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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Leukemia and Biostatistics, The
University of Texas M. D. Anderson Cancer Center, Houston, TX.
It has been unclear whether regimens containing topotecan + ara-C (TA) or fludarabine + ara-C (FA) ± idarubicin are
superior to regimens containing idarubicin + ara-C (IA) without
either fludarabine or topotecan for treatment of newly diagnosed acute myeloid leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t), or RAEB. Of 1279 patients treated here for
these diagnoses between 1991 and 1999, 322 received IA regimens, 600 FA
regimens, and 357 TA regimens. All regimens used ara-C doses of 1 to 2 gm/m2/d, given by continuous infusion in IA, and over 2 to
4 hours in FA and TA. Complete remission (CR) rates were lower with FA (55%) and TA (59%) than with IA (77%). Both event-free survival (EFS) in CR and survival were shorter: median EFS in CR (95%
confidence interval) was 63 weeks (range, 55-76 weeks) for IA, 40 (range, 31-46 weeks) for FA, and 36 (range, 27-44 weeks) for TA; median survival was 77 weeks (range, 57-88 weeks) for IA, 30 (range, 27-35 weeks) for FA, and 41 (range, 35-50 weeks) for TA. These trials were
not randomized, and patients with worse prognoses were
disproportionately given the FA and TA regimens. Nonetheless, after
accounting for prognosis the FA and TA regimens remained highly
significantly associated with lower CR rates, shorter EFS in CR, and
shorter survival. Accounting for possible effects of individual trials
within each of the IA, FA, and TA groups did not alter these findings.
It is unlikely that, as given here, either FA or TA is, in general,
superior to IA, highlighting the need for new treatments.
(Blood. 2001;98:3575-3583) Over the past decade our group has emphasized the
development of regimens containing fludarabine or topotecan combined
with ara-C for treatment of newly diagnosed acute myeloid leukemia (AML), or those myelodysplastic syndromes (refractory anemia with excess blasts in transformation [RAEB-t], and in certain cases, RAEB), which are prognostically similar to AML.1
Fludarabine + ara-C (FA) was first investigated in 1991. In 1992, granulocyte colony-stimulating factor (G-CSF) was added to the FA
combination to form FLAG, and subsequently idarubicin was combined with
FA and given with or without G-CSF and/or all-trans retinoic
acid (ATRA). After its original use in 1997, topotecan + ara-C
(TA) was given together with cyclophosphamide + G-CSF (CAT). At
least partly as a result of reports of these trials,2-4
FA, FLAG, FLAG + idarubicin, and TA have found widespread use.
Thus, it appeared appropriate to compare the FA- and TA-containing
regimens with regimens containing idarubicin + ara-C (IA), but not
fludarabine or topotecan. During the years we were investigating fludarabine and topotecan, we also gave such IA regimens to patients with newly diagnosed AML, RAEB-t, or RAEB, with IA being given ± G-CSF, lisofylline, or ATRA. The IA regimens were not
"3 + 7"-type regimens but rather used daily ara-C doses of 1.5 gm/m2, as described below. Although the trials involving
IA, FA, and TA were not randomized studies, over the last decade, each
trial included adults of all ages, cytogenetic groups, and so forth, making it feasible to undertake comparisons. Here we report the results
of these comparisons.
We will consider all the fludarabine-containing regimens as "FA,"
all the topotecan-containing regimens as "TA," and all the IA
regimens, without fludarabine or topotecan, as "IA." Regression analyses will use the IA treatment group as the baseline, so that FA
and TA effects are defined relative to IA. Extended Cox model regression analyses of the FA and TA effects on survival and event-free survival (EFS), and logistic regression analyses of the FA and TA
effects on the probability of complete remission (CR), each will
account for patient prognostic covariates, including cytogenetic abnormalities, age, and performance status. Subsequently, these regression models will be expanded to include "trial effects," that
is, variations in outcome among each of the regimens comprising FA (FA,
FLAG, FLAG + idarubicin, etc), TA (TA, CAT), or IA (IA, IA + G-CSF, etc), in order to account for these trial effects while
evaluating the FA and TA effects. Similarly, because these trials were
conducted over a 9-year period, we also adjust for calendar year in
which treatment began in order to assess whether any apparent treatment
effects merely reflected changes over time in supportive care or in
patient characteristics that could not be captured by descriptions of
age, cytogenetics, etc. Part of this work was presented at the 2000 American Society of Hematology meeting.5
Patients
Assignment to treatment
Given that the IA, FA, and TA trials were open to patients regardless
of age, regardless of whether they had myelodysplasia (MDS) or AML, and
regardless of a documented history of abnormal blood counts for 1 month
or more before M. D. Anderson presentation (antecedent hematologic
disorder [AHD]), less than 10% of the 1279 patients included
in this report had inv(16) or t(8;21), whereas 54% were considered to
have worse prognosis cytogenetics [all abnormalities except inv(16) or
t(8;21)] for purposes of assignment to treatment (Table
2). Because, in some periods covered by
this report, patients were preferentially assigned to the IA regimens
if their cytogenetics were prognostically "better" (preceding paragraph), the IA group more often had a normal karyotype, or an
inv(16) or t(8;21) and was younger than the FA or TA groups. The IA
group also had a lower incidence of MDS or AHD. Similarly, because
patients with MDS were preferentially assigned to TA in the 1997-1998 period, proportionately more patients with RAEB or RAEB-t received
regimens containing TA (TA and CAT).
Descriptions of the regimens The IA, FA, and TA regimens (Table 3) delivered approximately the same amount of ara-C: 1000 to 2000 mg/m2/d × 4 to 5 days, with the 4-day duration used when ara-C was combined with idarubicin. A possibly significant difference between the regimens was that ara-C was given by continuous infusion in the IA studies, but over 2 to 4 hours daily in the FA and TA trials. Idarubicin in the IA regimen, and when used together with FA, was given at 12 mg/m2 daily on days 1 to 3 (IA) and 2 to 4 (FA). Fludarabine was given at 30 mg/m2/d, with each dose given 4 hours prior to a dose of ara-C. The topotecan dose was 1.5 mg/m2/d × 5 days by continuous infusion. When combined with TA, cyclophosphamide was given at 300 mg/m2 every 12 hours on days 1 to 3. When given with the IA, FA, or TA regimens, G-CSF at 200 to 400 µg/m2 was begun 1 day prior to chemotherapy and continued until the neutrophil count exceeded 1000/µL; if the presenting WBC count was more than 10 000/µL, G-CSF began 1 to 2 days after chemotherapy began. In both IA + G-CSF + ATRA and FAI + G-CSF + ATRA, the ATRA dose was 45 mg/m2/d, beginning 2 days prior to chemotherapy and continuing until response was known; if the presenting WBC count exceeded 10 000/µL, ATRA began on day 1 of chemotherapy. Lisofylline, a purported cytokine antagonist, had been reported to decrease complications of induction therapy10; it was given at 3 mg/kg every 6 hours for 28 days or until CR was observed, whichever came first.
Only 2% of the 789 patients entering CR after use of the regimens described in Table 3 received transplants in first CR (4% of the CRs obtained after IA, 1% of the CRs after FA, and 3% of the CRs after TA). Rather, post-CR therapy consisted of reduced doses of chemotherapy. With IA and FA, ara-C at 100 mg/m2 daily × 5 continuous infusion, alternated approximately every 5 weeks with reduced doses of the original regimen (Table 3). For IA, reduction entailed an idarubicin dose of 8 mg/m2 daily on days 1 to 2 and an ara-C dose of 1.5 gm/m2 daily × 2 days by continuous infusion. For FA, fludarabine was given at 30 mg/m2 and ara-C at 1 gm/m2 each day on days 1 to 3; when idarubicin was included (FAI-containing regimens), FA was administered on days 1 and 2, with idarubicin 8 mg/m2 administered on day 3. After CR with TA, patients received continuing cycles of TA at a topotecan dose of 1.25 mg/m2 daily by continuous infusion on days 1 to 3 and an ara-C dose of 1 gm/m2 daily on the same 3 days. After CR with CAT, patients alternated one course of IA, one course of FA, each as described above, and one course of CAT with a cyclophosphamide dose of 300 mg/m2 every 12 hours, days 1 to 3, an ara-C dose of 1 gm/m2 daily on days 1 and 2, and a topotecan dose of 1.25 mg/m2 daily by continuous infusion on days 1 to 3. The daily dose of each postremission regimen was decreased approximately 25% if duration of myelosuppression exceeded 5 weeks or if toxicity had ensued on the previous course. Therapy continued somewhat longer with the IA regimens (9-12 months of postremission therapy), than with the FA (6-12 months) or TA (6-9 months) regimens. Other practices Throughout the 9-year period covered by this report, patients aged 50 years or older received induction therapy in laminar air flow rooms (LAFRs) if these rooms were available; 72% of the 907 patients aged 50 years or older were treated in an LAFR. Patients remained in the LAFR until the neutrophil count was more than 500 to 1000/µL or until more than 42 days had elapsed from the start of treatment. From 1991 to 1995, infection prophylaxis consisted of trimethoprim/sulfamethoxazole and oral fluconazole; from 1995 on quinolones replaced trimethoprim/sulfamethoxazole, and oral itraconazole was added to fluconazole. Between 1991 and 1998, patients not in CR after a first course of induction therapy generally received a second course of the same therapy, changing to alternate therapy if CR, as conventionally defined, was not evident after course 2. Thus, 76% of patients not in CR after course 1 of an IA regimen and 72% of those not in CR after course 1 of an FA regimen received such a second course. By 1998, patients not in CR after course 1 were usually changed to alternative therapies. Thus, only 42% of patients not in CR after course 1 of TA or CAT received a second identical course. Criteria for starting a second course were 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, or the same picture in 2 consecutive marrows obtained after a marrow had shown decreased blasts or less than 20% cellularity as noted above. Relapse was defined by a marrow with more than 5% blasts unrelated to recovery from the previous course of chemotherapy. Marrow morphology was reviewed by a group of hematopathologists at M. D. Anderson.Statistical methods Unadjusted probabilities of survival and of EFS in CR were estimated, using the method of Kaplan and Meier.11 Unadjusted between-group comparisons of survival and of EFS were made using the log-rank test.12 The extended Cox proportional hazards regression model13,14 was used to assess the ability of patient characteristics or treatments to predict survival and EFS, with goodness-of-fit assessed by the Grambsch-Therneau test,15 Schoenfeld residual plots, Martingale residual plots, and likelihood ratio statistics. The extended Cox model allows the possibility that one or more treatment or covariate effects on the risk of the event (death in survival analysis; death or relapse in analysis of EFS) may vary over time, rather than taking on a single numerical value. Logistic regression16 was used to assess the ability of patient characteristics or treatments to predict the probability of CR, or of achieving CR in the first course of therapy, with goodness-of-fit assessed by residual and partial residual plots. All scatter plots were smoothed by using the lowness method of Cleveland,17 with predictive variables transformed as appropriate based on these plots. Multivariate logistic regression and extended Cox models were obtained by first performing a backward elimination with cutoff of P = .05, then allowing any variable previously deleted to enter the final model if its P value was < .05. Terms characterizing interactions between treatment and covariates were then added to the model and retained only if their P value was < .05. All computations were carried out on a DEC Alpha 2100 5/250 system computer (Digital Electronics Corporation, Nashua, NH) in Splus18 using standard Splus functions and the Splus survival analysis package of Therneau.19
CR rates Not surprisingly in view of their more favorable prognoses (Table 2), overall CR rates were higher in patients given one of the IA regimens (248 of 322, 77%) than in patients given either an FA regimen (330 of 600, 55%) or a TA regimen (211 of 357, 59%). However, the IA regimens were still superior after accounting for these prognostic variables via logistic regression. This finding is illustrated in Table 4, which lists the covariates that were significant predictors of the probability of CR in all 1279 patients. After accounting for the effects of patient prognostic variables, the null hypothesis that the FA regimens are equivalent to the IA regimens is rejected at P = .007; the corresponding P value for the TA regimens is < .001. As previously, after accounting for the covariates listed in Table 4, diagnosis (RAEB-t or RAEB rather than AML) was not predictive. Furthermore, after accounting for these covariates, there was no suggestion that there was an "interaction" between diagnosis and treatment such that the effect of FA or the effect of TA differed in patients with AML as opposed to MDS. Specifically, testing for an interaction between diagnosis and FA gave a P value of .67, whereas the analogous P value for TA was .59.
We observed that 92%, 91%, and 94% of the CRs with IA, FA, and TA, respectively, occurred on the first course of therapy. Among patients given a second course of their initial regimen, the CR rates were IA 20 of 39 (51%), FA 28 of 106 (26%), and TA 12 of 49 (24%), so that the superiority of IA in a second course was similar to that seen in the overall relative CR rates. However, as noted above, patients not in CR after an initial course of therapy were more likely to get a second course of their initial regimen if given an IA or FA regimen rather than a TA regimen. To account for the resultant possibility that there might be more CRs with TA if patients were equally likely to receive a second course of TA as of IA or FA, we repeated the logistic regression analysis with patients counted as CR only if CR was observed after course 1. The results were substantively the same; both FA (P = .06) and TA (P < .001) still had negative effects on the probability of achieving CR in one course after accounting for the prognostic covariates listed in Table 4. EFS in CR Among the 789 (62%) patients achieving CR, EFS (with an "event" defined as relapse or death in CR) was greatest in patients given the IA regimens (Figure 1). Covariates predictive of EFS (Table 5) were similar to those associated with CR. As for CR, the superior EFS with the IA regimens was not merely due to the more favorable constellation of covariates in IA-treated patients. In particular, after adjusting for significant prognostic variables, the relative risk (RR) of relapse or death with the TA regimens was 1.53 times that with the IA regimens (Table 5, e.426 = 1.53). The covariate-adjusted effect of FA was more complex in that it varied with time from CR (Table 5). Compared with IA, the RR of an event with FA was higher during the first year after CR, with a beneficial effect thereafter. After accounting for the covariates in Table 5, diagnosis (AML versus MDS) was not predictive of EFS.
Survival As might be expected given the effects of treatment on CR rate and EFS in CR, survival from start of treatment was shorter in both the FA and TA groups compared with the IA group (Figure 2). Table 6 summarizes the treatment and covariate effects in the fitted extended Cox model for survival. The unfavorable effects of both FA and TA relative to IA each varied over time from treatment, with both effects disappearing after 2 years. Additionally, the unfavorable effect of FA relative to IA was not seen in patients with inv(16) or t(8;21). Figure 3 illustrates the time-varying effect of FA compared with IA within each of 4 cytogenetic subgroups. Note the unfavorable effect in all groups but inv(16) or t(8;21). Figure 4 provides the analogous illustration of the TA effects, and this figure is simpler than Figure 3 because the TA effect does not change across the cytogenetic subgroups; rather TA is unfavorable relative to IA in all cytogenetic subgroups. The curvilinear patterns illustrated in the figures lead to the characterization of the effects of FA and TA as "quadratic" (Table 6). For each plot in Figures 3 and 4, the RR of death corresponding to IA is 1.0 (dotted line) because this is the baseline group, and each estimated RR (solid line) is accompanied by a 95% confidence band (dashed line). As shown by the 95% confidence bands, the RR of death was significantly higher with FA regimens than with IA regimens for at least 1 year in all patients except those with inv(16) or t(8;21) in which there was a lower RR with FA for approximately the first 20 weeks after start of treatment. The RR of death with FA compared with IA was greatest in patients with 5/7. The RR pattern was similar for
patients given the TA regimens, as it increased over time to a maximum
of 2.8 at approximately 38 weeks from start of therapy, subsequently
decreasing; by 78 weeks and thereafter it was similar to IA. After
adjustment for the prognostic covariates in Table 6, diagnosis (AML
versus MDS) had no effect on survival, nor was there any suggestion
that the effects of FA or TA on survival differed in AML as opposed to
MDS (P = .16 for FA and P = .99 for
TA).
Possible confounding factors Effects of individual trials. We next asked whether variations in outcomes between the trials collectively comprising the IA, FA, or TA treatment groups (Table 1) were sufficiently large to account for the unfavorable effects heretofore attributed to FA and TA. To assess whether the apparent effects of FA or TA were due to variation between trials, we distinguished the following trial groups: (1) the original IA trial; (2) the IA + G-CSF trial; (3) the IA + G-CSF + ATRA trial; (4) the 2-arm randomized trial of IA ± lisofylline, having previously published7 that these, the 2 arms of a randomized trial, produced similar CR, disease-free survival in CR, and survival; (5) a randomized 4-arm trial of FAI, FAI + G-CSF, FAI + ATRA, FAI + ATRA + G-CSF, with a previous publication8 indicating that each of these 4 regimens produced similar outcomes; (6) an FAI + G-CSF trial given outside the context of the randomized trial; (7) a trial of FA itself and a trial of FLAG, with a previous publication20 indicating these were similar; (8) the original TA trial; and (9) the trial of TA + CAT. We used the IA trial (trial 1 above) as the "baseline" trial in defining between-trial effects. After fitting this more detailed extended Cox model and then dropping nonsignificant individual trial effects via a backward elimination, the only individual trial effect that remained was that of the IA ± lisofylline trial (trial 4, negative trial effect P = .023), whereas the negative effects of the FA and TA regimens persisted. In particular, the inclusion in the model, described in Table 6, of the additional term for the lisofylline trial effect had a trivial effect on the numerical values of the parameter estimates, and the substantive conclusions regarding the FA and TA effects were unchanged. Treatment year. An alternative to adjusting for trial effects is to account for possible latent effects over time by including factors for the year in which each patient's treatment began. The regimens comprising the IA group were more often used in the early 1990s, whereas the FA and TA regimens were more often administered in the mid- and late-1990s, respectively. However, the IA, FA, and TA regimens were given in overlapping periods (Table 1; IA 1991-1997, FA 1991-1998, and TA 1997-1999). This fact made it possible to ascertain whether the treatment effects described above merely reflected an effect of the year in which treatment began. When separate terms for each of the calendar years 1991-1999 were added to the model summarized in Table 6, none of these terms provided significant additional information; the P values of the 9 tests for calendar year effects ranged from .13 to .96, suggesting that the effects of latent variables that may have changed over time were negligible. Therapies given after failure of IA, FA, or TA.
Might the longer survival in patients given an IA, rather than an FA or
a TA, regimen reflect the superiority of treatments given after
failure of IA, FA, or TA? Similar proportions of patients who
failed (relapse, or alive but no initial CR) IA, FA, or TA regimens
received an allogeneic transplant at failure: 7% of the 184 IA
failures, 6% of the 324 FA failures, and 5% of the 230 TA failures;
only one patient received an autologous transplant at failure. However,
a higher proportion of IA failures received an investigational
high-dose ara-C (
Non-model-based comparisons An important question is whether the conclusions from the model-based analyses described above are borne out by much simpler non-model-based comparisons within important patient subgroups. Figure 6 shows that IA appears superior in either younger or older patients. Very similar comparative patterns were found in subgroup analyses based on performance status (< 3 versus > 2), presence of an AHD, or diagnosis (AML versus MDS) (Figure 7). Figure 8 provides a similar comparison for the 4 cytogenetic groups considered here and illustrates longer survival with IA in patients with a normal karyotype and cytogenetic abnormalities other than5/7 or inv(16)/t(8;21). The longer survival with FA in
the inv(16)/t(8;21) group is based on a relatively small number of
patients (n = 47 IA, 14 FA). The slight inferiority of IA in the
5/7 group must be interpreted in light of the very poor survival
with all 3 regimens in this subgroup and the fact that, after
accounting for factors other than cytogenetics that affect prognosis,
IA was superior to FA and TA in this subset (Table 6,
Figures 3,4). Table 7 provides median
survival times for each of the 9 trials enumerated above, both overall
and within the subgroups for those aged younger than 60 years and 60 years or older. A similar survival breakdown by cytogenetic subgroup is
given in Table 8. These tables show that,
although there was substantial trial-to-trial variability in
survival when considering all 9 trials without regard to treatment, most of this variability was due to differences between the IA, TA, and
FA regimens. In particular, each of the 4 IA trials was associated with
a longer median survival than any of the 3 FA or 2 TA trials. Tables 7
and 8 also show that in both younger and older patients and in the
principal cytogenetic groups (normal and other abnormal) each IA
regimen outperformed each FA regimen and, in general, each TA
regimen.
The above data indicate that the various FA and TA regimens we
investigated may be inferior to our IA regimens, recalling again that
IA regimens are not equivalent to 3 + 7 regimens (Table 3). A
possible exception is that the FA regimens appear at least equivalent
to IA in patients with the best prognosis cytogenetics, ie, inv(16) or
t(8;21) (Figures 3,8), although this finding is based on a relatively
small number of patients. The limitations of our analysis must be
acknowledged. First, the IA, FA, and TA regimens were not studied
within the context of a randomized trial. Hence, it is possible that
outcomes were influenced by latent covariates that, although unknown,
were both unevenly distributed among the IA, FA, and TA groups (or
among the various IA, FA, and TA subgroups) and prognostically
important. The observation that patients in the IA ± lisofylline
trial had worse outcomes than patients in the other IA trials even
after accounting for known covariates such as age, cytogenetics, and so
forth, supports the existence of this possibility. In particular, our
previously published results indicate that, after accounting for
observed prognostic covariates, the IA Our statistical methodology has limitations in addition to those
inherent in the inability to account for latent covariates. In
particular, multivariate regression analyses may not take appropriate account of substantial differences in known covariates. The method "regresses" in the sense that there is an overall shrinkage of outlying results to some overall mean function. In addition, when treatment and prognosis are partially confounded, as here, treatment and prognosis share the differential load, thereby exaggerating treatment differences. To address the issue of exaggeration, we established prognostic categories of patients (eg, younger and older,
inv(16) or t(8;21), Another possible confounding factor is the somewhat longer duration of post-CR treatment in the IA group (Table 3). However, we are unaware of data indicating that differences, in the range of those noted in Table 3, in the duration of postremission therapy affect either EFS in CR or survival. Furthermore, the unfavorable effects of FA and TA on EFS in CR and survival were evident, while patients in each of the IA, FA, and TA groups were still receiving postremission therapy (Figures 3,4). A final confounder is that ara-C was administered solely by bolus (over 2-4 hours) in the FA and TA groups but solely by continuous infusion in the IA group (Table 2). Hence, the negative effects attributed to FA and TA may reflect a possible negative effect of receiving ara-C by bolus rather than by continuous infusion. There is little empirical evidence supporting this possibility. In a small randomized trial, Radomski et al22 reported a 24% CR rate in 24 children 15 days after beginning 2-CDA (9 mg/m2 daily × 5) + 500 mg/m2 ara-C over 2 hours daily × 5 versus a 64% rate in 25 children given 2-CDA + continuous infusion ara-C (500 mg/m2 daily × 5). In contrast, in similarly sized, sequential trials in adults with relapsed/refractory AML, we observed CR rates in 21 patients of 59 (36%) with fludarabine (30 mg/m2 daily × 5) + ara-C (1-3 g/m2) given as a short daily infusion (over 2-6 hours daily × 5) and in 5 patients of 21 (24%) with fludarabine (50 mg/m2 daily × 4) + continuous infusion ara-C (1.5 gm/m2 daily × 4)4 (E.H.E., unpublished observations, 2001). More specifically, in patients whose first CR duration exceeded 1 year, the bolus FA regimen gave a CR rate in 14 patients of 20 (70%) and the continuous FA regimen a CR rate in 3 patients of 6 (50%). In patients with shorter first CR durations, CR rates were 7 of 39 (18%) with bolus FA and 2 of 15 (13%) with continuous infusion FA. The TA regimens used here might be inferior to our IA regimens because neither TA nor CAT contained an anthracycline. In this context, it is interesting that, within the FA group, regimens combining idarubicin with FA were similar to the basic FA regimen. Although we lack convincing causal explanations for our findings, which cannot be viewed as definitive given the issues raised above, our results are of considerable clinical significance. As noted in the Introduction, TA- and FA-containing regimens, largely identical to those described here, are not uncommonly used outside the setting of a clinical trial, both in the United States and Europe. We hope that our data will lead to caution in the routine use of these regimens. Although it might fairly be debated whether FA and TA are truly inferior to IA, we believe that our data make it unlikely that these regimens, as used here, are in fact superior to IA, as used here. Nonetheless, the data also indicate that IA regimens themselves are not "good" in any absolute sense for the majority of patients. Hence, emphasis must be placed on investigating new regimens, optimally within the context of randomized clinical trials. These trials should as much as possible contain a "standard" treatment arm. Although inclusion of such a standard has been criticized as allowing patients to receive what may be a very poor therapy, our results highlight the lack of any a priori assurance that the new therapies (eg, FA or TA) will be superior to the standard. Furthermore, the future is likely to see increasing application of "adaptive randomization" designs23 in which, based on the accruing data, patients are more likely to be randomized to a therapy that appears to be performing well. These designs often have desirable statistical properties (eg, probabilities of correctly or incorrectly declaring therapies as useful) and thus serve both the scientific goal of identifying a promising therapy and the medical goal of maximizing the number of patients receiving that therapy.
We thank Angela Beasley for her expert secretarial assistance and Dr Donald Berry of the Department of Biostatistics at M. D. Anderson for helpful suggestions regarding data presentation.
Submitted February 12, 2001; accepted August 2, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Elihu H. Estey, Dept of Leukemia, Box 428, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: eestey{at}mdanderson.org.
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L. Ades, S. Boehrer, T. Prebet, O. Beyne-Rauzy, L. Legros, C. Ravoet, F. Dreyfus, A. Stamatoullas, M. Pierre Chaury, J. Delaunay, et al. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study Blood, April 23, 2009; 113(17): 3947 - 3952. [Abstract] [Full Text] [PDF]
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M. Yanada, G. Borthakur, F. Ravandi, C. Bueso-Ramos, H. Kantarjian, and E. Estey Kinetics of bone marrow blasts during induction and achievement of complete remission in acute myeloid leukemia Haematologica, August 1, 2008; 93(8): 1263 - 1265. [Full Text] [PDF]
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E. Atallah, J. Cortes, S. O'Brien, S. Pierce, M. B. Rios, E. Estey, M. Markman, M. Keating, E. J. Freireich, and H. Kantarjian Establishment of baseline toxicity expectations with standard frontline chemotherapy in acute myelogenous leukemia Blood, November 15, 2007; 110(10): 3547 - 3551. [Abstract] [Full Text] [PDF]
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S. M. Kornblau, D. E. Banker, D. Stirewalt, D. Shen, E. Lemker, S. Verstovsek, Z. Estrov, S. Faderl, J. Cortes, M. Beran, et al. Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 study Blood, April 1, 2007; 109(7): 2999 - 3006. [Abstract] [Full Text] [PDF]
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M. S. Tallman, D. G. Gilliland, and J. M. Rowe Drug therapy for acute myeloid leukemia Blood, August 15, 2005; 106(4): 1154 - 1163. [Abstract] [Full Text] [PDF]
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R. A. Mesa, D. Loegering, H. L. Powell, K. Flatten, S. J. H. Arlander, N. T. Dai, M. P. Heldebrant, B. T. Vroman, B. D. Smith, J. E. Karp, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine Blood, July 1, 2005; 106(1): 318 - 327. [Abstract] [Full Text] [PDF]
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M. S. Tallman New Strategies for the Treatment of Acute Myeloid Leukemia Including Antibodies and Other Novel Agents Hematology, January 1, 2005; 2005(1): 143 - 150. [Abstract] [Full Text] [PDF]
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E. H. Estey, P. F. Thall, X. Wang, S. Verstovsek, J. Cortes, and H. M. Kantarjian Effect of circulating blasts at time of complete remission on subsequent relapse-free survival time in newly diagnosed AML Blood, November 1, 2003; 102(9): 3097 - 3099. [Abstract] [Full Text] [PDF]
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F. J. Giles, H. M. Kantarjian, J. E. Cortes, G. Garcia-Manero, S. Verstovsek, S. Faderl, D. A. Thomas, A. Ferrajoli, S. O'Brien, J. K. Wathen, et al. Adaptive Randomized Study of Idarubicin and Cytarabine Versus Troxacitabine and Cytarabine Versus Troxacitabine and Idarubicin in Untreated Patients 50 Years or Older With Adverse Karyotype Acute Myeloid Leukemia J. Clin. Oncol., May 1, 2003; 21(9): 1722 - 1727. [Abstract] [Full Text] [PDF]
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F. J. Giles, S. Faderl, D. A. Thomas, J. E. Cortes, G. Garcia-Manero, D. Douer, A. M. Levine, C. A. Koller, S. S. Jeha, S. M. O'Brien, et al. Randomized Phase I/II Study of Troxacitabine Combined With Cytarabine, Idarubicin, or Topotecan in Patients With Refractory Myeloid Leukemias J. Clin. Oncol., March 15, 2003; 21(6): 1050 - 1056. [Abstract] [Full Text] [PDF]
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F. J. Giles, J. E. Cortes, D. A. Thomas, G. Garcia-Manero, S. Faderl, S. Jeha, R. L. De Jager, and H. M. Kantarjian Phase I and Pharmacokinetic Study of DX-8951f (Exatecan Mesylate), a Hexacyclic Camptothecin, on a Daily-Times-Five Schedule in Patients with Advanced Leukemia Clin. Cancer Res., July 1, 2002; 8(7): 2134 - 2141. [Abstract] [Full Text] [PDF]
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E. H. Estey, P. F. Thall, F. J. Giles, X.-M. Wang, J. E. Cortes, M. Beran, S. A. Pierce, D. A. Thomas, and H. M. Kantarjian Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinoside Blood, May 29, 2002; 99(12): 4343 - 4349. [Abstract] [Full Text] [PDF]
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F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian Acute Myeloid Leukemia Hematology, January 1, 2002; 2002(1): 73 - 110. [Abstract] [Full Text]
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P. L. Greenberg, N. S. Young, and N. Gattermann Myelodysplastic Syndromes Hematology, January 1, 2002; 2002(1): 136 - 161. [Abstract] [Full Text]
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Top
Abstract
Introduction
1gm/m2/dose)-containing regimen (47%
of IA failures, 24% of FA failures, and 28% of TA failures), with
these regimens being essentially equivalent
therapeutically.
