Novel Agents Increasingly Individualize CLL Care

William G. Wierda, MD, PhD

Treatment is far from a “one-size-fits-all” approach for chronic lymphocytic leukemia (CLL) and, with more novel agents emerging, selecting the right treatment for each patient is becoming a more complex process.

Age still remains a large factor in treatment decisions. In recent studies, novel CD20 antibodies have shown promise for older patients, who cannot tolerate fludarabine-based therapy due to advanced age and/or comorbidities.

In the COMPLEMENT 1 trial, ofatumumab (Arzerra), and chlorambucil demonstrated a 9.3- month improvement in progression-free survival (PFS) compared with chlorambucil alone in patients with a median age of 69 years. The combination also demonstrated an overall response rate of 82% versus 69% with chlorambucil alone.

Chromosome abnormalities, such as 17p deletion, also play a role in treatment selection. The FDA approved ibrutinib (Imbruvica) for high-risk patients with 17p deletions in July 2014, based on findings from the phase III RESONATE trial. In the study, treatment with ibrutinib was shown to lower the risk of progression by 75% in patients with CLL who harbored a 17p deletion and by 78% in the full population of the study when compared with ofatumumab.

Ibrutinib has also shown potential in other patient populations. An expanded approval application has been submitted for ibrutinib for use in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory CLL. This is based on the phase III HELIOS study, which found that adding ibrutinib to standard BR reduced the risk of disease progression by 80% compared with BR plus placebo in patients with pretreated CLL.

OncLive: What factors should be considered when determining frontline treatment for patients with CLL?

Several other agents, including idelalisib (Zydelig) and emerging immunotherapies have also generated excitement in the CLL community. To better understand the changing landscape of CLL and how treatment options vary among different patient subtypes, OncLive spoke with William G. Wierda, MD, PhD, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. Wierda: You can divide patients into two categories, based on age and comorbidities. For younger patients, we use more intensive chemoimmunotherapy. The standard treatment for those patients would be fludarabine, cyclophosphamide, and rituximab (FCR).

Patients with CLL tend to be older, and those who are older tend to have other medical problems. They can have diabetes, hypertension, heart disease, and other cancers. These illnesses can impact their ability to receive more intense chemotherapies. Also, we know that their bone marrow does not function normally, as it would if they were 40 or 50 years old. As we get older, there is some attrition to the bone marrow and it is less able to tolerate toxicities from chemotherapy. That can limit our ability to treat patients with chemotherapy who are in the older age group. The recommended treatment for patients over the age of 65 or those who have comorbidities are combinations of chemotherapy with CD20 antibodies, particularly chlorambucil plus ofatumumab, or rituximab. Those are the standard of care.

What role do you see ibrutinib and idelalisib playing in CLL?

We still use the standard criteria in terms of instating treatment that we have for years. Therefore, we do not start patients early on treatment if they have high-risk chromosome abnormalities; we only begin treatment if patients have an indication for treatment. These indications include decline in the hemoglobin or platelet count or disease-related symptoms that we want to eliminate by providing treatment. Things are changing very quickly. We now have oral agents. There was a large randomized trial, which evaluated chlorambucil versus ibrutinib for patients over 65. That trial was positive for ibrutinib, and we will hear about that trial at the 2015 ASH Annual Meeting. That trial has not yet been published but, once it is, I think the FDA will be reviewing that data, if they are not already. Moreover, they will likely expand the label to include first-line therapy with ibrutinib monotherapy because it had superior outcomes on that study.

Secondly, 17p deletions represent a high-risk feature. Ibrutinib monotherapy is currently the standard of care frontline for those patients. Currently, ibrutinib is only approved for patients with this mutation who are untreated.

Are there other immunotherapy agents you see potential for?

Idelalisib is currently only approved for previously treated patients. These are both very active oral agents that are very effective at controlling the disease. However, their response is a partial remission, meaning they have at least a 50% reduction in the amount of disease, but there is still disease present. We have impressive PFS curves for both idelalisib and ibrutinib in the salvage setting, so we have durable responses for these agents as monotherapy, or with idelalisib in combination with rituximab. Over the next several years, we will likely see the addition of new agents in combination to try and improve on that response and push patients over into a complete remission. The CAR T-cell therapy strategy is exciting. We are modifying patients’ own T cells to react against leukemia cells through recognition of CD19. We also have trials now that are opening with the checkpoint inhibitor monoclonal antibodies. These have been remarkable advances with these agents for patients with solid tumors, so now we are working on seeing if there is activity in CLL.