Years of Clinical Trial Research Produces Promising Therapies for CLL/SLL

Brain T. Hill, MD, PhD

In a space that less than a decade ago treated patients with chemotherapy in the frontline, clinicians now have their choice of options when treating patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Currently, there are 3 available oral covalent Bruton's tyrosine kinase (BTK) inhibitors available for this patient population, including ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanbrutinib (Brukinsa). Each of these agents have shown activity in these patients.

During the National Comprehensive Cancer Network (NCCN) 2022 Annual Congress: Hematologic Malignancies, experts, including Brian T. Hill, MD, PhD, explained the most recent updates regarding treatment options for patients CLL or SLL. Over the course of 2 sessions, optimal frontline treatment options and the data supporting their use was shared.

“In terms of frontline use of BTK inhibitors, we've seen direct comparisons with chemotherapy such as bendamustine and rituximab [Rituxan] vs BTK inhibitors. Specifically, ibrutinib and zanabrutinib have been compared in a head-to-head fashion, and have shown that with continuous oral treatment with a covalent BTK inhibitor, the progression-free survival is superior compared with a 6 month duration of bendamustine and rituximab chemotherapy,” said Hill, a physician in the Department of Hematology and Medical Oncology at the Cleveland Clinic, in an interview with Targeted Oncology^TM.

Regarding the next steps for this field, investors are developing the non-covalent BTK inhibitor pirtobrutinib (L0X0-305), finding optimal treatment sequences, and enrolling patients in more trials, including the CAPTIVATE study (NCT02910583) and the EVOLVE CLL/SLL study (NCT04269902).

In the interview, Hill discussed making treatment decisions for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Targeted Oncology: How have the treatment landscapes of CLL and SLL changed over the past few years?

Hill: Whereas probably 5 years ago it was common to use chemotherapy for the frontline treatment of CLL, we now have many different options with targeted agents. There are 3 available oral covalent BTK inhibitors, ibrutinib, acalabrutinib, and zanbrutinib, that are all active. We also have the option of what we call time-limited therapy with venetoclax and abituzumab, which is an oral agent combined with a monoclonal antibody, which are administered for 12 months and 6 months respectively. After 12 months, patients are typically monitored in a form of remission for a lengthy period thereafter.

Small lymphocytic lymphoma [SLL], really is the same disease as CLL. They sound different and sometimes that can be a point of confusion to patients and even physicians and healthcare providers. Even though CLL and SLL sound different, they're the same malignant clone or the same disease, just in different compartments where CLL is primarily in the bloodstream, and SLL is primarily in the tissue or lymph nodes.

What have been some of the most recent updates in these fields?

In terms of frontline use of BTK inhibitors, we've seen direct comparisons with chemotherapy such as bendamustine and rituximab [Rituxan] vs BTK inhibitors. Specifically, ibrutinib and zanabrutinib have been compared in a head-to-head fashion, and have shown that with continuous oral treatment with a covalent BTK inhibitor, the progression-free survival is superior compared with a 6 month duration of bendamustine and rituximab chemotherapy.

The differential benefit is primarily in what we call high-risk patients. Those with an unfavorable or unmutated IGVH gene tend to have more benefit to the oral covalent BTK inhibitors, whereas those with mutated IGVH tend to have pretty good outcomes no matter what you do, including with bendamustine and rituximab chemotherapy.

What influences a clinicians treatment decision when treating patients with CLL/SLL?

When starting treatment for CLL patients, you can go down 2 different paths if you're talking about the targeted agents. You can go down the path of a continuous, oral, covalent BTK inhibitor, which is typically given daily until intolerance or progression. We now have long-term follow-up from all 3 BTK inhibitors showing very favorable long-term progression-free survival with this approach.

Alternatively, if a patient has a preference to not be on oral therapy for an indefinite period of time, or if they have a contraindication to a BTK inhibitor, for instance, if they're on anticoagulation with warfarin [Jantoven], or have some other reason to not be on an oral BTK inhibitor, for instance, cost or other factors, then time-limited treatment with the venetoclax plus obinutuzumab [Gazyva] combination is very active, very effective, and again, tends to have very high rates of deeper mission. [It also allows] for a cessation of therapy and monitoring of the patient until they need to be treated again.

What unmet needs still exist in space?

During our session [at NCCN], Anthony Mato, MD, covered relapsed/refractory CLL and SLL. It's true that all the novel agents that we've been discussing are also available for relapsed patients. In fact, that's where they were first developed. The seminal studies or registrational trials that led to the approval of these target agents in the relapsed patient population, primarily enrolled patients who had previously been treated with chemoimmunotherapy. The big question that we don't have good prospective clinical trial data for is, what is the optimal sequence of these agents?

For instance, if you start treatment with an oral BTK inhibitor and you develop intolerance but you're responding as most people do, it's reasonable to switch to another covalent BTK inhibitor in that class. If you develop treatment resistance from a BTK inhibitor, it's probably not going to work to switch to another covalent BTK inhibitor of the 3 that are available. In that setting, moving to venetoclax makes sense. The other sequences are also discussed, though there's less prospective data on this scenario, because some patients are now being initiated with the venetoclax/ obinutuzumab combination. It's uncommon to see intolerance, but if it were to occur during those 12 months, then switching to a BTK inhibitor makes sense.

The other scenario is that after a period of remission, patients have a recurrence, relapse, or disease progression, and require treatment. In that setting, you can retreat with venetoclax, but there is limited data on that approach. The other option is to move to a BTK inhibitor in that setting. The sequencing of these is something that we're still working on. The real unmet need is [knowing] what happens when patients have had both, if they've had a BTK inhibitor and venetoclax-based treatment, and now have developed treatment resistance to both these classes of agents.

Looking forward, we have late-stage clinical development of non-covalent BTK inhibitors, specifically pirtobrutinib, which is not currently approved by regulatory agencies, but many people are looking forward to using that agent because it does have activity in patients who develop point mutation in BTK that's found in the covalent BTK inhibitors.

Is any research evaluating the optimum treatment for patients?

The best we can say for optimizing treatment sequences would be based on observational data from large cohorts in what we call real-world experience. In that setting, we do know that switching from 1 BTK inhibitor to another, if the first one was stopped because of intolerance, is an effective strategy. We do know from at least 1 prospective trial and observational data that if you are resistant to a covalent BTK inhibitor, venetoclax works reasonably well. Additionally, the non-covalent BTK inhibitors are active in that setting.

Where do you see research headed for the future of this space?

Looking forward, we see that there are now combinations with BTK inhibitors and venetoclax. Particularly, the CAPTIVATE study combined venetoclax with ibrutinib for 12 months and showed high rates of undetectable minimal residual disease status at the end of treatment. Then in that setting, it seems appropriate to stop all therapy and observe even deeper into the future. We do believe that challenging the notion of active surveillance or watchful waiting in high-risk patients may not be the best approach.

There is a large intergroup trial undergoing enrollment right now called the EVOLVE CLL/SLL study. This study is randomizing patients with high-risk CLL to immediate treatment with venetoclax/obinutuzumab or standard of care, which is active surveillance or watchful waiting for a period. When a traditional treatment indication develops, then treating with venetoclax/obinutuzumab. Patients who have high-risk features like unmutated IGVH, 17p deletion, or other factors may be considered candidates for this study, and I would encourage oncologists and community members to consider seeking out a site for the EVOLVE CLL/SLL study if it is available at a site near you.