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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2478-2484
Randomized Phase II Study of Fludarabine + Cytosine Arabinoside + Idarubicin ± All-Trans Retinoic Acid ± Granulocyte
Colony-Stimulating Factor in Poor Prognosis Newly Diagnosed Acute
Myeloid Leukemia and Myelodysplastic Syndrome
By
Elihu H. Estey,
Peter F. Thall,
Sherry Pierce,
Jorge Cortes,
Miloslav Beran,
Hagop Kantarjian,
Michael J. Keating,
Michael Andreeff, and
Emil Freireich
From the Department of Leukemia, Division of Medicine, The University
of Texas M.D. Anderson Cancer Center, Houston, TX.
 |
ABSTRACT |
Preclinical data suggest that retinoids, eg, all-trans retinoic acid
(ATRA), lower concentrations of antiapoptotic proteins such as bcl-2,
possibly thereby improving the outcome of anti-acute myeloid leukemia
(AML) chemotherapy. Granulocyte colony-stimulating factor (G-CSF) has
been considered to be potentially synergistic with ATRA in this regard.
Accordingly, we randomized 215 patients with newly diagnosed AML (153 patients) or high-risk myelodysplastic syndrome (MDS) (refractory
anemia with excess blasts [RAEB] or RAEB-t, 62 patients)
to receive fludarabine + ara-C + idarubicin (FAI) alone, FAI + ATRA, FAI + G-CSF, or FAI + ATRA + G-CSF. Eligibility required
one of the following: age over 71 years, a history of abnormal blood
counts before M.D. Anderson (MDA) presentation, secondary AML/MDS,
failure to respond to one prior course of chemotherapy given outside
MDA, or abnormal renal or hepatic function. For the two treatment arms
containing ATRA, ATRA was given 2 days (day-2) before beginning and
continued for 3 days after completion of FAI. For the two treatment
arms including G-CSF, G-CSF began on day-1 and continued until
neutrophil recovery. Patients with white blood cell (WBC) counts
>50,000/µL began ATRA on day 1 and G-CSF on day 2. Events (death,
failure to achieve complete remission [CR], or relapse
from CR) have occurred in 77% of the 215 patients. Reflecting the poor
prognosis of the patients entered, the CR rate was only 51%, median
event-free survival (EFS) time once in CR was 36 weeks, and median
survival time was 28 weeks. A Cox regression analysis indicated that,
after accounting for patient prognostic variables, none of the three
adjuvant treatment combinations (FAI + ATRA, FAI + G, FAI + ATRA + G) affected survival, EFS, or EFS once in CR compared with
FAI. Similarly, there were no significant effects of either ATRA
ignoring G-CSF, or of G-CSF ignoring ATRA. As previously found, a
diagnosis of RAEB or RAEB-t rather than AML was insignificant. There
were no indications that the effect of ATRA differed according to
cytogenetic group, diagnosis (AML or MDS), or treatment schedule.
Logistic regression analysis indicated that, after accounting for
prognosis, addition of G-CSF ± ATRA to FAI improved CR rate versus
either FAI or FAI + ATRA, but G-CSF had no effect on the other
outcomes. We conclude that addition of ATRA ± G-CSF to FAI had no
effect on CR rate, survival, EFS, or EFS in CR in poor prognosis, newly
diagnosed AML or high-risk MDS.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
RECENT PUBLICATIONS have reported
associations between high levels of the protein bcl-2 and unfavorable
outcome of therapy of acute myeloid leukemia (AML).1-2
These findings have marked bcl-2 and related proteins, which, like
bcl-2, decrease the rate of cell death (apoptosis) as potential targets
of anti-AML treatment.3-4 In particular, some have
speculated that decreases in the concentrations of such antiapoptotic
proteins could increase the effectiveness of chemotherapy. In the late
1980s and early 1990s, data from McCulloch's laboratory in Toronto
indicated that addition of retinoids, eg, all-trans retinoic acid
(ATRA), to cultures of AML cells containing ara-C or daunorubicin
increased killing of those clonogenic cells thought responsible for
perpetuation of the disease.5,6 Subsequent data from the
same lab suggested that this effect was mediated by downregulation of
bcl-2,7 and that granulocyte
colony-stimulating factor (G-CSF) and retinoids might be synergistic in
this regard.8-9
With such in vitro data in mind and knowing that ATRA added to
chemotherapy decreases recurrence rate in acute promyelocytic leukemia
(APL),10-11 admittedly a different disease, we conducted a
randomized study designed to assess whether addition of ATRA and/or
G-CSF to chemotherapy might improve complete remission (CR) or survival
rates in AML and high-risk myelodysplastic syndromes (MDS). We have
found such syndromes (refractory anemia with excess blasts [RAEB] or
RAEB-t) identical to AML with regard to these outcomes.12
As described below, we limited eligibility to newly diagnosed patients
having a particularly poor prognosis. As of July 1998, failures have
occurred in over three quarters of the 215 patients treated. This has
led us to report our current results.
| |
MATERIALS AND METHODS |
Patients with AML (but not APL), RAEB-t, or RAEB were eligible provided
any of the following criteria were present: (1) age greater than 71 years, (2) an antecedent hematologic disorder (AHD) defined as a
history of an abnormal blood count (hemoglobin < 12 g/dL, or
neutrophils <1,500/µL, or white blood cells (WBC) >10,000/µL or
<4,000/µL, or platelet count < 150,000/µL) documented to be
present for at least 1 month before M.D. Anderson presentation, (3) AML
or MDS arising after chemotherapy for another cancer (secondary AML/MDS), (4) failure to respond to one course of induction therapy containing ara-C + anthracycline and delivered at another hospital, (5)
serum bilirubin greater than 2.9 mg/mL, or (6) serum creatinine >1.5
mg/mL. We conducted the study between September 28, 1995 and November
12, 1997. During this time, we saw 355 patients with newly diagnosed
AML (excepting APL), RAEB-t, or RAEB of whom 258 (73%) qualified for
the study. A total of 215 of the 258 (83%) were entered. All but four
of the 215 were eligible, and we include all 215 in this report. The
principal reason that 43 eligible patients did not go on this study was
the existence of a competing protocol for topotecan + ara-C in patients
with RAEB or RAEB-t. A total of 32 of the 43 patients went on this
study. The remaining 11 patients were given standard regimens by
patient choice. There were no significant differences in survival or
event-free survival (EFS), CR rate, or event-free survival once in CR
between the 215 treated on the study and the 43 who were eligible, but
not treated on the study (P > .05 for all tests).
We randomly assigned the 215 patients to receive (1) chemotherapy
(fludarabine + ara-C + idarubicin = FAI), (2) FAI + G-CSF, (3) FAI + ATRA, or (4) FAI + ATRA + G-CSF. Details of the treatments follow.
Patients were stratified at enrollment according to cytogenetics and
WBC count and randomized using a dynamic allocation scheme (see
Statistical Methods) to avoid imbalances between treatment groups with
regard to these variables. At MDA, cytogenetic results are available
within 3 working days. Patients whom attending physicians felt required
treatment before cytogenetic results were in hand (emergencies) were
randomized separately.
Doses of fludarabine, ara-C, and idarubicin were, respectively, 30 mg/m2 once daily on days 1 to 4, 2 g/m2 once
daily on these same days, and 12 mg/m2 once daily on days 2 to 4. Patients assigned to G-CSF received 200 µg/m2
daily. Patients assigned to ATRA received 45 mg/m2 daily in
two divided doses. Patients with WBC count < 10,000/µL began ATRA 2 days before starting chemotherapy (day -2) and began G-CSF on day -1.
If the WBC count was 10,000 to 50,000/µL, both ATRA and G-CSF were
started simultaneously with chemotherapy (day 1). Patients with higher
WBC counts began ATRA on day 1 and G-CSF on day 2. The dependency of
ATRA and G-CSF schedule on WBC count reflected our reluctance to begin
these drugs before chemotherapy if the WBC count was high. ATRA
administration continued for 3 days after completion of chemotherapy,
and G-CSF administration continued until the neutrophil count exceeded
1,000/µL. Documentation that patients assigned to ATRA actually
received this medicine is available for the period of remission
induction (the patients' medication records), but not for the period
of post CR therapy, which was generally given on an outpatient basis.
However, we have no reason to suspect a lack of compliance.
As in the past, we treated patients above age 50 years in laminar air
flow rooms, a protected environment (PE) whenever such rooms were
available. Patients routinely received trimethoprim/sufamethoxasole and
fluconazole by mouth to prevent infection. It should be noted that
fluconazole has been reported to increase plasma concentrations of
ATRA.13 However, our patients did not routinely receive
other medicines reported to affect these concentrations.13
Patients who had persistent disease (> 20% blasts in a marrow that
was at least 20% cellular in AML or RAEB-t, > 5% blasts in a
similarly cellular marrow in RAEB) 14 and 21 days after the start of
chemotherapy without improvement between these dates received a second
course identical to the first. The same criteria, in two consecutive marrow samples, were used for starting a second course in patients whose marrow had decreased blasts or was less than 20% cellular on
days 14 or 21, but in whom disease reappeared. Day 14 and 21 marrows
included a biopsy, as well as an aspirate; thereafter only weekly
aspirates were performed until CR status was established. CR was
defined as a marrow sample showing < 5% blasts, a platelet count > 100,000/µL, and a neutrophil count > 1,000/µL. Patients not in CR
after two courses of treatment were removed from the study and offered
other therapies. Once in CR, patients alternated courses of ara-C 100 mg/m2 daily × 5 days by continuous infusion with
courses of fludarabine 30 mg/m2 daily days 1 to 2, ara-C 1 g/m2 daily days 1 to 2, and idarubicin 8 mg/m2
day 3. Patients assigned to receive G-CSF and/or ATRA during induction
received the same treatment during and for the first 3 days after the
completion of each postremission course. The doses were those used
during induction. Therapy continued until 6 months had elapsed from CR
date, by which time most patients had received four to five courses of
postremission therapy. Relapse was defined as a marrow with > 5%
blasts unrelated to recovery of blood counts from the preceding course
of chemotherapy. At relapse, patients received salvage therapies as
previously described. Although the intent was to transplant only at
relapse, two patients (both with AML) received an allogeneic transplant
in first CR. These two constituted 2% of the 110 patients achieving
CR. We did not censor these patients at time of transplant because we could not be sure that the physician's decision to transplant and the
chances of relapse or death in CR were independent of each other.
Barring such independence, censoring is invalid.
Statistical Methods
Trial design.
The planned study sample size of 212 patients, equivalently 53 patients
per arm, was determined to detect a .20 difference in the probability
of success (alive and in CR at 6 months from start of treatment)
between the baseline treatment group (neither ATRA nor G-CSF) and each
of the three other treatment groups based on two-sided tests having
individual power .80 and overall type I error rate .05. This
computation was based on a logistic regression model including patient
covariates fit to historical data from similar studies to estimate
relevant quantities, which in particular yielded a baseline success
rate of 36%. The dynamic allocation scheme of Pocock and
Simon14 was used to achieve balance between the treatment
groups with regard to cytogenetics (group 1, inv(16) or t(8;21); group
2, -5, 5q-, -7, +8, or 11q-; group 3, other) and WBC count (group 1, WBC  10,000/µL; group 2, 10,000/µL < WBC < 50,000 µL; group
3, WBC  50,000/µL). The balanced allocation of patients by WBC
count before randomization was designed to address the possibility that
differences between the ATRA arm and the ATRA + G-CSF arm might result
only from a difference in ATRA schedule, which differed according to
WBC count as noted above, between the arms.
Data analysis.
Associations between patient characteristics (covariates) were assessed
graphically for pairs of numerical variables by examining scatterplots,
by Wilcoxon-Mann-Whitney and Kruskal-Wallis test statistics15 for categorical and continuous variables, and
by the Fisher exact test16 and its
generalizations17 for pairs of categorical variables. We
examined the following covariates as assessed before treatment: age,
hemoglobin, WBC count, platelet count, performance status (Zubrod 0-2 v 3-4), treatment in the PE, treatment as an emergency, receipt
of one prior course of induction therapy given outside MDA,
cytogenetics [normal karyotype, including patients with insufficient
metaphases for analysis (see below) v inv(16) or t(8;21)
v -5, 5q-, -7 or 7q-(-5/-7) v other abnormalities],
and presence of an AHD. Logistic regression was used to assess the
ability of treatment arm or the patients' characteristics to predict
the probability of CR, with goodness-of-fit assessed by residual and
partial residual scatter plots and likelihood ratio (LR) statistics.
Unadjusted survival and EFS analyses were performed using Kaplan-Meier
plots.18 Events were defined as death or relapse, and, in a
separate analysis, as death, relapse, or failure to achieve CR due to
resistant disease (scored at the time the patient was removed from
study). Unadjusted comparisons of survival and EFS between patient
subgroups were made using the logrank test.19 The Cox
proportional hazards model20 and its
generalizations21 were used to assess the ability of
treatment groups and patient characteristics to predict survival and
EFS, with goodness-of-fit assessed by the Grambsch-Therneau
test,22 Schoenfeld residual plots, martingale residual
plots,21 and LR statistics. All scatterplots were smoothed
using the lowess method of Cleveland,23 with variables
transformed as appropriate based on these plots. Multivariate logistic
and Cox models were obtained by performing a backward elimination with
P value cutoff .05, then allowing treatment-covariate
interactions or any variable previously deleted to reenter the final
model if its P value was < .05. All computations were
performed on a DEC Alpha 2100 5/250 system computer (Digital
Electronics Corporation, Nashua, NH) in StatXact (Cytel Software
Corporation, Cambridge, MA) and Splus,24 using both
standard Splus functions and the survival analysis package of
Therneau.25
| |
RESULTS |
In terms of the eligibility criteria described above, 32% of the 215 patients were over age 71 years, with a median of 65 years. Two thirds
had an AHD, with a median duration of 7 months. A total of 26% had
secondary AML/MDS, and 11% had failed to respond to one prior
induction course given outside MDA. A total of 12% had a creatinine
above 1.5 mg/mL, and 3% had a bilirubin greater than 2.9 mg/mL.
Cytogenetic abnormalities were defined using standard ISCN
guidelines. Reflecting the demographic features noted above, only 2%
of the patients had inv(16) or t(8;21). In contrast, 31% had monosomy
of, or loss of the long arm of, chromosomes 5 and/or 7 ("-5/-7"),
with the number of such patients (66) close to the number with a normal
karyotype (73). Note that for purposes of subsequent analyses, we
combined patients with a normal karyotype with patients with
insufficient metaphases for analysis. There were 5, 1, 1, and 3 patients with insufficient metaphase in the FAI, FAI + G, FAI + ATRA,
and FAI +ATRA + G arms, respectively, constituting 9%, 2%, 2%, and
6% of the patients in these arms. We have combined the normal
karyotype and insufficient metaphase groups because our previous
experience suggests that the prognosis of the latter group most
resembles that of patients with a normal karyotype.26 Only
12% of the patients had Zubrod performance status 3 or 4, but 16%
were treated as emergencies, primarily, but not exclusively, because of
a high WBC count (>50,000/µL). A total of 65% of the patients were
admitted to the PE. Table 1 compares the
distribution of these and other pretreatment characteristics in the
four different groups, showing that there were no significant imbalances for any of these covariates, with the exception that patients given FAI + ATRA were less likely to have secondary AML/MDS.
In view of the patients' pretreatment characteristics, overall results
were poor. The CR rate was 51% (110 of 215) with a median actuarial
EFS duration of 36 weeks (95% confidence interval [CI], 27 to 47 weeks) from CR date. Events have occurred in 166 of the 215 patients
(77%), with 105 patients failing to achieve CR, 55 having disease
recurrence, and six dying in CR. Recalling that the study aimed for a
6-month EFS rate of .56, the probability of EFS at 6 months is
currently .39 (95% CI, .33 to .47). Figure 1 illustrates that the actuarial median survival time is currently only
28 weeks (95% CI, 21 to 37 weeks) and that approximately 85% of the
patients are projected to be dead within 2 years. Median follow-up time
in 75 of the 215 patients who are currently alive is 35 weeks (range,
up to 108 weeks).
Within this context, there was some initial evidence for a beneficial
effect of G-CSF and, particularly, ATRA. The CR rates in the four arms
were: FAI, 21 of 53, 40%; FAI + G-CSF ("FAI + G"), 29 of 53, 55%; FAI + ATRA, 28 of 55, 51%; and FAI + ATRA + G, 32 of 54, 59%,
with the P value equal to .087 for the 2×2 comparison of
treatment with and without G-CSF. More interestingly, log rank tests
comparing survival with FAI to survival with each of the other three
treatment arms gave the following P values: FAI versus FAI + G
P = .15, FAI versus FAI + ATRA P = .023, and FAI versus
FAI + ATRA +G P = .055, thus suggesting a beneficial effect of
ATRA on survival without any added benefit from G-CSF. Figure 2 depicts Kaplan-Meier plots for the
four treatment groups. It should be noted that only one of 36 patients
who survived, but failed to achieve CR on one of the four study arms,
achieved a subsequent CR. Hence, the survival data are largely a
function of response to initial treatment. Intertreatment comparisons
of EFS from start of therapy gave analogous results: FAI versus FAI + G
P = .32, versus FAI + ATRA P = .053, versus FAI + G + ATRA P = .095. In the best arm, FAI + ATRA, the current
probability of EFS at 6 months is .52 (95% CI, .40 to .67). There was
no significant difference between FAI and any of the other three arms
with respect to EFS once in CR, with P values .95, .43, and .48 for tests of FAI versus FAI + G, FAI + ATRA, and FAI + ATRA + G,
respectively. Given this and given that there appeared to be no effect
of ATRA on CR rate, any survival advantage due to ATRA appeared to
result from an effect in patients not achieving CR.
Because, in general, there were no statistically significant
differences between the four treatment arms in the distribution of the
prognostic factors illustrated in Table 1, it appeared plausible that
the apparent beneficial effect of ATRA and/or G-CSF might remain after
accounting for these factors in Cox and logistic regressions.
Table 2 summarizes the multivariate Cox
model for survival. After accounting for the covariates indicated in
the Table 2, there was no evidence that any of the three
adjuvant treatment combinations FAI + G, FAI + ATRA, or FAI + ATRA + G prolonged survival compared with FAI. Additional tests
evaluating the effects of G-CSF ignoring ATRA (ie, G-CSF ± ATRA),
and of ATRA ignoring G-CSF (ATRA ± G-CSF) were also insignificant,
with all P values .28. Several points should be noted about
the model summarized in Table 2. In particular, patients regarded as
emergencies did worse than other patients even after accounting for
performance status, which did, and white cell count, which did not,
enter the model in Table 2. In contrast, survival was unaffected by whether patients had failed to respond to a previous course of outside
treatment (P = .85) or, as previously, by whether they had RAEB
or RAEB-t rather than AML (P = .54). Although it appeared that
whether patients had failed one prior course of outside treatment or,
rather, were previously untreated was prognostically insignificant, we
repeated the analysis excluding the previously treated patients. Again
there was no suggestion that ATRA ± G-CSF or G-CSF ± ATRA affected survival. The presence of secondary AML or MDS, which was
least frequent in patients given FAI + ATRA (Table 1) had no affect on
survival (P = .37). Finally, there was no evidence for an
interaction between ATRA ± G-CSF and cytogenetics (P = .52 for -5/ 7, P = .33 for other poor prognosis cytogenetics), diagnosis of RAEB or RAEB-t rather than AML (P = .49) or WBC
(P = .31). That is, there was nothing to suggest that the
effect of ATRA was different in patients with -5/-7, other cytogenetic abnormalities, a high WBC count, or MDS compared with other patients. The failure to find an interaction between ATRA and WBC count (considered either continuously or dichotomized above and below 10,000/µL) indicates that ATRA schedule had no effect on survival. The multivariate model for EFS from start of treatment was similar to
the survival model shown in Table 2 regardless of (1) whether events
were considered as death or relapse or, rather, as death, relapse, or
failure to achieve CR due to resistant disease, and (2) whether the
previously treated patients were excluded. In particular, there was no
effect of ATRA +/ G-CSF, or G-CSF +/ ATRA, and there was
no interaction between G-CSF and ATRA.
The beneficial effect of G-CSF +/ ATRA on CR rate suggested by
the preliminary analysis noted two paragraphs above was confirmed by a
logistic regression analysis (Table 3). The
P value testing the effect of G-CSF ± ATRA versus no G-CSF
was .018. ATRA +/ G-CSF was not predictive of CR (P = .264). Again, conclusions were unaffected by exclusion of previously
treated patients. Time required from start of treatment to reach a
neutrophil count of >1,000/µL was significantly less in the two
arms with G-CSF (P < .001, medians of 24 v 29 days,
considering patients requiring one course to achieve CR, such patients
constituting 94% of the CRs). ATRA had no effect on this outcome, and
neither G-CSF nor ATRA affected time to reach a platelet count
>100,000/µL. Perhaps the most quantifiable measure of a regimen's
toxicity is the early death rate associated with the regimen. There
were nine deaths in the first 2 weeks of therapy among 109 patients
receiving FAI + ATRA or FAI + ATRA + G versus a rate of 3 of 106 among
patients receiving FAI or FAI + G. The P value for this
comparison is .084 and must be interpreted in light of data indicating
that the difference in death rate between the arms with and without
ATRA was less considering deaths occurring in week 1 (5 of 109 v 3 of 106), weeks 1 to 3 (16 of 109 v 10 of 106), or
weeks 1 to 4 (22 of 109 v 18 of 106). These data suggest that
there was no difference in the early death rate between the arms with
and without ATRA. The early death rate was essentially equivalent on
FAI + ATRA and FAI + ATRA + G and was similarly equivalent on FAI and
FAI + G. The rate of major infection (pneumonia or documented fungal infection) was similar on all four arms, with these infections occurring in 38% of all patients. Other toxicity was infrequent and
again similar on all arms. ATRA syndrome was not observed. Nor did the
addition of ATRA result in cutaneous or hepatic toxicities or in
leukocytosis. This may reflect the short duration of ATRA exposure, and
in the case of leukocytosis, the administration of chemotherapy 2 days
after starting ATRA in patients presenting with WBC counts
<10,000/µL, and simultaneously with chemotherapy in patients
presenting with higher WBC counts and during postremission therapy.
Finally, Cox regression confirmed that all four treatments were
statistically equivalent with respect to EFS once in CR. P
values for treatments, each compared with FAI, were as follows: ATRA
+/ G-CSF, .18; G-CSF +/ ATRA, .40; ATRA without G-CSF, .59; G-CSF without ATRA, .99; and ATRA + G-CSF, .37. Again, results were substantively the same regardless of whether the previously treated patients were excluded.
| |
DISCUSSION |
The principal conclusion of this study is that the addition of ATRA
+/ G-CSF to FAI did not affect survival (Table 2), EFS either
from start of treatment or from CR date, or CR rate (Table 3) in poor
prognosis newly diagnosed AML, RAEB, or RAEB-t. Although addition of
G-CSF +/ ATRA to the same chemotherapy improved the CR rate
compared with FAI ± ATRA without G-CSF (P = .018 on
multivariate analysis), it had no effect on the other measures of outcome.
It is a truism that the inferences drawn from a study depend on the
methods used to analyze the data. This is certainly the case here. In
particular, before accounting for other relevant covariates, evidence
suggested that ATRA +/ G-CSF improved survival (P < .05, and Fig 2). Yet, despite the balanced randomization and the
seemingly even distribution of covariates in the four treatment arms
(Table 1, all P values > .1 with the exception of secondary
AML/MDS, which was not prognostically significant), the conclusion of
the study was otherwise. The reason for this is that data summaries
such as Table 1 are only one-dimensional representations of a
multidimensional phenomenon. The point is that, unless a randomized
study is very large, perfect covariate balance between the treatment
arms is rarely achieved and cannot be assumed, even if P values
are > .1 for the test of the hypothesis that there is balance with
respect to covariates examined individually. Thus, our study
illustrates the need to account for nontreatment-related covariates via
multivariate analysis in randomized studies.
Our results with G-CSF are reminiscent of those of Dombret et
al,27 who also found in a group of elderly patients with a high prevalence of unfavorable cytogenetic abnormalities, that G-CSF improved CR rate without affecting early mortality.
Although this might suggest that G-CSF increases sensitivity to
chemotherapy, this suggestion is difficult to reconcile with the
failure of G-CSF to prolong disease-free survival in either study. One
explanation for this apparent paradox is that G-CSF increases
neutrophil numbers in the marrow, thereby lowering blast percent, but
not the absolute number of blasts. Thus, some of the remissions seen in
the G-CSF cohort are cosmetic only. Furthermore, there are studies in
elderly patients in which G-CSF was given only after completion of
chemotherapy28-29 (as in the Dombret et al study) or in
which G-CSF was additionally given before and during
chemotherapy30 (as in the current study) that found no
effect on CR rate, although in two of these,28-29 there was
some reduction in days in hospital or antibiotic use. Our view is that,
given the failure to show beneficial effects on disease-free survival
or survival, a sufficient number of trials devoted to G-CSF
administration during induction therapy have been completed, and that
patient resources might be more profitably invested in clinical trials
examining other issues.
For the reasons given at the beginning of this report, the most
interesting part of this trial to us was the use of ATRA in non-APL AML
and RAEB/RAEB-t. Because we are unaware of any other trials combining
similarly myelosuppressive chemotherapy with ATRA in these diseases, we
are particularly eager to avoid a falsely negative conclusion about
ATRA. As discussed in Materials and Methods, we believe that we treated
enough patients to detect a medically beneficial effect had one
existed. When we presented results of this study at the 1997 American
Society of Hematology (ASH) meeting,31
multivariate analysis indicated that ATRA +/ G-CSF improved
survival and disease-free survival from start of treatment. Between
then and the writing of this report, another 24 events have occurred,
representing a 17% increase. It could be argued the occurrence of
still more events might alter our conclusions. However, events have
occurred in 77% of patients, and there are, perhaps unfortunately, no
conventions as to when to report results. Lastly, the population we
treated was dominated by poor prognostic features and thus not
completely representative of AML, the chemotherapy we gave was not
"standard", and other schedules of ATRA could have been tested,
eg, one in which ATRA began only after completion of chemotherapy.
Thus, we emphasize that our results should not be generalized to AML
patients having better prognostic features than those of the patients
in our trial. Given the results of our study, it seems advisable that
subsequent studies of ATRA be designed with careful consideration of
these issues.
| |
FOOTNOTES |
Submitted August 7, 1998; accepted December 1, 1998.
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 Elihu H. Estey, MD, Department of Leukemia,
Box 61, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: eestey{at}odin.mdacc.tmc.edu.
| |
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ABSTRACT
INTRODUCTION
