Closing the gap for detection of residual posttransplantation leukemia?

The detection of minimal residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (HSCT) by molecular methods has become an important diagnostic tool for clinical decision-making with regard to posttransplantation immunomodulatory measures, such as the withdrawal of immunosuppression or adoptive infusions of donor lymphocytes. The high efficacy of early interventions directed against residual molecular and cytogenetic disease after allogeneic HSCT is best documented for imminent relapses of chronic myelogenous leukemia as demonstrated by the induction of complete and durable cytogenetic, as well as molecular, responses in patients with residual cells bearing thebcr-abl gene rearrangement and its chimeric transcripts. Indeed, the success of adoptive cellular immunotherapy of MRD after allogeneic HSCT currently represents some of the most convincing clinical evidence supporting the concept of cellular immunotherapy of human cancer.

The Wilms tumor suppressor gene (WT1) encodes a zinc-finger transcriptional factor that can modulate the expression of several genes coding for growth factors and their receptors. Transient expression of WT1 has been detected in small fractions of uncommitted and lineage-committed hematopoietic progenitor cells, but the functional role of WT1 in the development and regulation of the normal hematopoiesis is currently not well characterized. Further, constitutive expression of wild-type or mutantWT1 has been demonstrated in a variety of hematologic malignancies and, particularly, in blasts of nearly all acute leukemias irrespective of lineage-specificity. Therefore, WT1expression may be regarded as a nonspecific “panleukemic” molecular marker, and quantitative monitoring of WT1 transcripts holds promise to become a universal tool for the evaluation of MRD after chemotherapy or HSCT, especially for the approximately 50% of acute leukemias without an established disease-specific gene rearrangement.

This expectation is further promoted by the work of Ogawa and coworkers (page 1698), which strongly supports that sequential analyses ofWT1 transcript expression levels in marrow cells after allogeneic HSCT can be used to reliably predict leukemic relapse and responses to immunomodulatory interventions against imminent or overt posttransplantation relapse. If confirmed by larger prospective studies, this work would substantially contribute to close the diagnostic gap of MRD detection and to define universal MRD thresholds for clinical decision-making after HSCT.