Venetoclax in addition to ibrutinib effective as a treatment for chronic lymphocytic leukemia

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1. High genetic risk participants with chronic lymphocytic leukemia (CLL) taking venetoclax in addition to ibrutinib achieved high rates of achievement of undetectable measurable disease, very low risk of on-treatment disease progression, and durable off-treatment remissions.

Evidence Rating Level: 2 (Good)

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK), and one of its indicated uses is in chronic lymphocytic leukemia (CLL). However, the standard of care for those receiving Ibrutinib for CLL is continuous and indefinite maintenance therapy since patients rarely achieve complete remission (CR) with undetectable measurable disease at sensitivity 10^-4 (U-MRD4). Adverse events (e.g., atrial fibrillation, major hemorrhage, hypertension, ventricular arrhythmia, sudden cardiac death), cost-related barriers, and rates of disease progression result in increased cumulative risk of treatment discontinuation of ibrutinib. The current study, a phase II, investigator-initiated, response-adapted clinical trial added venetoclax, a B-cell lymphoma-2 inhibitor with a mechanism distinct from ibrutinib, as an adjunct for patients already receiving ibutrinib to test whether this combination could achieve durable treatment-free remission those with CLL and at least one high-risk genetic feature (del[17p] or TP53 mutation, complex karyotype, del[11q]; or β2-microglobulin above the upper limit of normal). Venetoclax added to ibrutinib in patients with high-risk CLL was well-tolerated and achieved a cumulative bone marrow (BM) U-MRD4 rate of 73%. Additionally, 55% of patients improved response to complete remission, and there was a median 70% reduction in sum product diameters of target lymph node groups, indicating that benefits of venetoclax extended beyond the bone marrow compartment. The rate of BM U-MRD4 achievement was not affected by presence of TP53 abnormalities (p = 0.32), complex karyotype (p = 0.61), or treatment naïve versus relapsed/refractory CLL (p = 0.12). U-MRD4 did not change significantly between patients requiring venetoclax dose reduction versus not requiring it (p = 0.25), or those requiring ibrutinib dose reduction versus not requiring it (p = 0.64). The majority of patients who achieved BM U-MRD4 did so within 12 months of therapy, and at completion of venetoclax treatment (6, 12, 18, or 24 cycles), 22 of the 32 patients with BM U-MRD4 stopped ibrutinib with a three-year estimated progression free survival of 95%. At a median follow-up of 41 months, only 5 patients had progressed. Results of this study provide promising results that may allow patients to avoid cumulative risks of indefinite ibrutinib use and achieve BM U-MRD4 or complete remission for CLL.

Click to read the study in Nature

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