Dr Koff on Frontine and Maintenance Treatment Decision-Making in MCL

Jean L. Koff, MD, MS, associate professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, discusses 

factors that influence treatment decision-making for patients with mantle cell lymphoma (MCL)

 in the frontline and maintenance settings.

In the context of newly diagnosed MCL, treatment decisions are primarily driven by assessing a patient’s eligibility for autologous stem cell transplant (ASCT) and determining the appropriate induction regimen, Koff begins. Historically, ASCT has been a standard approach, but its role in MCL is currently evolving, she says. Patients are stratified based on their ability to tolerate aggressive induction regimens or their need for less intensive options, she notes.

The selection of BTK inhibitors in the frontline and maintenance settings has been guided by data from the phase 2 TRIANGLE trial (NCT02858258), which evaluated ibrutinib (Imbruvica) as part of a chemoimmunotherapy regimen and as single-agent maintenance therapy, with or without ASCT, Koff states. However, data now indicate that newer covalent BTK inhibitors, such as acalabrutinib (Calquence) and zanubrutinib (Brukinsa), generate efficacy profiles that are comparable with that of ibrutinib but offer improved tolerability, according to Koff. In 2017, 

 for the treatment of adult patients with MCL who have received at least 1 prior therapy. In 2019, 

 for this indication. Data with acalabrutinib and zanubrutinib have shifted clinical practice in favor of utilizing these newer agents over ibrutinib for the management of various lymphoma subtypes, including MCL.

Although the TRIANGLE trial supported the use of ibrutinib in the MCL treatment paradigm, the National Comprehensive Cancer Network guidelines for the management of MCL now provide a category 2B recommendation to consider substituting newer-generation BTK inhibitors for ibrutinib, Koff explains. This change underscores a trend toward individualized treatment plans based on tolerability and patient-specific factors, rather than strictly adhering to historical data with ibrutinib-based regimens, Koff concludes.

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Jean L. Koff, MD, MS, discusses factors that influence treatment decision-making for patients with MCL in the frontline and maintenance settings.

Dr Koff on the Role of Covalent BTK Inhibitors and Pirtobrutinib in MCL

Jean L. Koff, MD, MS, associate professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, discusses the role of covalent BTK inhibitors in the treatment of mantle cell lymphoma (MCL).

Covalent BTK inhibitors are increasingly recommended as part of frontline therapy and maintenance regimens in MCL, particularly in patients suitable for aggressive induction approaches, Koff notes. Agents such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) have shown efficacy in MCL, leading to improved response rates and progression-free survival; However, despite their efficacy, some patients eventually develop resistance or intolerance to these covalent BTK inhibitors, she adds.

the FDA approved pirtobrutinib (Jaypirca)

 for the treatment of adult patients with relapsed/refractory MCL who have undergone at least 2 lines of systemic therapy, including a covalent BTK inhibitor.

Pirtobrutinib, a noncovalent BTK inhibitor, has emerged as a therapeutic option for patients with MCL following treatment with 1 of the approved covalent agents, Koff explains. She highlights that pirtobrutinib has demonstrated clinically meaningful efficacy across various MCL subgroups, including those who have developed resistance to or have previously been treated with covalent BTK inhibitors. Moreover, there is emerging evidence suggesting that pirtobrutinib may be effective even in patients who have not been exposed to any prior BTK inhibitors, expanding its potential utility in MCL treatment, she says.

Pirtobrutinib has been well tolerated, and it has been associated with low rate of treatment discontinuation due to drug-related toxicities, which makes it a favorable option in the MCL treatment landscape, Koff explains. This safety profile supports its integration into clinical practice, providing an effective alternative for patients who may not tolerate other BTK inhibitors.

Pirtobrutinib should be considered a new standard of care for patients with MCL who have received prior covalent BTK inhibitors, she continues. Its safety and efficacy profile make it an important addition to the therapeutic options available for managing MCL, particularly in the context of relapsed or refractory disease, Koff concludes.

Jean L. Koff, MD, MS, discusses the role of covalent BTK inhibitors in the treatment of mantle cell lymphoma.

Dr Koff on BTK Inhibitors vs Venetoclax-Based Regimens in First-Line CLL

Jean L. Koff, MD, MS, associate professor, Department of Hematology and Medical Oncology; clinical investigator, Bone Marrow and Stem Cell Transplant Center, Emory University School of Medicine; member, Discovery and Developmental Therapeutics Research Program, Winship Cancer Institute, Emory University, discusses the considerations for deciding between BTK inhibitors vs venetoclax (Venclexta)-based regimens in the first-line treatment of patients with chronic lymphocytic leukemia (CLL).

Koff explains that both therapeutic options offer strong overall response rates (ORRs) and durable remissions; however, BTK inhibitors and venetoclax have present adverse effect (AEs) profiles and treatment administration schedules, which are crucial factors in clinical decision-making.

Treatment with BTK inhibitors is typically indefinite, requiring patients to adhere to a daily oral regimen, she says. This continuous treatment approach is well-suited for patients who prefer the convenience of a daily pill to maintain long-term control of their CLL, Koff explains. However, continuous treatment with BTK inhibitors could result in cumulative AEs, including cardiovascular toxicity, bleeding risks, and potential development of resistance over time, which require careful monitoring and management by clinicians, Koff notes.

Conversely, venetoclax-based regimens offer a time-limited therapy, which are typicallys completed within a 2-year period, Koff continues. This option can be appealing to patients who prefer a defined treatment duration. During the first 6 months of treatment, venetoclax-based regimens require a ramp-up period with close monitoring to mitigate the risk of AEs, Koff says. Some venetoclax-based regimens, such as venetoclax plus azacitidine, could require an agent to be given as an infusion, which necessitates hospital visits for patients, Koff adds.

Choosing between these regimens should be a joint decision between clinicians and patients, accounting for the patient’s treatment preferences, says Koff. Although some patients may prioritize the long-term control provided by BTK inhibitors despite the need for indefinite treatment, others may value the finite course of venetoclax despite the initial intensity of the regimen.

Ultimately, a thorough discussion with patients about these options allows for a more individualized treatment approach, optimizing outcomes and aligning with patients’ lifestyles and treatment goals, Koff concludes.

Jean L. Koff, MD, MS, discusses considerations around using BTK inhibitors vs venetoclax-based regimens in first-line chronic lymphocytic leukemia. 

Dr Koff on Toxicities Associated With Pirtobrutinib in MCL

Jean L. Koff, MD, MS, associate professor, Department of Hematology and Medical Oncology; clinical investigator, Bone Marrow and Stem Cell Transplant Center, Emory University School of Medicine; member, Discovery and Developmental Therapeutics Research Program, Winship Cancer Institute, Emory University, discusses 

 (Jaypirca) in patients with mantle cell lymphoma (MCL).

FDA approved pirtobrutinib for the treatment of adult patients with relapsed/refractory

 who have undergone at least 2 lines of systemic therapy, including a BTK inhibitor, Koff begins. This approval was granted under the FDA's accelerated approval pathway and was supported by data from the phase 1/2 BRUIN trial (NCT03740529), which was an open-label, single-arm study, she explains. In BRUIN, pirtobrutinib elicited an overall response rate of 50% (95% CI, 41%-59%) in patients who received the agent at a daily dose of 200 mg once daily (n = 120) and a complete response rate of 13%, as well as a partial response rate of 38%.

During the BRUIN trial, pirtobrutinib was primarily associated with constitutional symptoms, such as fatigue, along with gastrointestinal adverse effects (AEs), such as diarrhea, Koff continues. These AEs were generally manageable, she says, adding that as with other BTK inhibitors, infections were observed, which is common among patients undergoing lymphoma treatment. However, the incidence of severe infections specifically attributable to pirtobrutinib was low, she notes. Bruising was noted among the patients, but no cases of severe bruising or hemorrhage were reported, Koff reports.

Atrial fibrillation or flutter, which can be a concern with BTK inhibitors, occurred at a very low rate with pirtobrutinib, she expands. Similarly, hypertension is another AE that requires monitoring in patients receiving BTK inhibitors, Koff states, adding that the incidence of pirtobrutinib-related hypertension was very low, with no instances of severe-grade high blood pressure. Community oncologists should be aware of these potential AEs when considering pirtobrutinib for their patients but can be reassured by the relatively low incidence of severe AEs, she concludes.

Jean L. Koff, MD, MS, discusses the toxicities associated with pirtobrutinib in the BRUIN trial for mantle cell lymphoma.

Dr Koff on the Safety Profile of Pirtobrutinib in Pretreated CLL/SLL

Jean L. Koff, MD, MS, associate professor, Department of Hematology and Medical Oncology; clinical investigator, Bone Marrow and Stem Cell Transplant Center, Emory University School of Medicine; member, Discovery and Developmental Therapeutics Research Program, Winship Cancer Institute, Emory University, discusses the safety profile of pirtobrutinib (Jaypirca) according to data from the phase 1/2 BRUIN trial (NCT03740529) in chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The FDA granted accelerated approval to pirtobrutinib

 in December 2023 for the treatment of adult patients with CLL or SLL who previously received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. This regulatory decision was supported by updated findings from the phase 1/2 BRUIN trial (NCT03740529).

In the BRUIN trial, pirtobrutinib demonstrated favorable tolerability, Koff begins. The most commonly observed adverse effects (AEs) were constitutional symptoms such as fatigue, Koff reports. Diarrhea occurred in 28.4% of patients at a generally low grade and cough was reported in 27.3% of patients, she adds. Similar to other covalent BTK inhibitors, bruising and bleeding events were noted with pirtobrutinib; these were typically mild, Koff notes.

Other AEs of interest with BTK inhibitors, such as hypertension, were observed infrequently in the CLL cohort, Koff continues. The incidence of treatment-related hypertension was 3.5%, and few grade 3 or higher events (0.4%) were reported, she says, adding that the rates of treatment-related atrial fibrillation and flutter were also low at 1.4%. Neutropenia emerged as a notable cytopenia associated with pirtobrutinib, occurring in 28.4% of patients with CLL/SLL as a grade 3 or higher AE, Koff states. This AE is commonly observed when administering the majority of lymphoma-directed therapies, she notes.

These findings underscore pirtobrutinib's manageable safety profile in this heavily pretreated population, Koff emphasizes. Overall, the approval of pirtobrutinib represents a significant advancement in treatment options for patients with CLL and SLL who have exhausted other therapeutic options, providing a new targeted treatment approach with encouraging tolerability and efficacy data from the BRUIN trial.

Jean L. Koff, MD, MS, discusses the safety profile of pirtobrutinib in pretreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Jean L. Koff, MD, MS, assistant professor, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, discusses systemic therapies in follicular lymphoma.

There are many treatment options for patients with newly diagnosed or relapsed/refractory follicular lymphoma, explains Koff. Patient-related factors such as disease burden and personal preference may help guide treatment selection.

For example, the combination of lenalidomide (Revlimid) and rituximab (Rituxan; R

) is approved for patients with previously treated follicular lymphoma and marginal zone lymphoma.

Additional research regarding proper sequencing and patient selection will provide insight on optimal treatment approaches, concludes Koff.

Jean L. Koff, MD, MS, discusses systemic therapies in follicular lymphoma.

Jean L. Koff, MD, MS

Articles

Dr Koff on Frontine and Maintenance Treatment Decision-Making in MCL

Dr Koff on the Role of Covalent BTK Inhibitors and Pirtobrutinib in MCL

Dr Koff on BTK Inhibitors vs Venetoclax-Based Regimens in First-Line CLL

Dr Koff on Toxicities Associated With Pirtobrutinib in MCL

Dr Koff on the Safety Profile of Pirtobrutinib in Pretreated CLL/SLL

Dr. Koff on Systemic Therapy Options in Follicular Lymphoma