1150 - Past informs the future: outcomes post allogeneic stem cell transplantation in high risk chronic lymphocytic leukaemia (CLL)

Aim:
Emerging immunotherapies for CLL, bispecific antibodies and CAR-T, may challenge the established role of allogeneic stem cell transplantation (alloSCT) for eligible patients. This retrospective study analysed characteristics and survival outcomes for patients with CLL following alloSCT, including impact of TP53 aberrancy, over a 22-year period.

Method:
All patients with CLL who underwent first alloSCT between January 2000 – April 2022 (data cut-off 6/12/2022) at Royal Melbourne Hospital (RMH), Australia, were identified from the institutional alloSCT database. Additional patient details were extracted from institutional records. Relapse-free survival (RFS) and overall survival (OS) estimates/comparisons were analysed by Kaplan-Meier method/log-rank analyses on GraphPad Prism v.9.5.1.

Results:
Sixty-two patients, median age 52 (range, 25-75) years, 79% male, were identified for analysis. Patient characteristics are summarised in table 1. Median two prior lines of therapy were observed in both the pre-novel agent era cohort of 2000-2011(range 1-4) and 2012-2022 (range 1-9). Eighty-six percent (n=49) were purine-analogue-, 15.8% (n=9) venetoclax-, 15.8% (n=9) Bruton’s tyrosine kinase inhibitor (BTKi)-, and 3.5% (n=2) PI3 kinase inhibitor-exposed respectively. Two further patients had received alemtuzumab (3.5%). Overall, 26.3% (n=15) were treated with a targeted agent immediately prior to alloSCT and 45.6% (n=26) with chemoimmunotherapy. All patients who received targeted agents before alloSCT underwent alloSCT in 2012 or later.
Sixty-four percent (n=38) were in partial response (PR) (n=21) or CR (n=17) prior to alloSCT; 7/31 of whom had peripheral blood/bone marrow undetectable MRD by flow cytometry. The remaining patients had stable or progressive disease as best response to therapy immediately prior to alloSCT (n=17), or had untreated progressive disease (n=4).Seventeen (27.4%) had prior history of Richter transformation (RT), sixteen of whom received alloSCT in first complete response (CR1). Sixteen (35.6%) patients exhibited del(17p) +/- TP53 mutation (5/10, all del[17p] positive), four of whom had history of RT. Non-myeloablative/reduced-intensity conditioning was used for 71% (n=44) patients. Haematopoietic stem cells were obtained from sibling, unrelated, and haploidentical donor sources for 38 (61.2%), 23 (37.1%) and 1 (1.6%) patients, respectively.
At a median follow-up of 110 months, median RFS and OS were 45 (range, 0-256) months and 165 (range, 1-256) months respectively following alloSCT (see figure 1). One-year RFS and OS rates were 66.6% and 79.0%, and 5-year RFS and OS rates were 46.5% and 55.5% respectively. Twenty-two patients (35.5%) relapsed during study follow-up, including six (27.3%) with RT, four of whom had prior history of RT. For patients treated with alloSCT prior to 2012, two (20%) received BTKi following subsequent relapse compared with eight (66.7%) from 2012 onwards. At day 100 (median 101, range 71-118) post-alloSCT, 41.2% (n=21) demonstrated mixed T-cell chimerism ( < 95%). One-year non-relapse mortality (NRM) was 16.1% (n=10); 4/10 died due to infection, and 3/10 due to complications of GvHD. Overall incidence of grade 3/4 acute GvHD was 21.1% (n=12), and chronic GvHD 65.5% (n=38).
Presence of TP53 aberrancy was associated with inferior mRFS,12 months vs 84 months (hazard ratio [HR] 2.3 [0.93-5.65], p=0.027), but not mOS, 35 months vs not reached (HR 2.0 [0.76-5.26], p=0.107). Response < PR pre-alloSCT, D100 mixed T-cell chimerism, and history of previous RT were not associated with inferior RFS. Treatment with alloSCT pre-2012 was not associated with reduced overall survival; (HR 1.56 [0.75-3.24], p=0.240).

Conclusion:
RFS, OS, and NRM outcomes for CLL following alloSCT are consistent with other national and international registry data with inferior survival outcomes post-alloSCT for CLL exhibiting TP53 aberrancy. Despite availability of targeted therapies following relapse, post-alloSCT OS was not significantly longer for those receiving alloSCT from 2012 onwards. This is likely to reflect the small numbers of patients included in the study as an expected limitation. These data serve as future comparator for local outcomes following newer immunotherapies.