Advances Continue at Rapid Pace in CLL Paradigm

Bita Fakhri, MD

Bita Fakhri, MD

The chronic lymphocytic leukemia (CLL) paradigm has evolved significantly with the addition of combination strategies, more selective BTK inhibitors, and fixed-duration approaches. Therefore, the next question being asked in the field is how to choose among the various options for patients, explained Bita Fakhri, MD.

“The field of CLL is moving at a pace in which we no longer have to choose the lesser of 2 evils, so patients have very good options,” said Fakhri, an assistant professor of medicine at the University of California, San Francisco School of Medicine. “It is mutual decision-making [between myself and my patients].”

In an interview during the 2019 OncLive^® State of Science Summit™ on Hematologic Malignancies, Fakhri discussed data from several recent trials in CLL and focused on other regimens moving through the pipeline.

OncLive: Could you discuss the current state of CLL treatment prior to data that were presented at the 2019 ASH Annual Meeting?

Fakhri: In the upfront setting, 2 major landmark trials were presented at the 2018 ASH Annual Meeting. In one of them, in an older population, researchers compared the commonly used chemoimmunotherapy option of bendamustine and rituximab (Rituxan) versus the BTK inhibitor ibrutinib (Imbruvica) versus ibrutinib combined with rituximab. Researchers saw that both ibrutinib-containing arms beat the chemoimmunotherapy regimen and met their primary end point of progression-free survival (PFS).

Based on this study, single-agent ibrutinib or ibrutinib plus rituximab is the current standard of care for older patients with CLL. At the same time, another clinical trial of younger patients with CLL compared fludarabine, cyclophosphamide, and rituximab (FCR) when compared with ibrutinib plus rituximab, [in which ibrutinib/rituximab showed superior PFS].

[In both of these studies], the ibrutinib-containing regimens became the standard of care over traditional chemoimmunotherapy.

At the same time, [there were data from] the CLL14 trial, which [evaluated] a chemotherapy-free, [regimen: a fixed duration] of 6 cycles of obinutuzumab (Gazyva) with venetoclax (Venclexta). These findings were compared with findings of the CLL11 trial, which combined obinutuzumab and chlorambucil; the results were outstanding. The 2-year PFS rate of obinutuzumab combined with venetoclax was 88.2% compared with the 64.1% 2-year PFS rate observed with obinutuzumab  plus chlorambucil in the CLL11 trial.

Based on these trials, either ibrutinib as a single agent, combined with a monoclonal antibody, or a time-limited, chemotherapy-free regimen of venetoclax plus obinutuzumab are current standard options in the up-front setting.

During the 2019 ASH Annual Meeting, data were presented from the ELEVATE-TN trial, which compared the more selective BTK inhibitor acalabrutinib (Calquence), either alone or in combination, with obinutuzumab, and obinutuzumab plus chlorambucil. Both acalabrutinib-containing regimens [led to higher PFS rates compared with obinutuzumab/chlorambucil]. Specifically, the 2-year PFS rates were 93% for acalabrutinib/obinutuzumab, 87% with single-agent acalabrutinib, and 47% in the obinutuzumab/chlorambucil arm.

Based on these studies, we have 2 great BTK inhibitors that can be used in the up-front setting in patients with CLL. Additionally, we can recommend obinutuzumab plus 1 year of venetoclax to our patients who have a new diagnosis of CLL.

What factors do you take into consideration when deciding on a regimen for patients?

We have the data with BTK inhibitors, and we also have obinutuzumab and venetoclax; these are really good agents. Ibrutinib and acalabrutinib are lifelong treatments, so I always tell patients that they will be on this medicine as long as they tolerate it well and their disease is responding [to the therapy]. On the other hand, with venetoclax and rituximab, these are time-limited regimens for 12 months. Therefore, if someone cannot wrap their head around the fact that they have to be on a lifelong treatment, then venetoclax/rituximab is a better option for them.

Also, you always have to take into account the safety profile. BTK inhibitors have a risk of atrial fibrillation and [cardiac events], so if someone is coming in with a history of atrial fibrillation or they already have some cardiac risk factors, venetoclax with rituximab is a better option for them. At the same time, venetoclax is also associated with cytopenia. Then, if someone is going to be on a regimen for 12 months, and is constantly [dealing] with cytopenia, that can pose some challenges. Tumor lysis syndrome with venetoclax and rituximab [also] causes a lot of fear.

Both strategies have positives and negatives: lifelong treatments, longer follow-up data, and the adverse event of atrial fibrillation. In the ELEVATE-TN trial, the risk of atrial fibrillation was about 4%, but acalabrutinib and ibrutinib have not been compared with each other directly. With venetoclax and rituximab, cytopenia is always a risk; this is something patients have to take into account.

What role does chemotherapy have in a space with several targeted therapies?

We are very fortunate that we are living in the United States. I was at the International Workshop for CLL in June 2019 and we tend to forget that many countries, unfortunately, do not have access to these targeted agents; this includes some South American, Eastern European, and African countries.

For patients who have access to targeted agents, we have robust phase III clinical trial data showing that targeted agents are better than some chemoimmunotherapy regimens, especially in those with high-risk features. These include 17p deletion, 11q deletion, and unmutated IGHV; patients [with these] are not going to do well with chemoimmunotherapy.

Even when we come up with guidelines, we have to ensure that they are universal and as inclusive as possible. Until we get to a point where everybody has access to targeted agents, I do not think chemoimmunotherapy is dead. However, for patients who have access to targeted agents, the frontline agents are BTK inhibitors and venetoclax. 

[An example of] future directions and clinical trials is the CAPTIVATE trial, which combined ibrutinib with venetoclax. This showed really good overall response rates, durable responses, and high minimal residual disease (MRD)—negative outcomes. The field is not ready to practice based on MRD yet, but future clinical trial designs should focus on [fixed-duration] options, because we know that financial toxicities  are associated with lifelong treatments.

What advances are being made in the relapsed setting?

In the relapsed setting, PI3K inhibitors are definitely an option; [a trial] compared duvelisib (Copiktra) with ofatumumab (Arzerra), which can be offered as a sterile option for patients with relapsed/refractory CLL. The other PI3K inhibitor that has been approved for patients with relapsed/refractory CLL is idelalisib (Zydelig), and was evaluated in combination with rituximab compared with rituximab plus placebo. The results were outstanding.

The problem with PI3K inhibitors is the toxicities. At 2 years, 40% of patients are not able to tolerate them, mostly because of autoimmune complications such as colitis, pneumonitis, and hepatitis. If we can move toward a place that we can use them in a time-limited fashion rather than continuing them until disease progression, we can create a better place for them as treatment options for our patients with CLL.

So many options are on the horizon. At the 2019 ASH Annual Meeting, LOXO-305 went live; investigators found a noncovalent BTK inhibitor with activity against the most common resistance mutations in patients who have had previous BTK inhibitor exposure.

Of course, in patients who we call “double-refractory,” meaning they failed both a BTK inhibitor and a BCL-2 inhibitor, other therapies are definitely an option. TheTRANSCEND CLL 004 study, which involves many patients who have been heavily pretreated, has enrolled patients with up to 12 prior lines of therapy. The follow-up is short, but it is a very promising treatment strategy. Hopefully [this approach] can replace an allogeneic hematopoietic stem cell transplantation, which is very toxic. If we can get there by utilizing another cellular therapy approach, why not?

Is there anything else that you would like to highlight?

I definitely want to bring 2 amazing [ongoing] phase III clinical trials to everyone's attention. The  Alliance A041702 trial is enrolling patients older than 70 years who have a new diagnosis of untreated CLL, and randomizing them to receive  obinutuzumab plus  ibrutinib versus obinutuzumab, ibrutinib, and venetoclax in a time-limited fashion. It is an amazing study because it is focused on a time-limited approach with the help from MRD data. The ECOG-ACRIN EA9161 trial is evaluating the same regimens— obinutuzumab plus ibrutinib versus obinutuzumab, ibrutinib, and venetoclax—in a patient population with untreated CLL who are younger than 70 years. I believe [these studies] are going to read out pretty soon. The ECOG-ACRIN trial is a bit behind in enrollment, but if anyone has a patient with a new diagnosis of untreated CLL who wants to be on a clinical trial, both studies are going to be practice changing.