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© 2003 American Society for Clinical Oncology
Importance of Minimal Residual Disease Testing During the Second Year of Disease: Still No Answer?Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP), Palermo, Italy To the Editor: In their paper, Marshall et al1 report on the result of a trial designed to address two main issues: the prognostic value of polymerase chain reaction (PCR)-based minimal residual disease (MRD) of childhood acute lymphoblastic leukemia (ALL) measured during the second year of disease and the role of randomized, delayed chemotherapy intensification at 1 year to prevent disease relapse in patients showing MRD positivity at 12 months. The Australian and New Zealand Children’s Cancer Study Group has once more contributed to the development of research in this area: several years after reporting the prognostic value of PCR-based determination of MRD, this group has tried to use this information for treatment alteration. The design of this trial appears reasonable and appealing, which makes this report very interesting. The authors conclude that assaying MRD at 1 and 24 months can identify almost all patients who will experience disease relapse thereafter; these results are complementary in that they identify different subpopulations of patients at risk for ALL relapse. Unfortunately, one disappointing message from this article is that late treatment intensification, even with a treatment element—the Berlin-Frankfurt-Muenster protocol II—that has been recognized as very effective in childhood ALL, is not able to rescue patients with MRD positivity at 12 months. Although the design of the trial appears fully adequate for its aim, and the number of patients recruited for the study was elevated (N = 597), the number of patients remaining fully assessable for MRD (n = 85) is rather low. Furthermore, the patients’ outcome appears inadequate, with an overall 5-year relapse-free survival (RFS) rate of only 64% for the whole group and 60% for the MRD study subgroup. The study design made ineligible for the trial patients with major deviations, patients who did not achieve disease remission, and patients with t(9;22) translocation. This is expected to result in an even more favorable patient selection, which is not reflected in the present outcome data. Randomized application of delayed intensification at 12 months was aimed at investigating the ability of this treatment modification to rescue patients with either persistent or recurring MRD positivity. Surprisingly, the group receiving delayed intensification had an apparently, although not significantly, inferior outcome compared with that of patients who received regular continuation therapy (RFS, 66% v 71%; P = .23). Within the MRD study group of 82 assessable patients, the outcome was comparable for the 27 patients who received intensification compared with their 55 controls (RFS, 63% v 62%, respectively). Even more surprisingly, among the patients who were MRD-positive at 12 months, receiving delayed intensification was associated with a lower RFS rate (27% v 41%). In addition, the validity of these comparisons is jeopardized by the inclusion of patients who were not randomly assigned. In view of the numbers presented in Study Design and Statistical Analysis, these patients appear mostly to have undergone the standard maintenance (arm A) and to have been considered in this arm without ever being randomly assigned to it. Results should be given on properly randomly assigned patients. To obtain as much information as possible from this appealing trial, the authors might have included a description of the raw numbers of patients in the randomized treatment arms; MRD results at 1, 12, and 24 months; and the pattern of events in time. This would also clarify that the lack of relapses in the first 24 months, as seen in Figure 2 and 3, but not in Figure 1, is due to the necessity of time-dependent evaluation of MRD after 1 month. In addition, the two evaluations of the 12-month bone marrow relapses that occurred between 12 and 24 months should not have been excluded. This might explain why the authors obtained a lower predictive value for point 12 MRD than for point 24 MRD. Finally, although one can assume that most of the treatment failures were due to bone marrow relapse, it could be useful to have also details on the event-free-survival rates of these patients and the details of the type of failures. The message that late intensification of treatment for childhood ALL in patients who achieved remission but showed MRD positivity at 12 months is unable to prevent ALL relapse may have relevant implications, including additional criteria for eligibility to allogeneic hematopoietic stem-cell transplant. Before we accept this finding, we need to carefully evaluate the results of this study, including possible patients’ selection or treatment modification, which might have altered the study results. More is not always better, but we must know if and why it appears to be even worse. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCE
1. Marshall GM, Haber M, Kwan E, et al: Importance of minimal residual disease testing during the second year of therapy for children with acute lymphoblastic leukemia. J Clin Oncol 21:704–709, 2003
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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