Potential New Combination Options For CLL: What to Know

  • Recent advancements in FDA-approved treatments for chronic lymphocytic leukemia (CLL) give patients and oncologists more treatment options.
  • The new therapies include drugs like acalabrutinib (brand name: Calquence), zanubrutinib (brand name: Brukinsa), venetoclax (brand name: Venclyxto), and obinutuzumab (brand name: Gazyvaro). Many of these treatments can be used as frontline and second-line therapy.
  • Dr. Adam Kittai, an Associate Professor of Medicine at Mount Sinai, tells SurvivorNet that he’s hopeful the oral combination of BTK inhibitors and venetoclax—a time-limited approach—will be approved for frontline treatment so patients have another viable option, as opposed to the transfusion approach that involves venetoclax and obinutuzumab.

Several new therapies for chronic lymphocytic leukemia (CLL) have received FDA approval in recent years, giving oncologists more treatment options.

Among the therapies now available are the targeted cancer drugs acalabrutinib (Calquence), zanubrutinib (Brukinsa), venetoclax (Venclyxto), and obinutuzumab (Gazyvaro).

These frontline CLL treatments are go-to therapies early in the treatment regimen, but determining how to sequence them isn’t always straightforward. New clinical trials are bringing us closer to learning the most effective combination.

“We should know soon about whether or not the combination of these BTK inhibitors and venetoclax will be approved in the frontline, which will allow for another option in the treatment-naive use space that will only make the conversation of what to treat your patients with treatment-naive UCL longer,” Dr. Adam Kittai, Associate Professor of Medicine at Mount Sinai in New York, tells SurvivorNet.

Dr. Kittai’s research focuses on non-Hodgkin lymphoma. He’s hopeful the combination of BTK inhibitors and venetoclax will be approved partly because it’s an oral regimen that can be used instead of venetoclax plus Obinutuzumab, which requires infusion.

Sequence Combinations

Trials are underway to help determine the best treatment sequence with newly approved CLL therapies.

Potential combinations may include:

  • BTK inhibitors plus monoclonal antibody (venetoclax) as a frontline option
  • Oral regimen for treatment-naive CLL, which is a time-limited option
  • Venetoclax and obinutuzumab, which require transfusion

“When this new combination gets approved, that’s time-limited. It’s going to take away from those patients who would likely receive the Venetoclax plus obinutuzumab. Still, those patients who want the easy startup with continuous BTK inhibitors, those patients will likely remain the same. And so, I’m hopeful that this gets approved soon,” Dr. Kittai said.

Bruton Tyrosine Kinase Inhibitors

BTK inhibitors have transformed the therapeutic landscape for leukemias and lymphomas. They work by blocking the B-cell receptor signaling pathway, crucial for the survival and proliferation of CLL cells.

Dr. Kittai says what the patient wants should be factored into treatment choices as well.

“So in general, when I’m deciding what to treat a patient with who sees me in clinic, I’m really between acalabrutinib and zanubrutinib and venetoclax plus obinutuzumab. And what I really take in consideration is what the patient wants. Do they want a time-limited therapy or do they want a continuous therapy? And patient preference is what I use as my determining decision about what to treat that patient with,” he explains.

Acalabrutinib: A Second-Generation BTK Inhibitor

Acalabrutinib is a highly selective Bruton tyrosine kinase (BTK) inhibitor. Unlike first-generation BTK inhibitors, acalabrutinib is designed to have fewer off-target effects, making it better tolerated.

Acalabrutinib has demonstrated efficacy in both treatment-naïve and relapsed/refractory CLL patients. The ELEVATE-TN trial showed that acalabrutinib, either alone or in combination with obinutuzumab, significantly improved progression-free survival (PFS) compared to standard chemoimmunotherapy. Notably, acalabrutinib’s safety profile is superior, with lower incidences of atrial fibrillation and other cardiovascular toxicities.

Acalabrutinib is administered orally at a dose of 100 mg twice daily. It can be used as monotherapy or combined with obinutuzumab for increased efficacy, although the latter is associated with higher rates of cytopenias and infections. The choice between acalabrutinib and other BTK inhibitors often depends on patient-specific factors, such as cardiovascular risk and prior treatment history.

“If somebody comes in and they’re saying: wait a minute, I don’t really need to have time-limited therapy. I’d rather have an easier option where it doesn’t require so much therapy upfront. Then I usually air towards a covalent BTK inhibitor with acalabrutinib or zanubrutinib.

“Now, which to choose: acalabrutinib versus zanubrutinib? It’s really up in the air. In my opinion. These two drugs are very similar,” adds Dr Kittai.

Zanubrutinib: Enhanced Efficacy with Improved Safety

Zanubrutinib is another second-generation BTK inhibitor, known for its ability to achieve deep and sustained inhibition of BTK with minimal off-target effects. Its design aims to maximize efficacy while reducing adverse events common with earlier BTK inhibitors.

The SEQUOIA trial highlighted zanubrutinib’s superiority over traditional chemotherapy, particularly in patients with high-risk cytogenetic features. It showed improved PFS and overall response rates (ORR), with fewer adverse effects compared to ibrutinib, especially concerning cardiovascular events like atrial fibrillation.

Zanubrutinib’s favorable safety profile makes it a strong candidate for first-line therapy in CLL. It is generally well-tolerated, with the most common side effects being mild infections, bruising, and diarrhea. Its lower incidence of cardiovascular toxicity compared to ibrutinib makes it a preferred option for patients with pre-existing heart conditions.

“The only thing that we note that is different between these two drugs (acalabrutinib and zanubrutinib) is that in the second line, zanubrutinib did show an efficacy benefit compared to ibrutinib for all comers. Whereas when acalabrutinib was compared to ibrutinib, there was no efficacy benefit shown,” explains Dr Kittai.

“But this was in a high risk group of patients with deletion 17p and 11q. So now when I’m thinking in the frontline, really there’s not much to differentiate between the two drugs, but mostly I go by their side effect profile.”

“Acalabrutinib can be associated with headaches. And so typically I might avoid acalabrutinib in somebody who has chronic headaches. Zanubrutinib seems to have more hypertension. So maybe I would avoid zanubrutinib to somebody who has hypertension that’s difficult to control or has cardiac comorbidity. But in reality, I think these two drugs are very similar,” adds him.

Venetoclax and Obinutuzumab Combo

Venetoclax is a potent BCL-2 inhibitor that promotes apoptosis in CLL cells by disrupting the anti-apoptotic signaling mediated by BCL-2, a protein overexpressed in CLL. This action is particularly effective in combination therapies, allowing for deep remissions and MRD (minimal residual disease) negativity.

The MURANO and CLL14 trials have solidified venetoclax’s role in CLL treatment, particularly in combination with rituximab or obinutuzumab. These combinations have shown significant improvements in PFS and OS, with many patients achieving MRD-negative status, which is a predictor of longer-term remissions.

Venetoclax is always combined with obinutuzumab. Obinutuzumab is a glycoengineered monoclonal antibody targeting the CD20 antigen on B cells. It enhances antibody-dependent cellular cytotoxicity and induces direct cell death, making it more effective than earlier anti-CD20 antibodies like rituximab.

This combination is especially beneficial in patients with high-risk cytogenetic features and in elderly patients with comorbidities.

“If a patient wants time-limited therapy, they have to understand that the first couple of weeks of this time limited therapy, they have to come into clinic weekly in order to get their infusion of obinutuzumab for the first three weeks and we have to monitor their labs when we start Venetoclax to make sure that we’re not running into the issues with tumor lysis syndrome. So if a patient wants time-limited therapy and they understand that they have to come into clinic weekly, this is one of the options that I give to my patients,” says Dr Kittai.