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A.R. Mato et al.
therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully com- pleted and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibru- tinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.
Introduction
Venetoclax is an oral second-generation BCL2 inhibitor with demonstrated activity and durable responses in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with chromosome 17p deletion (del(17p)), unmutated IGHV, fludarabine-resistance, bulky disease, and progression on or following ibrutinib or ide- lalisib.1-5 Overall response rate (ORR) to venetoclax monotherapy was 79% in the phase II trial in del(17p) R/R CLL.3 Moreover, ORRs were 65% and 67% in R/R CLL following ibrutinib or idelalisib, respectively.4,5 In addition to data with monotherapy, progression free survival (PFS) was superior for patients treated with venetoclax and rit- uximab compared to bendamustine and rituximab in R/R CLL, and more venetoclax-treated patients achieved unde- tectable minimal residual disease (MRD) (83.5% vs. 23.1%).6
Knowledge about venetoclax efficacy, dose-escalation, and toxicity in CLL patients has almost entirely been informed by experiences from clinical trials.3 As several real-world evidence series showed that toxicity profiles and outcomes for kinase inhibitor-treated patients may differ from those reported in the clinical trial setting, studying whether these differences apply to venetoclax- treated patients is essential.7-11 Furthermore, there is one study to date regarding strategies for early identification of high-risk patients, particularly those previously treated with kinase inhibitor based therapy, for progression on venetoclax and how treatment is selected after its discon- tinuation is selected.2
We aimed to better understand disease characteristics and toxicities of CLL patients treated with venetoclax in clinical practice and contrast their outcomes to those reported in key clinical trials. We explored prognostic fac- tors that predict early progression on venetoclax and stud- ied treatment selection following discontinuation. To our knowledge, this analysis reports the largest series of CLL patients treated with venetoclax in a real-world setting with a focus on outcomes following venetoclax discontin- uation.
Methods
We conducted a multicenter, retrospective cohort study of all CLL patients treated with venetoclax across 19 United States aca- demic and community cancer centers. The study was approved by the institutional review board at each US institution. Investigators conducted a detailed review of the institutional electronic medical records to identify patients with CLL treated with venetoclax. Collected data included demographics, clinical and genetic prog- nostic factors, venetoclax dose-escalation management, long-term dosing, toxicities, tumor lysis syndrome (TLS) prophylaxis strate- gies and outcomes, ORR, complete response (CR), survival out-
comes, and reasons for discontinuation. Investigators were asked to follow the National Cancer Institute working group interna- tional workshop guidelines for CLL (iwCLL) published in 2008 to define rates of response and progression of disease.12 Disease bur- den as a predictor for TLS risk was categorized as low, medium, and high per the treating physician. Physicians were asked to use the venetoclax package insert to guide the categorization, which was developed based on United States approval of the drug in 2016.13 TLS events were defined as per Howard criteria, which specify criteria for laboratory and clinical TLS.14 Adverse events (AEs) were graded using the NCI Common Toxicity Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). Cytogenetics, FISH results and next generation sequencing (NGS) were reported for patients where available.
The primary endpoint was PFS, defined as the time from vene- toclax initiation until progression or death from any cause as per the Kaplan Meier method.15 Patients were censored at the time of last follow up or at the time of next therapy regardless of progres- sion status. Outcomes were stratified by prognostic characteristics where available, including del(17p) status, complex karyotype (>3 abnormalities), and venetoclax monotherapy versus combinations. Secondary endpoints included overall survival (OS), venetoclax dosing and toxicities, TLS incidence, dose escalation schema, response rates, and reasons for discontinuation.
Comparisons of survival outcomes data were made using the long rank (LR) test.16 Hazard ratios were estimated using Cox regression analyses.17 Other analyses were descriptive. Tests were two-sided at the 5% level. Statistical analyses were performed using STATA 10.1 (Stata Statistical Software: Release 10, 2007; StataCorp LP, College Station, TX).
Results
Patient characteristics
We identified 141 CLL patients treated with venetoclax. Males and Caucasians represented most patients at 66% and 87%, respectively. The median age at diagnosis was 59 years (range 30-88), and median age at venetoclax initi- ation was 67 years (range 37-91). The population consist- ed almost entirely of patients with R/R CLL, with only 2 (1.4% of 141) of patients being treatment-naïve. Patients had received a median of 3 prior therapies (range 0-11). Venetoclax was administered in combinations in 18.4% (n=26 of 141) of patients. Ibrutinib (36%), obinutuzumab (32%), and rituximab (24%) were the most commonly used drugs with venetoclax. Almost 89% of patients were treated with a B-cell receptor signal transduction inhibitor prior to venetoclax; 82% (n=115/141) received ibrutinib. Patient characteristics are summarized in Table 1.
Most patients in this cohort had at least one traditional- ly poor-risk feature: 45% (n=61/136 tested) patients had chromosome del(17p), 26% (n=34/131) had deletion of chromosome 11q (del(11q)), 44% (n=42/95) had p53 mutations, 26.8% (n=52/130) had a complex karyotype
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haematologica | 2018; 103(9)