Over the past several years, there has been a paradigm shift in treating Chronic Lymphocytic Leukemia (CLL) from chemoimmunotherapy to novel targeted agents. There are several different classes of targeted therapies, including Bruton’s tyrosine kinase Inhibitors, with ibrutinib being the first to be released in that category, and in a distinct class, a B-cell lymphoma-2 inhibitor, venetoclax. These two groups of drugs act through distinctly different yet synergistic mechanisms to target separate cellular pathways. Ibrutinib blocks a key enzyme, Bruton tyrosine kinase, in the B-cell receptor pathway of cell signaling to disrupt cell growth and free malignant cells from the lymph nodes into the peripheral blood, where they are more susceptible to the effects of venetoclax. Alternatively, venetoclax blocks the B-cell lymphoma 2 protein, also known as Bcl-2, that stimulates CLL cells to keep growing. Blocking this protein results in the death of the malignant cells, a process known as apoptosis. To learn more about targeted therapy, see here: https://cllsociety.org/cll-sll-patient-education-toolkit/brief-overview-of-types-of-treatments/
Unfortunately, drug resistance may develop over time despite the excellent efficacy of both ibrutinib and venetoclax. When resistance arises and the disease progresses, therapy may sequentially be changed from one of these agents to the next. In some cases, resistance to both medications may ultimately occur. The medical options for patients with progressive disease following treatment failure, especially when resistant to both classes of drugs, are limited though clinical trials continue to study potential interventions. Unfortunately, many patients may not have access to a clinical trial, and there is limited data independent of the research setting to guide therapy for these patients. Therefore, an exploration was undertaken to evaluate options for these individuals.
This paper, presented at the American Society of Hematology in December 2021, looks at patients outside of a clinical trial with progressive CLL who have developed resistance to ibrutinib, or venetoclax, or both ibrutinib and venetoclax at separate times and then, despite having prior resistance were treated with both agents together.
Takeaways:
- This study was a retrospective review of chart data from 2012-2021 of CLL patients who failed treatment with ibrutinib or venetoclax or both and were subsequently treated with the combination of ibrutinib and venetoclax. These patients were not enrolled in a clinical trial.
- 33 patients with progressive disease previously treated with ibrutinib alone or sequentially with ibrutinib and venetoclax were identified.
- 22 patients with progressive CLL on ibrutinib not having previously received venetoclax were treated with a combination of ibrutinib and venetoclax. Of these 22 patients, 13 required additional therapy, but the time needed before the subsequent treatment was 27 months. Nine patients either remained on the combination therapy or were able to stop one or both agents. Overall survival was 4 years.
- 11 patients with prior resistance to both ibrutinib and venetoclax were treated with a combination of both ibrutinib and venetoclax. Of these 11 patients, 8 required additional therapy but gained 14 months before the subsequent treatment was needed. Of the remaining 3 patients, 1 remained on therapy, and 2 died from progressive disease. Overall survival was 2 years.
- For those patients who went on to require further therapy, there was a substantial time interval gained from this regimen before the subsequent treatment was initiated, time which may have better prepared a patient for successful allogeneic stem cell transplant or CAR-T cell therapy or allowed time to access an existing clinical trial or for a new clinical trial or a new drug to be developed.
- Despite having known prior resistance to both ibrutinib and venetoclax, patients responded to retreatment with these agents in combination.
Conclusion:
Options for patients with progressive disease are limited, especially outside a clinical trial. However, this combination of ibrutinib and venetoclax is a potential intervention for patients with progressive disease and prior resistance to ibrutinib or both ibrutinib and venetoclax. For patients on ibrutinib with progressive disease, adding venetoclax extended the time to the next treatment and provided a durable benefit with overall survival of 4 years. For patients with resistance to both drugs and progressive disease, treating with this combination extended the time to the next treatment by over one year and provided an overall survival of 2 years. Further study with a larger number of patients and ongoing research to understand how these agents work in synergy when resistance has previously developed remain important areas for future research.
Dr. Brian Koffman attended the ASH meeting held live and virtually in December 2021 in Atlanta, Georgia. Below is his interview with Dr. Sameer Parikh, a co-author of this study and Hematologist/Oncologist at the Mayo Clinic in Rochester.
You can read the actual abstract here:
For another recent study regarding progressive disease following ibrutinib and venetoclax, see here: ASH 2021: Outcomes for Patients with Chronic Lymphocytic Leukemia Previously Treated with a Covalent BTK Inhibitor and BCL2 Inhibitor in the United States: A Real-World Database Study.
We share in this journey together.
Kim Davidson, MD
CLL patient and physician
