Analysis of Outcomes for Patients With CLL Disease Progression While on Ibrutinib

In a recent study, Paul Hampel, MD, Division of Hematology at the Mayo Clinic, in Rochester, Minnesota, and colleagues investigated the data on patients with chronic lymphocytic leukemia (CLL) who experience disease progression while receiving ibrutinib. Although many patients stop ibrutinib treatment because of disease progression and/or toxicity, the researchers explored the outcomes for patients who experienced disease progression and continued to take ibrutinib. Their goal was to understand why the overall survival rates are worse for patients that continue treatment.

The researchers obtained institutional review board approval for the study before they reviewed the medical records of patients with CLL who were treated with ibrutinib. These records were from multiple Mayo Clinic Cancer Center locations in Florida, Arizona, and Minnesota between April 2012 and June 2021. Characteristics such as baseline relevant clinical features, previous therapies, length of ibrutinib treatment, and post-ibrutinib therapy were assessed and recorded in a chart review. SAS 9.4 was used for all statistical analyses and the NeoGenomics reference laboratory was used for resistance mutation sequencing. Researchers established treatment-free survival (TFS) as the length of time from the beginning of treatment after ibrutinib failure to the end of life or new therapy undertaken. Overall survival (OS) rate was determined as the beginning of disease progression on ibrutinib until end of life, and the authors used the Kaplan-Meier method and Cox proportional hazards model for OS analysis. In the Cox proportional hazards models, they included the association with OS and venetoclax treatment (given any time post–disease progression) as a time-dependent covariate.

Researchers identified 144 patients who showed disease progression after ibrutinib therapy. Within this group, 106 patients experienced CLL progression, while others developed Richter transformation. The median age at disease progression was approximately 68 years old. The authors also found that 69% of patients had BTK and/or PLCG2 mutations and 76% of these were found in patients that experienced CLL progression. 

The authors found that the median OS for patients who experienced disease progression after ibrutinib treatment was about 25.5 months per patient (95% confidence interval [CI], 17.7-31.0). They also found that patients with CLL disease progression who used ibrutinib in the first line of therapy experienced longer OS in comparison to the relapsed/refractory setting. The median OS from time of progression on ibrutinib therapy was 17.7 months for patients that had lymphadenopathy without lymphocytosis; for patients with lymphadenopathy and lymphocytosis it was 22.6 months, and for patients with lymphocytosis without lymphadenopathy it was 46.7 months.

Dr Hampel and colleagues also found that patients who continued ibrutinib treatment with venetoclax had similar TFS results to patients that discontinued ibrutinib (median 23.7 months vs 16.7 months; P = .26). Median OS was found to be significantly longer when patients were treated with chimeric antigen receptor T-cell therapy or venetoclax regimens compared to other approved treatments. However, they also found that venetoclax therapy started at any point after disease progression on ibrutinib had no effect on OS. 

Finally, Dr Hampel and colleagues found that their results show a need for more research on the disease progression of CLL after ibrutinib therapy. They determined that venetoclax-based treatments when given to address CLL progression on ibrutinib offered the best TFS and OS rates in their analysis, but more research needs to be done. “We speculate that the role for continued ibrutinib beyond progression in combination with venetoclax in certain patients and the impact and optimal timing of cellular therapy remain important questions,” Dr Hampel and colleagues wrote.

Source: 

Hampel PJ, Rabe KG, Call TG, et al. Clinical outcomes in patients with chronic lymphocytic leukemia with disease progression on ibrutinib. Blood Cancer J. 12, 124 (2022). doi:10.1038/s41408-022-00721-6