Outcomes of Therapies Following Discontinuation of Non-Covalent Bruton’s Tyrosine Kinase Inhibitors for Patients with Chronic Lymphocytic Leukemia and Richter Transformation: Results from an International, Multicenter Study

Background: Non-covalent Bruton’s Tyrosine Kinase inhibitors (ncBTKi) have shown durable responses for pts (pts) with Chronic Lymphocytic Leukemia (CLL) and activity in pts with Richter Transformation (RT). Pirtobrutinib is a standard treatment (tx) for CLL pts after covalent BTKi (cBTKi) and venetoclax (ven), and additional ncBTKi including nemtabrutinib are in development. As ncBTKi are used in clinical practice, data to inform sequencing are needed. Specifically, clinicians require data on activity of tx after ncBTKi and whether ncBTKi may be used in sequence after cBTKi, but prior to BCL2i, in pts with CLL.

Methods: We conducted an international, multicenter retrospective study of CLL and RT pts who were treated with and discontinued a ncBTKi for any reason. Data were collected by investigators using a standardized data template. Data included: pt and disease characteristics, prior tx, response to ncBTKi and subsequent tx and survival. Outcomes were described separately for subsequent tx in those who received ncBTKi for a diagnosis of CLL vs RT. The primary objective was the overall response rate (ORR), including partial response with lymphocytosis (PR-L), for therapies following ncBTKi. Data were collected on up to 2 lines of therapy after ncBTKi discontinuation (dc), and ORR was calculated by tx type, inclusive of pts who received the tx during 2 lines of tx after ncBTKi dc. Progression free survival (PFS) was estimated using Kaplan Meier for first tx after ncBTKi. CLL pts treated with ncBTKi for CLL who had subsequent progression of disease (PD) to RT were censored at RT. Other analyses were descriptive.

Results: 156 pts (124 CLL, 32 RT) were treated with and discontinued ncBTKi. The median tx prior to ncBTKi was 4, and most pts received prior cBTKi (95.2% CLL cohort of whom 84.8% dc BTKi for PD; 87.5% RT cohort) and ven (40.3% CLL cohort of whom 82.6% dc for PD; 53.1% RT). At ncBTKi start, characteristics for pts treated with ncBTKi for CLL included: 86% unmutated IGHV, 42% del17p, 47% TP53 mut, 51% complex karyotype.

For the CLL cohort, ORR to ncBTKi was 56.1% (n=123 with available data). Median duration of ncBTKi exposure was 10.5 months (range 1-58). Reasons for ncBTKi dc were: CLL PD 67.2%, CLL PD to RT 8.2%, toxicity 11.5%, death not due to PD or toxicity 4.9%, stem cell transplant (SCT) 3.3%, CAR T cell therapy 1.6%, and other 3.3% (n=122 with data).

92 CLL pts received tx after ncBTKi; 43 received at least 2 tx. For the CLL cohort, tx after ncBTKi included (ORR inclusive of pts receiving tx in line 1 or 2 post ncBTKi): ven-based tx (including ven +/- antiCD20 mAb and/or BTKi): ORR 72% (n=53; CR 11, PR 25, SD 5, PD 9, unknown (uk) response 3; 88.6% of 53 pts previously ven-naive); CAR T-cell therapy: ORR 62.5% (n=10; CR 3, PR 2, SD 1, PD 2, uk 2); alternative ncBTKi: ORR 75% (n=8; PR 6, SD 2; dc reason for prior ncBTKi: toxicity 4, PD 3, other 1); PI3Ki: ORR 20% (n=7; PR 1, PD 4, uk 2); chemo+/-immunotherapy (CIT): ORR 28.6% (n=7; PR 2, SD 2, PD 3); cBTKi +/- antiCD20 mAb: ORR 80% (n=6; PR 4, PD 1, uk 1); antiCD20 mAb: ORR 0% (n=6; SD 2, PD1, uk 3); SCT: ORR 80% (n=5; CR 4, SD 1), and other tx (n=32).

For CLL pts, the median PFS for first tx after ncBTKi dc was 15 months (n=90 with available data). For CLL pts treated with ven-based tx as first tx following ncBTKi, the median PFS was 23 months (n=45 with data). Among ven-treated pts, the median PFS for previously ven-naïve pts was 23 months (n=39) vs 8 months for previously ven-exposed pts (n=6).

For the RT cohort (n=32), ORR to ncBTKi was 31.3%. Median duration of ncBTKi exposure was 3 months (range 1-27, n=31 pts with data). Reasons for ncBTKi dc were: PD 75.0%, other reason 12.5%, sudden death 3.1%, SCT 3.1%, CAR T-cell therapy 3.1%, MD/pt preference 3.1% (n=32 with data). 25 pts from the RT cohort received tx post ncBTKi; 13 received at least 2 tx post ncBTKi. Tx after ncBTKi included: CAR T-cell therapy: ORR 66.7% (n=10; CR 6, PR 1, PD 2, uk 1); CIT: ORR 11.1% (n=10; CR 1, SD 1, PD 7, uk 1); SCT: ORR 100% (n=2; CR 2), and other tx or uk: n=16. For RT pts, the median PFS for the first tx after ncBTKi was 2 months (n=24 with data).

Conclusions: The PFS for tx following ncBTKi dc was relatively short for CLL pts (15 months) and RT pts (2 months). For CLL pts, ven-based tx had a high ORR (72%). The median PFS for ven as first tx following ncBTKi dc was 23 months in this largely ven-naïve, but heavily pre-treated pt population, supporting that ven may be sequenced after ncBTKi dc. There is an unmet need for novel tx approaches for CLL and RT pts following ncBTKi dc.