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In Reply

Department of Medicine, Hematology, and Oncology, University of Münster, Germany

Claudia Schoch, Torsten Haferlach

Department of Internal Medicine III, University of Munich, Germany

Hubert L. Serve, Joachim Kienast

Department of Medicine, Hematology, and Oncology, University of Münster, Germany

Susanne Schnittger, Wolfgang Kern

Department of Internal Medicine III, University of Munich, Germany

Joelle Tchinda

Department of Human Genetics, University of Münster, Germany

Albrecht Reichle

Department of Hematology and Oncology, University of Regensburg, Germany

Eva Lengfelder

Department of Hematology and Oncology, University of Mannheim, Heidelberg, Germany

Peter Staib

Department of Hematology and Oncology, University of Cologne, Germany

Wolf-Dieter Ludwig

Department of Hematology and Oncology, University of Berlin, Germany

Carlo Aul

Department of Hematology and Oncology, St Johannes Hospital, Duisburg, Germany

Hartmut Eimermacher

Catholic Hospital, Hagen, Germany

Leopold Balleisen

Evangelian Hospital, Hamm, Germany

Maria Cristina Sauerland, Achim Heinecke

Department of Medical Informatics and Biomathematics, University of Münster, Germany

Bernhard J. Wörmann

Department of Hematology and Oncology, Municipal Medical Centre, Braunschweig, Germany

Wolfgang Hiddemann

Department of Internal Medicine III, University of Munich, and the GSF National Center for Environment and Health, Munich, Germany

Up-front randomization in acute myeloid leukemia (AML; Fig 1) is a method for strictly prospective comparison of complete treatment strategies according to intention-to-treat, avoiding patient withdrawals and selection by later randomization.¹

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Design of the Acute Myeloid Leukemia (AML) CG 1999 trial using up-front randomization (R) for the two different intensity induction regimens thioguanine, cytarabine, and daunorubicin (TAD) –high-dose cytarabine plus mitoxantrone (HAM) versus HAM-HAM and for the two postremission treatments maintenance versus autologous stem-cell transplantation (Auto Transplant). Patients with family donors preferentially undergo allogeneic stem-cell transplantation (Allo Transplant). Randomizations are balanced against each other and balanced for prognostic groups defined by age, lactate dehydrogenase (LDH), de novo AML/secondary AML plus high-risk myelodysplastic syndrome (MDS), and cytogenetics.

General problems lie in the small numbers of patients eventually undergoing autologous SCT. Among the patients assigned up-front to autologous SCT versus maintenance and achieving CR only 51% started maintenance and 24% underwent autologous SCT. Wheatley et al in their AML 10 trial (Hann et al²; Burnett et al³) used late randomization for autologous SCT versus no further treatment (Hann et al²) or for one more consolidation course followed by autologous SCT versus consolidation and no further treatment (Burnett et al³). Their compliance rates of randomization (37% of patients chose nonrandomly assigned treatment) was 25% of the primary CR patients and their proportion of autologous SCT received was 17%. Thus, autologous SCT patients whether assigned up-front or randomly assigned late are a small highly selected and poorly defined population where the therapeutic effects are hard to translate into treatment standards.

Regarding the fundamental controversy with Drs Hills and Wheatley, we also refer to three sequential publications (Büchner et al⁴; Hills et al⁵; Büchner et al⁶) discussing up-front randomization in the context of cross-trial networking.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported by Grants No. M17/92/Bü1 and 70-2839-Bü4 from Deutsche Krebshilfe; Grant No. 01 GI 9976 from Bundesministerium für Bildung und Forschung Competence Network Acute and Chronic Leukemias; Grant No. LSH-2002-2.2.0-3 European LeukemiaNet from European Commission; and an unrestricted grant from AMGEN (Munich, Germany).

REFERENCES

1. Büchner T, Berdel WE, Schoch C, 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 24:2480-2489, 2006[Abstract/Free Full Text]

2. Hann IM, Stevens RF, Goldstone AH, et al: Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: Results of Medical Research Council's 10^th AML trial (MRC AML 10). Blood 89:2311-2318, 1997[Abstract/Free Full Text]

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

4. Büchner T, Döhner H, Ehninger G, et al: Up-front randomization and common standard arm: A proposal for comparing AML treatment strategies between different studies. Leuk Res 26:1073-1075, 2002[CrossRef][Medline]

5. Hills RK, Richards SM, Wheatley K: Corner cutting compromises clinical trials: The inherent problems with up-front randomization and a common standard arm. Leuk Res 27:1071-1073, 2003[CrossRef][Medline]

6. Büchner T, Döhner H, Ehninger G, et al: Cross-trial networking in AML: A step forward rather than corner cutting. Leuk Res 28:649-650, 2004[CrossRef][Medline]

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