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Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 150-156 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.016 Pilot Study of Idarubicin-Based Intensive-Timing Induction Therapy for Children With Previously Untreated Acute Myeloid Leukemia: Children's Cancer Group Study 2941From the Children's Hospital of Philadelphia, Philadelphia, PA; Food and Drug Administration; Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Mayo Clinic, Rochester, MN; Izaak W. Killam Hospital for Children; University of California Los Angeles School of Medicine; Children's Hospital of Los Angeles, Los Angeles; Children's Hospital of Oakland, Oakland; Children’s Oncology Group, Arcadia, CA; and Children's National Medical Center, Washington, DC. Address reprint requests to Shaun Mason, Children's Oncology Group, PO Box 60012, Arcadia, CA 91066-6012; e-mail: smason{at}childrensoncologygroup.org
PURPOSE: Randomized comparisons of idarubicin (IDA) with daunorubicin (DNR) show that in adults with acute myeloid leukemia (AML), IDA achieves higher remission rates and longer remission durations. In Children's Cancer Group Pilot Study CCG-2941, we assessed toxicity and feasibility of substituting 4 mg of DNR with 1 mg of IDA in intensive-timing daunorubicin-based induction therapy (DNR/DNR) used in CCG-2891. PATIENTS AND METHODS: On days 1 through 3 and 10 through 14, patients received two courses of dexamethasone, cytarabine, 6-thioguanine, etoposide, and IDA (IDA/IDA). After enrollment of 65 patients, toxicity prompted replacement of IDA with DNR (IDA/DNR) on days 10 through 14 for the remaining 28 patients. Outcomes were compared with those of intensive timing in CCG-2891. RESULTS: Treatment-related mortality after two courses of induction was not significantly different among the three regimens: 14% with IDA/IDA, 7% with IDA/DNR, and 9% with DNR/DNR. In course 1 of CCG-2941 IDA/IDA, 11% of patients withdrew compared with 1.5% in CCG-2891 (P < .001) and 5% in CCG-2941 IDA/DNR (P = not significant). Compared with CCG-2891 DNR/DRN, CCG-2941 IDA/IDA increased days in hospital (43 v 36 days; P = .007), mean duration of course 1 by a week (P = .002), and risk of grade 3 or 4 hyperbilirubinemia (18% v 5%; P = .02). Toxicity of IDA/DNR was not different from that of DNR/DNR in CCG-2891. The mean day 7 marrow blast percentage was 11.4% in CCG-2941 versus 21.1% in CCG-2891 (P = .004). Remission induction, survival, and event-free survival rates were not significantly different from those of CCG-2891. CONCLUSION: In CCG-2941, excessive toxicity and withdrawals outweighed potential benefits of early response with IDA.
Induction therapy with cytarabine and daunorubicin (DNR), with or without other agents such as 6-thioguanine (6-TG) or etoposide, are the essential components of induction therapy for acute myeloid leukemia (AML) in young patients [1-4]. In the early 1990s, four studies showed that in young adults with AML, idarubicin (IDA) was a more effective anthracycline than DNR for remission induction: IDA increased the remission induction rate and prolonged remission duration without significant increases in toxic mortality [5-8]. In these studies based on the 7 days of cytarabine and 3 days of anthracycline, 3 days of DNR were compared with 3 days of IDA in dose ratios of 3.5 to 4.2 mg of DNR to 1 mg of IDA. Subsequently, the Medical Research Council's meta-analysis of eight randomized comparisons of IDA with DNR confirmed the superiority of IDA [9]. The relative efficacy of IDA compared with DNR in adults prompted the Children's Cancer Group (CCG) to introduce IDA into the intensive-timing paradigm successfully used in the CCG-2891 study [10,11]. In that study, a dose-intensified schedule of the five-drug combination of dexamethasone, etoposide, cytarabine, 6-thioguanine, and daunorubicin (DCTER) effected a significantly higher event-free survival (EFS) and survival than a standard schedule of induction therapy, despite a 12% induction mortality with intensive DCTER compared with 4% with standard timing [10,11]. CCG-2941 was a pilot study to assess feasibility of substitution of 4 mg of DNR with 1 mg of IDA in the DCTER regimen. After two courses containing four cycles of intensive induction, patients with matched related donors were assigned to bone marrow transplantation; all others were assigned to high-dose cytarabine-based (Capizzi II) chemotherapy intensification [12]. Three months of relatively low-dose continuation therapy in CCG-2891 were eliminated in the CCG-2941 study, because randomized trials of the CCG-213 and the Leucamie Aique Myeloide Enfant 89/91 trials showed that low-dose continuation therapy actually reduced survival [13,14]. After chemotherapy intensification, patients on CCG-2941 were eligible to enter a phase II feasibility study of interleukin-2 (IL-2) in the setting of minimal residual disease as described previously [15,16]. This report describes 93 patients treated with IDA-based therapy, of whom 65 received IDA as the only anthracycline (IDA/IDA) and 28 received hybrid IDA/DNR therapy after the protocol was amended. Results are compared with DNR/DNR in the CCG-2891 intensive-timing DCTER regimen.
Patients from birth through 20 years of age with untreated AML or myelodysplastic syndrome were eligible for registration after institutional review board approval and parental signing of written informed consent as stipulated by the Declaration of Helsinki. Patients with Down's syndrome, Fanconi anemia, acute promyelocytic leukemia, acute undifferentiated leukemia, or treatment-related AML were not eligible. AML and MDS were classified according to French-American-British (FAB) criteria [17-21]. Morphology and histochemistry were centrally reviewed in 94% of patients as previously described [10,22].
Treatment Plan
CR consisted of trilineage recovery of hematopoiesis with an absolute neutrophil count of greater than 1,000 x 109/L and platelets greater than 100,000 µL and  5% blasts in the marrow. PR or M2 marrow status was greater than 5% but less than 30% blasts in the marrow; hematopoietic recovery was not required after course 1. Withdrawals included patients who prematurely discontinued protocol therapy because of toxicity, patient, parent or physician preference, major error in drug dosage or delivery, or introduction of nonprotocol therapy. Other outcome measures included the day 14 marrow blast percentages, induction rate after one and two courses of induction, early response as measured by percentage of blasts in marrow aspirate on day 7, EFS, and survival. EFS was defined as the time from study enrollment to induction failure, relapse, or death. Disease-free survival (DFS) was defined as the time from induction-achieved remission to relapse or death owing to progressive disease. Additionally, grade 3 and 4 toxicity duration of phase and total days in the hospital were evaluated.
Statistical Methods The protocol contained provisions for closure or amendment at the discretion of CCG Operations. After 65 patients had completed therapy, it was appreciated that the number of withdrawals was more than seven times higher than in the previous CCG-2891 intensive-timing regimen. The protocol was amended to replace IDA with DNR in the second cycle of the two induction courses.
This report summarizes analyses of data collected in CCG-2941 through March 21, 2002. Outcomes and toxicities were compared for the 65 CCG-2941 patients who received IDA/IDA, 28 CCG-2941 patients who received hybrid IDA/DNR, and CCG-2891 patients who received intensive-timing DNR/DNR, roughly half of whom received G-CSF. The significance of observed differences in proportions was tested using the
CCG-2941 opened on January 30, 1995, and closed on February 29, 1996. Ninety-six patients enrolled. Three patients were later deemed ineligible because of diagnoses: Down's mosaicism in one patient, acute promyelocytic leukemia in one patient, and reclassification as non-Hodgkin's lymphoma in one patient. The 93 patients who were assessable for outcomes and toxicity form the basis of the remainder of this analysis. Table 1 lists their presenting characteristics. The demographic and disease characteristics of eligible patients was similar to previous CCG AML studies, except for the exclusion of patients with Down's syndrome.
In the two CCG-2941 regimens, eight patients (9%) withdrew before outcome after the first course of therapy could be assessed. Among 85 patients whose outcomes were known, the CR rate after one course of therapy was 77.7%, the PR rate was 3.5%, the percentage of patients who had no remission was 9.4%, and the rate of death was 9.4% (Table 2). Three patients with less than 5% blasts at the end of course 1 withdrew primarily because of delays in count recovery. Two patients with M2 marrows were brought into remission by the second course. Sixty-nine patients proceeded to the second course of therapy: 90.5% achieved or continued in remission, 4.8% experienced relapse or did not achieve a CR, and 4.8% died. Six patients withdrew before outcome could be determined.
Fifty-seven patients proceeded to consolidation. Fourteen underwent matched related donor transplantation and 43 received chemotherapy, of whom 21 elected to receive IL-2 and 22 chose standard follow-up. Figure 2 shows EFS and Figure 3 shows survival of CCG-2891 intensive timing and the two regimens in CCG-2941. At 4 years, EFS in CCG-2941 is 36% ± 5% and survival is 46% ± 5%. There were no significant differences in estimates of survival at 4 years between the IDA/IDA and IDA/DNR regimens: mean survival was 46% ± 6% standard deviation versus 44% ± 10% (P = .937), respectively; EFS was 36% ± 6% versus 37% ± 10% (P = .992), respectively. There were no significant differences in 3-year estimates of outcomes between bone marrow transplantation and chemotherapy regimens in CCG-2941: survival was 63% ± 13% in patients who underwent bone marrow transplantation versus 69% ± 7% in those who had chemotherapy (P = .142); DFS was 46% ± 14% versus 53% ± 8% (P = .704), respectively. There were no significant differences in 3-year estimates between those who received IL-2 and follow-up from the end of consolidation: survival was 70% ± 10% for IL-2 versus 75% ± 10% for follow-up (P = .645); DFS was 46% ± 11% versus 60% ± 11% (P = .614), respectively. These outcomes are similar to those in CCG-2891.
Table 2 compares the remission induction outcomes for the first course of intensive DCTER in CCG-2891 and the two regimens used in CCG-2941. There were no significant differences in CR, PR, treatment failure, or death rates among the three regimens. In CCG-2941, there were 13 treatment-related deaths. Nine deaths were from infection, one was from hemorrhage, one was from hepatotoxicity, and two were from other causes. There was, however, a significant difference in early response: in CCG-2941, the mean percentage of blasts on day 7 ± 2 was 11.4% compared with 21.1% (P = .004) in CCG-2891, and the respective medians were 4% and 8% (P = .006). A significantly greater number of patients withdrew from the IDA/IDA regimen in CCG-2941 compared with CCG-2891 (Table 2). In CCG-2941, there were no differences in 4-year estimates of outcome from on-study between those who withdrew and those who remained on study: survival was 42% ± 14% for the withdrawn versus 46% ± 6% for those who remained on study (P = .920); EFS was 42% ± 14% versus 35% ± 6% (P = .400), respectively. Table 3 lists the reasons for withdrawal.
Table 4 addresses the relative toxicity and resource use of CCG-2891 induction compared with that of the two regimens in CCG-2941. Increasing IDA caused a significant increase in the duration of the phase and number of days in the hospital, both of which were indirectly related to hematopoietic toxicity and infection. Grade 3 or 4 hyperbilirubinemia occurred in 18% of patients who received IDA/IDA compared with 9% in IDA/DNR patients (P = .30) and 5% in DNR/DNR patients (P = .02).
Although the literature suggests that IDA is a more effective remission-induction agent than the standard DNR, in this study its potential benefits were nullified by excess toxicity and withdrawals. Previous studies in adults with AML showed that except for a possible increase in hepatotoxicity with IDA, 4 mg of DNR and 1 mg of IDA were equitoxic [5-8]. However, in CCG-2941, duration of induction phase and duration of hospitalization were significantly longer with IDA/IDA than with DNR/DNR used in CCG-2891. Duration of induction is an indirect measure of hematopoietic toxicity and of infectious complications, suggesting that in this schedule, 1 mg of IDA and 4 mg of DNR were not equitoxic. As observed in previous studies in adults with AML, hepatic toxicity was also greater with IDA than with DNR [5-8]. Compared with the first 4-day cycle of DNR/DNR, the first cycle of IDA/IDA significantly reduced the mean and median percentage of blasts on day 7. However, this did not translate into an overall improvement in remission rate or duration, as it did in studies in adults. The risk-stratified AML Berlin-Frankfurt-Münster (AML-BFM) 93 study compared 5 mg of DNR with 1 mg of IDA [27]. Hematopoietic toxicity was similar in the IDA and DNR arms, but the number of patients with less than 5% blasts on day 15 was significantly higher in the IDA regimen, a finding consistent with those of this study. By reducing the number of slow early responders, substitution of IDA seemed to increase the pool of standard-risk patients. However, the standard-risk group, defined as those with FAB M1/M2 morphology with Auer rods or FAB M3 or M4eo and less than 5% blasts on day 15 marrow, showed no improvement in outcome compared with historical controls. Toxicity was similar in the IDA and DNR groups. This AML-BFM 93 study also experienced a substantial number of withdrawals (26%), primarily for randomization refusals. Withdrawal outcomes were similar to those of the patients who remained on study, but their impact on the whole study could not be assessed because they were not included in the primary analysis [27]. Likewise, in CCG-2941, outcomes of patients who withdrew were not significantly different from those who remained in the study, but neither study was powered to assess this variable. At the time of designing CCG-2941, no one appreciated withdrawal as an important arbiter of feasibility. However, after two-thirds of planned accrual, it became clear that the observed rate of withdrawal was a feasibility-limiting problem for the planned phase III trial involving two randomizations to chemotherapy plus the biologic randomization to matched related donor transplantation or none. Typically there is roughly 15% to 20% withdrawal for delayed randomizations. A phase III trial in which potentially over half the patients would withdraw was viewed as unacceptable. The Australian Pediatric AML Group has examined the impact of IDA on outcome in a series of studies in which all patients underwent autologous or allogeneic marrow transplantation after induction and consolidation. In this study, toxicity was also similar in the IDA and DNR groups. The investigators concluded that they could not measure a significant impact of IDA on outcome [28]. The relatively greater toxicity of IDA compared with DNR in CCG-2941 compared with the other two large pediatric trials probably derives from interactions of dose, schedule, and pharmacology of IDA in pediatric patients. CCG studies of bioavailability of IDA in children with relapsed ALL showed substantial interpatient variation in duration of the active alcohol metabolite and significant differences between children and adults [29]. In some cases, pediatric patients experienced potentially toxic doses of the idarubicin metabolite 10 or more days after the last dose of IDA [29]. Given in the dose-intensified schedule in CCG-2941, it is possible that some children in this study experienced exposure to active drug for weeks after the first dose was given. Prolonged exposure may have led to long intervals between courses, a high treatment-related mortality, and an unprecedented rate of withdrawal compared with CCG-2891. Nonetheless, IDA remains an agent of interest. The day 7 marrow blast percentage in CCG-2941 and day 15 marrow in AML-BFM 93 show that IDA effects a rapid early response in more patients than DNR. When DNR replaced IDA in the second cycle 2 of each induction course in CCG-1941, toxicity approximated that of DNR/DNR in CCG-2891. Hence, IDA/DNR will undergo further investigation in CCG.
The authors indicated no potential conflicts of interest.
We thank Christine Curran for typing the manuscript and Shaun Mason for editorial support.
The work was supported by the following institutional grants from the National Institutions of Health. B.J.L.'s contributions were supported by the Yetta Dietch Novotny Chair in Clinical Oncology. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10,000 µL, which was later reduced to 
2 test and Fisher's exact test when data were sparse. The Kaplan-Meier method [
