Chronic Lymphocytic Leukemia Treatment Evolving With Some Challenges

Where once limited treatment options existed for patients with CLL, medical oncologists now have a plethora of agents from which to choose, making disease management in CLL more effective with fewer toxicities.

Thomas Kipps, MD, PhD

Where once limited treatment options existed for patients with chronic lymphocytic leukemia (CLL), medical oncologists now have a plethora of agents from which to choose, making disease management in CLL more effective with fewer toxicities, according to Thomas Kipps, MD, PhD, of the UC San Diego Moores Cancer Center. Despite these and other breakthroughs, however, challenges in CLL still remain.

“It is a very exciting time for patients with CLL,” said Kipps who is a professor of Medicine, Evelyn and Edwin Tasch Chair in Cancer Research, and deputy director of research operations at the Moores Cancer Center. Kipps thinks that drugs such as obinutuzumab (Gazyva) and other similar second- and third-generation anti—CD-20 antibodies look particularly promising in the frontline setting.

The FDA approved obinutuzumab for use in combination with chlorambucil to treat patients with previously untreated CLL in November 2013, based on the phase III CLL11 trial. Patients in the study received chlorambucil (n = 118), chlorambucil plus obinutuzumab (n = 238), or chlorambucil plus rituximab (n = 233). An additional, 192 patients were enrolled for a second stage of the study to allow for the direct comparison of the obinutuzumab and rituximab combinations.

In stage I of the study, obinutuzumab plus chlorambucil reduced the risk of progression by 81% compared with chlorambucil alone (27.2 vs 11.2 months; HR = 0.19; 95% CI, 0.14-0.27;P<.0001). In stage II of the study, obinutuzumab plus chlorambucil led to a median progression-free survival (PFS) of 26.7 months compared with 14.9 months with rituximab and chlorambucil (HR = 0.42; 95% CI, 0.33-0.54; P<.0001).

The novel Bcl-2 inhibitor venetoclax (ABT-199) has also shown promise in the frontline setting, according to Kipps. In a phase II study of patients with relapsed or refractory CLL harboring the 17p deletion, venetoclax met its primary endpoint for overall response rate (ORR). Full study results have not been presented; however, previous studies have shown an ORR of 79% with venetoclax in CLL, with 26% of patients experiencing a complete response, and 53% of patients experiencing a partial response.

Venetoclax received a breakthrough therapy designation from the FDA for patients with 17p deletion CLL in May 2015.

Clearly, medical oncologists are seeing a positive shift in treatment paradigms for CLL. “The antibody that we have been excited about for years now is rituximab, which has been very useful and clearly has improved survival for patients with this disease,” said Kipps. “Now we have second- and third-generation anti—CD-20 antibodies, ofatumumab (Arzerra) and obinutuzumab. These antibodies are showing a great deal of activity.”

Kipps noted the clinical trial of obinutuzumab, where patients were treated with chemotherapy alone, chemotherapy plus rituximab, or chemotherapy plus obinutuzumab. Patients taking the antibody combination had deeper and longer remissions than those who did not receive the antibody, according to Kipps.

Obinutuzumab showed longer, more durable, remissions when added to chemotherapy compared with rituximab. “This is being shown in subsequent follow-up studies. There has been a clear improvement in PFS, and now we are also seeing overall survival advantage. We’ve had the opportunity to test this drug in combination with other chemotherapies, including bendamustine, which is typically used in the treatment of patients with CLL,” Kipps said, noting the phenomenal 90% overall response rates with the combination.

As previously mentioned, another novel agents generating excitement in the treatment of patients with CLL is the Bcl-2 inhibitor, venetoclax. “This is a protein that actually protects the leukemia cell from dying. When you inhibit that protein, you can actually induce the death of the cell. They have been proven very effective in patients,” he said.

Kipps stated that too much of an effect may actually cause problems, for example, patients that have very large tumor burdens, have experienced tumor lysis, which may release higher amounts of potassium into the blood, causing damage to many cardiovascular functions. “Right now steps are being taken to ensure that oncologists watch very carefully for tumor lysis and that they very carefully escalate the dose, monitoring the patient with each escalation.” Kipps said. “Once we get past that initial hurdle, patients are able to tolerate this drug; it is orally active, and some patients are seeing very deep and profound remissions.

Ventoclax is being studied as a monotherapy, and in combination with the novel antibodies. Kipps mentioned that some patients have developed complete remissions, without evidence of detectable leukemic cells in the marrow. Some of his patients have experienced a complete remission for longer than they were treated with the drug. “Hopefully, with drugs that can chase away this disease and completely eradicate it from the bone marrow, we might be able to have some of these patients potentially be cured of this disease. It doesn’t get any better than that.”

Kipps believes that challenges still remain in the treatment of CLL. He emphasized the fact that there is no treatment without side effects. “With CLL, we have a disease that is very heterogeneous; in other words some patients might get diagnosed and have a very indolent clinical course and be free of any symptoms for many years, while other patients can actually progress rather rapidly and have disease-related complications,” he said.

Kipps recommends treating patients who are exhibiting clear signs of disease who have disease-related complications within a relatively short amount of time. These complications include anemia, thrombocytopenia, neutropenia, and immune-related dysfunctions. Kipps stated that immune-related dysfunctions are difficult to address with current therapies because oftentimes therapies make immune functions worse.

However, Kipps warned, “I think it is important that we don’t jump the gun and treat patients prematurely, because for patients that don’t have any symptoms, have no disease progression, and have a good quality of life that is not impacted but the disease, it doesn’t always make sense to put them on a therapy that may have some side effects. I think even with advent of these new treatments, we still need to use common-sense approaches.”