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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 × 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.

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Acknowledgements

The present study was supported by grants from the BMBF Competence Network ‘Acute Leukemias’ Grant No. 01G19971, the German Genome Research Network (NGFN) and the Adolf Messer Stiftung, Germany.

We are indebted to S Kriener, MD for the pathological review of marrow histologies, to Anja Binckebank for coordinating the study and to Anja Goodwin, Rabia El Kalaäoui, Heike Nürnberger, Martine Pape, Holger Thüringer and Sandra Wagner for their excellent technical assistance.

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Scheuring, U., Pfeifer, H., Wassmann, B. et al. Serial minimal residual disease (MRD) analysis as a predictor of response duration in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) during imatinib treatment. Leukemia 17, 1700–1706 (2003). https://doi.org/10.1038/sj.leu.2403062

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