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Sustained Complete Molecular Remissions After Treatment With Imatinib-Mesylate in Patients With Failure After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia: Results of a Prospective Phase II Open-Label Multicenter Study

From the III. Med. Klinik, Johannes Gutenberg-University, Mainz; University of Ulm, II. Med. Klinik, Charité; Humboldt University, Berlin; Deutsche Klinik für Diagnostik Wiesbaden, University of Munich, University of Frankfurt, University of Düsseldorf, University of Dresden, University of Heidelberg at Mannheim, Novartis AG, Nürnberg, Germany

Address reprint requests to address: Thomas Fischer III, MD. Department of Medicine, Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany; e-mail: t.fischer{at}3-med.klinik.uni-mainz.de

PURPOSE: In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial.

PATIENTS AND METHODS: As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. Forty-four patients were enrolled and received the BCR-ABL tyrosine kinase inhibitor imatinib (IM) at a starting dose of 400 mg/d. The quality of molecular responses achieved then decided on discontinuation of IM or dose escalation up to 800 mg/d, and finally, on application of donor lymphocyte infusions.

RESULTS: Seventy percent of patients achieved a complete molecular response (CMR), defined as nested PCR-negativity for BCR-ABL in three consecutive samples. Interestingly, in four out of 10 patients who discontinued IM, CMR was durable even after cessation of IM with a median follow-up of 494 days. This suggests the possibility of long-term tumor control in a subset of patients.

CONCLUSION: The treatment strategy showed that IM treatment was well-tolerated and highly efficacious in MRD after allogeneic SCT. Moreover, this study demonstrated that evaluation of a molecular end point within a multicenter trial can be a safe and effective tool for clinical decision making.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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