Second-Line Venetoclax Associated With Real-World Cost Savings vs BTK Inhibitors in CLL/SLL


Patients with CLL/SLL who received second-line venetoclax experienced monthly cost savings compared with those who received a second-line BTK inhibitor.

Bita Fakhri, MD, MPH

Bita Fakhri, MD, MPH

Patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who were treated with second-line venetoclax (Venclexta) experienced a total monthly cost saving compared with those who received a second-line BTK inhibitor, according to retrospective observational study findings that were published in JCO Oncology Practice.1

The monthly cost difference (MMCD) per patient per month (PPPM) between all-cause venetoclax ($14,319.51) and BTK inhibitor ($16,817.15) treatment was $–2,497.64 (standard error [SE], $1,006.77; P = .01). The lower all-cause total costs with venetoclax vs BTK inhibitors were driven by lower medication costs ($–3,645.96; SE, $736.68) fully offsetting medical costs ($1,148.31; SE, $691.42). The respective medication costs were $9,671.94 vs $13,317.90 in the venetoclax and BTK inhibitor arms. In these respective arms, the medical costs were $4,647.57 vs $3,499.25.

Previously, a retrospective study using the Optum Research Database demonstrated a mean monthly per-patient, all-cause cost estimate of $17,442 (standard deviation [SD], $15,715) for patients with CLL receiving systemic therapy.2 Six percent of the average total patient-per-month costs were patient out-of-pocket costs (mean, $1,012).

“Fixed-duration therapies administered for a finite period present an opportunity for possible cost savings in a competitive CLL landscape,” lead study author Bita Fakhri, MD, MPH, an assistant professor of medicine (hematology) in the Division of Hematology at Stanford University School of Medicine in California, and coauthors, wrote in the paper.1 “However, there is a paucity of literature characterizing real-world benefits regarding cost and health care resource utilization [HRU] of a fixed-duration therapy such as venetoclax, compared with BTK inhibitors. This study represents one of the first economic analyses to include venetoclax, which is important to fully assess the benefits of a newer treatment given the competitive CLL landscape.”

This retrospective observational study used data from the Optum Clinformatics Data Mart of patients aged 18 years and older with confirmed CLL/SLL who received second-line treatment with either venetoclax-based or BTK inhibitor-based therapy between January 2018 and December 2021. Eligible patients included those with at least 1 claim with CLL diagnosis codes after initiation of second-line therapy and evidence of at least 2 claims for venetoclax- or BTK inhibitor-based regimens. Patients in the venetoclax and BTK inhibitor cohorts must not have been treated with their respective agents previously. Thus, patients who received second-line venetoclax or a BTK inhibitor were excluded from this analysis if they had received venetoclax or a BTK inhibitor in the frontline setting.

Patients were also excluded if they had end-stage renal disease, previously participated in a clinical trial, had missing data on sex and race, or at least 1 claim with diagnosis codes for mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia (BTK inhibitor cohort), or acute myeloid leukemia (venetoclax cohort) before initiating second-line therapy to ensure the sole enrollment of patients with CLL; venetoclax and/or BTK inhibitors are approved for patients with these diseases.

Investigators used a claims-based line of therapy algorithm to identify patients initiating second-line therapy. Line of therapy was defined as all CLL drugs used within the first 35 days of the first identified medication. The first service date of a qualifying medication was used as the start date of the line of therapy. Treatment line advancement occurred if there was an addition of a new agent at any time after the 35-day window, the entire regimen was switched, or treatment was reinitiated with the same agent after a 90-day gap.

The study outcomes were MMCD for all-cause and CLL-related PPPM costs, including medication and medical costs. Investigators also estimated all-cause and CLL-specific total cost savings at 12 months and calculated all-case and CLL-specific PPPM-HRU. These costs represented the allowable amount by patients’ health plans and did not represent the amount paid by the health plan nor the patient. All costs were measured in United States dollars.

This study included 280 patients with a median age of 75.5 years (BTK inhibitor cohort, n = 181; 76.0 years [range, 68-81]; venetoclax cohort, n = 98; 74.0 years [range, 66-80]); 64.6% and 35.4% of patients received second-line BTK inhibitor- and venetoclax-based regimens, respectively. Most patients were male (65.2%; 68.7%) and White (84.5%; 84.8%). Across both cohorts, the most frequently observed comorbidities were hypertension (66.9%; 72.7%), renal disease (30.9%; 27.3%), and diabetes (26.5%; 22.2%). Most patients received insurance coverage through Medicare (75.1%; 76.8%), which the authors noted was expected because of the prevalence of CLL in older patients.

The most common frontline therapies among the BTK inhibitor and venetoclax cohorts, respectively, were chemotherapy/chemoimmunotherapy (61.9%) and BTK inhibitor– based regimens (59.6%). The mean all-cause medication cost PPPMs in the BTK inhibitor and venetoclax cohorts were $2,200 (SD, 43,224) and $4828 (SD, $5,295), respectively. After weighting, all variables were balanced, and the effective sample size was 279 patients.

At a median follow-up of 14.9 months (IQR, 7.9-24.6) and an overall median second-line duration of therapy of 11.6 months (IQR, 6.5-21.2), most patients (88.4%) in the BTK inhibitor cohort received monotherapy. At a median follow-up of 16.0 months (IQR, 8.1-24.7) and an overall median second-line duration of therapy of 11.0 months (IQR, 5.9-21.6), most patients (62.3%) in the venetoclax cohort received venetoclax in combination with anti-CD20 agents. In total, 24.9% and 19.4% of patients in the BTK inhibitor and venetoclax cohorts received subsequent therapy.

The MMCD PPPM between CLL-specific venetoclax ($12,933.19) and BTK inhibitor ($14,345.27) treatment was $–1,412.73 (SE, $887.73). The respective medication costs were $9,228.13 vs $12,192.36 in the venetoclax and BTK inhibitor arms (MMCD, $–2964.23; SE, $700.88). In these respective arms, the medical costs were $3,705.06 vs $2,152.91 (MMCD, $1552.15; SE, $584.15).

Regarding MMCD, the estimated 12-month all-cause and CLL-specific total cost savings were $16,944.96 and $29,970.68 among patients on the BTK inhibitor and venetoclax arms, respectively.

A sensitivity analysis confirmed the primary findings, with respective cost ratios of 0.85, 0.73, and 1.33 for all-cause total, medication, and medication costs for the venetoclax vs BTK inhibitor cohorts.

In total, the use of all-cause and CLL-specific PPPM outpatient services was higher in the venetoclax cohort than the BTK inhibitor cohort (all-cause: rate ratio [RR], 1.22 [95% CI, 1.05-1.42]; CLL-specific: RR, 1.64 [95% CI, 1.35-2.01]). The rates of all-cause and CLL-specific PPPM inpatient admissions (all-cause: RR, 1.43 [95% CI, 0.49-4.17]; CLL-specific: RR, 2.31 [95% CI, 0.74-7.22]) and PPPM ER visits (all-cause: RR, 0.94 [95% CI, 0.32-2.8]; CLL-specific: RR, 0.93 [95% CI, 0.02-40.48]) were similar between cohorts.

The authors noted that limitations of this study included its administrative claims-based nature, through which coding errors are possible. Furthermore, differences may exist between patients who received venetoclax vs BTK inhibitors, and unobserved confounders could have affected the HRU and cost outcomes of the study. Moreover, financial values in Optum are derived using the proprietary algorithm of Optum and thus, may not reflect the actual allowable financial amounts from patients’ health plans, although the authors emphasized that this is not likely to disproportionately affect a specific patient cohort and therefore should have a negligible impact on the study findings.

“Our study demonstrates the economic value of fixed-duration venetoclax-based regimens in the second-line CLL setting,” the authors concluded. “In a competitive CLL landscape where costs of treatment are expected to rise, financial toxicity experienced by patients and health care burden on payers are important considerations in treatment selection.”


  1. Fakhri B, Emechebe N, Manzoor BS, et al. Real-world health care resource use and costs among patients with chronic lymphocytic leukemia treated with venetoclax-based and bruton tyrosine kinase inhibitor-based regimens in the second-line setting. JCO Oncol Pract. Published online April 16, 2024. doi:10.1200/OP.23.00630
  2. Matasar MJ, Byfield SD, Blauer-Peterson C, Montez M, Reyes C, Masaquel A. Real-world health care utilization and costs among patients newly initiating systemic therapy for chromic lymphocytic leukemia (CLL) in the United States. Blood. 2016;128(22):5928. doi:10.1182/blood.V128.22.5928.5928
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