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Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. 2480-2489 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.5013 Double Induction Containing Either Two Courses or One Course of High-Dose Cytarabine Plus Mitoxantrone and Postremission Therapy by Either Autologous Stem-Cell Transplantation or by Prolonged Maintenance for Acute Myeloid Leukemia
From the Department of Medicine, Hematology and Oncology, the Department of Human Genetics, and the Department of Medical Informatics and Biomathematics, University of Muenster, Muenster; Department of Hematology and Oncology, University of Regensburg, Regensburg; Department of Hematology and Oncology, University of Heidelberg, Mannheim; Department of Hematology and Oncology, University of Cologne, Cologne; and Department of Hematology and Oncology, University of Berlin, Berlin; Department of Hematology and Oncology, St Johannes Hospital, Duisburg; Catholic Hospital, Hagen; and Evangelian Hospital, Hamm; Department of Hematology and Oncology, Municipal Medical Centre, Braunschweig, Braunschweig; Department of Internal Medicine III, University of Munich, Munich; and the Clinical Cooperative Group Acute Leukemias of the National Center for Environment and Health, Munich, Germany Address reprint requests to Thomas Büchner, MD, PhD, University of Muenster, Department of Medicine, Hematology/Oncology, Albert-Schweitzer-Str 33, 48129 Muenster, Germany; e-mail: buechnr{at}uni-muenster.de
PURPOSE: Intensification by high-dose cytarabine in postremission or induction therapy and prolonged maintenance are established strategies to improve the outcome in patients with acute myeloid leukemia (AML). Whether additional intensification can add to this effect has not yet been determined. PATIENTS AND METHODS: A total of 1,770 patients (age 16 to 85 years) with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation.
RESULTS: The complete remission rate in patients younger than 60 and CONCLUSION: The regimen of one course with standard-dose cytarabine and one course with high-dose cytarabine for induction, and prolonged maintenance for postremission chemotherapy in patients with AML is not improved by additional escalation in cytotoxic treatment.
Dose-response effects in both induction and postremission therapy have been reported from randomized multicenter trials. First, in postremission therapy, a prolonged monthly myelosuppressive maintenance after an induction-type consolidation produced a superior relapse-free survival (RFS) compared with consolidation and no maintenance.1 In a later trial, myelosuppressive maintenance also proved superior to one course of high-dose cytarabine/mitoxantrone instead of maintenance.2 The Cancer and Leukemia Group B compared postremission therapy with four courses of cytarabine 3 g/m2 for six single doses, 400 mg/m2 for five doses, or 100 mg/m2 for five doses, and found a dose dependency in the RFS and survival (SV) of patients younger than age 60.3 Similarly, in the remission induction therapy, a high-dose cytarabine combination improved the RFS versus that from a standard-dose combination.4,5 Introduced by the German Acute Myeloid Leukemia Cooperative Group, the strategy of double-induction also attempted an improvement in quality and duration of remission.6 A version incorporating one course of high-dose cytarabine and mitoxantrone (HAM)7 was associated with a longer overall survival (OS) in patients with poor prognostic features.6 In our trial, the German Acute Myeloid Leukemia Cooperative Group investigated an additional intensification of double induction: two courses of HAM and an intensification of the postremission regimen by myeloablative chemotherapy and autologous stem-cell transplantation (SCT). To compare treatment effects prospectively in prognostic subgroups, all random assignment was done upfront in one step and patients were stratified for prognostic features such as de novo acute myeloid leukemia (AML)/secondary AML/myelodysplastic syndrome (MDS), age, lactate dehydrogenase (LDH), WBC, and cytogenetic groups.
Patients Patients  16 years of age with AML by common classification8,9 who had never received antileukemic therapy were eligible, including de novo AML, AML secondary to myelodysplasia or other antecedent hematologic disorder, and AML secondary to treatment with cytotoxic drugs or radiotherapy. According to the WHO criteria, AML was defined as the presence of 20% or more blasts in the blood or bone marrow.10,11 In addition to overt AML, also high-risk MDS12 with 11% to 19% bone marrow blasts was included in the trial. Patients with promyelocytic leukemia and translocation t(15;17) were excluded and treated in a separate trial.13 Patients with another active cancer or a severe organ failure not explained by leukemia were not eligible. The trial was approved by the ethics committees of the participating centers and was conducted in accordance with the Declaration of Helsinki. A written informed consent was provided by all participants.
Prognostic Factors
Study Design and Treatment Before treatment started, all patients were randomly assigned upfront to one of the two induction therapies (thioguanine, cytarabine, and daunorubicin [TAD] –HAM or HAM-HAM), and in the same step patients younger than age 60 were randomly assigned for postremission therapy by either prolonged maintenance or by autologous SCT. The two randomizations were balanced against each other and were also balanced for the prognostic categories age  or older than 60 years; LDH or more than 700 U/L; de novo AML/secondary AML plus MDS; and favorable, intermediate, or unfavorable karyotype. Given that cytogenetic analyses were not available at treatment start, this factor was only effective as a stratum for the postremission random assignment.
The TAD regimen for induction consisted of cytarabine 100 mg/m2/d by continuous intravenous (IV) infusion on days 1 and 2 and via 30-min IV infusions every 12 hours on days 3 to 8; daunorubicin 60 mg/m2 via 60-minute IV infusions on days 3, 4, and 5; and thioguanine 100 mg/m2 orally every 12 hours on days 3 to 9. The HAM induction regimen combined cytarabine 3 g/m2 (in patients younger than 60 years) or 1 g/m2 (in patients
After achieving complete remission by bone marrow and peripheral blood criteria,21 all patients received consolidation with one course identical to the TAD induction regimen. For maintenance treatment, patients were administered monthly courses of cytarabine 100 mg/m2 every 12 hours by subcutaneous injections on days 1 to 5, and as a second agent from course to course, daunorubicin 45 mg/m2 via 60-minute IV infusions on days 3 and 4, thioguanine 100 mg/m2 orally every 12 hours on days 1 to 5, or cyclophosphamide 1 g/m2 by IV injection on day 3, with the second agent changing in a rotating sequence. In patients age
Maintenance continued for 3 years, and dose reductions by 50% were made after critical nadirs in absolute neutrophils of less than 500/µL or platelets of less than 20,000/µL were observed. Patients younger than age 60 years who were randomly assigned to autologous SCT underwent collection of granulocyte colony-stimulating factor (G-CSF) –mobilized peripheral-blood stem cells, with at least 2 x 106/kg body weight CD34+ cells considered an adequate recovery. Collection was done after the second course (HAM) in patients with less than 5% blasts in their bone marrow after the first course, and after the TAD consolidation course in patients with Independent of random assignment, younger patients with histocompatible family donors underwent allogeneic SCT in the first complete remission (CR). In a subtrial within the trial conducted at 32 of the 52 centers, patients were randomized upfront to G-CSF priming or no G-CSF. G-CSF was administered daily by subcutaneous injections of 150 µg/m2 from 48 hours before until the last dose of each chemotherapy course during the first year.32
Statistical Analyses
When each prognostic factor was considered, the groups were dichotomized into a more favorable and a more unfavorable prognostic subgroup. Regarding cytogenetics, the groups were subdivided into favorable, intermediate, and unfavorable karyotypes. Among the criteria of outcome, CR was defined by a cellular bone marrow with less than 5% blasts and a peripheral blood with at least 1,500/µL absolute neutrophils and 100,000/µL platelets, and persistent leukemia was defined by more than 5% blasts in the bone marrow after the complete induction treatment. Early or hypoplastic death was defined as death before 1 week from the end of the first induction course and later death in hypoplasia with less than 5% bone marrow blasts. SV was measured from treatment start to death. Remission duration (RD) was counted from achievement of CR until relapse, and RFS was counted from achievement of CR until relapse or death in CR. The response criteria essentially adhered to the recommendations of an international consensus.21 The outcome was evaluated according to intention to treat. Significances were calculated for response rates by
Patient Population Between June 1999 and February 2005, a total of 1,795 patients entered onto the trial at the 52 participating centers; 25 patients were excluded because of medical contraindications (20 patients) or protocol violation (five patients). Characteristics of the 1,770 patients included are listed in Table 1.
Drug Delivery Among those assigned to autologous SCT, 24% underwent this treatment. The reasons for not performing autologous SCT were relapse (13%), death in CR (2%), lack of sufficient stem cells mobilized and collected (12%), planned SCT (1%), toxicity (9%), and refusal (4%) or unknown (11%). In addition, the proportions of patients with allogeneic SCT in the maintenance and autologous SCT arm were 19% and 24% (P = .19). Considering the entire patient group with CR distributed to two treatment arms, the present proportions of maintenance and autologous SCT compare well with calculations from previous trials.23-26
Toxicity
Outcome by Random Assignment for Induction Figure 1 presents the outcome for patients of all ages and Figure 2 presents the outcome for patients younger than 60 and 60 years of age separately. The data of outcome are concordant between patients entering before and those entering after January 1, 2002. Of the older patients, 30% in the TAD-HAM arm and 36% in the HAM-HAM arm were in CR after the first course (P = .049).
Outcome by Random Assignment for Postremission Treatment The outcome in patients younger than age 60 who were initially randomly assigned to autologous SCT or prolonged maintenance and achieved a CR is shown in Figure 3.
Because it was part of the protocol, allogeneic SCT in first CR remained uncensored. Allogeneic SCT when remaining uncensored, when being censored, or being excluded, resulted in median RFS of 22, 22, and 21 months with 41%, 40%, and 38% at 3 years, respectively and equally in both arms.
Outcome by Postremission Treatment Administered Based on treatment administered, we also evaluated allogeneic SCT versus maintenance using a matched-pair system. In 98 of the 128 patients undergoing allogeneic SCT, a matched partner in the maintenance group could be identified concordant in age, cytogenetic group, de novo/secondary AML, and RFS achieved at the time of SCT. At 3 years, allogeneic SCT versus maintenance shows 77% v 46% patients relapse free (P = .0007), and an OS of 56% v 60% (P = .65; Kaplan-Meier estimates not shown).
Multivariate Analysis of Prognostic Factors
Outcome by Random Assignment in Prognostic Groups As for younger and older patients (Fig 2), other prognostic subgroups were analyzed for differences in therapeutic outcome between the randomly assigned arms (Fig 4; Tables 4 and 5). There is a general concordance in OS and RD between the randomly assigned arms. Only patients younger than 60 years with more than 40% bone marrow blasts after the first course show a trend to longer OS from maintenance in the log-rank test (P = .044), and patients 60 years with more than 700 U/L LDH show a trend to longer OS from HAM-HAM induction (P = .024). In both cases, the projections to 3 years are concordant between the randomly assigned arms.
Outcome by Random Assignment for G-CSF Priming A total of 895 patients entered the subtrial on G-CSF priming versus no G-CSF. As published before,32 there was no difference in OS or RFS between the randomly assigned arms in any subgroup according to age, cytogenetics, LDH, and blast clearance.
Dose-response effects in AML have been reported for the induction as well as postremission period of therapy.1-5 Remaining open questions currently discussed are whether further intensification of induction by additional high-dose cytarabine or myeloablative chemotherapy with autologous SCT can further improve the outcome, and how these effects are expressed in prognostic subgroups. The open questions are addressed here in 1,770 enrolled adult patients at all ages, with 53% older than 60 years of age, and diagnosed with de novo AML, AML secondary to cytotoxic treatment, AML secondary to MDS, and high-risk MDS. Importantly, the more intensive induction regimen using two courses of HAM did not result in any change in outcome, such as response, persistent leukemia, and early death rate, or in OS, RD, and RFS. This finding in the entire population was seen equally in younger and in older patients. Although the patients older than 60 years received age-adapted treatment of 1 g/m2 instead of 3 g/m2 cytarabine and, if possible, only one induction course, the more intensive regimen HAM-HAM regimen did not compromise its tolerability and even tended to increase the CR rate after the first induction course. However, there were no significant benefits from the more intensive induction in the outcome for any prognostic subgroup such as secondary AML/MDS, cytogenetic groups, higher or lower levels in LDH, WBC, or day 16 residual bone marrow blasts. Unlike in postremission therapy19 the dose-response to high-dose cytarabine administered here in induction therapy did not vary by cytogenetic groups. The equivalence in outcome from the two randomized induction regimens is remarkable considering the cytotoxicity actually delivered. Thus, TAD-HAM and HAM-HAM are calculated to differ by about a factor of 2 in their total dose of cytarabine within both the younger and the older patients. Similar to the two induction treatments, the two different postremission strategies (autologous SCT and maintenance chemotherapy) did not result in different OS, RD, or RFS in the group of patients younger than age 60, in the only group randomly assigned for autologous SCT, or in any of their prognostic subgroups. Although the two randomly assigned arms were balanced for prognostic factors and for the two versions of induction treatment, there are certain imbalances in the delivery between the maintenance chemotherapy and the autologous SCT. Thus, autologous SCTs were abandoned if insufficient stem cells were collected (37 of 287 patients). In addition, contraindications against autologous SCT due to toxicity or refusal were more frequent (40 of 287 patients) than contraindications against maintenance treatment (12 of 277 patients). Finally, the decision for an allogeneic SCT was more frequent in the autologous SCT arm (74 of 287 patients) than in the maintenance arm (54 of 277 patients; P = .075). However, if patients with allogeneic SCT are censored or excluded, there is no deviation from the uncensored analyses of OS, RD, and RFS. Although multicenter trial results on the relative value of autologous SCT are conflicting,23-26,33 our prospective analysis based on intention to treat and avoiding dropouts of CR patients does not show a superiority of autologous SCT over prolonged chemotherapy. Beyond intention to treat, these findings are emphasized by the comparisons of the therapies administered, for which autologous SCT also exhibits the problem of inferior OS. Allogeneic SCT as a priority option for patients with family donors could be evaluated by a matched-pair system and confirmed its high antileukemic potential by a superior freedom from relapse; however, this result was counterbalanced in the OS by a higher treatment-related death rate. In a subtrial within this trial, 32 of the 52 participating centers addressed the question of whether the effect of antileukemic therapy can be augmented by the addition of G-CSF before and during each chemotherapy course administered in the first year of treatment. G-CSF was administered alone during 48 hours and together with cytarabine during an additional 48 hours before the administration of the S-phase toxic daunorubicin or mitoxantrone. There was no trend of a difference in OS, RD, or RFS according to the randomization for G-CSF priming or no G-CSF, as observed in a recent interim analysis of this issue.32 The results of G-CSF priming presented by the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) group34 thus could not be reproduced (to date) in the setting of high-dose cytarabine induction. On the basis of two cytarabine/anthracycline induction courses (one of them containing high-dose cytarabine) combined with prolonged maintenance, patient outcome is not improved by a second high-dose induction course and myeloablative treatment with autologous SCT. Once a certain treatment intensity has been reached, the antileukemic potential may be exhausted and not augmented by additional intensification. A more promising approach may be provided by allogeneic SCT when its high antileukemic potential is combined with a reduced transplantation-related death rate.35 It will take another 2 to 3 years of observation to detect potential effects of treatment alternatives in smaller subgroups of patients. This preliminary analysis may be helpful to other groups for designing new protocols based on different induction and postremission strategies.
The following centers and persons participated in the study: Study coordinators: T. Büchner, W. Hiddemann, W. E. Berdel, and B. Wörmann; statistician, A. Heinecke; cytogenetic review, C. Schoch; cytology review, T. Haferlach (Appendix Table A1).
The authors indicated no potential conflicts of interest.
We thank Birgit Mayerhoffer for secretarial assistance.
Supported by Grants No. M17/92/Bü1 and 70-2839-Bü4 from Deutsche Krebshilfe, 01 GI 9976 from BMBF Competence Network Acute and Chronic Leukemias, LSH-2002-2.2.0-3 European LeukemiaNet from European Commission, and an unrestricted grant from AMGEN. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukemias. Br J Haematol 33:451-458, 1976[Medline] 9. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia. Ann Intern Med 103:620-625, 1985[Medline] 10. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the clinical advisory committee meeting- Airlie House, Virginia. J Clin Oncol 17:3835-3849, 1999 11. Vardiman J, Harris NL, Brunning RD: The World Health Organisation (WHO) classification of the myeloid neoplasms. Blood 100:2292-2302, 2002 12. Greenberg P, Cox X, LeBeau M, et al: International scoring system for evaluating prognosis in myelodysplastic syndrome. Blood 89:2079-2088, 1997 13. 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Schoch C, Kern W, Schnittger S, et al: The influence of age on prognosis of de-novo acute myeloid leukemia differs according to cytogenetic subgroups. Haematologica 89:1082-1090, 2004 17. Mitelmann F: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, Karger, 1995 18. Dastugue D, Payen C, Lafage-Pochitaloff M, et al: Prognostic significance of karyotype in de novo adult acute myeloid leukemia. Leukemia 9:1491-1498, 1995[Medline] 19. Bloomfield CD, Lawrence D, Byrd JC, et al: Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 58:4173-4179, 1998 20. Grimwade D, Walker H, Harrison G, et al: The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): Analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98:1312-1320, 2001 21. 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Burnett AK, Goldstone AH, Stevens RM, et al: Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy of acute myeloid leukaemia in first remission: Results of MRC AML10 trial. Lancet 351:700-708, 1998[CrossRef][Medline] 26. Cassileth PA, Harrington DP, Appelbaum FR, et al: Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 339:1649-1656, 1998 27. Brenner MK, Rill DR, Moen RC, et al: Gene marking and autologous bone marrow transplantation. Ann N Y Acad Sci 716:204-214, 1994[Abstract] 28. Gorin NC: Autologous stem cell transplantation in acute myeloid leukemia. Blood 92:1073-1090, 1998 29. Gorin NC, Labopin M, Laporte JP, et al: Importance of marrow dose on posttransplant outcome in acute leukemia: Models derived from patients autografted with mafosfamide-purged marrow at a single institution. Exp Hematol 27:1822-1830, 1999[CrossRef][Medline] 30. Reiffers J, Labopin M, Sanz M, et al: Autologous blood cell vs. marrow transplantation for acute myeloid leukemia in complete remission: An EBMT retrospective analysis. Bone Marrow Transplant 25:1115-1119, 2000[CrossRef][Medline] 31. Linker CA: Autologous stem cell transplantation for acute myeloid leukemia. Bone Marrow Transplant 31:731-738, 2003[CrossRef][Medline] 32. Büchner T, Berdel WE, Hiddemann W. Priming with granulocyte colony-stimulating factor: Relation to high-dose cytarabine in acute myeloid leukemia. N Engl J Med 350:2215-2216, 2004 33. Suciu S, Mandelli F, de Witte T, et al: Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): An intention-to-treat analysis of the EORTC/GIMEMA AML-10 trial. Blood 102:1232-1240, 2003 34. Löwenberg B, van Putten W, Theobald M, et al: Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 349:743-752, 2003 35. Stelljes M, Bornhäuser M, Kröger M, et al: Conditioning with 8 Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood 106:3314-3321, 2005 Submitted October 6, 2005; accepted March 8, 2006. Related Correspondence
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test; for OS, SV, RFS, and RD by log-rank test; and for multivariate analyses by logistic and Cox regression. 
