3006 - High-risk International Prognostic Score for early asymptomatic CLL (IPS-E) identifies chronic lymphocytic leukaemia at risk of progression to treatment in the OXPLORED study, a prospective observational study for early lymphoproliferative disease

Title: High-risk IPS-E identifies CLL at risk of progression to treatment in the OXPLORED study, a prospective observational study for early lymphoproliferative disease

Early identification of people with MBL and CLL who will experience disease progression is challenging. Randomised trials of early intervention reported fewer progressors in the untreated arm than predicted by scoring systems (Hoechstetter et al. 2017; Langerbeins et al. 2022). Robust tools to delineate CLL prognostic subgroups at diagnosis are needed to enable future trials of targeted treatment. In a large retrospective analysis, the one year risk of requiring treatment was < 1%, 3% and 14% with a cumulative incidence of treatment at 5 years of 8%, 28% and 61% for patients with low-risk, intermediate-risk and high-risk International Prognostic Score for asymptomatic early-stage CLL (IPS-E), respectively (Condoluci et al. 2020). The Oxford Pre-malignant Lympho-proliferative Disorders (OXPLORED) study (REC 19/SC/0065; NCT04023747) offers the opportunity for prospective assessment of these data.

OXPLORED is an observational multi-centre study recruiting 800 participants with newly diagnosed MBL and early asymptomatic CLL at 15 sites across England. Participants provide sequential blood, plasma and in selected participants marrow samples over five years and optional informed consent for WGS via the National Genome Research Library (NGRL; REC: 20/EE/0035).

241 participants (137 male; 104 females; median age 67 years (IQR 60-73 years)) enrolled prior to the interim data lock on 30th September 2022. After mean follow-up of 11.4 months, 10/241 MBL/CLL participants had progressed to requiring treatment. To date, paired CD19+ B-cells (tumour) and salivary (germline) have been whole genome sequenced from 165 MBL/CLL participants and IGHV status determined by NGS from an additional 76 participants. So far, IPS-E has been calculated for 85 participants, based on available data. Participants scored 1 for palpable lymphadenopathy, 1 for lymphocytosis > 15 x109/L and 1 for unmutated IGHV (u-IGHV; baseline on germline homology > 98%). The V3-21 #subset 2 rearrangement detected in two participants was considered equivalent to u-IGHV. The sum of the three variables was translated into low-risk (score 0), intermediate-risk (score 1) and high-risk (score 2-3) IPS-E scores. After of 11.4 months follow-up, no participant with low-risk IPS-E progressed, two of 27 (7.4%) intermediate-risk IPS-E and 5/31 (16.1%) high-risk IPS-E participants required treatment.

In our prospective study, progression to treatment parallels the cumulative incidence of treatment predicted at 1 year by the IPS-E score. The full dataset on all 241 participants will be available for presentation at IWCLL 2023.