In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib

Abstract

It is not clear if absence of BCR-ABLtranscripts-complete molecular response (CMR)-is synonymous with, or required for, cure of chronic myeloid leukemia (CML). Some patients achieve CMR with imatinib (IM), but most relapse shortly after treatment discontinuation. Furthermore, most patients in long-term remission (LTR) post-stem cell transplantation (SCT) are considered functionally cured, although some remain occasionally positive for low-level BCR-ABL mRNA. Interpretation of the latter is complicated because it has been observed in healthy subjects. We designed a patientspecific, highly sensitive, DNA quantitative polymerase chain reaction to test follow-up samples for the original leuke-

Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR

“…19 The methodological approach was very similar to our own, except that nesting was not used. Nesting was found not to confer higher sensitivity than an efficient and specific real-time PCR.…”

Standardized definitions of molecular response in chronic myeloid leukemia

“…One possibility is the measurement of BCR-ABL fusion junctions from genomic DNA, an approach that is technically demanding and labor intensive because the genomic breakpoints need to be characterized for each patient and individual detection assays designed and validated. 20,30,31 Notwithstanding these technical hurdles, one study reported that all patients (n ¼ 10) who lost CMR after imatinib cessation had detectable levels of BCR-ABL on analysis of genomic DNA, and patients who maintained CMR displayed a stable level of BCR-ABL DNA. 20 These data may provide a rationale to use genomic DNA as a methodology to monitor residual disease, at least on a research basis.…”

Do we have to kill the last CML cell?

“…This has led us and others to investigate the use of patient-specific BCR-ABL genomic DNA breakpoints as an investigational test to improve the lower limit of detection of MRD. [17][18][19][20] In order to perform patient-specific DNA PCR in CML, it is necessary to identify the BCR-ABL fusion region and to design primers for each patient to ensure specificity for the unique fusion sequence (Figure 1). The use of a patient-specific DNA sequence as the marker of the leukaemic clone is well established in acute lymphoblastic leukaemia, in which the target sequence is either the immunoglobulin gene or the T cell receptor gene rearrangement.…”