Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome.

METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1^st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined.

RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%.

Regarding baseline characteristics, we found significant associations: TP53^mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATM^mut with high WBC (p=0.02), and 11q- (p<0.01); MYD88^mut with mutated IGHV (p=0.02); FBXW7^mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3^mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1^mut (p=0.05). POT1^mut was more frequent in NOTCH1^mut cases (p=0.02) without associations with any other baseline parameter.

Regarding response to treatment, TP53^mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes.

At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53^mut (HR 2.07, p<0.01), NOTCH1^mut (HR 1.50, p=0.01) and SF3B1^mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATM^mut: HR 1.40, p=0.07).

Analyzing both treatment arms separately, TP53^mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1^mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATM^mut and BIRC3^mut mutations were only adverse prognostic factors with Chl monotherapy (ATM^mut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3^mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53^mut cases (HR 3.69, p<0.01). Of note, none of the MYD88^mut cases (n=10) had died within the follow-up period.

To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53^mut (HR 1.81, p=0.03), NOTCH1^mut (HR 1.63, p<0.01) and SF3B1^mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53^mut showing a trend (HR 2.14, p=0.10).

CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1^st line O-Chl against Chl. An independent prognostic impact was identified for TP53^mut, NOTCH1^mutand SF3B1^mut regarding PFS. Notably, NOTCH1^mut affected outcome mainly with O-Chl treatment, whereas ATM^mut and BIRC3^mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact.