Benjamin Heyman, MD, hematologist, medical oncologist, the University of California San Diego, discusses the phase 3 ALPINE trial (NCT03734016) in chronic lymphocytic leukemia (CLL).

The ALPINE trial compared the overall response rate of zanubrutinib (Brufkinsa) vs ibrutinib (Imbruvica) in patients with relapsed/refractory CLL.

ALPINE demonstrated zanubrutinib improved progression-free survival (PFS) vs ibrutinib in the head-to-head comparison, Heyman says. This was notable because previous trials comparing ibrutinib and acalabrutinib (Calquence) did not demonstrate a PFS benefit with either agent.

Moreover, the safety profile of zanubrutinib should be considered when deciding on which BTK inhibitor to administer to patients with CLL, Heyman continues. Zanubrutinib is associated with a lower incidence of cardiovascular adverse effects, specifically atrial fibrillation, Heyman explains. However, zanubrutinib carries a higher risk of cytopenia and neutropenia, Heyman adds.

If zanubrutinib receives FDA approval for the treatment of patients with CLL, it will be another beneficial treatment option when considering the use of a BTK inhibitor, Heyman concludes.

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Benjamin Heyman, MD, discusses the phase 3 ALPINE trial in chronic lymphocytic leukemia.


Dr. Heyman on the ALPINE Trial in CLL

Benjamin Heyman, MD, assistant clinical professor, Medicine, hematologist, Moores Cancer Center, University of California, San Diego Health, discusses the evolution of BTK inhibitors in relapsed/refractory mantle cell lymphoma (MCL).

The introduction of single-agent BTK inhibitors transformed the treatment of patients with relapsed/refractory MCL, Heyman says. Long-term data with single-agent ibrutinib (Imbruvica) demonstrated an overall response rate of approximately 70% and complete response rate of approximately 30%. However, responses appear to be dependent on timing of treatment. For example, patients with 1 prior line of therapy have superior responses compared with those who received 2 or more prior lines of therapy, Heyman explains.

The second-generation covalent BTK inhibitors acalabrutinib (Calquence) and zanubrutinib (Brukinsa) are also FDA approved for use in patients with relapsed/refractory MCL, Heyman says. Without cross-trial comparisons, it is difficult to determine whether these agents demonstrate improved efficacy vs ibrutinib; however, acalabrutinib and zanubrutinib are associated with less hematologic adverse effects and reduced risk of cardiovascular toxicities compared with ibrutinib, Heyman says.

Additionally, noncovalent BTK inhibitors, such as pirtobrutinib (LOXO-305), as well as combination regimens with ibrutinib and venetoclax (Venclexta) or CD20-directed monoclonal antibodies appear to be promising strategies to improve response rates, outcomes, and duration of response, Heyman concludes.

Benjamin Heyman, MD, discusses the evolution of BTK inhibitors in relapsed/refractory mantle cell lymphoma. 



Dr. Heyman on the Evolution of BTK Inhibitors in Relapsed/Refractory MCL  

Benjamin Heyman, MD, hematologist, Moores Cancer Center, University of California, San Diego Health, discusses the phase 3 SYMPATICO trial (NCT03112174) examining the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) vs ibrutinib alone in patients with relapsed or refractory mantle cell lymphoma (MCL). 

Data from a safety run-in cohort showed that at a median follow-up of 31 months, the doublet elicited an overall response rate of approximately 80%; this proved to be similar to results reported from the phase 2 AIM study (NCT02471391), where the same combination was previously examined in patients with MCL, Heyman says. 

The majority of patients in this cohort achieved complete and durable responses, as well as a median progression-free survival (PFS) of approximately 3 years, Heyman adds. A threefold increase in PFS was observed in patients who received the combination vs the monotherapy, Heyman explains. 

Updated data from the trial are anticipated to see whether the combination will alter the treatment paradigm for patients with relapsed or refractory MCL; these data could potentially support a chemotherapy-free approach with ibrutinib plus venetoclax in this setting, Heyman concludes.

Benjamin Heyman, MD, discusses the phase 3 SYMPATICO trial examining the combination of ibrutinib and venetoclax vs ibrutinib alone in patients with relapsed or refractory mantle cell lymphoma.

Dr. Heyman on Ibrutinib Plus Venetoclax in Relapsed/Refractory MCL 

Benjamin Heyman, MD, hematologist, Moores Cancer Center, University of California, San Diego Health, discusses future therapeutic directions in mantle cell lymphoma (MCL).

Significant progress has been made regarding the treatment of patients with relapsed/refractory MCL, particularly with the emergence of BTK inhibitors and CD19-directed CAR T-cell therapy, Heyman says. These advances changed the treatment paradigm of MCL and improved survival for patients.

However, improvements upon single-agent BTK inhibitors are needed, Heyman says. For example, combination approaches with BTK inhibitors could provide more durable and robust responses to patients with MCL. Moreover, as BTK inhibitors are currently given indefinitely until progression or unacceptable toxicity, combination strategies could offer patients time-limited, response-adapted options, Heyman says.

Additionally, moving targeted therapies into the frontline setting as single agents or in combination regimens could provide tolerable up-front options that still confer durable responses to elderly patients with MCL, Heyman concludes.

Benjamin Heyman, MD, discusses future therapeutic directions in mantle cell lymphoma.  



Dr. Heyman on Future Therapeutic Directions in MCL 

Benjamin Heyman, MD, hematologist, University of California, San Diego, discusses agents targeting ROR1 in patients with relapsed/refractory mantle cell lymphoma (MCL). 

One ROR1-targeting drug of interest for this patient population is the antibody-drug conjugate zilovertamab vedotin (formerly cirmtuzumab or UC-961). The agent has a similar payload to brentuximab vedotin (Adcetris), but is conjugated to a ROR1 monoclonal antibody, according to Heyman.

Results from a phase 1/2 trial demonstrated that approximately 50% of patients with relapsed/refractory MCL responded to single-agent zilovertamab vedotin, and the responses proved to be durable over time, Heyman explains. The most common adverse effects experienced with the agent were neutropenia and neuropathy, which proved to be reversible once the medication was stopped, Heyman adds.

The monoclonal antibody zilovertimab has also been explored in combination with ibrutinib (Imbruvica) for those with relapsed/refractory disease, Heyman adds. Although it is still early, the regimen does appear to possess the potential to improve overall response and the durability of response, Heyman concludes. 

Benjamin Heyman, MD, discusses agents targeting ROR1 in patients with relapsed/refractory mantle cell lymphoma. 

Dr. Heyman on ROR1-Targeted Approaches in Relapsed/Refractory MCL 

Benjamin Heyman, MD, assistant clinical professor of medicine, University of California, San Diego, discusses the use of maintenance rituximab (Rituxan) in patients with follicular lymphoma.

The 10-year follow-up from the phase III PRIMA study demonstrated a progression-free survival advantage versus observation as well as an improvement in the time to next chemotherapy treatment. While there was no overall survival benefit with rituximab, there are a few select situations where it may be of benefit to patients, says Heyman.

For example, rituximab can be used in a patient who does not have a complete response (CR) after induction chemotherapy. These patients are at risk of early relapse, and maintenance rituximab could help get patients to a CR, says Heyman.

Rituximab maintenance can also be used in elderly patients who may not be able to tolerate another round of chemoimmunotherapy upon relapse. Patients may also prefer to be on maintenance rituximab in order to prolong their remission despite the potential for increased toxicity, concludes Heyman.

Dr. Heyman on the Use of Maintenance Rituximab in Follicular Lymphoma

Benjamin Heyman, MD, assistant clinical professor of medicine, University of California, San Diego, discusses frontline treatment options for patients with follicular lymphoma.

Currently, the combination of rituximab (Rituxan) and chemoimmunotherapy is a standard of care in the frontline treatment of patients with follicular lymphoma, says Heyman.

The results of the phase III RELEVANCE trial demonstrated that the combination of rituximab and lenalidomide (Revlimid; R

) elicits similar efficacy compared with rituximab plus chemoimmunotherapy in patients with advanced, untreated follicular lymphoma.

Ultimately, patient preference and disease biology should guide treatment selection, says Heyman.

 is given over the course of 18 months, whereas rituximab in combination with bendamustine or obinutuzumab (Gazyva) is given over the course of 6 months, says Heyman. Data with R

 suggests that patients have a decreased risk of infection and cytopenia, but an increased risk of developing cutaneous toxicities.

Balancing therapy duration and potential toxicity is necessary in selecting the optimal regimen for patients, concludes Heyman.

Benjamin Heyman, MD, discusses frontline treatment options for patients with follicular lymphoma.

Benjamin Heyman, MD

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