Characteristics and Outcomes of Patients with Double Refractory (DR) or Double Exposed (DE) CLL
Authors: Yoon James T. , Zhou Yinglu , Tyekucheva Svitlana , Mikhaleva Mariia , Fernandes Stacey M. , Armand Philippe , Bessnow Amy C. , Crombie Jennifer L. , Fisher David C. , Jacobsen Eric D. , Jacobson Caron A. , Kim Austin I. , LaCasce Ann S. , Merryman Reid W. , Odejide Oreofe O. , Parry Erin M. , Qualls David A. , Ryan Christine E. , Sekar Aswin , Soumerai Jacob D. , Arnason Jon E. , Davids Matthew S. , Brown Jennifer R. , Ahn Inhye E. 
Published: December 2024

Introduction
Treatment resistance and toxicity are leading clinical challenges in CLL. Limited data exist on outcomes for patients exposed to both Bruton tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is). DR CLL is defined as having progressive disease (PD) on both continuous BTKi- and continuous BCL2i-containing therapy. DE CLL refers to the discontinuation of BTKi and/or BCL2i due to reasons other than PD. In studies including both DR and DE patients, the reported median progression-free survival has been consistently below 2 years for non-covalent BTKi (ncBTKi) pirtobrutinib (Woyach et al, 2023 ASH Meeting) and CD19 chimeric antigen receptor-modified T (CAR T) liso cel (Siddiqi et al, 2023 ASH Meeting), which are the approved third-line treatments for CLL in the United States. We hypothesized that outcomes are worse for DR patients than for DE patients. Here, we report a large cohort of patients with DR or DE CLL, their molecular characteristics, and outcomes.
Methods
We conducted a retrospective review of data from the Dana-Farber Cancer Institute CLL database. Patients who progressed on sequential or combination therapy with BTKis and BCL2is were included in the DR group. Patients who progressed on only one of these treatment classes were included in the DE group provided that they had been exposed to the second class. Patients who developed histologic transformation before the landmark timepoint (when each patient met the definition of DR or DE) were excluded from the analysis. PD with CLL (PD-CLL) and histologic transformation (PD-T) were considered PD events if they occurred on or after the landmark timepoint. We applied 90-gene NGS, IGHV sequencing, and FISH and cytogenetics to available blood and/or bone marrow samples. The Kaplan-Meier method was used to estimate time to first treatment (TTFT), time to next treatment (TTNT), and overall survival (OS) (R version 4.4.1).
Results
Of 1,024 CLL patients in the database, 483 patients received at least one line of CLL therapy. Chart review of all treated patients identified 30 DR and 65 DE patients. Median age was similar for both groups (57 years for DR, 58 years for DE). Both groups had a male predominance (73% of DR, 65% of DE). The DR group had a higher proportion of patients with unmutated IGHV (97% of DR, 75% of DE), TP53 mutation and/or deletion 17p (73% of DR, 46% of DE), and BTK mutations (59% of DR, 27% of DE). Complex karyotype (≥3 abnormalities) did not differ significantly between DR (77%) and DE (56%, p=0.07). Median number of total lines of therapy (LOT) was 6 for DR and 3 for DE. Median number of LOT before the landmark timepoint was 4 for DR and 3 for DE.
In the DR group, 29 of 30 patients were treated after the landmark timepoint. The most commonly used treatment after the landmark timepoint was ncBTKi (34%, median TTNT 16 months), followed by concurrent covalent BTKi(cBTKi)/BCL2i (28%, median TTNT 12 months). CAR T and allogeneic stem cell transplant (alloSCT) were used in 24% and 10%, respectively. In the DE group, 17 of 65 patients received treatment after the landmark timepoint, most commonly with alloSCT (29%, median TTNT not reached) followed by cBTKi (18%, median TTNT not reached).
At a median follow-up of 15 years since CLL diagnosis, deaths occurred in 63% of the DR group and 25% of the DE group. PD-T was more frequently observed in DR (30%) than in DE (6%). The leading cause of death differed between DR (42% PD-CLL) and DE (25% infection). Median TTFT and median OS since CLL diagnosis were significantly shorter for DR (1.1 and 11.6 years, respectively) than DE (2.2 and 21.4 years, both p&lt;0.05), reflecting the more aggressive disease biology of DR CLL. Patients developed DR CLL at a median of 7.3 years after the first CLL therapy and received a median of 2 LOT thereafter. Median OS was 2.2 years once DR developed, which contrasted with the DE group whose median OS was not reached. The estimated 3-year OS after the landmark timepoint was 29% for DR and 64% for DE.
Conclusions
DR and DE CLL, defined by resistance vs. exposure to BTK and BCL2 inhibition, substantially differed in terms of patient characteristics and outcomes. Median survival of patients with DR CLL was 2.2 years in our dataset despite frequent utilization of ncBTKis and cellular therapy. DE CLL represented a less aggressive disease state with preserved sensitivity to targeted and cellular therapies. Given these differences, DR and DE CLL should be clearly distinguished in clinical trials.