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5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen.

ABSTRACT: PURPOSE:A randomized trial of oblimersen plus fludarabine/cyclophosphamide (OBL-FC; n = 120) versus FC (n = 121) was conducted in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The primary end point was met: the complete response (CR) rate, defined as complete or nodular partial response, was significantly greater with OBL-FC than with FC (17% v 7%; P = .025). Among patients with CR, response duration was significantly longer with OBL-FC than with FC (median not reached; > 36 months v 22 months; P = .03). Maximum benefit with OBL-FC, including a four-fold increase in CR rate and a survival benefit with 3 years of follow-up (hazard ratio, 0.53; P = .05), was observed in patients with fludarabine-sensitive disease. We evaluated long-term survival and poststudy CLL therapy among all randomly assigned patients. METHODS:Poststudy CLL treatment information was collected. Patients were observed for survival for up to 5 years from the date of random assignment. RESULTS:Poststudy CLL treatment was balanced between arms. Intent-to-treat analysis of 5-year survival showed no significant between-treatment difference (hazard ratio, 0.87; P = .34). Among the greater than 40% of patients with complete or partial remission, a significant 5-year survival benefit was observed with OBL-FC (hazard ratio, 0.60; P = .038). Among patients with fludarabine-sensitive disease who had previously demonstrated maximum benefit with OBL-FC, the previously observed survival benefit improved: a 50% reduction in the risk of death was observed (P = .004). CONCLUSION:In relapsed/refractory CLL, OBL combined with FC offers patients who achieve complete or partial remission, as well as those who have fludarabine-sensitive disease, a significant survival benefit.

SUBMITTER: O'Brien S

PROVIDER: S-EPMC5321078 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen.

O'Brien Susan S Moore Joseph O JO Boyd Thomas E TE Larratt Loree M LM Skotnicki Aleksander B AB Koziner Benjamin B Chanan-Khan Asher A AA Seymour John F JF Gribben John J Itri Loretta M LM Rai Kanti R KR

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20090908 31

<h4>Purpose</h4>A randomized trial of oblimersen plus fludarabine/cyclophosphamide (OBL-FC; n = 120) versus FC (n = 121) was conducted in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The primary end point was met: the complete response (CR) rate, defined as complete or nodular partial response, was significantly greater with OBL-FC than with FC (17% v 7%; P = .025). Among patients with CR, response duration was significantly longer with OBL-FC than with FC (median not re ...[more]

PMID: 19738118

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Project description:BACKGROUND: Fludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL). Over time, however, virtually all CLL patients become fludarabine-refractory. To elucidate whether microRNAs are involved in the development of fludarabine resistance, we analyzed the expression of 723 human miRNAs before and 5-days after fludarabine mono-therapy in 17 CLL patients which were classified as responder or refractory to fludarabine treatment based on NCI criteria. RESULTS: By comparing the expression profiles of these two groups of patients, we identified a microRNA signature able to distinguish refractory from sensitive CLLs. The expression of some microRNAs was also able to predict fludarabine resistance of 12 independent CLL patients. Among the identified microRNAs, miR-148a, miR-222 and miR-21 exhibited a significantly higher expression in non-responder patients either before and after fludarabine treatment. After performing messenger RNA expression profile of the same patients, the activation of p53-responsive genes was detected in fludarabine responsive cases only, therefore suggesting a possible mechanism linked to microRNA deregulation in non-responder patients. Importantly, inhibition of miR-21 and miR-222 by anti-miRNA oligonucleotides induced a significant increase in caspase activity in fludarabine-treated p53-mutant MEG-01 cells, suggesting that miR-21 and miR-222 up-regulation may be involved in the establishment of fludarabine resistance. CONCLUSIONS: This is the first report that reveals the existence of a microRNA profile that differentiate refractory and sensitive CLLs, either before and after fludarabine mono-therapy. A p53 dysfunctional pathway emerged in refractory CLLs and could contribute in explaining the observed miRNA profile. Moreover, this work indicates that specific microRNAs can be used to predict fludarabine resistance and may potentially be used as therapeutic targets, therefore establishing an important starting point for future studies.

Dataset Information

5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen.

Publications

5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen.

Similar Datasets

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