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In Reply:

Children’s Cancer Institute Australia for Medical Research, and Sydney Children’s Hospital, Sydney, Australia

We believe the poor overall survival rate seen in our study may have been related to the use of the weekly Erwinia, rather than E. Coli, L-asparaginase intensification, as has now been reported by other groups.¹ The inferior asparagine depletion achieved by weekly Erwinia L-asparaginase was unknown as the time of the study. Indeed, one treatment arm of Australian and New Zealand Childhood Cancer Study Group acute lymphoblastic leukemia (ALL) Study 5, the precursor study to our minimal residual disease (MRD) Study 6, included an identical arm of therapy, but instead E. Coli L-asaparaginase was used. The overall 5-year survival was 10% higher than in our MRD study. Although it is possible that the lower than expected survival rate in the MRD study may have affected the survival benefit of late therapy intensification, the prognostic impact of MRD testing at the end of induction confirms previous studies that have analyzed MRD at this time point.^2,3 The independent prognostic value of MRD testing at the end of therapy requires confirmation in a larger study an in this regard another trial is currently underway.

Dr Aricò et al suggest that in order to properly assess the impact of intervention therapy at 12 months, it would be worthwhile to know the outcome data on those children who were truly randomly assigned. In the article, we do explain that only 67% of patients in the study cohort were truly randomly assigned. For these patients, the relapse-free survival rate was 58% for arm A and 53% for arm B, indicating that late intensification of therapy did not produce a statistically significant (P = .90) benefit in our study. Although patients in this group who were MRD positive at 12 months and received late intensification of therapy (n = 22) had an inferior survival rate compared with those who did not, this was again statistically nonsignificant (P = .80). Thus, the effects that we observed were the same, even with the exclusion of patients not randomly assigned, and these effects support the data presented in the article indicating no significant difference in the risk of relapse between arm A and arm B. In addition, the relapse rates were not significantly different for these randomly assigned patients when they were subdivided on the basis of the arm of therapy received at 1, 12, or 24 months.

In response to the query regarding the number of relapses in Figure 2 and 3,⁴ the assessment of MRD was only made in bone marrow samples at 12 or 24 months, if those patients from whom the samples were taken were still in first remission at the time of the MRD assessment. For MRD testing on the 12-month bone marrow samples, we agree with Dr Aricò that relapses occurring between 12 and 24 months should not be excluded from the analyses, and in fact they were not. Finally, among the cohort of MRD-assessable patients in our study, there were no deaths in remission.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

We thank Dr. Aricò and his coauthors for their comments and suggestions.

REFERENCES

1. Duval M, Suciu S, Ferster A, et al: Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: Results of a randomized European Organization for Research and Treatment of Cancer—Children’s Leukemia Group phase III trial. Blood 99:2734–2739, 2002[Abstract/Free Full Text]

2. Cave H, van der Werff ten Bosch J, Suciu S, et al: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia: European organization for research and treatment of cancer—Childhood leukemia cooperative group. N Engl J Med 339:591–598, 1998[Abstract/Free Full Text]

3. van Dongen JJM, Seriu T, Panzergrumayer ER, er al. Prognostic value of minimal residual disease in acutre lymphoblastic leukaemia in childhood. Lancet 352:1731–8, 1998[CrossRef][Medline]

4. Marshall GM, Haber M, Kwan E, et al: Importance of minimal resideual disease testing during the second year of therapy for children with acute lymphoblastic leukemia. J Clin Oncol 21:704–709, 2003[Abstract/Free Full Text]

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