Michael Choi, MD, discusses the potential FDA approval of lisocabtagene maraleucel in patients with relapsed/refractory chronic lymphocytic leukemia.

Dr Choi on the Implications of Approving Liso-Cel in Patients With CLL

Michael Choi, MD, hematologist/medical oncologist, associate professor, medicine, Moores Cancer Center, University of California San Diego (UCSD) Health, 

 (Breyanzi; liso-cel) for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), citing why CAR T-cell therapy has been more difficult to integrate into the CLL treatment armamentarium compared with in other hematologic malignancies.

Choi begins by stating that many of his patients inquire about the potential approval of certain CAR T-cell therapies, such as liso-cel, for CLL. Notably, 

 to the supplemental biologics license application seeking approval to expand the indication of liso-cel to include patients with relapsed/refractory CLL or small lymphocytic lymphoma. The desire for the approval of liso-cel for patients in this population is understandable, considering the proven efficacy of other CAR T-cell products in patients with CLL, he states. Choi states that the initial successes with CAR T-cell therapy in hematologic malignancies were observed in patients with CLL, some of whom remain in remission approximately 10 years after CAR T-cell infusion.

However, the lack of approvals of CAR T-cell therapies for patients with CLL patients stems from several factors, he notes.

Firstly, there's a heightened risk of toxicity associated with CAR T-cell treatment compared with BTK inhibitors, Choi expands. For many patients, this risk isn't deemed necessary unless indications of resistance to existing drugs emerge, according to Choi. Presently, CAR T-cell therapy may find its place in later lines of CLL therapy, he states, adding that there are still areas for improvement in CAR T-cell therapy's effectiveness. Patients with CLL exhibit immune system deficiencies that may differ from those of patients with other cancers, necessitating different disease management strategies, he elucidates.

Some studies have shown improved efficacy of CAR T-cell treatment when combined with ibrutinib (Imbruvica) or other BTK inhibitors, indicating a potential treatment strategy for patients with CLL, Choi continues. With each trial and advancement in CAR T-cell therapy, incremental enhancements are being achieved, he says. Hopefully, the CLL field will reach a stage where CAR T-cell therapy becomes a viable option for patients in need, Choi concludes.

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Dr Choi on Potential Treatment Options in R/R CLL Following Progression on a Covalent BTK Inhibitor

Michael Choi, MD, hematologist/medical oncologist, associate professor of medicine, Moores Cancer Center, University of California San Diego (UCSD) Health, discusses treatment options for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) following progression or unacceptable toxicity on treatment with a prior covalent BTK inhibitor.

The number of viable options for patients following disease progression on a previous covalent BTK inhibitor and BCL-2 inhibitor has increased with 

the FDA approval of pirtobrutinib (Jaypirca)

 in pretreated CLL or small lymphocytic lymphoma (SLL), Choi begins. The noncovalent BTK inhibitor gained accelerated FDA approval on December 1, 2023, based on data from the phase 1/2 BRUIN trial (NCT03740529), in which pirtobrutinib produced an overall response rate of 72% in the cohort of patients with CLL/SLL (n = 108).

The agent also exhibits a favorable safety profile, with an adverse effect profile comparable with that of other BTK inhibitors and a potentially lower cardiovascular event rate, Choi adds. Initial data suggest that many patients can achieve and sustain remission for at least a year, indicating encouraging outcomes with this therapy, he notes.

There are several promising options are coming down the pike for patients who experience progression on pirtobrutinib, Choi continues. The novel class of BTK degraders are currently being evaluated in clinical trials and have shown early signals of activity, he states. Moreover, bispecific antibodies and CAR T-cell therapy have been explored in this space for several years, Choi adds. The ongoing development of CAR T constructs, novel targets, and innovative combinations regimens with BTK inhibitors indicates the field's commitment to addressing evolving challenges in CLL treatment, Choi emphasizes. Although the hope is that most patients can be effectively managed with covalent BTK inhibitors and venetoclax, these emerging alternatives ensure a prepared and adaptable approach to meet the diverse needs of patients with CLL, he concludes.

Michael Choi, MD, discusses subsequent treatments for patients with relapsed/refractory CLL who progressed on a prior covalent BTK inhibitor.

Dr Choi on the Potential Role For BTK Degraders in Relapsed/Refractory CLL  

Michael Choi, MD, hematologist/medical oncologist, associate professor of medicine, Moores Cancer Center, University of California San Diego (UCSD) Health, discusses key mechanistic differences between BTK degraders and BTK inhibitors in the management of relapsed/refractory chronic lymphocytic leukemia (CLL), as well as highlights how this approach could address unmet needs within the CLL treatment paradigm.

Clinicians have become increasingly familiar with the use of BTK inhibitors in recent years, Choi begins. However, the emergence of degraders represents a novel and notable advancement in targeting the B-cell receptor signaling pathway, he states. BTK degraders aim to go beyond the inhibition of BTK by leveraging the ubiquitin proteasome pathway to completely degrade the kinase receptor, Choi details. Through this mechanism, BTK degraders may be able to overcome point mutations affecting inhibitor binding with a high degree of specificity, making them an appealing drug class for further investigation, he explains.

Several BTK degraders are currently in development, Choi continues. The observed toxicity profile of this drug class aligns with that of BTK inhibitors, and remissions have been documented, he adds. Promising early results were seen with the novel BTK degrader BGB-16673, which was well tolerated and produced clinically meaningful on-target effects in patients with relapsed/refractory B-cell malignancies, according to results from the phase 1 BGB-16673-101 study (NCT05006716) 

presented during the 2023 ASH Annual Meeting.

Ongoing exploration of BGB-16673 is being conducted at USCD, Choi states, adding that some patients have achieved partial responses with the agent despite being refractory to previous treatments. This development is not only a positive outcome for patients but also generates interest in the innovative nature of this approach, he says. Unlike continued efforts to improve upon existing variations of BTK inhibitors, BTK degraders represent an entirely new approach in terms of chemistry and pharmacology, Choi emphasizes. This not only bodes well for the ongoing success of these therapies, but also opens up the possibility for targeting other pathways and devising novel treatment strategies for patients in the future, he adds. Overall, the advent of degraders marks a significant step forward in the field, offering a potential new avenue for addressing the challenges of refractory diseases, Choi concludes.

Michael Choi, MD, discusses key differences between BTK degraders & BTK inhibitors in the management of relapsed/refractory chronic lymphocytic leukemia.

Dr Choi on the Potential Role For BTK Degraders in Relapsed/Refractory CLL

Michael Choi, MD, hematologist/medical oncologist, associate professor of medicine, Moores Cancer Center, University of California San Diego Health, discusses the results of the phase 3 GENUINE trial (NCT02301156) examining ublituximab in combination with ibrutinib (Imbruvica) vs ibrutinib alone in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

Data demonstrated the combination of ublituximab, an investigational anti-CD20 monoclonal antibody, and ibrutinib elicited an improvement in progression-free survival in patients with high-risk CLL, including those with deletion 17p, Choi says.

This high-risk patient population generally delivers a lower depth and durability of response when administered ibrutinib alone, which could factor into the improvement with the addition of ublituximab, Choi continues. However, the difference may be due to the maintenance-based dosing strategy of ublituximab, as opposed to earlier trials where treatment was administered for only the first 6 months, Choi concludes.

Michael Choi, MD, discusses the results of the phase 3 GENUINE trial examining ublituximab in combination with ibrutinib vs ibrutinib alone in patients with relapsed/refractory chronic lymphocytic leukemia.


Dr. Choi on the Addition of Ublituximab to Ibrutinib in R/R CLL

Michael Choi, MD, hematologist/medical oncologist, associate professor of medicine, Moores Cancer Center, University of California San Diego Health, discusses future research directions in chronic lymphocytic leukemia (CLL).

Developing next-generation BTK inhibitors and PI3K inhibitors will likely benefit patients with CLL, Choi explains. Additionally, encouraging data with noncovalent BTK inhibitors have emerged for patients with CLL who progress on available covalent BTK inhibitors. Noncovalent BTK inhibitors are also being evaluated before patients receive a covalent BTK inhibitor, Choi adds. 

Regarding PI3K inhibitors, the efficacy observed with umbralisib (Ukoniq) is representative of the idea that a drug class should not be overlooked even if initial trials of early-generation agents demonstrate limiting toxicities because the field can develop improved methods of mitigating adverse effects and dosing, Choi concludes.

Michael Choi, MD, discusses future research directions in chronic lymphocytic leukemia. 



Dr. Choi on Future Research Directions in CLL 

Michael Choi, MD, a medical staff physician and associate clinical professor of medicine at the University of California, San Diego (UCSD) Medical Center, discusses emerging treatments in chronic lymphocytic leukemia (CLL).

Combinations with BTK inhibitors, BCL-2 inhibitors, and CD20-directed monoclonal antibodies are being investigated in the frontline setting, says Choi.

In the second-line setting, novel classes of agents such as noncovalent BTK inhibitors could demonstrate utility for patients with BTK alterations since they have distinct binding for BTK, explains Choi. Moreover, these agents could be suitable for patients who progress on ibrutinib (Imbruvica) and want to remain on oral therapy.

PI3K inhibitors such as umbralisib are currently under investigation in combination with ublituximab and venetoclax (Venclexta) in clinical trials in order to optimize the effects of umbralisib in CLL, concludes Choi.

Dr. Choi on Emerging Treatments in CLL

Michael Choi, MD, a medical staff physician and associate clinical professor of medicine at the University of California, San Diego (UCSD) Medical Center, discusses the utility of duvelisib (Copiktra) in chronic lymphocytic leukemia (CLL).

In September 2018, duvelisib was approved for the treatment of adult patients with relapsed/refractory CLL/small lymphocytic lymphoma or relapsed/refractory follicular lymphoma after ≥2 prior therapies. Patients with CLL who are eligible for duvelisib have typically received a BTK inhibitor and venetoclax (Venclexta), says Choi.

PI3K inhibitors like duvelisib can also be used for patients with bleeding disorders or who require a strong anticoagulant agent, explains Choi.

Currently, duvelisib is being explored in combinations with venetoclax and obinutuzumab (Gazyva) in clinical trials. Pending the results of these trials, duvelisib may be moved into earlier lines of treatment for these patients, concludes Choi.

Michael Choi, MD, discusses the utility of duvelisib in chronic lymphocytic leukemia.



Dr. Choi on the Utility of Duvelisib in CLL

Michael Choi, MD, a medical staff physician and associate clinical professor of medicine at the University of California, San Diego (UCSD) Medical Center, discusses how up-front treatment decisions impact what options can be given in the relapsed/refractory setting for patients with chronic lymphocytic leukemia (CLL).

With defined durations of treatment, it is expected that all treatment options given in the first-line setting will be maintained as options upon relapse because patients will not have progressed or will not have developed overt clinical resistance to many of these agents; however, that theory needs to be tested, admits Choi. Some initial data indicate that patients who had achieved complete remission on venetoclax (Venclexta), stopped, and then resumed venetoclax upon progression, experienced equally excellent responses to the agent the second time around. If those results are repeated in other trials, that will support that this strategy can help preserve treatment options, says Choi.

For patients with CLL who stay on a BTK inhibitor, progress on a BCL-2 inhibitor, or have to stop either agent due to toxicity, it is clear that switching to other drug classes is the standard of care in the second-line setting, adds Choi. Many other treatment options are available in the second-line setting, including PI3K inhibitors and clinical trials, concludes Choi.

Michael Choi, MD, discusses how up-front treatment decisions impact what options can be given in the relapsed/refractory setting for patients with chronic lymphocytic leukemia.

Dr. Choi on Impact of Frontline Treatment Decisions on Relapsed/Refractory CLL

Michael Choi, MD, an associate clinical professor of medicine at the University of California, San Diego (UCSD) Medical Center, discusses frontline treatment considerations in chronic lymphocytic leukemia (CLL).

BTK inhibitors and BCL-2 inhibitors are 2 of the most commonly used drug classes in CLL, says Choi. Patients with newly diagnosed disease can receive ibrutinib (Imbruvica), acalabrutinib (Calquence), or venetoclax (Venclexta) in combination with obinutuzumab (Gazyva). Long-term follow-up with BTK inhibitors shows that the agents are safe and that most patients who remain on therapy will remain in remission, says Choi. The toxicities with these agents are mild, but usually manageable, adds Choi.

The combination of venetoclax and obinutuzumab is given as a 1-year treatment with the expectation that patients will remain in remission for several years. The combination is more intensive, so patients should be closely monitored for tumor lysis syndrome and undergo serial laboratory assessments; however, most patients can tolerate the combination as the pivotal trial was intended for older patients with other comorbidities, says Choi.

Based on the rates of atrial fibrillation or bleeding observed with BTK inhibitors, and the concern for tumor lysis syndrome with venetoclax, treatment can be tailored to avoid potential toxicity concerns and adhere to patients’ preferences, concludes Choi.

Michael Choi, MD, discusses frontline treatment considerations in chronic lymphocytic leukemia.

Michael Choi, MD

Articles

Dr Choi on the Implications of Approving Liso-Cel in Patients With CLL

Dr Choi on Potential Treatment Options in R/R CLL Following Progression on a Covalent BTK Inhibitor

Dr Choi on the Potential Role For BTK Degraders in Relapsed/Refractory CLL

Dr. Choi on the Addition of Ublituximab to Ibrutinib in R/R CLL

Dr. Choi on Future Research Directions in CLL

Dr. Choi on Emerging Treatments in CLL

Dr. Choi on the Utility of Duvelisib in CLL

Dr. Choi on Impact of Frontline Treatment Decisions on Relapsed/Refractory CLL

Dr. Choi on Frontline Treatment Considerations in CLL