NOTCH1, SF3B1 and TP53 mutations in fludarabine-refractory CLL patients treated with alemtuzumab: results from the CLL2H trial of the GCLLSG

Andrea Schnaiter, Peter Paschka, Marianna Rossi, Thorsten Zenz, Andreas Bühler, Dirk Winkler, Mario Cazzola, Konstanze Döhner, Jennifer Edelmann, Daniel Mertens, Sabrina Kless, Silja Mack, Raymonde Busch, Michael Hallek, Hartmut Döhner and Stephan Stilgenbauer

Key points

  • In the refractory cohort of the CLL2H trial PFS was significantly longer in patients with NOTCH1 mutation.

  • SF3B1 mutation had no impact on response rates or survival times in fludarabine-refractory patients.


We studied the incidences, associations and prognostic roles of NOTCH1 and SF3B1 mutations (NOTCH1mut, SF3B1mut) as compared to TP53mut in fludarabine-refractory chronic lymphocytic leukemia (CLL) patients treated with alemtuzumab on the CLL2H trial. We found NOTCH1mut, SF3B1mut and TP53mut in 13.4%, 17.5% and 37.4% of patients, respectively. NOTCH1mut and SF3B1mut were mutually exclusive, whereas TP53mut were evenly distributed within both subgroups. Apart from correlation of SF3B1mut with 11q deletion (p=.029), there were no other significant associations of the mutations with any baseline characteristics or response rates. However, NOTCH1mut cases had a significantly longer progression-free survival (PFS) compared to wild type (WT) cases (15.47 vs. 6.74 months; p=.025) while there was no significant difference regarding OS. SF3B1mut had no significant impact on PFS and overall survival (OS). In multivariable analyses, NOTCH1mut was identified as an independent favorable marker for PFS. This clinical trial is registered at as #NCT00274976.

  • Submitted March 11, 2013.
  • Accepted June 10, 2013.