1119 - Treatment Strategies and Outcomes for Double Refractory chronic lymphocytic leukemia; A single center experience

Background:
There remains an unmet need for patients with aggressive disease refractory to both Bruton Tyrosine Kinase inhibitors (BTKi) and Venetoclax. We conducted a single-center retrospective study to identify the treatment strategies and outcomes for these ‘double refractory’ patients.

Methods:
The data was gathered using the pharmacy dispensing records from H Lee Moffitt Cancer and Research Institute. All patients with chronic lymphocytic leukemia (CLL) that filled a Venetoclax prescription from the in-house pharmacy from 2016-2021 were identified. The medical record charts of these patients were accessed to determine double-refractory patients who had progression of disease (POD) while on BTKi followed by Venetoclax-based therapy or vice-versa. Only patients with POD were selected. Patients who had their treatment regimen changed due to intolerance or adverse effects were not included. The patient’s charts were followed till January 1st,2023. The Mantel-Cox test was used to determine differences in survival outcomes among various cohorts. A p-value of ≤0.05 was considered significant.

Results:
A total of 17 double refractory CLL patients were identified between 2016 to 2021. The median age was 66 years (range 47-80 years), and 10 (58.8%) patients were female. At the time of double refractory status, 15 (88.2%) patients had unmutated IgHV disease, 11 (64.7%) had 17p deletion, while 9 (52.9%) had complex karyotype identified on the CLL fluorescence in situ hybridization (FISH) test. Next-generation gene sequencing identified a BTK mutation in 7 (41.2%) of the patients. All patients progressed on a BTKi before receiving one venetoclax except for one. The median lines of therapies prior to Venetoclax was 3 (range 1-7) (Figure 1). Seven (41.2%) patients had Richter’s transformation during their disease course. There was no survival difference among patients with 17p deletion or Richter’s transformation compared to those with neither (p= 0.75 and 0.48 respectively). The overall survival at 1 year of follow-up was 58.8%. Six patients (35.3%) were bridged to chimeric T cell therapy (CAR-T) following double refractory status. Among these, 2 patients relapsed and eventually needed to be bridged to HSCT. The overall survival of patients that received CAR-T cell therapy was significantly better (median 33 months versus 6 months, p = 0.05). Overall, 3 patients had a complete response as the best response to CAR-T.
Four patients (23.5%) were started on phosphoinositide 3 kinase (PI3-K) inhibitor, 1 as definitive therapy, 1 as successful bridging therapy to CAR-T, and 2 as bridging therapy for an allogeneic stem cell transplant (HSCT) but died prior to receiving a transplant. Overall, 4 patients were considered for an HSCT, however, only two patients were able to receive it while the other two died due to complications during the bridging therapy. Both patients that received HSCT had previously relapsed on CAR-T cell therapy. Two patients received acalabrutinib and obinutuzumab, one patient had a sustained partial response while the other died due to POD. One patient was started on vecabrutinib and died due to POD. Two patients died while on chemotherapy, while one patient was started on lenalidomide and died during the follow-up period. (Figure 2).