J Clin Oncol 24: by American Society of Clinical Oncology INTRODUCTION. Dose-response effects in both induction and postremission

VOLUME 24 NUMBER 16 JUNE 1 2006 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T 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. Submitted October 6, 2005; accepted March 8, 2006. 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. 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@uni-muenster.de. 2006 by American Society of Clinical Oncology 0732-183X/06/2416-2480/$20.00 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 Thomas Büchner, Wolfgang E. Berdel, Claudia Schoch, Torsten Haferlach, Hubert L. Serve, Joachim Kienast, Susanne Schnittger, Wolfgang Kern, Joelle Tchinda, Albrecht Reichle, Eva Lengfelder, Peter Staib, Wolf-Dieter Ludwig, Carlo Aul, Hartmut Eimermacher, Leopold Balleisen, Maria-Cristina Sauerland, Achim Heinecke, Bernhard Wörmann, and Wolfgang Hiddemann A B S T R A C T 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 60 years of age was 70% and 53%, respectively. The overall survival at 3 years in the two age groups was 42% and 19%, the relapse-free survival was 40% and 19%, and the ongoing remission duration was 48% and 22%, respectively. There were no significant differences in these results between the two randomized induction arms or between the two postremission therapy arms. There was no significant difference in any prognostic subgroup according to secondary AML/MDS, cytogenetics, WBC, lactate dehydrogenase, and early blast clearance. 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. J Clin Oncol 24:2480-2489. 2006 by American Society of Clinical Oncology INTRODUCTION 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/m 2 for six single doses, 400 mg/m 2 for five doses, or 100 mg/m 2 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 doubleinduction also attempted an improvement in quality and duration of remission. 6 A version incorporating one course of high-dose cytarabine and mitoxantrone 2480

Intensified Induction and SCT for AML Characteristic Table 1. Patient Characteristics and Prognostic Factors by Randomization for Induction and Postremission Therapy Induction TAD-HAM HAM-HAM Maintenance Postremission Autologous SCT Age 60 years No. of patients 430 410 411 429 Favorable karyotype, % 15 12 14 13 Intermediate karyotype, % 62 67 64 64 Unfavorable karyotype, % 23 21 22 22 WBC 20,000/ L, % 44 43 44 43 LDH 700 U/L, % 30 27 29 28 Bone marrow blasts one week after 17 6 12 11 first course 40%: patients, % Secondary AML and high-risk MDS, % 18 19 19 18 Randomly assigned to HAM-HAM, % 49 48 Age 60 years No. of patients 473 457 Favorable karyotype, % 4 4 Intermediate karyotype, % 66 67 Unfavorable karyotype, % 30 29 WBC 20,000/ L, % 36 35 LDH 700 U/L, % 23 21 Bone marrow blasts one week after 16 16 first course 40%: patients, % Secondary AML and high-risk MDS, % 31 33 Abbreviations: TAD, thioguanine, cytarabine, and daunorubicin; HAM, high-dose cytarabine and mitoxantrone; SCT, stem-cell transplantation; LDH, lactate dehydrogenase; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome. In the total of 1,770 patients, the median age was 60 years (range, 16 to 85 years) and 52% were age 60 years. Favorable karyotypes included t(8;21)(q22;22), inv(16)(p13q22), or t(16;16)(p13;q22). Unfavorable karyotypes included losses or deletions of chromosomes 5 or 7 ( 5, 5q, 7, 7q ), chromosome 3(q21q26) abnormalities, abnormal chromosome 11(q23), or complex aberrant karyotypes with at least three structural and/or numerical abnormalities. Intermediate karyotypes were defined by normal karyotype or abnormalities not considered favorable or unfavorable. Between TAD-HAM and HAM-HAM, P.001 A total of 74% of the patients had de novo AML, 17% had AML emerging from MDS, 6% had treatment-related AML and 3% had high-risk MDS. (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 AND METHODS Patients Patients 16 years of age with AML by common classification 8,9 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 MDS 12 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. Table 2. Adverse Events (WHO grades 3 and 4) According to the Two Randomized Induction Arms Event TAD-HAM Induction HAM-HAM Induction % 95% CI % 95% CI Age 60 years Nausea/vomiting 16 13 to 20 16 12 to 20 Stomatitis 13 10 to 17 9 6 to 12 Diarrhea 15 12 to 19 14 11 to 18 Hemorrhage 10 7 to 13 8 5 to 11 Infection 55 50 to 60 56 51 to 60 Cardiac events 8 6 to 11 5 3 to 8 CNS toxicity 8 6 to 11 5 3 to 7 Age 60 years Nausea/vomiting 10 8 to 13 10 7 to 13 Stomatitis 9 6 to 12 7 5 to 10 Diarrhea 18 15 to 22 13 10 to 16 Hemorrhage 7 5 to 10 7 5 to 10 Infection 48 43 to 52 50 44 to 54 Cardiac events 10 7 to 13 10 8 to 13 CNS toxicity 7 5 to 10 7 5 to 10 Abbreviations: TAD, thioguanine, cytarabine, and daunorubicin; HAM, highdose cytarabine and mitoxantrone. www.jco.org 2481

Büchner et al Prognostic Factors In earlier analyses 2,6,14-16 age, cytogenetics, serum LDH, and residual bone marrow blasts 1 week after the first induction course were substantiated as independent prognostic factors. Cytogenetic groups were defined in accordance with results from other studies (Table 1). 17-20 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/m 2 /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/m 2 via 60-minute IV infusions on days 3, 4, and 5; and thioguanine 100 mg/m 2 orally every 12 hours on days 3 to 9. The HAM induction regimen combined cytarabine 3 g/m 2 (in patients younger than 60 years) or 1 g/m 2 (in patients 60 years) via 3-hour IV infusions every 12 hours on days 1 to 3, with mitoxantrone 10 mg/m 2 via 60-minute IV infusions on days 3 to 5. One week after the first induction course, a bone marrow aspirate was examined. A second induction course was administered to all patients younger than 60 years in any case, and in patients 60 years if 5% or more residual blasts appeared in their bone marrow. 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/m 2 every 12 hours by subcutaneous injections on days 1 to 5, and as a second agent from course to course, daunorubicin 45 mg/m 2 via 60-minute IV infusions on days 3 and 4, thioguanine 100 mg/m 2 orally every 12 hours on days 1 to 5, or cyclophosphamide 1 g/m 2 by IV injection on day 3, with the second agent changing in a rotating sequence. In patients age 60 years, dosages of TAD 22 and maintenance courses were the same as those in younger patients. Maintenance continued for 3 years, and dose reductions by 50% were made after critical nadirs in absolute neutrophils of less than 500/ L or platelets of less than 20,000/ L 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 10 6 /kg body weight CD34 cells considered an adequate recovery. Collection was done after the second course (HAM) in Fig 1. Outcome by random assignment for thioguanine, cytarabine, and daunorubicin (TAD) high-dose cytarabine and mitoxantrone (HAM) versus HAM-HAM induction. Respective response data are complete response (CR), 61% v 60%; persistent leukemia, 23% v 24%; early or hypoplastic death, 16% v 16% (not significant). (A) Overall survival; (B) remission duration; (C) relapse-free survival; and (D) survival of CR patients. Vertical bars represent censored patients at risk. 2482 JOURNAL OF CLINICAL ONCOLOGY

Intensified Induction and SCT for AML Fig 2. Outcome by age and random assignment for thioguanine, cytarabine, and daunorubicin (TAD) high-dose cytarabine and mitoxantrone (HAM) versus HAM-HAM induction. Respective response data are for age younger than 60 years: complete response (CR), 71% v 68%; persistent leukemia (PL), 17% v 18%; early or hypoplastic death (EHD), 12% v 14% (not significant). For age 60 years: CR, 53% v 53%; PL, 28% v 30%; EHD, 19% v 17% (not significant). (A) Age younger than 60 years, overall survival; (B) age younger than 60 years, remission duration; (C) age 60 years, overall survival; and (D) age 60 years, remission duration. patients with less than 5% blasts in their bone marrow after the first course, and after the TAD consolidation course in patients with 5% blasts after the first course. This compares with precollection consolidation courses in previous trials. 23-26 After recovery from TAD consolidation, patients received busulfan/ cyclophosphamide conditioning ( busulfan 4 mg/kg/d for 4 days orally on days 7to 4, and cyclophosphamide 60 mg/kg/d IV infusion on days 3 and 2) before the autologous stem cells were reinfused. Effective methods of in vitro purging have been developed to avoid reinfusion of autologous leukemic cells. 27-29 However, adequate prospective investigations are lacking 30,31 and purging was used in only one 26 of four previous trials. 23-26 Thus, in vitro purging was not selected for this study protocol. 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 g/m 2 from 48 hours before until the last dose of each chemotherapy course during the first year. 32 Statistical Analyses The primary objective of this trial was to compare the therapeutic effects of the two induction therapies TAD-HAM versus HAM-HAM, and (restricted to patients younger than age 60) to compare the effects of the two postremission therapies of prolonged maintenance versus autologous SCT. The comparisons in outcome were done for the total cohort of patients at all ages, for patients younger than 60 years and those 60 years separately, and for defined prognostic groups within the age groups. 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/ L absolute neutrophils and 100,000/ L 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 2 test; for OS, SV, RFS, and RD by log-rank test; and for multivariate analyses by logistic and Cox regression. www.jco.org 2483

Büchner et al Fig 3. Outcome by random assignment for postremission treatment. (A) Overall survival; (B) remission duration. Auto SCT, autologous stem-cell transplantation. RESULTS 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 According to the protocol, 87% of patients younger than 60 years received two induction courses (88% in the TAD-HAM and 86% in the HAM-HAM arm). The reasons for not administering a second course were early death (8% and 8% in the two arms, respectively) and toxicity (4% and 6%, respectively). Among the patients 60 years, 37% received two induction courses (41% in the TAD-HAM arm and 33% in the HAM-HAM arm; P.01). A second course was not administered to those older patients with 5% or more residual bone marrow blasts because of early death (5% and 4% in the two arms, respectively) or toxicity (11% and 15%, respectively). Among the patients younger than age 60 who were randomly assigned for the postremission therapy and achieved CR, 51% of those assigned to prolonged maintenance received maintenance treatment. The reasons for not receiving maintenance were relapse (8%), death in CR (4%), preferred autologous SCT (1%), planned SCT (2%), toxicity (3%), and refusal (1%) or unknown (11%). 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 Risk Factor Table 3. Multivariate Analysis of Independent Risk Factors in Patients Age 60 and Age 60 Years Favorable Unfavorable BM Blasts 40% After First Course LDH 700 U/L WBC 20,000/ L De Novo AML Age (years) Age (years) Age (years) Age (years) Age (years) Age (years) 60 60 60 60 60 60 60 60 60 60 60 60 CR, odds ratio 0.5 0.3 0.3 0.3 0.6 1.5 2.0 P.0003.0001.0001.0001.024.059.0002 OS, hazard ratio 2.1 0.5 0.4 0.7 0.6 0.7 1.3 1.4 P.0008.0001.0001.028.0002.0029.044.0014 RFS, hazard ratio 3.7 0.6 0.5 0.5 0.7 0.7 1.5 1.4 P.0001.0095.0001.0020.048.015.039.035 RD, hazard ratio 4.2 0.7 0.5 0.4 0.6 0.7 P.0001.060.0001.0002.046.029 Abbreviations: BM, bone marrow; LDH, lactate dehydrogenase; AML, acute myeloid leukemia; CR, complete remission; OS, overall survival; RFS, relapse-free survival; RD, remission duration. Odds ratio and hazard ratio indicate the factor by which the outcome according to the related end points is improved. 2484 JOURNAL OF CLINICAL ONCOLOGY

Intensified Induction and SCT for AML Fig 4. Outcome by random assignment in patients with unfavorable karyotype. (A) Age younger than 60 years, overall survival by induction; (B) age younger than 60 years, remission duration by induction; (C) age younger than 60 years, overall survival by postremission treatment; (D) age younger than 60 years, remission duration by postremission treatment; (E) age 60 years, overall survival by induction; and (F) age 60 years, remission duration by induction. TAD, thioguanine, cytarabine, and daunorubicin; HAM, high-dose cytarabine and mitoxantrone; CR, complete remission; Auto SCT, autologous stem-cell transplantation. Toxicity There are no significant differences in severe adverse events between the two induction arms (Table 2). 4 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 www.jco.org 2485

Büchner et al Outcome Table 4. Outcome by Randomization in Prognostic Groups: Percent Probability of OS and RD at 3 Years; Age 60 Years % Probability Induction Postremission TAD-HAM HAM-HAM Maintenance Autologous SCT 95% CI % Probability 95% CI % Probability 95% CI % Probability OS Total 44 39 to 50 40 34 to 46 41 35 to 47 43 37 to 49 Favorable 69 56 to 82 77 62 to 90 66 52 to 81 77 65 to 90 Intermediate 50 43 to 57 41 33 to 48 45 37 to 53 45 38 to 53 Unfavorable 16 7 to 24 17 7 to 28 13 5 to 21 18 8 to 29 LDH, U/L 700 50 44 to 57 39 32 to 46 43 36 to 49 46 39 to 54 700 33 24 to 43 40 29 to 51 39 28 to 49 34 24 to 43 WBC, / L 20,000 49 41 to 57 37 29 to 45 41 33 to 48 45 37 to 53 20,000 39 31 to 47 42 34 to 51 43 34 to 51 39 31 to 47 BM blasts 1 week after first course 40% 51 45 to 58 41 35 to 48 43 36 to 50 49 42 to 56 40% 24 10 to 37 40 18 to 62 37 20 to 54 20 6 to 34 De novo AML 47 41 to 53 45 38 to 51 44 38 to 51 48 41 to 54 saml and MDS 33 20 to 46 21 9 to 34 30 18 to 43 23 10 to 37 RD Total 45 37 to 53 49 42 to 57 46 38 to 54 48 41 to 56 Favorable 78 63 to 92 79 62 to 96 74 57 to 91 82 68 to 96 Intermediate 44 34 to 53 46 36 to 55 43 33 to 52 47 37 to 56 Unfavorable 14 0 to 29 38 19 to 58 21 2 to 39 25 7 to 43 LDH, U/L 700 51 41 to 60 48 39 to 57 46 37 to 55 52 43 to 61 700 36 22 to 50 54 41 to 67 49 35 to 63 39 26 to 53 WBC, / L 20,000 51 41 to 62 46 36 to 56 43 32 to 53 54 43 to 64 20,000 38 27 to 49 53 42 to 64 50 39 to 62 40 29 to 51 BM blasts 1 week after first course 40% 52 44 to 61 48 39 to 56 49 40 to 57 51 43 to 59 40% 12 0 to 27 30 0 to 64 20 1 to 40 11 0 to 32 De novo AML 48 39 to 55 50 42 to 59 49 40 to 57 48 40 to 56 saml and MDS 34 14 to 54 44 25 to 64 31 13 to 49 47 24 to 70 Abbreviations: OS, overall survival; RD, remission duration; TAD, thioguanine, cytarabine, and daunorubicin; HAM, high-dose cytarabine and mitoxantrone; SCT, stem-cell transplantation; LDH, lactate dehydrogenase; BM, bone marrow; AML, acute myeloid leukemia; saml, secondary acute myeloid leukemia; MDS, myelodysplastic syndrome. 95% CI 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 The two randomly assigned arms were also evaluated selectively for patients who received at least one course of maintenance or underwent autologous SCT. There was again no difference in RD (50% v 44% at 3 years; P.31) and RFS (48% v 43% at 3 years; P.35). OS, however, showed an advantage for maintenance (71% v 53% at 3 years; P.005; Kaplan-Meier estimates not shown). The two treatments delivered were balanced for de novo and other AML and for cytogenetics. 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% 2486 JOURNAL OF CLINICAL ONCOLOGY

Intensified Induction and SCT for AML patients relapse free (P.0007), and an OS of 56% v 60% (P.65; Kaplan-Meier estimates not shown). Multivariate Analysis of Prognostic Factors Table 3 lists a multivariate analysis of patient features independently predicting for outcome, in patients younger than 60 and those 60 years of age. 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. DISCUSSION 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 Outcome Table 5. Outcome by Randomization in Prognostic Groups: Percent Probability of OS and RD at 3 Years; Age 60 Years TAD-HAM Induction HAM-HAM % Probability 95% CI % Probability 95% CI OS Total 18 13 to 23 19 15 to 24 Favorable 54 29 to 79 Intermediate 26 19 to 33 25 19 to 32 Unfavorable 4 0 to 9 4 0 to 8 LDH, U/L 700 21 15 to 27 18 13 to 24 700 20 11to30 WBC, / L 20,000 22 16 to 29 17 11 to 23 20,000 10 2 to 18 22 14 to 30 BM blasts 1 week after first course 40% 21 15 to 28 25 19 to 31 40% 14 3to25 7 0to16 De novo AML 21 15 to 27 24 18 to 30 saml and MDS 10 3 to 17 92 to 17 RD Total 17 8 to 26 28 20 to 37 Favorable 68 37 to 100 Intermediate 19 9 to 30 31 21 to 41 Unfavorable 9 0 to 21 LDH, U/L 700 17 8to27 28 18to38 700 27 11to44 WBC, / L 20,000 14 4 to 24 27 17 to 37 20,000 25 11 to 39 32 17 to 47 BM blasts 1 week after first course 40% 18 9to28 28 19to37 40% 26 0 to 64 De novo AML 21 11 to 31 30 21 to 40 saml and MDS 22 6 to 39 Abbreviations: OS, overall survival; RD, remission duration; TAD, thioguanine, cytarabine, and daunorubicin; HAM, high-dose cytarabine and mitoxantrone; SCT, stem-cell transplantation; LDH, lactate dehydrogenase; BM, bone marrow; AML, acute myeloid leukemia; saml, secondary acute myeloid leukemia; MDS, myelodysplastic syndrome. www.jco.org 2487

Büchner et al 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 highrisk 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/m 2 instead of 3 g/m 2 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 therapy 19 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 treatmentrelated 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) group 34 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. REFERENCES 1. Büchner T, Urbanitz D, Hiddemann W, et al: Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): Two multicenter studies of the German AML Cooperative Group. J Clin Oncol 3:1583-1589, 1985 2. Büchner T, Hiddemann W, Berdel W, et al: 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM- TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de-novo acute myeloid leukemia (AML): A randomized trial by the German AML Cooperative Group. J Clin Oncol 21:4496-4504, 2003 3. Mayer RJ, Davis RB, Schiffer CA, et al: Intensive post-remission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331:896-942, 1994 4. Bishop JF, Matthews JP, Young GA, et al: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87:1710-1717, 1996 5. Weick JK, Kopecky KJ, Appelbaum FR, et al: A randomized investigation of high-dose versus standard dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: A Southwest Oncology Study Group. Blood 88:2841-2851, 1996 6. Büchner T, Hiddemann W, Wörmann B, et al: Double induction strategy for acute myeloid leukemia: The effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine A randomized trial by the German AML Cooperative Group. Blood 93:4116-4124, 1999 7. Hiddemann W, Kreutzmann H, Straif K, et al: High-dose cytosine arabinoside and mitoxantrone: A highly effective regimen in refractory acute myeloid leukemia. Blood 69:744-749, 1987 8. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukemias. Br J Haematol 33:451-458, 1976 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 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. Lengfelder E, Reichert A, Schoch C, et al: Double induction strategy including high-dose cytarabine in combination with all-trans retinoic acid: 2488 JOURNAL OF CLINICAL ONCOLOGY

Intensified Induction and SCT for AML Effects in patients with newly diagnosed acute promyelocytic leukemia German AML Cooperative Group. Leukemia 14:1362-1370, 2000 14. Kern W, Haferlach T, Schoch C, et al: Early blast clearance by remission induction therapy is major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: Data from the German AML Cooperative Group (AMLCG) 1992 trial. Blood 101:64-70, 2003 15. Haferlach T, Schoch C, Löffler H, et al: Morphologic dysplasia in de-novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: Results of a multiparameter analysis from the German AML Cooperative Group studies. J Clin Oncol 21:256-265, 2003 16. 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. 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Cheson BD, Bennett J, Kopecky K, et al: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642-4649, 2003 22. Hiddemann W, Kern W, Schoch C, et al: Management of acute myeloid leukemia in elderly patients. J Clin Oncol 17:3569-3576, 1999 23. Zittoun R, Mandelli F, Willemze R, et al: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 332: 217-223, 1995 24. Harousseau JL, Cahn JV, Pignon B, et al: Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood 90:2978-2986, 1997 25. 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 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 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 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 31. Linker CA: Autologous stem cell transplantation for acute myeloid leukemia. Bone Marrow Transplant 31:731-738, 2003 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 Acknowledgment We thank Birgit Mayerhoffer for secretarial assistance. Appendix The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe Reader ). Authors Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions Conception and design: Thomas Büchner, Wolfgang E. Berdel, Claudia Schoch, Torsten Haferlach, Hubert L. Serve, Joachim Kienast, Eva Lengfelder, Achim Heinecke, Bernhard Wörmann, Wolfgang Hiddemann Administrative support: Thomas Büchner, Wolfgang E. Berdel, Bernhard Wörmann, Wolfgang Hiddemann Provision of study materials or patients: Thomas Büchner, Wolfgang E. Berdel, Claudia Schoch, Torsten Haferlach, Hubert L. Serve, Susanne Schnittger, Wolfgang Kern, Joelle Tchinda, Albrecht Reichle, Eva Lengfelder, Peter Staib, Wolf-Dieter Ludwig, Carlo Aul, Hartmut Eimermacher, Leopold Balleisen, Bernhard Wörmann, Wolfgang Hiddemann Collection and assembly of data: Thomas Büchner, Claudia Schoch, Torsten Haferlach, Joelle Tchinda, Eva Lengfelder, Hartmut Eimermacher, Leopold Balleisen, Maria-Cristina Sauerland, Achim Heinecke Data analysis and interpretation: Thomas Büchner, Wolfgang E. Berdel, Claudia Schoch, Torsten Haferlach, Hubert L. Serve, Joachim Kienast, Maria-Cristina Sauerland, Achim Heinecke Manuscript writing: Thomas Büchner, Wolfgang E. Berdel, Torsten Haferlach, Hubert L. Serve, Joachim Kienast, Wolfgang Kern, Maria-Cristina Sauerland, Achim Heinecke, Wolfgang Hiddemann Final approval of manuscript: Thomas Büchner, Wolfgang E. Berdel, Claudia Schoch, Torsten Haferlach, Hubert L. Serve, Joachim Kienast, Susanne Schnittger, Wolfgang Kern, Joelle Tchinda, Albrecht Reichle, Eva Lengfelder, Peter Staib, Wolf-Dieter Ludwig, Carlo Aul, Hartmut Eimermacher, Leopold Balleisen, Maria-Cristina Sauerland, Achim Heinecke, Bernhard Wörmann, Wolfgang Hiddemann www.jco.org 2489

The August 1, 2009, article by Gradishar et al, entitled, Significantly Longer Progression-Free Survival With nab- Paclitaxel Compared With Docetaxel As First-Line Therapy for Metastatic Breast Cancer (J Clin Oncol 27:3611-3619, 2009), contained an error. In the Results section, under Safety, the last sentence of the second paragraph was given as: Median time to improvement in grade 3 sensory neuropathy (to grade 1) was 22, 22, and 19 days, respectively, for patients who received nab-paclitaxel 300 mg/m 2 q3w, 100 mg/m 2 weekly, and 150 mg/m 2 weekly compared with 37 days for patients who received docetaxel 100 mg/m 2 q3w. CORRECTIONS Author Correction Whereas it should have been: Median time to improvement in grade 3 sensory neuropathy (to grade 2) was 22, 22, and 19 days, respectively, for patients who received nab-paclitaxel 300 mg/m 2 q3w, 100 mg/m 2 weekly, and 150 mg/m 2 weekly compared with 37 days for patients who received docetaxel 100 mg/m 2 q3w. The online version has been corrected in departure from the print. The authors apologize to the readers for the mistake. DOI: 10.1200/JCO.2011.37.3159 Journal Corrections The June 1, 2006 article by Büchner et al entitled, 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 (J Clin Oncol 24:2480-2489, 2006), contained an error. In the Patients and Methods section, under Study Design and Treatment, the fifth sentence of the fourth paragraph was incorrectly stated as: After recovery from TAD consolidation, patients received busulfan/cyclophosphamide conditioning (busulfan 41 mg/kg per day for 4 days orally on days 7 to 4, and cyclophosphamide 60 mg/kg/d IV infusion on days 3 and 2) before the autologous stem cells were reinfused. Whereas it should have been: After recovery from TAD consolidation, patients received busulfan/cyclophosphamide conditioning (busulfan 4 mg/ kg/d for 4 days orally on days 7 to 4, and cyclophosphamide 60 mg/kg/d IV infusion on days 3 and 2) before the autologous stem cells were reinfused. The online version has been corrected in departure from the print. Journal of Clinical Oncology apologizes to the authors and readers for the mistake. DOI: 10.1200/JCO.2011.37.3126 The May 10, 2011, review article by Cheson entitled, Role of Functional Imaging in the Management of Lymphoma (J Clin Oncol 29:1844-1854, 2011), contained an error. The following Acknowledgment was inadvertently omitted: The author would like to thank Heiko Schöder, MD, for his contributions to Figure 1 and Lale Kostakoglu, MD, for her contributions to Figure 2. Journal of Clinical Oncology apologizes to the author and readers for the mistake. DOI: 10.1200/JCO.2011.37.3142-2011 by American Society of Clinical Oncology 2739