Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997

Abstract

Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F vs. FC trial in untreated CLL^#. With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 vs. 48.1 months for F (n = 109) and FC (n = 118), respectively (p < 0.0001), and median overall survival (OS) was 88.0 vs. 79.1 months (p = 0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were age (p = 0.002, p < 0.001), Rai stage (p = 0.006, p = 0.02) and sex (p = 0.03, PFS only). Del(17)(p13.1) predicted shorter PFS and OS (p < 0.0001 for each), as did del(11q)(22.3) (p < 0.0001, p = 0.005, respectively), trisomy 12 with mutated Notch1 (p = 0.003, p = 0.03, respectively) and unmutated IGHV (p = 0.009, p = 0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL.

Keywords::

• Fludarabine
• cyclophosphamide
• chemotherapy
• chronic lymphocytic leukemia

Acknowledgements

The authors would like to thank the patients and physicians who participated in E2997 and contributed samples, and the cooperative groups (ECOG, SWOG and CALGB, now Alliance) that joined in this effort. The correlative studies described here were supported by the US National Institutes of Health (NIH) (R01 CA88647 and P50 CA140158). The E2997 clinical study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis and Mitchell D. Schnall, Co-Chairs) and supported in part by NIH grants CA23318, CA66636, CA21115, CA180820, CA180794, CA16116, CA180802, CA180791, CA14958, CA11083, CA13650, CA180790, CA35431, CA31946, CA32102, CA20319 and CA17145. R.C. receives a fellowship from the German Research Society (DFG) and is supported by the German Cancer Aid (Max Eder stipend, DKH 110461). C.P. is supported by the NIH (P01 CA101956), the German Cancer Research Center and the German Cancer Consortium. The content of this paper is solely the responsibility of the authors, and does not necessarily represent the official views of the NIH.

Potential conflict of interest

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