CORRESPONDENCE

RESPONSE: Re: Consolidation Therapy With Autologous Bone Marrow Transplantation in Adults With Acute Myeloid Leukemia: A Meta-analysis

Paul C. Nathan, Lillian Sung, Michael Crump, Joseph Beyene

Affiliations of authors: National Cancer Institute, Pediatric Oncology Branch, Bethesda, MD (PCN); Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children (LS), Department of Medicine, Princess Margaret Hospital, University Health Network (MC), Department of Health Policy Management and Evaluation (LS), Department of Public Health Sciences (JB), The University of Toronto, Toronto, Ontario, Canada; Program in Population Health Sciences, The Hospital for Sick Children, Toronto (LS, JB).

Correspondence to: Lillian Sung, MD, FRCPC, The Hospital for Sick Children, Division of Haematology/Oncology, 555 University Ave., Toronto, ON, Canada M5G 1X8 (e-mail: lillian.sung{at}sickkids.ca)

In their letter to the Journal, as well as in their meta-analysis (1), Levi et al. contend that a decline in the treatment-related mortality associated with the use of peripheral blood stem cells instead of bone marrow for autologous transplantation supports the routine use of autologous stem cell transplantation (ASCT) in adults with acute myeloid leukemia in first remission. Although we agree that this strategy warrants further study in a prospective, randomized clinical trial, we have several concerns about the assumptions that the authors have made in order to reach their conclusions.

First, the simulations presented by Levi et al. assume that improvements in supportive care and the development of safer transplant techniques have decreased treatment-related mortality among patients who receive an ASCT. The simulations do not account for improvements in survival as a result of better supportive care in patients who receive chemotherapy alone. Such a decrease in treatment-related mortality over time, for example, was observed among children who were treated with chemotherapy alone on the Tenth Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML 10) (2). The authors’ supposition that treatment-related mortality has decreased only among transplant recipients biases their analysis in favor of ASCT. In our meta-analysis, we noted that the pooled treatment-related mortality among patients who were randomly assigned to receive chemotherapy (or no further treatment) was 4.4% (3). The authors’ assumption of a 3% treatment-related mortality in the ASCT arm of their second simulation suggests that ASCT results in a lower risk of treatment-related mortality than chemotherapy alone—a contention that is not supported by the available literature.

Second, the authors’ assertion that the treatment-related mortality among patients receiving ASCT is currently 0%–6% is based on data from patients who actually received ASCT (4). However, such an analysis by treatment received is biased in favor of ASCT. Patients who actually undergo transplantation will have better outcomes when compared with all patients randomly assigned to receive transplantation because some of the latter patients will relapse or die before receiving the procedure or will be too ill to proceed to transplantation. Therefore, an intent-to-treat analysis is more appropriate for comparing transplantation with chemotherapy than an analysis by treatment received. Both the original meta-analysis published by Levi et al. (1) and our meta-analysis (3) based calculations of survival on intent-to-treat analyses. In the absence of data from a randomized clinical trial, it is impossible to know whether a decrease in mortality among patients who receive peripheral blood stem cells is attributable to a true reduction in treatment-related mortality or, at least in part, to the use of an analysis of only patients who received the treatment.

Third, the formula used by Levi et al. to calculate the expected deaths in the ASCT arm is unconventional. We urge the authors to clarify their calculations and provide a reference for their approach.

Although we agree that the role of ASCT among patients in first remission of acute myeloid leukemia warrants further study, we caution against drawing conclusions by combining the results of previous randomized studies of autologous bone marrow transplantation with estimates of survival of ASCT derived from current single-arm studies.

REFERENCES

1 Levi I, Grotto I, Yerushalmi R, Ben-Bassat I, Shpilberg O. Meta-analysis of autologous bone marrow transplantation versus chemotherapy in adult patients with acute myeloid leukemia in first remission. Leuk Res 2004;28:605–12.[CrossRef][ISI][Medline]

2 Riley LC, Hann IM, Wheatley K, Stevens RF. Treatment-related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML 10). Br J Haematol 1999;106:436–44.[CrossRef][ISI][Medline]

3 Nathan PC, Sung L, Crump M, Beyene J. Consolidation therapy with autologous bone marrow transplantation in adults with acute myeloid leukemia: a meta-analysis. J Natl Cancer Inst 2004;96:38–45.[Abstract/Free Full Text]

4 Gorin NC. Autologous stem cell transplantation in acute myelocytic leukemia. American Society of Hematology Education Program Book. 1999:119–37.



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