Chemoimmunotherapy Role in CLL Shifting With Rise of Novel Agents

Jonathon B. Cohen, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Jonathon B. Cohen, MD

The introduction of novel and oral therapeutics has revolutionized chronic lymphocytic leukemia (CLL) management, and has also diminished the role for chemoimmunotherapy for both patients with newly diagnosed and relapsed/refractory disease, said Jonathon B. Cohen, MD, MS.

"CLL is an evolving field," said Cohen, an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. "Although there are some specific cases where I may offer chemoimmunotherapy, these oral agents appear to be better."

In May 2019, the FDA approved the combination of obinutuzumab (Gazyva) and venetoclax (Venclexta) for the frontline treatment of patients with previously untreated CLL, based on the results of the phase III CLL14 trial. Findings demonstrated prolonged progression-free survival (PFS) with the combination compared with obinutuzumab plus chlorambucil in patients with previously untreated CLL who had comorbidities. At a median follow-up of 28.1 months, 30 primary endpoint events occurred in the venetoclax/obinutuzumab arm compared with 77 in the chlorambucil/obinutuzumab group (HR, 0.35; 95% CI, 0.23-0.53; P <.001).

"One caveat to CLL14 is that it enrolled patients with multiple comorbidities," added Cohen. "Although the findings were encouraging, it may not be fully applicable to the general CLL population. Still, many people are considering using venetoclax in the frontline setting."

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Cohen, co-director of the Lymphoma Program, and medical director of Infusion Services at Winship Cancer Institute of Emory University, discussed the integration of novel agents into clinical practice and the changing role of chemoimmunotherapy in CLL.

OncLive^®: What role does chemoimmunotherapy have in CLL, and how has that role changed with the introduction of newer agents?

Cohen: For years, chemoimmunotherapy was the standard approach for patients with CLL in the upfront and relapsed settings. We know that patients who receive fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) for example, often have prolonged disease remissions without requiring additional therapy.

Unfortunately, that is not the case for every patient and many times there are significant short- and long-term toxicities that negatively impact quality of life.

Now, a number of studies have suggested that novel approaches using oral therapies may result in longer remissions in patients with CLL, so we are using chemoimmunotherapy less frequently than we did previously.

In my own practice, I typically only use chemoimmunotherapy for young patients who have select low-risk features that suggest they can enjoy a long PFS. In almost all other cases, however, I am using novel approaches with oral agents.

Could you expand on some of these newer approaches?

One large trial compared FCR with ibrutinib (Imbruvica); another trial looked at bendamustine plus rituximab versus ibrutinib-containing regimens in older patients.

In both studies, patients who received ibrutinib were more likely to have prolonged PFS than those who received a chemotherapy-based approach. Many investigators, including myself, have transitioned away from chemoimmunotherapy in favor of these oral agents based on these trials.

CLL14 was another pivotal trial. Could you discuss the data reported from it?

CLL14 evaluated the BCL-2 inhibitor venetoclax. This is an agent that has been approved for CLL for several years, and it was initially evaluated in the relapsed setting.

In this study, interestingly, patients were administered 1 year of obinutuzumab plus venetoclax, whereas prior studies using oral agents had [administered them indefinitely]. It does appear that the combination of obinutuzumab and venetoclax is highly effective.

Can you expand on the importance of trying to examine such combinations as a fixed-duration approach versus indefinite use?

Although ibrutinib is very effective, is typically well tolerated, and results in prolonged PFS, it has been designed to be administered indefinitely.

Some patients are OK with taking a pill every day; however, for others, the idea of indefinite treatment that may have low-grade side effects and significant cost is potentially challenging.

We need to determine if there are patients in whom could potentially discontinue therapy. Are there combinations we could use to deepen responses [and therefore stop treatment]?

Are there any other notable combinations under investigation?

A couple of studies have looked at combining ibrutinib with venetoclax in both the upfront and relapsed settings. Although it does appear to be a very effective combination, it has yet to be determined whether the combination is better than giving the 2 agents sequentially.

This combination could certainly be considered for patients with high-risk disease features or where you may be worried about a patient's response to a single-agent.

What unanswered questions remain in this space?

We have not fully figured out what role cellular therapy will play in CLL. CAR T-cell therapy is currently available for patients with diffuse large B-cell lymphoma, but it is also being investigated in CLL and other indolent B-cell lymphomas. We are still determining which patients will benefit the most from CAR T-cell therapy and when it should be employed.

Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi: 10.1056/NEJMoa1815281.