Monica D. Mead, MD, assistant clinical professor, medicine, the University of California, Los Angeles (UCLA), UCLA Health, UCLA Jonsson Comprehensive Cancer Center, discusses the importance of addressing unanswered questions in the treatment of patients with mantle cell lymphoma (MCL).

There are many important unanswered questions within the MCL treatment landscape, Mead begins. The phase 3 TRIANGLE trial (NCT02858258) evaluated the combination of ibrutinib (Imbruvica) and standard induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) and fixed 2-year maintenance, Mead explains. Induction therapy consisted of R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone)/R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin).

After a median follow-up of 31 months, ASCT alone did not produce superior failure-free survival (FFS) vs ibrutinib alone, whereas ibrutinib and ASCT elicited a higher FFS compared with ASCT alone. Based on these data, the authors concluded that sufficient efficacy is seen with the addition of a BTK inhibitor to conventional chemotherapy in the frontline setting, Mead emphasizes. However, the the role of transplantation in the frontline setting has yet to be confirmed, she adds. Therefore, longer follow-up data from the TRIANGLE study could elucidate whethersequencing ASCT prior to treatment with rituximab and BTK inhibitor maintenance provides superior benefit vsproceeding to maintenance therapy in the absence of a transplant, Mead says.

Another pressing question in the field of MCL is how to optimally manage patients with MCLdisplaying 

 mutations, Mead continues. This is considered a particularly challenging patient subset to treat, Mead notes. Studies utilizing various agents have shown decreased efficacy in the 

-mutant patient population, Mead highlights. It remains important to understand how other MCL-directed agents perform in this patient subset.Several ongoing clinical trials in this space aim to develop more creative treatment strategies for this difficult-to-treat population, Mead concludes.

Videos

Monica D. Mead, MD, discusses the importance of addressing unanswered questions in the treatment of patients with mantle cell lymphoma.

Dr Mead on Unanswered Questions in the Treatment of MCL 

Monica D. Mead, MD, assistant clinical professor, medicine, Hematologic Malignancy, the University of California, Los Angeles (UCLA), UCLA Health, UCLA Jonsson Comprehensive Cancer Center, discusses the efficacy and safety differences between the second-generation BTK inhibitor zanubrutinib (Brukinsa) and the first-generation BTK inhibitor ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL).

As a second-generation BTK inhibitor, zanubrutinib binds to BTK proteins with greater precision than ibrutinib, Mead says. Since zanubrutinib does not bind to some of the off-target receptors that ibrutinib binds to, it has a more favorable toxicity profile, Mead explains. The binding precision of zanubrutinib also allows for a more favorable pharmacokinetic profile. Accordingly, treatment with zanubrutinib induces earlier, deeper responses than treatment with ibrutinib, according to Mead.

Clinical trials investigating zanubrutinib currently have shorter follow-up intervals compared with trials evaluating ibrutinib, Mead notes. However, in ibrutinib trials, longer follow-up correlated with deeper responses. Similar response patterns have emerged in the zanubrutinib trials as well, Mead says.

The phase 1/2 BGB-3111-AU-003 trial (NCT02343120) investigated zanubrutinib in patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Extended follow-up data from this trial provide evidence that complete response rates in patients with hematologic malignancies treated with zanubrutinib increase over time, Mead explains. Moreover, long-term findings from the single-arm, phase 2 BGB-3111-206 trial (NCT03206970), which supported the 

 in patients with relapsed/refractory MCL, showed that 83.7% of patients responded with the agent at a median follow-up of 35.3 months. The median duration of response was not reached.

Overall, zanubrutinib has produced early responses with a tolerable safety profile in patients with MCL, Mead emphasizes. Zanubrutinib is also associated with fewer adverse effects (AEs) of interest than ibrutinib, Mead notes. In BGB-3111-206, the most common AEs of grade 3 or higher were decreased neutrophil counts (18.6%) and pneumonia (12.8%). Conversely, the toxicity profile of ibrutinib in the confirmatory phase 3 SHINE trial (NCT01776840) informed AbbVie’s 

voluntary withdrawal of the FDA indication for the agent

 in patients with relapsed/refractory MCL.

Monica D. Mead, MD, discusses the efficacy and safety differences between the second-generation BTK inhibitor zanubrutinib and the first-generation BTK inhibitor ibrutinib in patients with mantle cell lymphoma. 

Dr Mead on the Use of Zanubrutinib vs Ibrutinib in MCL

Monica D. Mead, MD, assistant clinical professor, medicine, Hematologic Malignancy, the University of California, Los Angeles (UCLA), UCLA Health, UCLA Jonsson Comprehensive Cancer Center, discusses reasons for the declining use of the BTK inhibitor ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL).

As ibrutinib was the first BTK inhibitor to gain FDA approval for patients with MCL, it was once the only BTK inhibitor in use in this population, Mead says. In 2013, 

the FDA granted accelerated approval to ibrutinib

 for patients with MCL who had received at least 1 prior therapy. This approval was supported by findings from a single-arm phase 2 trial (NCT01236391), in which 68% of patients responded with ibrutinib.

However, ibrutinib use declined with the FDA approvals of 2 second-generation BTK inhibitors, acalabrutinib (Calquence) and zanubrutinib (Brukinsa). In 2017, 

acalabrutinib gained accelerated FDA approval for patients with MCL

 who have received at least 1 prior therapy. This regulatory decision was supported by findings from the phase 2 ACE-LY-004 trial (NCT02213926), in which 81% (95% CI, 73%-87%) of patients who received acalabrutinib achieved an objective response.

FDA granted accelerated approval to zanubrutinib for patients with MCL

 who have received 1 or more prior therapies. This approval was backed by findings from 2 single-arm trials. In both the phase 1 BGB-3111-206 trial (NCT03206970) and the phase 1/2 BGB-3111-AU-003 trial (NCT02343120), zanubrutinib elicited an objective response rate of 84% (95% CI, 74%-91%).

The declining use of ibrutinib in patients with MCL was motivated by the agent’s more severe toxicity profile when compared with acalabrutinib or zanubrutinib rather than inferior efficacy, Mead explains. Although trials comparing ibrutinib with zanubrutinib and acalabrutinib in patients with chronic lymphocytic leukemia (CLL) revealed that the 3 agents have similar efficacy profiles, ibrutinib was associated with more substantial adverse effects. Thus, the National Comprehensive Cancer Network removed ibrutinib from its list of preferred regimens for patients with CLL. Moreover, on April 6, 2023

AbbVie voluntarily withdrew the FDA indication for ibrutinib

in patients with pretreated MCL based on safety findings from the confirmatory phase 3 SHINE (NCT01776840) and SELENE (NCT01974440) trials.

Monica D. Mead, MD, discusses reasons for the declining use of the BTK inhibitor ibrutinib in patients with mantle cell lymphoma.

Dr Mead on the Decreased Use of Ibrutinib in Pretreated MCL

Monica D. Mead, MD, assistant clinical professor of medicine, Department of Hematologic Malignancy, the University of California, Los Angeles (UCLA), UCLA Health, UCLA Jonsson Comprehensive Cancer Center, discusses the impact of key data on the role of ibrutinib (Imbruvica) in the treatment of mantle cell lymphoma (MCL).

The FDA approvals of acalabrutinib (Calquence) in 2017 and zanubrutinib (Brukinsa) in 2019 have led to a decrease in the use of ibrutinib in both clinical trials and in practice, Mead begins. Despite this, ibrutinib remains the most studied BTK inhibitor in the frontline setting, Mead says. Currently, there are 2 randomized, phase 3 trials investigating the use of first-line ibrutinib for patients with MCL: the TRIANGLE trial (NCT02858258) and SHINE trial (NCT01776840), Mead states.

In the TRIANGLE study, treatment-naïve patients with MCL were randomly assigned to 3 different treatment arms: ibrutinib plus induction chemotherapy and autologous stem cell transplant (ASCT); ibrutinib plus induction chemotherapy without ASCT; and induction chemotherapy and ASCT alone, Mead explains. Patients in both experimental arms received 2 years of ibrutinib maintenance therapy following treatment. Results showed that adding ibrutinib to conventional therapy improved failure-free survival (FFS) rates vs ASCT alone but did not produce a superior FFS rate vs ibrutinib alone. Ibrutinib alone was also associated with a more favorable safety profile.

The SHINE trial was designed to confirm the efficacy of ibrutinib in combination with bendamustine (Avastin) and rituximab (Rituxan), followed by rituximab maintenance, for elderly patients with MCL in the treatment-naïve setting, Mead details. This trial did not meet its primary end point of improved progression-free survival, and it resulted in a higher rate of adverse effects (AEs).

Supported by data from the confirmatory SHINE trial, 

the FDA voluntarily withdrew their indication for ibrutinib in MCL

, based on FDA requirements related to accelerated approval status.

The decision to utilize ibrutinib in clinical practice continues to be a topic of substantial debate, with many oncologists opting to substitute acalabrutinib or zanubrutinib for ibrutinib in combination with chemotherapy for older, frailer patients or younger, more intensive induction–eligible patients, Mead concludes.

Monica D. Mead, MD, discusses the impact of key data on the role of ibrutinib in the treatment of mantle cell lymphoma.


Dr Mead on the Shifting Role of Ibrutinib in the Treatment of MCL 

Monica D. Mead, MD, a clinical instructor of hematology and oncology at the University of California, Los Angeles (UCLA), discusses the role of BTK inhibition after venetoclax (Venclexta) in relapsed/refractory chronic lymphocytic leukemia (CLL).

During the 2020 ASH Annual Meeting and Exposition, findings from a subanalysis of the phase 3 MURANO trial revealed that patients who relapsed on venetoclax plus rituximab (Rituxan) derived substantial benefit from a subsequent BTK inhibitor or retreatment with a venetoclax-based regimen. As such, investigators concluded that early use of fixed-duration therapy with venetoclax plus rituximab is reasonable and does not compromise subsequent responses to therapy or overall survival in patients with relapsed/refractory CLL. 

Up until this research, the success of BTK inhibition post-venetoclax in patients with CLL was unknown, says Mead. Now, evidence suggests that utilizing a venetoclax-based regimen in the second-line setting does not limit the effectiveness of BTK inhibition in the third-line setting, nor does it limit the utility of retreatment with venetoclax because many patients obtained minimal residual disease negativity with retreatment, concludes Mead.

Monica D. Mead, MD, discusses the role of BTK inhibition after venetoclax in relapsed/refractory chronic lymphocytic leukemia.  



Dr. Mead on the Role of BTK Inhibition After Venetoclax in Relapsed/Refractory CLL

Monica D. Mead, MD, a clinical instructor of hematology and oncology at the University of California, Los Angeles (UCLA), discusses ongoing research efforts to overcome BTK inhibitor resistance in patients with chronic lymphocytic leukemia (CLL).

Currently, UCLA is participating in numerous CLL clinical trials, according to Mead. In 1 clinical trial in particular, the institution is partnering with the biotechnology company ArQule, Inc. to examine the novel BTK inhibitor ARQ 531, Mead says. Thus far, the agent has demonstrated promising activity, even in patients who have developed resistance to prior BTK inhibitors, Mead concludes.

Monica D. Mead, MD, discusses ongoing research efforts to overcome BTK inhibitor resistance in patients with chronic lymphocytic leukemia.

Dr. Mead on Ongoing Research Efforts to Overcome BTK Inhibitor Resistance in CLL

Monica D. Mead, MD, clinical instructor, Hematology and Oncology, University of California, Los Angeles, discusses the utility of venetoclax (Venclexta) in combination with rituximab (Rituxan) in the second-line setting for patients with chronic lymphocytic leukemia (CLL).

Not all patients with CLL receive the same frontline therapy; therefore, it is difficult to standardize second-line therapy, says Mead. However, patients who received fludarabine, cyclophosphamide, and rituximab (Rituxan) or bendamustine/rituximab could be considered for venetoclax/rituximab in the second-line setting rather than a BTK inhibitor, Mead explains.

Venetoclax/rituximab offers patients a time-limited treatment option, says Mead. Conversely, BTK inhibitors require indefinite dosing that can put more strain on a patient than the adverse effects associated with the therapy, Mead says. However, venetoclax/rituximab does not appear to confer significant or limiting toxicities and should be considered as second-line or salvage therapy in this patient population, concludes Mead. 

Monica D. Mead, MD, discusses the utility of venetoclax in combination with rituximab in the second-line setting for patients with chronic lymphocytic leukemia.  



Dr. Mead on the Utility of Second-Line Venetoclax/Rituximab in CLL 

Monica D. Mead, MD, clinical instructor, Hematology and Oncology, University of California, Los Angeles, discusses the clinical significance of the phase 3 MURANO trial in chronic lymphocytic leukemia (CLL).

Prior to the MURANO trial, the standard of care for patients with relapsed/refractory CLL was bendamustine/rituximab (Rituxan; BR), says Mead. However, the survival advantage demonstrated with venetoclax (Venclexta) plus rituximab vs BR in the MURANO trial established the novel regimen as the new standard salvage option for this patient population, Mead adds. 

Moreover, the introduction of venetoclax/rituximab shifted the treatment of patients with relapsed/refractory CLL away from chemotherapy-containing strategies, concludes Mead.

Monica D. Mead, MD, discusses the clinical significance of the phase 3 MURANO trial in chronic lymphocytic leukemia.  



Monica D. Mead, MD

Articles