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Importance of Minimal Residual Disease Testing During the Second Year of Therapy for Children With Acute Lymphoblastic Leukemia

Glenn M. Marshall, Michelle Haber, Edward Kwan, Ling Zhu, Daniella Ferrara, Chengyuan Xue, Michael J. Brisco, Pamela J. Sykes, Alexander Morley, Boyd Webster, Luciano Dalla Pozza, Keith Waters, Murray D. Norris

From the Children’s Cancer Institute Australia for Medical Research, Sydney Children’s Hospital Randwick, and Children’s Hospital at Westmead, Sydney; Flinder’s Medical Centre, Adelaide; Royal Children’s Hospital, Melbourne, Australia; and the Australian and New Zealand Children’s Cancer Study Group.

Address reprint requests to Murray Norris, PhD, Children’s Cancer Institute Australia for Medical Research, PO Box 81, Randwick, 2031, Sydney, Australia; email: m.norris{at}unsw.edu.au

Purpose: A high level of minimal residual disease (MRD) after induction chemotherapy in children with acute lymphoblastic leukemia (ALL) is an indicator of relative chemotherapy resistance and a risk factor for relapse. However, the significance of MRD in the second year of therapy is unclear. Moreover, it is unknown whether treatment intervention can alter outcome in patients with detectable MRD.

Patients and Methods: We assessed the prognostic value of MRD testing in bone marrow samples from 85 children at 1, 12, and 24 months from diagnosis using clone-specific polymerase chain reaction primers designed to detect clonal antigen receptor gene rearrangements. These children were part of a multicenter, randomized clinical trial, which, in the second year of treatment, compared a 2-month reinduction-reintensification followed by maintenance chemotherapy with standard maintenance chemotherapy alone.

Results: MRD was detected in 69% of patients at 1 month, 25% at 12 months, and 28% at 24 months from diagnosis. By univariate analysis, high levels of MRD at 1 month, or the presence of any detectable MRD at 12 or 24 months from diagnosis, were highly predictive of relapse. Multivariate analysis showed that MRD testing at 1 and 24 months each had independent prognostic significance. Intensified therapy at 12 months from diagnosis did not improve prognosis in those patients who were MRD positive at 12 months from diagnosis.

Conclusion: Clinical outcome in childhood ALL can be predicted with high accuracy by combining the results of MRD testing at 1 and 24 months from diagnosis.

Supported by research grants from the National Health and Medical Research Council, Government Employees Medical Research Fund, and the New South Wales Cancer Council, Australia.

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