Molecular evidence for minimal residual bone marrow disease in children with 'isolated' extra-medullary relapse of T-cell acute lymphoblastic leukemia.

Central nervous system (CNS) relapse confers a poor prognosis in children with acute lymphoblastic leukemia (ALL). It is uncertain whether morphologically undetectable leukemia is present in the bone marrow at the time of CNS relapse, or whether the CNS acts as a 'sanctuary' site to allow reseeding of the marrow at a later time. We examined DNA from bone marrow samples from six patients with T-cell ALL with isolated CNS relapse using sensitive polymerase chain reaction (PCR) assays to detect minimal residual disease. One of these PCR assays was based on amplification of leukemia-specific TCR-delta gene rearrangements, while the other assay relied upon detection of the c-tal deletion. In four patients, where bone marrow samples were taken at the time of CNS relapse, residual disease was detectable in every sample at a level below morphological detection. In addition, three patients had residual disease detected in their subsequent bone marrow when CNS disease was not evident. Our findings, although preliminary, suggest that relapse of leukemia in the CNS reflects resurgence of the disease in the bone marrow that is first detected clinically in the CNS. The concomitant molecular detection of bone marrow leukemia at time of 'isolated' CNS relapse in children with T-cell ALL explains subsequent bone marrow relapse in some of these children, and argues for intensive systemic therapy of these patients.