Kategorie: Maligní lymfomy a leukémie
Téma: Chronic lymphocytic leukemia and related disorders - Clinical
Číslo abstraktu: S1344
Autoři: Dr. Eugen Tausch; Christina Galler; M.D. Richard F. Schlenk; Peter Hillmen, M.B. ChB, Ph.D.; MD Fritz C. Offner, PhD; MD Ann Janssens; Dr. K. Govind Babu, D.M.; M.D. Sebastian Grosicki; prof. MUDr. Jiří Mayer, CSc.; M.D. Panagiotis Panagiotidis; Astrid McKeown, Ph.D.; Paul D. Winter; MD Ira (V.) Gupta; Prof. Dr. med. Hartmut Döhner (Doehner); MD Stephan Stilgenbauer
Background: Mutations in SF3B1 (SF3B1mut), a gene of the spliceosome machinery, have been found in CLL with an incidence of 10 to 20% and have been associated with male gender, CD38 positivity, unmutated IGHV, 11q-, absence of +12q and poor outcome. In the UK CLL4 and GCLLSG CLL8 trials SF3B1mut was found as an independent unfavorable prognostic factor for progression free survival (PFS).
Aims: We assessed the incidence and impact of SF3B1mut in the OMB110911 trial (1st line Chl vs. O+Chl) in patients considered inappropriate for fludarabine-based therapy.
Methods: Pretreatment samples were available from 376 (84.1%) patients with informed consent and representative for the full trial population (signed informed consent). We performed Illumina MiSeq amplicon based NGS for exons 14, 15, 16 and 18 of SF3B1. Exact variant frequency calling of the mutant allele was possible due to deep sequencing with a median depth of 2278x.
Results: In total, 56 mutations in SF3B1 were found in 53 of 376 patients (14.1%). All mutations were missense variants, and 50 of 56 mutations have been previously reported in CLL. Mean variant fraction among patients with one SF3B1mut was 0.31 whereas it was 0.16 in 3 patients carrying two distinct SF3B1mut mutations, indicating different subclones.
SF3B1mut was significantly associated with higher white blood cell count (WBC) at baseline (129G/L vs. 90G/L, p=0.01), male sex (p=0.02) and a trend to absence of +12q (p=0.06) and 17p- (p=0.09). Mutations in NOTCH1 andSF3B1 were mutually exclusive (p=0.01). There was no association of SF3B1mut with age, Binet stage, B symptoms, splenomegaly, lymph node size, CIRS, ECOG, ß2-MG, IGHV status, deletion of 6q, 11q, and 13q.
Regarding response to treatment, SF3B1mut had no significant impact on OR or CR rate in both arms. At a median follow-up time of 29.0 months, there were 249 (66.2%) events for PFS and 63 (16.8%) for OS. SF3B1mut was associated with shorter PFS (median 13.4 vs. 17.7 months, HR 1.662, p<0.01) and this impact was found in both treatment arms (O+Chl: HR=1.652 vs. Chl: HR=1.515). Comparison of treatments confirmed the beneficial effect of O+Chl in the subgroup with SF3B1mut (median 17.3 vs. 10.8 months, HR=0.496, p=0.03).
To identify factors of independent prognostic impact, we performed multivariable Cox regressions for PFS and OS including the following variables: treatment, sex, age, Binet stage, ECOG status, CIRS, B symptoms, WBC, ß2-MG, 11q, 17p, IGHV, NOTCH1 and SF3B1. For PFS, the following independent prognostic factors were identified: O+Chl (HR 0.40, p<0.001), WBC > 50Gl/l (HR 2.59, p<0.001), CIRS Score >8 (HR 1.66 p<0.01), male gender (HR 1.40 p=0.04), unmutated IGHV (HR 1.38 p=0.04), 17p- (HR 3.32 p<0.001) and and NOTCH1mut (HR 1.46 p=0.04), but not SF3B1 (HR=1.10 p=0.62). Interestingly, multivariable analysis with exclusion of WBC, as was frequently performed in previous studies, led to inclusion of SF3B1mut as an independent adverse prognostic factor (HR 1.45, p=0.04).
Regarding OS, WBC > 50Gl/l (HR 2.60 p=0.01), ß2-MG > 5mg/l (HR 2.56 p<0.01), Binet Stage C (HR 2.16 p=0.01), 17p- (HR 4.83 p=0.001) and unmutated IGHV (HR 1.90 p=0.05) were identified as independent prognostic factors. There was no significant impact of SF3B1mut on OS, neither in univariate (median survival not reached, HR 1.26, p=0.5) nor in multivariate analysis, and independently of WBC inclusion.
Summary/Conclusion: In the OMB110911 trial evaluating 1st line O+Chl against Chl, SF3B1mut was associated with high WBC, male sex, absence of NOTCH1mut and showed a trend to absence of +12q and 17p-. SF3B1mut was significantly associated with shorter PFS in univariate analysis but not in multivariable analysis possibly due to its association with high WBC. Subjects with SF3B1mut benefited from the addition of Ofatumumab to Chl (O+Chl).
Keywords: CD20, Chronic lymphocytic leukemia, Clinical trial, Mutation analys
Datum přednesení příspěvku: 15. 6. 2014