Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster I
Hematology Disease Topics & Pathways:
Leukemia, Diseases, CLL, Therapies, Combinations, Lymphoid Malignancies, Clinically relevant
Aims - Here we evaluated the ability of telomere lenght (TL) and CD49d to cooperate with IGHV gene status to predict progression-free survival (PFS) in patients treated with FCR-based regimens in the frontline setting in three UK trials, ARCTIC, ADMIRE and CLL4.
Methods - The study included a discovery cohort of 245 CLL treated with FCR/FCR-like regimens according to the two UK trials ARCTIC and ADMIRE. As there was no significant difference in PFS between the three arms of the study (P = 0.97), analysis was performed on the combined cohort. The median follow-up was 77.5 months with 157 progressions and 76 deaths. Twenty-nine patients were TP53 deleted and/or mutated, with shorter PFS compared to cases without TP53 disruption (final cohort, 216 TP53 wild-type CLL). The validation cohort was composed of 119 CLL samples derived from patients randomised to receive fludarabine, cyclophosphamide (FC) from the UK CLL4 trial. The median follow-up was 67.2 months with 99 progressions and 77 deaths. Fifteen CLL were TP53 mutated/deleted, with shorter PFS compared to cases without TP53 disruption (final cohort, 104 TP53 wild-type CLL). TL was measured using the high-throughput STELA assay and patients were bifurcated into two groups with either short telomeres inside the fusogenic range (TL-IFR) or long telomeres outside the fusogenic range (TL-OFR). CD49d was measured by flow cytometry and dichotomized as CD49dpos and CD49dneg based on the established 30% cut-off. For IGHV gene status, the 2% cutoff was used to split patients in mutated (IGHV-M) and ummutated (IGHV-UM).
Results - In the 216 CLL with wild-type TP53 status from the ARCTIC/ADMIRE trials, CD49d expression was a predictor of PFS (P=0.02; HR=1.46 [1.03-2.06]). In keeping with previous reports, patients with IGHV-UM genes (P<.0001; HR=2.53 [1.79-3.58]) or TL-IFR (P=0.0002; HR=1.97 [1.30-2.98]) showed also significantly shorter PFS. This data was used as a starting point for a risk-stratification algorithm (Figure 1A). IGHV-UM cases could not be further dissected by TL or CD49d expression (P=0.76 log-rank test), their 8-year PFS being just 19.0%; (HR=5.58 [3.70-8.42]). In contrast, the IGHV-M group could be stratified by TL and CD49d expression (P<0.001 log-rank test). In particular, 13/84 (15.5%) of IGHV-M CLL with TL-IFR showed a median PFS of 3.0 years with a 8-year PFS of 15.4% (HR=6.45 [1.84-22.58]), similar to IGHV-UM cases (P = 0.19). Patients with IGHV-M genes and TL-OFR could be further stratified by CD49d expression into categories with different 8-year PFS: 43.1% in IGHV-M/TL-OFR/CD49dpos cases (HR=2.52 [1.08-5.89]), and 75.5% in the IGHV-M/TL-OFR/CD49dneg reference group (Table 1). Figure 1B shows the overlaid Kaplan-Meier curves for this hierarchical stratification. The proposed algorithm was then evaluated in the UK CLL4 trial. In keeping with the known inferiority of FC when compared with FCR, the 8-year PFS was just 5.2% in the IGHV-UM subset, irrespective of TL or CD49d expression. In concordance with the discovery cohort, the IGHV-M subset with TL-IFR had a similar median PFS to IGHV-UM cases (P=0.84). Furthermore, CD49d expression was able to stratify cases with TL-OFR; in particular, 18/104 (17.3%) were IGHV-M/TL-OFR/CD49dneg CLL which had a 8-year PFS of 77.8% ( summary in Table 1 and Figure 1C).
Conclusion - Our analysis shows that only IGHV-M/TL-OFR/ CD49dneg patients may benefit from CIT; this group represented just 56/321 cases (17.4%) of the combined cohort, suggesting that approximately 82% of patients should be considered for alternative therapies. Incorporation of this algorithm into clinical trial design and real-world practice would enable rational, risk-adapted, clinical management with the aim of treating all CLL patients with the optimal therapeutic regimen in the frontline setting.
Disclosures: Norris: TeloNostiX Ltd: Current equity holder in private company, Patents & Royalties. Hillmen: Gilead: Other: Financial or material support, Research Funding; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau. Rawstron: BD Biosciences (Intrasure): Patents & Royalties. Baird: TeloNostiX Ltd: Current equity holder in private company, Patents & Royalties. Fegan: TeloNostiX Ltd: Current equity holder in private company, Patents & Royalties. Pepper: TeloNostiX Ltd: Current equity holder in private company, Patents & Royalties.
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