The Significance of BCR-ABL Transcripts after Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia

Abstract

The discovery of the BCR-ABL fusion gene was a landmark in our understanding of the molecular basis of chronic myeloid leukemia (CML) [1]. This led rapidly to the demonstration that BCR-ABL transcripts could be identified using the PCR [2]. Next, it was shown that some patients in complete cytogenetic remission after an allogeneic transplantation had no detectable BCR-ABL transcripts in their blood or bone marrow [3]. A technically rather demanding technique for quantitating BCR-ABL transcripts was then developed [4], which showed that, at least for CML patients, blood and marrow gave comparable results. The advent of Taqman methodology greatly simplified measurement of BCR-ABL transcripts in the blood of transplant recipients and today results are routinely expressed as a ratio of BCR-ABL transcript numbers related to a control gene. This ratio is usually reported as a percentage on a log scale, where 100% reflects a hypothetical untreated patient with CML. A patient with a 3-log reduction (0.1%) in BCR-ABL transcript numbers is said to have achieved a major molecular response and a patient with no detectable transcripts is said to be in complete molecular response (CMR). Another landmark was the report by Kolb and colleagues in 1990 that patients in relapse after an allotransplantation could be treated successfully by infusion of lymphocytes collected from the original donor togetherwith interferon [5]. Later, it was shown that this effect resulted from the donor lymphocytes and not interferon [6]. The capacity for these donor lymphocyte infusions (DLI) to restore CMR is presumed to be due to a “graft-versus-leukemia” effect and this observation remains one of the most convincing examples of the potential beneficial effect of immune therapy in man. Kaeda et al. reported in 2006 that patients in seeming complete remission posttransplantation sometimes had BCR-ABL transcripts detected at low levels, yet relapse was not inevitable and subsequent testing may show no evidence of transcripts without any further therapy [7]. Because of the potential to treat the patients in relapse with DLI, it became important to agree on a definition of relapse and it was proposed that a patient with a transcript level of >.02% on 3