title: Serial minimal residual disease (MRD) analysis as a predictor of response duration in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) during imatinib treatment.
abstract: Patients with refractory or relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) rarely have prolonged responses to salvage therapy, including imatinib, resulting in a short opportunity for potentially curative stem cell transplantation. To identify minimal residual disease (MRD) parameters predictive of imminent relapse, we quantitated Bcr-Abl expression by real-time PCR in peripheral blood (PB) and bone marrow (BM) of 24 Ph+ALL patients after achieving a complete response and MRD minimum. The ratio of Bcr-Abl and glyceraldehyde-3-phosphate dehydrogenase copies, magnitude of increase and velocity of increase were evaluated regarding subsequent time intervals to relapse, death or censoring. High Bcr-Abl levels >/=5 x 10(-4) in PB (n=23) and >/=10(-4) in BM (n=18) were significantly associated with short time periods to relapse. Bcr-Abl increases >2 logarithmic units (log) in PB, but not in BM preceded short-term relapse. The velocity of Bcr-Abl increases predicted response duration in PB (cutoff: 1.25 log/30 days) and BM (0.6). Bcr-Abl level and velocity of increase in BM as well as magnitude of increase in PB correlated with remaining periods of survival and predicted relapse within 2 months in nine of 10, 10 of 11 and four of four patients, respectively. Thus, these MRD parameters may guide timing and intensity of therapeutic modifications.
authors.affiliation: Department of Hematology and Oncology, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany.
authors.forename: U J
authors.initials: UJ
authors.lastname: Scheuring
authors.forename: H
authors.initials: H
authors.lastname: Pfeifer
authors.forename: B
authors.initials: B
authors.lastname: Wassmann
authors.forename: P
authors.initials: P
authors.lastname: Brück
authors.forename: B
authors.initials: B
authors.lastname: Gehrke
authors.forename: E K
authors.initials: EK
authors.lastname: Petershofen
authors.forename: H
authors.initials: H
authors.lastname: Gschaidmeier
authors.forename: D
authors.initials: D
authors.lastname: Hoelzer
authors.forename: O G
authors.initials: OG
authors.lastname: Ottmann
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D018365:Neoplasm, Residual / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis*; D012334:RNA, Neoplasm / Q000235:genetics; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016879:Salvage Therapy; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000068877:Imatinib Mesylate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl