Targeted Therapies Take Center Stage in the CLL Treatment Paradigm

Seema A. Bhat, MD

BTK inhibitors have raised the bar in the treatment of patients with chronic lymphocytic leukemia (CLL) and the armamentarium continues to expand, according to Seema A. Bhat, MD, who added that ongoing research efforts are now focused on reversible BTK inhibitors, PI3K inhibitors, and novel combinations to provide time-limited options.

“Targeted agents continue to expand in in this space. We are very familiar with ibrutinib (Imbruvica), and have a lot of experience with it; however, we are now aware of some of the issues associated with this agent that we face in our day-to-day practice,” said Bhat. “We now have acalabrutinib (Calquence) as a second-generation BTK inhibitor, which probably has less adverse effects (AEs) when compared with ibrutinib. The field is moving very quickly.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Bhat, a hematologist specializing in CLL at The Ohio State University Comprehensive Cancer Center–James, spotlighted the advances that have been made with BTK inhibitors in CLL, shares emerging approaches under exploration, and forecasts where the field is headed.

OncLive^®: What were the lessons learned from the E1912 trial for treatment-naïve patients with CLL?

Bhat: E1912 was a study designed by the Eastern Cooperative Oncology Group and conducted in younger patients with CLL [and examined ibrutinib plus rituximab] in the first-line setting. Prior to this study, ibrutinib was already approved for the treatment of [patients with] CLL in this setting; however, that approval was a bit controversial because the partner arm in the RESONATE-2 study was chlorambucil and we rarely use chlorambucil—especially in young, fit patients. Based on the CLL10 study, which compared the combination of fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) with bendamustine plus rituximab, FCR was established as the standard of care for young and fit patients.

[E1912] included treatment-naïve patients who were younger than 70 years of age; it excluded the those with high-risk deletion 17p. Patients were randomized 2:1 to receive ibrutinib plus rituximab or FCR, given in the standard fashion of 6 cycles. The primary end point [of the trial] was progression-free survival (PFS), which was met; ibrutinib plus rituximab performed much better than FCR. We have prolonged follow-up data, which showed a 3-year PFS of around 89% with ibrutinib/rituximab versus 71% with FCR.

Interestingly, even with a short follow-up for a chronic disease, we were surprised to see an overall survival benefit with ibrutinib/rituximab versus FCR. With prolonged follow-up, we saw that about 73% of the patients continued on ibrutinib plus rituximab and about 95 patients discontinued treatment; this was due to various reasons such as progressive disease, death, and AEs, among others.

Patients who ended up discontinuing treatment because of AEs or other reasons beyond progressive disease had a median time off treatment of about 22 months. This is significant because, in our clinical practice, if a patient discontinues treatment due to an AE, we are pressured to move on to a second-line therapy, even if the patient is doing well. These data tell us that patients can have a treatment-free interval of up to 2 years, so that’s very interesting.

As far as AEs on this study were concerned, they were expected. With FCR, we saw greater hematological AEs, including neutropenic fever compared with ibrutinib plus rituximab. We did see BTK inhibitor–related AEs such as atrial fibrillation, bleeding, and hypertension. However, if we compare this to what we saw in the [Alliance] A041202 trial,the incidence of cardiac AEs was much less [in E1912]; this is probably because it was a younger population compared with the [other study]. Ibrutinib is now an established frontline treatment for patients with CLL.

What is the benefit of adding rituximab to the BTK inhibitor? Is obinutuzumab (Gazyva) potentially a better partner?

We saw that ibrutinib plus rituximab was superior to FCR. However, how much rituximab adds to this is still unknown. In a similar study that was conducted in older patients, there were 2 ibrutinib-containing arms: ibrutinib as a single agent or ibrutinib combined with rituximab; the comparator arm was bendamustine plus rituximab. In the study, both ibrutinib-containing arms performed better than bendamustine/rituximab. Based on that, we do not believe rituximab significantly adds to ibrutinib.

However, other studies have evaluated another anti-CD20 monoclonal antibody, obinutuzumab. Based on data from the CLL11 study, where rituximab plus chlorambucil was compared with chlorambucil plus obinutuzumab, [we saw that] the latter regimen performed better than the former.

Also, with regard to the ELEVATE-TN study, although it was only seen in a post-hoc analysis, we evaluated acalabrutinib as monotherapy and acalabrutinib plus obinutuzumab and we found a separation between the curves with acalabrutinib/obinutuzumab, suggesting a benefit. We need longer follow-up to truly understand what that means, but it does tell us that probably the better partner for BTK inhibitors is obinutuzumab. As such, research efforts are now focusing on this agent.

ELEVATE-TN trial was another major trial conducted in the frontline setting. What was the impact of this research on the paradigm? Can safety be improved by using acalabrutinib instead of ibrutinib?

The ELEVATE-TN study led to the frontline approval of acalabrutinib in patients with CLL. This was an international study conducted in older or younger patients who had comorbid conditions. These patients were randomized 1:1:1 to 3 arms. The standard arm was chlorambucil plus obinutuzumab, given in a standard fashion for 6 cycles, and the 2 experimental arms included acalabrutinib monotherapy and acalabrutinib plus obinutuzumab. Notably, obinutuzumab was started on cycle 2 and given for a total of 6 cycles and acalabrutinib was given indefinitely. This trial allowed crossover to the acalabrutinib/obinutuzumab arm if patients experienced progressive disease.

The primary end point of the study was PFS, which was met. Results showed that at a median follow-up of 28.3 months, the median PFS for the acalabrutinib-containing arms was not reached, whereas it was 22.6 months for chlorambucil plus obinutuzumab. The 3-year estimated PFS rates were 90% for acalabrutinib/obinutuzumab, 82% for acalabrutinib versus 34% for chlorambucil/obinutuzumab.

Again, the comparison made between the 2 acalabrutinib-containing arms was not a preplanned analysis; however, we found some separation between the curves in a post-hoc analysis. Also, the complete response (CR) rates were higher in the acalabrutinib/obinutuzumab arm at 13% versus 1% [with single-agent acalabrutinib]. Even so, we know from the RESONATE-2 study that CR rates with BTK inhibitors increase over time. Long-term follow-up is needed, but these are highly encouraging data.

Regarding safety, no unexpected or additional safety signals were observed. We saw increased atrial fibrillation and bleeding versus the comparator arms. However, if we compare these data to other studies with ibrutinib, these effects happened far less [with acalabrutinib]. Infusion reactions were another interesting component of this research. With the 2 obinutuzumab -containing arms, infusion reactions were far less compared with the combination of chlorambucil plus obinutuzumab.

Furthermore, acalabrutinib is associated with a headache. I have made it part of my own practice to warn patients that they can expect headaches, although they are transient; they will go away after a couple of treatment cycles. The headaches are very manageable with hydration, acetaminophen (Tylenol), and caffeine.

The ASCEND trial led to the approval of acalabrutinib in the relapsed/refractory setting. Could you speak to those data?

ASCEND was a phase 3 international study of acalabrutinib, which is a next-generation BTK inhibitor. Similar to ibrutinib, it’s covalently binding; however, it’s also highly selective for BTK. Since this agent is highly selective for BTK with lesser off-target effects, we believe that the AEs that are commonly seen with ibrutinib may not be as prevalent with acalabrutinib.

This study was done in patients with relapsed/refractory CLL who received at least 1 prior line of treatment. Here, a total of 155 patients were randomized to [acalabrutinib] and an equal number were given investigator’s choice of either idelalisib (Zydelig) plus rituximab or bendamustine plus rituximab.

Notably, out of the 155 patients who received investigator’s choice of therapy, only 36 received bendamustine plus rituximab while 119 received idelalisib plus rituximab. This actually highlights the changing trend where we are preferentially using targeted agents for our patients.

The primary end point [of the trial] was PFS and, at a median follow-up of 16.1 months, it was discovered that the acalabrutinib arm was far superior to the investigator’s choice of therapy. When looking at idelalisib plus rituximab and bendamustine plus rituximab, both arms were inferior to the acalabrutinib arm.

Regarding safety, pneumonitis and diarrhea was reported with idelalisib. Less of an incidence of cardiac effects was observed with acalabrutinib; however, there were reports of atrial fibrillation and hypertension, which is emerging as a common AE observed with BTK inhibitors. This gives us another option for patients with relapsed/refractory disease.

Are any emerging approaches under exploration that you are excited about?

The CLL field is ever-expanding, which is exciting. We have many choices that are readily available. We have the 2 approved BTK inhibitors, ibrutinib and acalabrutinib, and the BCL-2 inhibitor venetoclax. Now, with ibrutinib and acalabrutinib, we found that resistance develops over time, which can lead to progression of disease.

Reversible BTK inhibitors, such as LOXO-305 and ARQ-531, are also under development. Zanabrutinib (Brukinsa) is another covalently-binding agent, similar to ibrutinib and acalabrutinib. A head-to-head study comparing ibrutinib with zanubrutinib is currently ongoing.

In terms of PI3K inhibitors, we have idelalisib and duvelisib (Copiktra). We also have the next-generation PI3K inhibitor umbralisib (TGR-1202), [that is being examined] in combination with anti-CD20 antibodies as well as other agents. We're really excited about this expanding field of targeted agents for CLL.

Where is future research headed? Are time-limited options on the horizon?

Other next steps will focus on combining targeted agents. One of the caveats with targeted agents is that they are delivered indefinitely; that contributes to AEs and it impacts compliance and cost of treatment. We don’t talk about this often, but we should be talking about it. We are trying to see whether we can combine and achieve a stronger, deeper response so that we can administer time-limited treatment. That’s where the field of CLL research is headed.