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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 of the German AML Cooperative Group

Thomas Büchner, Wolfgang Hiddemann, Wolfgang E. Berdel, Bernhard Wörmann, Claudia Schoch, Christa Fonatsch, Helmut Löffler, Torsten Haferlach, Wolf-Dieter Ludwig, Georg Maschmeyer, Peter Staib, Carlo Aul, Andreas Grüneisen, Eva Lengfelder, Norbert Frickhofen, Wolfgang Kern, Hubert L. Serve, Rolf M. Mesters, Maria Cristina Sauerland, Achim Heinecke

From the Department of Medicine, Hematology/Oncology, University of Münster, Münster, Germany.

Address reprint requests to Thomas Büchner, MD, PhD, University Medical Center, Department of Medicine, Hematology and Oncology, Albert-Schweitzer-Str 33, D-48129 Münster, Germany; e-mail: buechnr{at}uni-muenster.de.

	ABSTRACT

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Purpose: To examine the efficacy of prolonged maintenance chemotherapy versus intensified consolidation therapy for patients with acute myeloid leukemia (AML).

Materials and Methods: Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were randomly assigned to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m² [age < 60 years] or 1 g/m² [age 60 years] x 6) induction, TAD consolidation, and monthly modified TAD maintenance for 3 years, or TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m² (age < 60 years) or 0.5 g/m² (age 60 years) x 8 instead of maintenance.

Results: A total of 69.2% patients went into complete remission (CR). Median relapse-free survival (RFS) was 19 months for patients on the maintenance arm, with 31.4% of patients relapse-free at 5 years, versus 12 months for patients on the S-HAM arm, with 24.7% of patients relapse-free at 5 years (P = .0118). RFS from maintenance was superior in patients with poor risk by unfavorable karyotype, age 60 years, lactate dehydrogenase level greater than 700 U/L, or day 16 bone marrow blasts greater than 40% (P = .0061) but not in patients with good risk by complete absence of any poor risk factors. Although a survival benefit in the CR patients is not significant (P = .085), more surviving patients in the maintenance than in the S-HAM arm remain in first CR (P = .026).

Conclusion: We conclude that TAD-HAM-TAD-maintenance first-line treatment has a higher curative potential than TAD-HAM-TAD-S-HAM and improves prognosis even among patients with poor prognosis.

	INTRODUCTION

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AS DEMONSTRATED in recent trials of patients with acute myeloid leukemia (AML), postremission treatment with high-dose cytarabine produces longer relapse-free survival (RFS) and survival (SV) than standard-dose cytarabine,¹ in addition to superior RFS, when used in induction treatment.^2,3 Autologous transplantation results in superior RFS when compared with intensive chemotherapy⁴ or no further treatment.⁵ Similarly, RFS from allogeneic transplantation is significantly longer than that achieved with intensive chemotherapy.⁴

Other trials, however, have failed to confirm the superiority of autologous or allogeneic transplantation.^6,7 Furthermore, the effect of high-dose cytarabine was restricted to favorable and intermediate-risk patients when administered postremission⁸ but was restricted to poor-risk patients when used in induction.⁹

A question remains regarding the relative value of prolonged myelosuppressive monthly maintenance chemotherapy in the context of current intensification strategies. In the 1981 trial of the German Acute Myeloid Leukemia Cooperative Group (AMLCG), patients were randomly assigned to receive maintenance chemotherapy according to a study by the Cancer and Leukemia Group B CALGB¹⁰ after consolidation with 6-thioguanine, cytarabine, and daunorubicin (TAD) or consolidation alone. The RFS in adult patients of all ages was 18% at 10 years in the maintenance arm and 6% in the no maintenance arm (P = .0001).^11,12

Combining maintenance chemotherapy with the double-induction strategy led to a 5-year RFS rate of 32% in patients 16 to 60 years of age; incorporating high-dose cytarabine into double induction improved overall survival (OS), specifically in patients with poor prognosis (P = .012).⁹ On the basis of TAD and high-dose cytarabine and mitoxantrone (HAM) double induction and TAD consolidation, with prolonged maintenance as the standard, the present trial compared maintenance chemotherapy with intensive consolidation (IC).

	MATERIALS AND METHODS

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Patients
Patients 16 years of age and older with AML by common classification^13,14 who had never received antileukemic therapy were eligible for study. As in the previous trial of the AMLCG⁹ and similar to other comparable trials,^1,2,4,15 patients with a history of myelodysplasia or other antecedent hematologic disorder and related abnormal blood counts for at least 6 months or previous exposure to cytotoxic drugs or radiotherapy were excluded from study, as were patients with preexisting non–leukemia-related severe and refractory liver, renal, heart, and other organ failure. Patients with promyelocytic leukemia and translocation t(15;17) were excluded and treated in a separate trial.¹⁶ The study was approved by a university ethical committee, and written informed consent was obtained from each patient entering the trial.

Study Design
Before treatment started, all patients were randomly assigned by phone call to the statistical center. Patients then received the first induction course, consisting of cytarabine 100 mg/m² by continuous intravenous (IV) infusion daily on days 1 and 2 and by 30-minute infusion every 12 hours on days 3 through 8, daunorubicin 60 mg/m² by 30-minute IV infusion on days 3, 4, and 5, and 6-thioguanine 100 mg/m² administered orally every 12 hours on days 3 through 9 (TAD), as published.^9,17 On day 16 of therapy, bone marrow was examined for the percentage of blasts. On day 21, all patients younger than 60 years of age received a second induction course (double induction). In the older patients, the second course was given only if bone marrow contained 5% blasts on day 16, irrespective of its cellularity. For the second course, cytarabine 3 (age < 60 years) or 1 (age 60 years) g/m² was administered by 3-hour IV infusion every 12 hours on days 1 through 3, with mitoxantrone 10 mg/m² by 30-minute IV infusion on days 3, 4, and 5 (HAM).¹⁸ If bone marrow continued to contain 5% blasts after HAM or if similar features reappeared in weekly bone marrow sampling, then the patient was treated off study. After entering complete remission (CR), patients started with a consolidation course of TAD 2 to 4 weeks later. After TAD, patients were given either maintenance chemotherapy or one course of IC according to their initial randomization. Although maintenance chemotherapy started at reachievement of CR criteria after TAD consolidation, IC started 6 weeks later. Maintenance chemotherapy was as published,^9,11 with monthly courses of cytarabine 100 mg/m² injected subcutaneously every 12 hours for 5 days, as with a second drug, daunorubicin, 45 mg/m² by 30 minute IV infusion on days 3 and 4 (course 1), 6-thioguanine 100 mg/m² orally administered every 12 hours on days 1 to 5 (course 2), cyclophosphamide 1 g/m² IV on day 3 (course 3), 6-thioguanine again (course 4), and restarting with course 1. If absolute neutrophil count decreased to less than 500/µL and/or platelets to less than 20,000/µL after each of two sequential courses, the doses of all antileukemic drugs were reduced by 50%, permanently. Using this policy it was found that from the third maintenance course, almost all patients required adjustment and continued at 50% dosage, whereas further reductions were possible accordingly. Maintenance chemotherapy continued until patients had been in remission for 3 years,¹¹ which was largely fulfilled in the majority of patients achieving RFS of at least 3 years. IC consisted of cytarabine 1 (age < 60 years) or 0.5 (age 60 years) g/m² by 3-hour IV infusion every 12 hours on days 1, 2, 8, and 9, with mitoxantrone 10 mg/m² 30-minute IV infusion on days 3, 4, 10, and 11 (sequential HAM [S-HAM]).¹⁹ As alternative to maintenance or IC chemotherapy, allogeneic transplantation in first CR was offered to all patients up to 50 years of age who had a histocompatible sibling.

Evaluation
Patients underwent full physical examinations and assessment of blood counts and liver and renal function tests before each chemotherapy course. Bone marrow examinations were performed before the start of maintenance and IC and then every 3 months, unless earlier bone marrow examinations were indicated by peripheral-blood changes inconsistent with CR.

Criteria for Response
As published,⁹ a CR was defined by bone marrow with normal hematopoiesis of all cell lines and less than 5% blasts and peripheral blood with at least 1,500 neutrophils and 100,000 platelets per microliter. Therapeutic failures were classified as persistent leukemia, death fewer than 7 days after completion of the first induction therapy course (early death), and death during treatment-induced bone marrow hypoplasia, irrespective of the time after chemotherapy (hypoplastic death). Relapse was defined as reinfiltration of the bone marrow by 5% leukemic blasts or a proven leukemic infiltration at any other site. RFS was measured from the achievement of CR until relapse or death in remission, and freedom from relapse counted from the achievement of CR until relapse. SV and OS were recorded from randomization until death.

Cytogenetics
Cytogenetic examination was performed on pretreatment bone marrow specimens as published.⁹ Chromosome analyses were conducted after short-term cultures using standard protocols for G- or R-banding technique. Karyotype changes were interpreted according to the 1995 International System for Human Cytogenetic Nomenclature.²⁰ All cytogenetic results were centrally reviewed. Similarly, as in other large series,^8,21 karyotypes classified as favorable included translocations t(8;21) and inversion/translocation of chromosome 16, whereas deletions and losses of chromosomes 5 and 7, abnormalities involving 11q23, and complex karyotypes with three or more numerical or structural abnormalities were considered unfavorable. All other karyotypes were considered as intermediate.

Statistical Analysis
The primary objective of the study was the randomized comparison of the two alternative sequences of treatment regimens TAD-HAM-TAD plus maintenance and TAD-HAM-TAD plus IC according to RFS. The number of eligible patients and of responders per year was expected to be 150 and 100, respectively, and the expected median RFS was approximately 16 months. Setting the upper limit of probability of the type I error to alpha = .05, the accrual time to at least 6 years, and the additional follow-up period to at least 2 years, this resulted in a power of 80% to detect a difference in the median RFS of 5 months. The distributions of the time-to-event variables were estimated using the Kaplan-Meier method,²² and comparisons were based on the log-rank test.²³ All P values reported are two-sided. Potential prognostic factors were tested using the Cox proportional hazards model,²⁴ including the dichotomized variables age (< 60 v 60 years), karyotype (favorable v unfavorable), lactate dehydrogenase (LDH; 700 v > 700 U/L), WBC ( 40,000 v > 40,000/µL), and day 16 bone marrow blasts ( 40% v > 40%). The comparator groups for the calculation of relative risk were the respective counterparts of the dichotomized variables, whereas interactions with other factors were not accounted for.

	RESULTS

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Patient Population
Between December 1992 and June 1999, a total of 946 patients at all ages from 47 institutions were entered onto the trial. One hundred fourteen patients were excluded according to protocol criteria, such as medical contraindications in 79 patients and nonrandomized treatment in 35 patients. A total of 832 patients were eligible and randomly assigned to treatment (Fig 1). The 88% eligibility compares with 92% in the previous trial⁹ in patients younger than 60 years.

View larger version (24K): [in this window] [in a new window]   Fig 1. Flow diagram showing assessable patients according to treatment arms and numbers of patients receiving the assigned treatment. TAD, 6-thioguanine, cytarabine, and daunorubicin; HAM, high-dose cytarabine and mitoxantrone; CR, complete remission; allo BMT, allogeneic bone marrow transplantation.

Therapeutic Outcome by Randomization
The essential data on patient outcome are listed in Table 2. The median observation time for patients alive in CR is 4.5 years and for patients alive is 3.8 years. Kaplan-Meier life-table plots comparing patients in the maintenance arm with those in the IC arm are shown for RFS in Figure 2. The OS of all patients entering the trial is shown in Figure 3, and the survival of all responders is shown in Figure 4. Among the 429 and 403 patients assigned to maintenance chemotherapy and IC (272 and 263 younger patients and 157 and 140 older patients), respectively, 292 and 288 have died (165 and 173 younger patients and 127 and 115 older patients, respectively). Among the 294 and 282 patients achieving CR (197 and 200 younger patients and 97 and 82 older patients), 153 and 171 experienced relapse (94 and 110 younger patients and 59 and 61 older patients), respectively, and another 30 and 28 patients died in remission (17 and 21 younger patients and 13 and seven older patients), respectively.

View larger version (14K): [in this window] [in a new window]   Fig 2. Relapse-free survival according to randomization in patients at all ages. Tick marks indicate patients alive in remission. S-HAM, sequential high-dose cytarabine and mitoxantrone; CR, complete remission.

View larger version (14K): [in this window] [in a new window]   Fig 3. Overall survival in all patients entering the trial according to randomization. Tick marks indicate patients alive. S-HAM, sequential high-dose cytarabine and mitoxantrone.

View larger version (14K): [in this window] [in a new window]   Fig 4. Survival of complete responders at all ages. Tick marks indicate patients alive. S-HAM, sequential high-dose cytarabine and mitoxantrone.

View larger version (12K): [in this window] [in a new window]   Fig 5. Relapse-free survival in patients who did receive sequential high-dose cytarabine and mitoxantrone (S-HAM) consolidation or at least two courses of multiple-course maintenance. Tick marks indicate patients alive in remission. CR, complete remission.

View larger version (12K): [in this window] [in a new window]   Fig 6. Relapse-free survival according to randomization in the good prognostic group including patients with non-unfavorable karyotype and age younger than 60 years and day 16 bone marrow blasts 40% and LDH 700 U/L. Tick marks indicate patients alive in remission. S-HAM, sequential high-dose cytarabine and mitoxantrone; CR, complete remission.

View larger version (13K): [in this window] [in a new window]   Fig 7. Relapse-free survival according to randomization in the poor prognostic group including patients with unfavorable karyotype or age > 60 years or day 16 blasts > 40% or LDH > 700 U/L. Tick marks indicate patients alive in remission. S-HAM, sequential high-dose cytarabine and mitoxantrone; CR, complete remission.

	DISCUSSION

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Because all patients were randomly assigned up front for their complete therapy, a selection bias resulting from exclusions at later randomizations was avoided. This design provided an investigation of complete preselected treatment strategies, including their therapeutic effects, toxicity, practicability, and acceptance on the basis of intent to treat in a multicenter setting.

The difference in RFS cannot be explained by imbalances in the prognostic groups according to karyotype, day 16 blasts, age, and LDH. Although there is a tendency in the total population to a more frequent favorable karyotype (P = .057) and less frequent unfavorable karyotype (P = .080), in the maintenance arm this tendency becomes still less expressed in the target group of CR patients (P = .082 and .129). Notably, favorable karyotype excluding t(15;17) failed to be an independent risk factor. Furthermore, both arms were equal in the rates of CR, persistent leukemia, and early or hypoplastic death. Thus the only variable to be considered is the different first-line treatment strategy according to randomization, with maintenance chemotherapy reducing the risk of relapse more effectively than IC (56% v 68% at 3 years; P = .0094).

The superior RFS and freedom from relapse in the maintenance versus IC arm did not improve the average responder’s SV (P = .085). Influences from the salvage treatment not being part of the present protocol may account for this discrepancy. However, 111 of 128 patients surviving in the maintenance arm compared with 83 of the 110 patients surviving in the IC arm (P = .026) are still in their first CR. These data suggest that despite a similar SV so far, first-line treatment using maintenance chemotherapy in this setting provides a higher curative potential than IC.

The present trial also showed that the benefit from maintenance chemotherapy in RFS was most expressed in the poor-risk subgroup according to karyotype, day 16 blasts, age, and LDH. Other groups had reported previously that high-dose cytarabine in the postremission period⁸ and autologous transplantation⁵ improved remission duration mainly in good-risk patients according to cytogenetics⁸ or additional early response.⁵ These discrepancies in responsive groups suggest that there may be scheduling effects of treatment intensification. After first data about a specific effect of high-dose cytarabine in poor-risk patients,⁹ present data on maintenance chemotherapy again confirm an improvement of a poor prognosis by adequate chemotherapy. Good-risk patients, indeed, seemed not to further benefit from maintenance chemotherapy versus IC in their RFS (P = .28) and freedom from relapse (P = .66). Excluding the 20% good-risk patients would result in a 3-year RFS of 37% versus 21% (P = .0005) in favor of maintenance chemotherapy, also translating into a SV benefit of 47% versus 30% (P = .0085).

In conclusion, by a strict intent-to-treat comparison, maintenance chemotherapy as part of first-line treatment proved superior to IC in providing continuing first CR in the overall patient group and in poor-risk patients.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	ACKNOWLEDGMENTS

 
We thank Wolfgang Köpcke, PhD, University of Münster, for his biostatistical advice, and Sandra Cebulla for assistance in the preparation of the manuscript. We also thank the following clinicians for their cooperation: W. Augener, M. Baldus, L. Balleisen, D. Bartholomäus, H. Bartels, K. Becker, I. Blau, D. Braumann, R. Dengler, V. Diehl, I. Dörges, R. Donhuijsen-Ant, H. Eimermacher, B. Emmerich, J. Fischer, A. Föller, R. Fuchs, H.G. Fuhr, W. Gassmann, A. Giagounidis, D. Haase, F.G. Hagmann, A. Harms, J. Hartlapp, A. Heyll, W.D. Hirschmann, G. Just, J. Karow, C. Kerschgens, H. Kreiter, U. Kubica, A. Lang, M. Notter, B. Pahnke, A. Peyn, H.J. Pielken, M. Planker, H. Rasche, H.E. Reis, C. Schadeck-Gressel, B. Schlag, U. Schmitz-Hübner, G. Schott, S. Sommer, A. Thomalla, G. Trenn, A. Trittin, M. Uppenkamp, D. Urbanitz, M. Welslau, K. Ziegert.

	NOTES

 
Supported by Deutsche Krebshilfe, Bonn, Germany, grant no. M 17/92/Bü 1.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... REFERENCES

 
1. Mayer RJ, Davis RB, Schiffer CA, et al: Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331:896–903, 1994[Abstract/Free Full Text]

2. 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[Abstract/Free Full Text]

3. 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 Group study. Blood 88:2841–2851, 1996[Abstract/Free Full Text]

4. Zittoun RA, 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[Abstract/Free Full Text]

5. Burnett AK, Goldstone AH, Stevens RMF, et al: Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: Results of MRC AML 10 trial. Lancet 351:700–708, 1998[CrossRef][Medline]

6. 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[Abstract/Free Full Text]

7. Cassileth RA, 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[Abstract/Free Full Text]

8. 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[Abstract/Free Full Text]

9. 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[Abstract/Free Full Text]

10. Rai KR, Holland JF, Glidewell OJ, et al: Treatment of acute myelocytic leukemia: A study by Cancer and Leukemia Group B. Blood 58:1203–1212, 1981[Free Full Text]

11. 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[Abstract/Free Full Text]

12. Büchner T, Heyll A, Hiddemann W, et al: Superiority of allogeneic BMT in AML and subgroups: A donor vs no-donor and transplant vs matched control analysis by the AMLCG. Blood 96:201a, 2000 (abstr 859)

13. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukemias. Br J Haematol 33:451–458, 1976[Medline]

14. 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[Abstract/Free Full Text]

15. Stone RM, Berg DR, George SL, et al: Postremission therapy in older patients with de novo acute myeloid leukemia: A randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 98:548–553, 2001[Abstract/Free Full Text]

16. Lengfelder E, Reichert A, Schoch C, et al: Double induction strategy including high-dose cytarabine in combination with all-trans retinoic acid: Effects in patients with newly diagnosed acute promyelocytic leukemia—German AML Cooperative Group. Leukemia 14:1362–1370, 2000[CrossRef][Medline]

17. Büchner T, Urbanitz D, Emmerich B, et al: Multicenter study on intensified remission induction therapy for acute myeloid leukemia. Leuk Res 6:827–831, 1982[CrossRef][Medline]

18. 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[Abstract/Free Full Text]

19. Kern W, Schleyer E, Unterhalt M, et al: High antileukemic activity of sequential high dose cytosine arabinoside and mitoxantrone in patients with refractory acute leukemias: Results of a clinical phase II study. Cancer 79:59–68, 1997[CrossRef][Medline]

20. Mitelmann F (ed): An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, Karger, 1995

21. Grimwade D, Walker H, Oliver F, et al: The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. Blood 92:2322–2333, 1998[Abstract/Free Full Text]

22. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

23. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and example. Br J Cancer 35:1–39, 1977[Medline]

24. Cox DR: Regression models and life-tables (with discussion). J R Stat Soc B 34:187–220, 1972

25. 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 on 614 patients treated within the German AML Cooperative Group studies. J Clin Oncol 21:256–265, 2003[Abstract/Free Full Text]

26. Kern W, Haferlach T, Schoch C, et al: Early blast clearance by remission induction therapy is a 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 1992 Trial. Blood 101:64–70, 2003[Abstract/Free Full Text]

Submitted February 24, 2003; accepted September 30, 2003.

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				T. Buchner, W. E. Berdel, C. Schoch, T. Haferlach, H. L. Serve, J. Kienast, S. Schnittger, W. Kern, J. Tchinda, A. Reichle, et al. 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., June 1, 2006; 24(16): 2480 - 2489. [Abstract] [Full Text] [PDF]

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				T. Buchner, W. E. Berdel, C. Schoch, T. Haferlach, H. L. Serve, J. Kienast, S. Schnittger, W. Kern, J. Tchinda, A. Reichle, et al. Double Induction Containing Two Courses Versus One Course of High- Dose AraC/ Mitoxantrone (HAM) and Autologous Stem Cell Transplantation Versus Prolonged Maintenance for Acute Myeloid Leukemia (AML). Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 272 - 272. [Abstract]

				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]

				T. Haferlach, A. Kohlmann, S. Schnittger, M. Dugas, W. Hiddemann, W. Kern, and C. Schoch Global approach to the diagnosis of leukemia using gene expression profiling Blood, August 15, 2005; 106(4): 1189 - 1198. [Abstract] [Full Text] [PDF]

				W. Kern, D. Voskova, C. Schoch, W. Hiddemann, S. Schnittger, and T. Haferlach Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia Blood, November 15, 2004; 104(10): 3078 - 3085. [Abstract] [Full Text] [PDF]

				R.F. Schlenk, A. Benner, J. Krauter, T. Buchner, C. Sauerland, G. Ehninger, M. Schaich, B. Mohr, D. Niederwieser, R. Krahl, et al. Individual Patient Data-Based Meta-Analysis of Patients Aged 16 to 60 Years With Core Binding Factor Acute Myeloid Leukemia: A Survey of the German Acute Myeloid Leukemia Intergroup J. Clin. Oncol., September 15, 2004; 22(18): 3741 - 3750. [Abstract] [Full Text] [PDF]

				T. Buchner, W. E. Berdel, and W. Hiddemann Priming with Granulocyte Colony-Stimulating Factor -- Relation to High-Dose Cytarabine in Acute Myeloid Leukemia N. Engl. J. Med., May 20, 2004; 350(21): 2215 - 2216. [Full Text] [PDF]

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