Real-World Evaluation of the Treatment Landscape for Chronic Lymphocytic Leukemia
Authors: Smith Timothy W. , Owusu Henry F. , Wormser David , Woo Janghee 
Published: November 2021

Abstract
Introduction:
The treatment paradigm of chronic lymphocytic leukemia (CLL) has changed significantly with the introduction of targeted oral therapies, including Bruton's tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (Bcl-2is). As more therapies enter the clinic, real-world data (RWD) are important to understand changes in the CLL treatment landscape and describe treatment patterns, to guide decisions on treatment strategies.
Methods:
This retrospective analysis used 2 RWD sources. Patients (pts) diagnosed with CLL and treated with chemotherapy, CD20 monoclonal antibodies (mAbs), BTKis, or Bcl-2is were studied in the Optum Clinformatics® Data Mart (CDM), a de-identified US administrative claims database. Pts in the CDM analysis received at least 1 prescription for or administration of a treatment of interest between 2016 and 2020 Q2, and a diagnosis of CLL within 12 months (mo) of treatment start. Cross-sectional annual cohorts were used to understand changes in treatment mix over time, and longitudinal cohorts were formed to identify treatment patterns. Medication adherence was assessed with persistence at 12 mo using a 60-day gap and proportion of days covered (PDC) at 12 mo. Electronic health records from oncology practices were extracted through December 2020 from the COTA real-world evidence database. Adults diagnosed with CLL/small lymphocytic lymphoma and treated with BTKis and/or Bcl-2is were included. Treatment discontinuation was assessed using physician-documented treatment dates and reasons for discontinuation, and overall duration of treatment with targeted therapy was assessed using Kaplan-Meier analysis.
Results:
In CDM, annual treatment rate among pts diagnosed with CLL increased from 16% (1788/10911) in 2016 to 26% (2441/9349) in 2020. The proportion of pts treated with BTKis and Bcl-2is increased from 40% (2016) to 65% (2020) and &lt;1% (2016) to 13% (2020), respectively; corresponding decreases in the use of chemotherapies and CD20 mAbs were observed (Figure 1A). In pts initiating BTKis, most pts were not previously treated (937/1438; 65%); the most common initial regimens were BTKi monotherapy (mono) (1367/1438; 95%) and BTKi + CD20 mAb (54/1438; 4%). Few pts switched from BTKi mono to CD20 mAb mono (43/1367; 3%) or added CD20 mAb to BTKi mono (44/1367; 3%) within 12 mo. In pts initiating Bcl-2is, most received prior treatment (169/198; 85%); most common regimens were Bcl-2i mono (159/198; 80%), Bcl-2i + CD20 mAb (31/198; 16%), and Bcl-2i + BTKi (8/198; 4%). Among pts initiating Bcl-2i mono, 30% (48/159) added CD20 mAb within 12 mo; among pts initiating Bcl-2i + CD20 mAb, 94% (29/31) switched to Bcl-2i mono within 12 mo. Persistence at 12 mo was similar for BTKis (899/1438; 63%) and Bcl-2is (120/198; 61%) and mean (SD) PDC was similar for BTKis 0.69 (0.31) and Bcl-2is 0.68 (0.29). In COTA, 469 pts treated with BTKis and/orBcl-2is were included. More pts initiated BTKis as first-line (1L) (185/449; 41%) compared with Bcl-2is (13/109; 12%). Among pts initiating targeted therapy as 1L, most pts (81%; 149/185) initiated BTKi mono. Discontinuation rates were high for pts receiving BTKis (62%; 279/449) and Bcl-2is (61%; 67/109). Among BTKi discontinuers, toxicity (54%; 150/279) was the most common reason for discontinuation, followed by disease progression (12%; 34/279) (Figure 1B). Among Bcl-2i discontinuers, toxicity (36%; 24/67) was the most common reason for discontinuation, followed by completion of regimen (30%; 20/67) (Figure 1C). Median duration of treatment was 777 days (95% CI: 632-920) for the BTKis group and 639 days (95% CI: 335-755) for the Bcl-2is group. Median treatment duration in days was comparable between mono and combination regimens in both BTKis (782 vs. 809) and Bcl-2is (747 vs. 718) groups.
Conclusions:
RWD show standard of care shifted from chemoimmunotherapy to targeted therapies. Pts receiving targeted therapies had high rates of discontinuation, most commonly due to toxicity. Most targeted regimens were mono; more BTKi pts were treatment naive compared to Bcl-2i pts. Slow adoption of fixed-duration therapy with the Bcl-2i combination regimen was observed. The duration of Bcl-2i mono was comparable to that of the Bcl-2i combination regimens, and a high number of pts initiating combo regimens continued on mono regimens in contrast to regimens studied in randomized controlled trials.
Figure 1 Figure 1.

Disclosures
Smith: Novartis: Current Employment; Pfizer: Ended employment in the past 24 months. Owusu: Novartis: Current Employment; Roche: Ended employment in the past 24 months. Wormser: Roche: Current equity holder in publicly-traded company; Novartis: Current Employment, Current equity holder in publicly-traded company. Woo: Novartis: Current Employment, Current equity holder in publicly-traded company.