publication of the CALGB 8525 treatment trial,
repetitive cycles of HDAraC became the preferential post-induction chemotherapy for
patients not receiving SCT. 2 The Southwest Oncology Group (SWOG) 8601 study also
suggested that inclusion of HDAraC in both induction and consolidation phases gave the best
long-term outcome. 15
Overall, induction and survival results in our trial compared favorably with those obtained in
patients of comparable age who were treated with standard-dose regimens. 16,17 CR proportion
was 89% and the overall long-term EFS was 38%, but ranged from 62% for the favorable risk
group to 23% for the poor risk group. Actually, the major finding of the present study is that
no significant difference exists in terms of outcome, as measured by EFS following
consolidation randomization, between the two groups receiving either cycles of HDAraC or
TSC. This confirms a previous publication showing no differences between four courses of
standard-dose chemotherapy versus three courses of HDAraC in post-remission therapy in
adult AML. 18 However, there was a trend indicating better results with HDAraC and several
factors support the use of repeated sequences of HDAraC as consolidation.
First of all, HDAraC consolidations were preferential in terms of treatment-related toxicity.
The major toxicity encountered in the present study was hematological toxicity. Despite the
repetition of consolidation courses in the arm with HDAraC, toxicity was more acceptable in
this arm than the arm with only one course of TSC. Myelosuppression was much deeper after
TSC than after each cycle of HDAraC. After HDAraC, however, myelosuppression was
longer than that observed in the previously published report by the CALGB. 2 Although the
difference did not translate into a significantly higher treatment-related death rate,
consolidation with TSC was significantly marked by a higher frequency of severe infections
and digestive tract complications.
Second, HDAraC consolidations were preferential in terms of treatment outcome. Cytogenetic
and molecular changes in leukemic cells at diagnosis remain one of the most powerful
prognostic factors for predicting outcome in AML. 19 It appears therefore essential to compare
consolidation treatments according to these factors. Although analysis of our data, taking into
account prognostic risk groups based on those markers, only showed a trend in favor of
repetitive courses with HDAraC, the difference between the two randomization arms became
significant when considering intermediate-risk cytogenetics and CN-AML in particular. This
confirms results previously published by the CALGB showing that certain subsets of patients
benefit from this therapy more than others. Indeed, several studies have shown that both
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t(8;21) and inv(16) sensitize AML blasts to HDAraC given as consolidation therapy. 3-5
Although there was a trend, the superiority of HDAraC over TSC was not demonstrated for
CBF-AML by a significant p value in our study. This can be explained by the overall good
prognosis of this type of leukemias and by the small number of CBF-AML patients in each
arm. Our results are also not in accordance with those of the Japonese group, which showed a
beneficial effect of HDAraC courses on DFS essentially in CBF-AML. 18 In the CALGB
study, the higher post-remission cytarabine dose was associated with a better 5-year
continuous CR (3 g/m2, 42%; 400 mg/m2, 33%; 100 mg/m2, 17%; p < 0.001) not only in CBF
AML, but also in CN-AML. 3,6 Approximately 40% of adult patients with AML have normal
cytogenetics at diagnosis. Several studies have shown that CN-AML patients have an
intermediate outcome. Differences in intensity of post-remission therapy can significantly
affect outcome in CN-AML. It has been previously suggested that CN-AML patients also
exhibit an improved outcome with the use of HDAraC after remission. 6 However, a
limitation of this study is the lack of molecular subtyping. CN-AML is molecularly
heterogeneous. 20 Mutations in the CEBPA gene have been described in approximately 10%
of AML patients and are associated with a good prognosis; in particular, those with CN-AML
lacking an internal tandem duplication in the fms-like tyrosine kinase-3 gene (FLT3-ITD). 21
NPM1 mutations, also thought to be early events in leukemogenesis, have a similar outcome
with or without CEBPA mutation in CN-AML. Conversely, the genotype “mutated NPM1
without FLT3-ITD” represents a favorable prognostic marker with survival data very similar
to that of CN-AML patients with mutated CEBPA without FLT3-ITD. 22 The different
outcomes predicted by these specific molecular abnormalities were confirmed in our study. In
this cohort of younger adult patients with AML, the outcome of CN-AML NPM1+ or
CEBPA+ wt FLT3-ITD was similar to that reported for CBF leukemias. Overall, 56/59 (95%)
cases of CN-AML NPM1+ or CEBPA+ wt FLT3-ITD can achieve CR. Repetitive cycles of
HDAraC are also considered a reasonable choices for AML with mutated NPM1 without
FLT3-ITD and with mutated CEBPA, which certainly took into consideration the population
of CN-AML NPM1+ or CEBPA+ wt FLT3-ITD. 20 This was confirmed in our study in which
patients defined as favorable intermediate-risk tend to do better with HDAraC consolidations
than with TSC. This difference became probably significant with a higher number of patients
in each arm. Outcome after HDAraC consolidation showed 70% of long-term survival
comparable to that observed for CBF-AML, and compare favorably with regard to results
obtained with HDAraC for the other CN-AML. It is therefore likely that CN-AML patients
may benefit from specific post-remission treatments, but previous favorable results published
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by the CALGB emphasizing the role of HDAraC on CN-AML is mainly related to the impact
of HDAraC on the population of CN-AML NPM1+ or CEBPA+ wt FLT3-ITD. No advantage
has been shown for allogeneic SCT in frontline treatment for patients with CBF-AML. 23-27 A
recent study also provided evidence that patients with CN-AML with mutated NPM1 without
FLT3-ITD may also not benefit from allogeneic SCT. 20 In our study, the outcome of CN-
AML NPM1+ or CEBPA+ wt FLT3-ITD, referred to as favorable intermediate-risk, was
similar to that reported for CBF leukemias, which confirms the absence of indication for
allogeneic SCT in frontline therapy.
At present, it is unknown whether other genetic alterations also influence response of AML
patients to treatment with HDAraC. Overall, patients with adverse risk cytogenetics fared
equally worse with cycles of HDAraC compared to consolidation with TSC, indicating that
radically therapeutic approaches will be necessary to improve the outcome of these patients.
A recent study also provided evidence that patients with primary AML harboring RAS
mutations treated with HDAraC as post-remission therapy were significantly less likely to
experience relapse than patients treated with lower doses of cytarabine. 28 Although our series
was small, patients with MLL abnormalities tended to benefit more from HDAraC repeated
cycles of consolidation than from one course of TSC. For most patients with unfavorable
cytogenetics, outcome remains dismal with conventional consolidation chemotherapy. 19,29
However, this is still the case even when using repetitive courses of HDAraC. 3 An allogeneic
SCT from either matched related or unrelated donors is currently considered the treatment of
choice for those patients as recommended by single studies 24,30 or meta-analyses. 25,31
Repetitive use of HDAraC-based post-remission chemotherapy may be one of the main
explanations for the superior outcome as compared to TSC. However, several questions
remain open including the number of cycles, the most appropriate dose and schedule, and the
role of combining HDAraC with other agents. Four cycles of HDAraC have been shown to be
superior to 4 courses of intermediate- or standard-dose. 2 The use of prolonged intensive
consolidation 32 or of multiagent chemotherapy does not appear to be superior to HDAraC
alone. 33,34 It remains uncertain as to whether receiving more than 2 or 3 cycles of HDAraC is
necessary. For CBF-AML, retrospective studies by CALGB suggest that 3 or more cycles are
superior to only one cycle. 4,5 The four monthly maintenance courses were administered
according the initial therapeutic schedule from the CALGB. 2 However, they were given up
because of a low compliance in the present trial (only 66% of the patients who received the
four consolidation courses received a full maintenance therapy) and, as previously reported, 2
the lack of clues regarding their efficacy. In our ongoing ALFA-0702 trial, we are raising the
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issue whether the combination of clofarabine with intermediate-dose cytarabine (CLARA),
which gave promising responses in high-risk AML patients, 35 might be superior to ‘standard’
HDAraC consolidations in first line therapy in this patient population.
In conclusion, this study demonstrates that TSC did not bring any benefit when used as
consolidation therapy in younger adult as compared to HDAraC. A clear benefit of HDAraC
is present even in patients with intermediate-risk cytogenetics, especially those with CN-
AML. Furthermore, toxicity related to the repetition of cycles is acceptable and manageable.
Multiple cycles of HDAraC are currently considered as the most important component of
curative therapy for CBF-AML, and by extension for the favorable intermediate-risk group.
This treatment strategy may also be considered as a realistic alternative to allogeneic SCT in
other patients with intermediate-risk cytogenetics who did not have a HLA-compatible donor.
Acknowledgements
Schering Plough (Kenilworth, N.J., USA) and Amgen (Neuilly sur Seine, France) provided
grants for central data management to the Edouard Herriot Hospital (Department of
Hematology). This trial is registered at www.clinicaltrials.gov as no. NCT00880243.
The authors thank all ALFA investigators and especially C.Pautas and H.Dombret for
reviewing the manuscript.
Authorship contributions and Disclosure of conflicts of interest
All authors participated actively in the study conception, design, and acquisition of data. XT
(principal investigator) included patients, conducted the statistical analysis, interpreted the
data, and was the main author of the manuscript; ME collected the data and provided
technical support; ER, SdB, TdR, OR, CG, YC, NB, BQ, YH, JHB, PF, MM, and SC
included patients; CP included patients and reviewed the manuscript; CT was responsible for
co-ordinating cytogenetics; CP and AR were responsible for co-ordinating molecular biology;
HD (president of the ALFA group) included patients, reviewed the manuscript, and gave final
approval. The authors reported no potential conflicts of interest.
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Appendix
The following ALFA investigators participated in the ALFA-9802 study: X.Thomas,
E.Archimbaud†, M.Michallet, D.Fiere, C.Charrin, I.Tigaud, S.Hayette, D.Treille-Ritouet,
C.Dumontet, E.Tavernier, Y.Chelghoum, A.Thiebaut, J.Troncy, F.Nicolini, E.Wattel,
M.Elhamri, C.Pivot, QH.Le (Hôpital E.Herriot, Lyon); H.Dombret, JM.Micléa, E.Raffoux,
N.Boissel, L.Degos, JM.Cayuela, S.Chevret, A.de Labarthe, H.Espérou, E.Gluckman,
T.Leblanc, V.Levy, O.Maarek, D.Réa, G.Socié, J.Soulier, C.Chomienne, MT.Daniel,
J.Delaunay, F.Treilhou, C.Parmentier (Hôpital Saint-Louis, Paris); B.Quesnel,
C.Preudhomme, F.Bauters, JP.Jouet, JL.Lai, P.Lepelley, H.Djeda, S.Darre, A.Renneville,
N.Philippe (Hôpital C.Huriez, Lille); C.Cordonnier, S.Maury, D.Bories, H.Jouault, M.Kuentz,
C.Pautas, Y.Hicheri, K.Yacouben, J.Beaune, C.Perot (Hôpital H.Mondor, Créteil); S.de
Botton, JH.Bourhis, P.Arnaud, C.Fermé, N.Itzhar, A.Bernheim, N.Fresnoy, M.Leste,
JM.Ventelon (Institut Gustave Roussy, Villejuif); C.Martin, B.Corront, J.Provencal (Centre
Hospitalier, Annecy); O.Reman, E.Lepesant, M.Macro, G.Plessis, S.Cheze, M.Leporrier
(Hôpital G.Clémenceau, Caen); S.Castaigne, P.Rousselot, C.Terré, AL.Taksin, JN.Bastie,
F.Suzan, P.Piesvaux, S.Rigaudeau, E.Henry, D.Legrand (Hôpital A.Mignot, Versailles); T.de
Revel, T.Fagot, G.Nedellec, G.Auzanneau, B.Souleau, F.Desangles, I.Garnier, JV.Malfuson
(Hôpital des Armées Percy, Clamart); P.Fenaux, C.Gardin, L.Ades, J.Briere, JJ.Kiladjian,
B.Beve, V.Eclache, MP.Lemonnier, P.Casassus (Hôpital Avicenne, Bobigny, and Hôpital
Beaujon, Clichy); JO.Bay, B.Choufi, M.Legros, O.Tournilhac (Centre Jean Perrin, Clermont-
Ferrand); I.Plantier, L.Detourmignies (Hôpital V.Provo, Roubaix); N.Cambier (Hôpital
Saint-Vincent, Lille); C.Soussain, J.Frayfer, C.Allard (Centre Hospitalier, Meaux);
M.Beaumont, P.Agape, B.Pollet (Centre Hospitalier, Boulogne sur Mer); M.Janvier,
S.Glaisner, A.Bourguignat, E.Baumelou, F.Turpin (Centre René Huguenin, Saint-Cloud, and
Hôpital Foch, Suresnes), France.
†E.Archimbaud, who participated to the design of the study, died on March 25, 1998.
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Table 1. Characteristics of patients according to the arm of consolidation therapy
Characteristics HDAraC (P1 arm)
(117 patients) TSC (P2 arm) (120 patients)
Age (years) 45 (18 – 50) 46 (17 – 50) Biology at diagnosis WBC count (x 109/l) Hb level (g/l) Platelets (x 109/l) PB blasts (%) BM blasts (%)
12.6 (0.8 – 230)
91 (33 – 149) 59 (11 – 404) 43 (0 – 97)
70 (20 – 100)
12.1 (0.6 – 206)
90 (37 – 136) 67 (9 – 346) 38 (0 – 98)
74 (20 – 100) Clinical presentation Hepatomegaly (%) Splenomegaly (%) CNS + (%) Bleeding (%) Fever (%)
8 (7%)
11 (9%) 0 (0%)
32 (27%) 38 (32%)
6 (5%)
11 (9%) 2 (2%)
27 (23%) 42 (35%)
FAB classification M0 (%) M1 (%) M2 (%) M4 (%) M5 (%) M6 (%) M7 (%) Not performed (%)
3 (3%)
18 (15%) 34 (29%) 23 (20%) 28 (24%)
4 (3%) 1 (1%) 6 (5%)
6 (5%)
30 (25%) 28 (23%) 30 (25%) 17 (14%)
1 (1%) 2 (2%) 6 (5%)
WHO PS (%) 0 1 2
47 (40%) 62 (53%) 8 (7%) c
39 (32%) 61 (51%)
20 (17%) c Cytogenetics Favorable Intermediate Unfavorable Failure Not performed
12 (11%) 71 (61%)
28 (24%) d 5 (4%)
1
19 (16%) 72 (60%)
15 (13%) d 13 (11%)
1 Risk stratification Favorable risk group a Poor risk group b Unclassified
32 (28%) 79 (66%)
6 (6%)
39 (32%) 67 (56%) 14 (12%)
Abbreviations: BM, bone marrow; CNS+, central nervous system involvement; FAB, French-American-British; HDAraC, high-dose cytarabine; Hb, hemoglobin; PB, peripheral blood; PS, performance status; TSC, timed sequential chemotherapy; WBC, white blood cell; WHO, World Health Organization. a included patients with favorable cytogenetics and CN-AML NPM1+ or CEBPA+ wt FLT3-ITD; b included patients with unfavorable cytogenetics and those with intermediate cytogenetics other than CN-AML NPM1+ or CEBPA+ wt FLT3-ITD; c p = 0.03; d p = 0.03.
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Table 2. Toxicity of consolidation therapy
Toxicity P1 arm P2 arm HDAraC 1
(110 pts) HDAraC 2
(95 pts) HDAraC 3
(81 pts) HDAraC 4
(74 pts) TSC
(93 pts) Extra-hematologic (WHO grade ≥ 3)
Bilirubine AST ALT ALP GGT
Mucositis Nausea/vomiting
Diarrhea Creatinine Hemostasis Cutaneous
Allergy Cardiac
Pulmonary Other
0
1% 2% 5% 1% 3% 3% 1% 0 0 0 0 0
1% 4% a
1% 1% 4% 0
1% 0 0
1% 0 0 0 0 0 0 0
0 0
4% 0
3% 0
5% 3% 0 0 0 0 0
1% 0
1% 0
4% 0
3% 0 0
3% 0 0 0 0 0 0 0
10% 1% 7% 0
22% 26% 24% 24%
0 6% 5% 3% 3%
15% 0
Infection WHO grade ≥ 3 Days with fever*
Days with antibiotics*
16%
3 days 8 days
18%
4 days 10 days
19%
2 days 8 days
10%
2 days 8 days
39%
16 days 35 days
Hematologic WBC < 1 x 109/l*
ANC < 0.5 x 109/l* Plat < 50 x 109/l* Plat < 100 x 109/l* RBC transfusions* Plat transfusions*
13 days 15 days 17 days 23 days
6 4
14 days 14 days 16 days 25 days
5 4
12 days 14 days 17 days 23 days
4 3
13 days 14 days 16 days 27 days
4 4
37 days 37 days 47 days 62 days
10 12
* median. a one patient presented pancreatitis and 3 patients a severe cerebellar syndrome. Abbreviations: ANC, absolute neutrophil count; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase; HDAraC, high-dose cytarabine; Plat, platelets; Pts, patients; RBC, red blood cell; TSC, timed-sequential chemotherapy; WBC, white blood cell; WHO, World Health Organization.
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Table 3. Outcome of consolidation trial according to cytogenetic and molecular characteristics
Patient population HDAraC (P1 arm) Median* Pts 5y-EFS (months)
TSC (P2 arm) Median* Pts 5y-EFS (months)
P value
All patients
23.3 117 41% 13.7 120 35% 0.24
Risk groups Favorable risk group Favorable cytogenetics Favorable intermediate-risk a Poor risk group Poor intermediate-risk b Unfavorable cytogenetics
NR 32 67% NR 12 67% NR 20 67% 15.1 79 31% 25.9 51 42% 12.2 28 12%
NR 39 50% NR 19 53% 14.0 20 49% 11.0 67 21% 11.9 52 23% 7.5 15 13%
0.10
0.45
0.12
0.13
0.06
0.53
Test for heterogeneity between subgroups by arm: p = 0.09; NS Mantel-Haenszel test for consolidation randomization: p < 0.0001
Cytogenetic groups Favorable cytogenetics Intermediate cytogenetics Unfavorable cytogenetics
NR 12 67% 32.8 71 49% 12.2 28 12%
NR 19 53% 14.8 72 29% 7.5 15 13%
0.45
0.02
0.53
Test for heterogeneity between subgroups by arm: p = 0.06; NS Mantel-Haenszel test for consolidation randomization: p = 0.0002
CN-AML
29.6 59 48%
13.7 55 31%
0.04
MLL AML
12.2 12 25%
5.9 7 -
0.03
* Median EFS. Abbreviations: AML, acute myeloid leukemia; CN-AML, cytogenetically normal acute myeloid leukemia; HDAraC, high-dose cytarabine; NR, not reached; MLL, mixed-lineage leukemia gene; Pts, patients; TSC, timed sequential chemotherapy. a included CN-AML NPM1+ or CEBPA+ wt FLT3-ITD; b included patients intermediate cytogenetics other than CN-AML NPM1+ or CEBPA+ wt FLT3-ITD.
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Figure legends: Figure 1. Schema of the ALFA-9802 trial Figure 2. EFS of the entire cohort (459 patients): (A) all patients, and (B) according to risk classification. In the Cox model, a RR value > 1 indicates that the outcome is worse in that category as compared with the baseline. P-value was given by the Wald’s test. Figure 3. Comparison between P1 arm (HDAraC consolidation) and P2 arm (TSC consolidation) (237 patients). Figure 4. Comparison between P1 arm (HDAraC consolidation) and P2 arm (TSC consolidation) in patients with intermediate cytogenetics: (A) all randomized patients with intermediate cytogenetics (143 patients), and (B) patients with normal cytogenetics (CN-AML) (114 patients).
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Figure 1.
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Figure 2A.
0 2 4 6 8 10
Time from diagnosis (years)
0,0
0,2
0,4
0,6
0,8
1,0
EF
S pr
obab
ilit
y
Median 3y-EFS 5y-EFS 7y-EFS
15.9 months 39% 38% 37%
Figure 2B.
0 2 4 6 8 10
Time from diagnosis (years)
0
0.2
0.4
0.6
0.8
1
EF
S pr
obab
ilit
y
Unfavorable cytogenetic
Median 5y-EFS RR 95%CI p
Not reached 62% 1 - -
Not reached 61% 1.04 0.61-1.82 0.88
14.3 months 29% 2.61 1.84-4.11 <0.001
8.2 months 16% 3.89 2.62-6.09 <0.001
Favorable intermediate-risk
Poor intermediate-risk
Favorable cytogenetic
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Figure 3.
0 2 4 6 8 10
Time from randomization (years)
0
0,2
0,4
0,6
0,8
1,0E
FS
prob
abil
ity
p = 0.24
HDAraCTSC
Median 3y-EFS 5y-EFS 7y-EFS
23.3 months 42% 42% 41%13.7 months 36% 35% 33%
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Figure 4A.
0 2 4 6 8 10
Time from randomization (years)
0,0
0,2
0,4
0,6
0,8
1,0E
FS
prob
abil
ity
HDAraCTSC
p = 0.02
Median 3y-EFS 5y-EFS 7y-EFS
31.4 months 49% 49% 49%13.4 months 32% 29% 27%
Figure 4B.
0 2 4 6 8 10
Time from randomization (years)
0,0
0,2
0,4
0,6
0,8
1,0
EF
S pr
obab
ilit
y
p = 0.04
HDAraCTSC
Median 3y-EFS 5y-EFS 7y-EFS
29.6 months 48% 48% 48%13.7 months 31% 31% 26%
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doi:10.1182/blood-2011-04-349258Prepublished online June 20, 2011;
Mauricette Michallet, Sylvie Castaigne and Hervé DombretBoissel, Bruno Quesnel, Yosr Hicheri, Jean-Henri Bourhis, Pierre Fenaux, Claude Preudhomme,Botton, Thierry de Revel, Oumedaly Reman, Christine Terré, Claude Gardin, Youcef Chelghoum, Nicolas Xavier Thomas, Mohamed Elhamri, Emmanuel Raffoux, Aline Renneville, Cécile Pautas, Stéphane de ALFA-9802 studyas consolidation for younger adults with AML in first remission: the Comparison of high-dose cytarabine and timed-sequential chemotherapy
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