The landscape of CLL is changing fast. Novel therapies and combinations are being studied and approved at a significant pace. Venetoclax is a very potent anti-CLL agent that’s approved in the relapsed setting both as a single-agent and in combination with rituximab, and has recently been approved as frontline therapy in combination with obinutuzumab.
Venetoclax acts by restoring the ability of CLL cells to die. Healthy cells go through a normal life cycle: they are born, they mature and do the work they are supposed to do, they age and then they die a natural death. The cell death process is called apoptosis. Cancer cells create mechanisms to escape apoptosis. In CLL cells, they overexpress a molecule called BCL-2, which acts like an anchor: it prevents “pro-death” (pro-apoptotic proteins) from starting the apoptosis process. Venetoclax is a BCL-2 inhibitor that dislodges these pro-apoptotic proteins from their binding sites with BCL-2, allowing the CLL cells to enter apoptosis and die. This potent mechanism of action leads to disease control and improved survival in patients with CLL.
In the relapsed setting, venetoclax was initially studied in patients with CLL harboring deletion of the short arm of chromosome 17 (17p del), a high-risk molecular abnormality. Patients with 17p del have a lesser chance of responding to traditional chemotherapy, and their responses are short-lived. In this pivotal trial (Stilgenbauer et al; J Clin Oncol. 2018 Jul 1;36(19):1973-1980) patients took venetoclax daily continuously until disease progression or intolerable toxicities. With a median follow-up of 26.6 months, responses were seen in 77% of patients (mostly partial responses) and progression-free survival (patients alive and without disease progression) at 2 years was 54%.
Venetoclax then was studied in combination with rituximab in the MURANO trial (Seymour et al, N Engl J Med 2018; 378:1107-1120). Patients with relapsed CLL, with or without 17p deletion, were randomized to receive venetoclax for 2 years plus rituximab for 6 months versus bendamustine and rituximab for 6 months. After 2 years of follow-up, progression-free survival (PFS) in the venetoclax/rituximab (ven-R) group was 84.9% versus 36.3% in the bendamustine/rituximab (BR) group. For patients who had 17p deletion, the 2-year PFS was 81.5% for ven-R versus 27.8% for BR. Rituximab is an antibody that targets a surface molecule present in CLL cells and normal B-cells called CD20, allowing the patient’s immune system to target those cells with more efficacy.
Given the bulky activity of venetoclax as a single agent, it raises the question whether using rituximab in addition to it is truly necessary. Rituximab adds cost to the therapy and has potential side effects, such as infusion reactions, hepatitis B reactivation and lower blood cell counts. With that in mind, a large international cooperative group evaluated patients in the “real-world” (outside of clinical trials) who received venetoclax for relapsed CLL, with or without rituximab (Mato et al, Blood Advances 2019 3:1568-1573). We were able to retrospectively evaluate 321 patients who received venetoclax as monotherapy (VenMono) or in combination with an anti-CD20 (rituximab or obinutuzumab; VenCombo). Surprisingly, the response rates were similar between both arms: overall response – 81% for VenMono; 84% for VenCombo; complete response- 34% for VenMono and 32% for VenCombo. With a median follow-up of 13.4 months, no differences were seen in PFS or overall survival in both groups. These data show that in the relapsed CLL setting, the addition of an anti-CD20 to venetoclax may not be necessary. Although these are interesting findings, they are not confirmatory, as this study was retrospective, which has multiple caveats including accuracy of records, non-centralized evaluation of responses, patient adherence to treatment, etc. Ideally, such findings should be validated in a prospective trial of venetoclax monotherapy versus venetoclax combinations, although such trials are not currently underway.
Alan Skarbnik, MD serves as Director of the lymphoproliferative disorders program and experimental therapeutics, malignant hematology at Novant Health. Dr. Skarbnik specializes in hematology/oncology, and has extensive experience in a range of medical volunteer work conducted across the globe.
Originally published in The CLL Tribune Q3 2019.