Dr Seymour on the Role of Mutational Profiling in CLL

John Seymour, MBBS, FRACP, PhD, director, Department of Hematology, the Peter MacCallum Cancer Centre, medical oncologist, Hematology Department, the Royal Melbourne Hospital, shared considerations for community oncologists regarding the role of mutational profiling in the treatment of patients with chronic lymphocytic leukemia (CLL).

The CLL treatment armamentarium has expanded over the past decade, with multiple targeted agents now available for this patient population, Seymour begins. However, he explains that understanding a the mutational profile of an individual patient’s disease is crucial to inform treatment decision-making.

 mutational status play a pivotal role in informing treatment decisions and optimizing patient outcomes in both the short and long term. He highlights that the integration of mutational profiling into routine clinical practice is essential. For example, 

 mutations or deletions, which are associated with poorer prognoses and resistance to chemoimmunotherapy, may steer clinicians toward the use of targeted therapies, such as BTK inhibitors or BCL-2 inhibitors, Seymour says.

Seymour also emphasizes the importance of involving patients in the decision-making process, ensuring they are fully informed about the implications of each treatment option. This includes discussing the logistics of therapy, such as the frequency of visits, monitoring requirements, and potential impact on their quality of life, he adds.

Through effective education, Seymour notes that patients can better understand pros and cons between different therapies; for example, some regimens may be given as continuous therapy, and others could feature time-limited treatment. He explains that these differences need to be discussed with patients to help them make informed decisions that align with their personal preferences and lifestyle.

A personalized approach to CLL management through the integration of both biological insights and patient involvement is useful, he continues. This strategy enhances adherence to treatment and allows for tailoring therapeutic choices to the specific disease characteristics and personal needs of each patient. By aligning treatment plans with patient preferences and the biological profile of their disease, clinicians can achieve improved outcomes and greater patient satisfaction, particularly in the community oncology setting, Seymour concludes.

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John Seymour, MBBS, FRACP, PhD, discusses the role of genetic profiling in the treatment of chronic lymphocytic leukemia. 

John Seymour, MBBS, FRACP, PhD, director, Department of Hematology, the Peter MacCallum Cancer Centre, medical oncologist, Hematology Department, the Royal Melbourne Hospital, discusses the characteristics of patient subgroups with chronic lymphocytic leukemia (CLL) who may benefit from curative treatment with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR). 

The curative potential of FCR therapy in CLL is best derived by specific subgroups defined by disease biology, age, and renal function. Identifying and appropriately selecting these patients for FCR treatment is a nuanced process, and remains a critical consideration when determining the optimal course of CLL management. Accordingly, investigators must understand patients' individual biologic profiles, as well as their disease-related risk, he explains.

These patients typically exhibit favorable disease biology, Seymour says, displaying either 

alterations. The presence of other rare mutations may also factor into treatment decisions, he adds. 

Additionally, consideration is given to a patient's age and renal function, as these factors influence a patient's ability to tolerate treatment with FCR, Seymour notes. Ideal candidates for FCR are typically younger than 65 years of age and possess adequate renal function, as indicated by a creatinine clearance above 60, he details. The subset of patients with curative potential is relatively small, accounting for approximately 15% of all patients with CLL who require treatment, Seymour elaborates. Of this 15%, approximately half achieve long-term remission with FCR and will not require any subsequent treatment throughout their natural lifespan. 

Although targeted agents, such as BTK inhibitors or long-term venetoclax-based regimens, have demonstrated favorable short-term tolerability, they require continuous administration, Seymour continues. This is associated with an increased, cumulative risk of developing toxicities such cardiac arrhythmias, he states. Unfortunately, there is currently a lack of evidence demonstrating the curative potential of these time-limited venetoclax-based therapy, Seymour notes.

John Seymour, MBBS, FRACP, PhD, discusses the characteristics of patient subgroups with chronic lymphocytic leukemia who may benefit from curative treatment with fludarabine, cyclophosphamide, and rituximab.
 

Dr Seymour on Patient Subsets That May Benefit From Curative FCR in CLL  

John Seymour, MBBS, FRACP, PhD, director, Department of Hematology, the Peter MacCallum Cancer Centre, medical oncologist, Hematology Department, the Royal Melbourne Hospital, discusses the importance of targeted therapy in patients with chronic lymphocytic leukemia (CLL).

At the 2023 SOHO Annual Meeting, Seymour shared information on the curative potential of fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) in a small subset of patients, detailing the combination’s potential role despite the emergence of other treatment approach within the CLL landscape. In hispresentation, Seymour highlighted that FCR has curative potential for patients with 

 aberrations. Additionally, Seymour highlighted that patient age plays a role in responses with FCR, as younger, fit patients with adequate renal function are more likely to derive benefit and tolerate this regimen.

®, Seymour added that one of the key elements to treating patients in this population is the use of targeted therapy. When considering the potential application of FCR, understand the individual biologic profiles of the patients being treated, as well as their individual risks associated with their disease , he explains.

Targeted agents, particularly the use of BTK inhibitors, are generally beneficial for most patient subsets in CLL, he expands. However, the agents’ full potential may not always be reached. For example, treatment regimens might be selected without conducting genetic testing. In turn, the nuance of the individual’s disease remains unknown without genetic testing, he notes, and could prevent oncologists from understanding how a patient’s disease may behavelong-term, Seymour says. Furthermore, not testing patients leaves oncologists less equipped to identify whether more intensive therapies or immunotherapies would benefit their patient, and whether bone marrow transplant or CAR T-cell therapy may be advantageous in the future, he concludes.

John Seymour, MBBS, FRACP, PhD, discusses the importance of targeted therapy in patients with chronic lymphocytic leukemia.

Dr Seymour on the Importance of Targeted Therapy in CLL

John Seymour, MBBS, FRACP, PhD, director, Department of Hematology, the Peter MacCallum Cancer Centre, medical oncologist, Hematology Department, the Royal Melbourne Hospital, discusses the curative potential of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with chronic lymphocytic leukemia (CLL).

At the 2023 SOHO Annual Meeting, Seymour shared information on the development and implementation of various treatments within the CLL landscape, specifically focusing on FCR. In the presentation, Seymour emphasized that the treatment arena for patients with CLL has continued to shift and has come a long way since the development of FCR treatment, leaving behind this potentially curative treatment for a select subgroup of patients.

Seymour explains that this approach has curative potential for patients with 

aberrations, since these patients have a favorable disease biology. Patients age also plays a role, as younger patients and those with adequate renal function are more likely to tolerate the FCR regimen. This subgroup of patients represents approximately 15% of all patients who may need treatment for CLL, Seymour says. However, only approximately half of this subgroup will be cured with FCR, Seymour concludes.

Although FCR could represent a curative option for small subset of patients, the regimen has been associated with myelosuppression, short- and long-term infection risks, nausea, renal and marrow impairment, and the risk for secondary acute myeloid leukemia (AML), Seymour shares.

John Seymour, MBBS, FRACP, PhD, discusses the curative potential of fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia.


Dr Seymour on the Curative Potential for FCR Treatment in CLL

John F. Seymour, M​BBS, FRACP, PhD, director, ​Integrated Haematology Department, clinical hematologist, associate director of Clinical Research, Peter MacCallum Cancer Centre, Victoria Australia, discusses the findings from a post-hoc analysis of the phase 3 ELEVATE-RR trial (NCT02477696) examining the adverse effects (AEs) experienced with the BTK inhibitors acalabrutinib (Calquence) and ibrutinib (Imbruvica) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Data from the analysis, which were presented during the 

, revealed that acalabrutinib was generally better tolerated than ibrutinib, with a lower cardiovascular-related toxicity burden observed, according to Seymour. The exposure-adjusted time with event with the cardiovascular AEs were two- to four-fold higher with ibrutinib vs acalabrutinib, particularly for hypertension and atrial fibrillation, Seymour adds. This was observed irrespective of age, number of prior therapies received, and prior history of AEs, Seymour explains.

Lower-grade AEs, such as diarrhea, arthralgias, back pain, muscle spasm, and dyspepsia, occurred 1.4 to 13 times more frequently in their exposure-adjusted incidence and exposure-adjusted time with event with ibrutinib compared with acalabrutinib, Seymour concludes.

John F. Seymour, discusses the findings from a post-hoc analysis of the phase 3 ELEVATE-RR trial examining the adverse effects experienced with the BTK inhibitors acalabrutinib and ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia.

Dr. Seymour on the Safety of Acalabrutinib Vs Ibrutinib in Relapsed/Refractory CLL 

John F. Seymour, MBBS, FRACP, PhD, from the Department of Hematology at the Peter MacCallum Cancer Centre in East Melbourne, Australia, discusses the results of the PRIMA study, which evaluated the benefit of maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy in patients with advanced follicular lymphoma.

In this study, patients with high-volume follicular lymphoma were treated with chemoimmunotherapy and then randomized to either maintenance or observation, Seymour says. The maintenance arm was given therapy once every 2 months for 2 years.

At the 2013 ASH Annual Meeting, the 6-year follow-up results were presented. Seymour says results have shown that the patients are still showing an approximately 20% improvement in progression free survival (PFS). Seymour believes these results reinforce the durable benefit of maintenance rituximab after primary chemoimmunotherapy. The results of this follow-up have shown that maintenance rituximab prolongs benefit and does not impair the ability to treat at subsequent progression, Seymour says.

Dr. Seymour Discusses the Results of the PRIMA Study

John F. Seymour, MBBS, FRACP, PhD, from the Department of Hematology at the Peter MacCallum Cancer Centre in East Melbourne, Australia, discusses the efficacy of single-agent ABT-199 (GDC-0199), a novel Bcl-2 inhibitor, in high-risk relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

In the phase I trial, 56 patients received treatment with ABT-199 at doses from 150 mg to 1200 mg. The overall response rate for patients treated with ABT-199 was 84% with a complete remission rate of 23%, Seymour notes. In general, 90% of patients had received prior treatment with fludarabine with approximately 50% of patients developing fludarabine resistance. On average, patients received 4 median treatments prior to receiving ABT-199, representing a very heavily pretreated patient population.

Furthermore, Seymour says, response rates were sustained in patients with 17p deletions, which have conventionally indicated a poor response to treatment. In a phase I context, this agent has generated exciting response across poor prognostic groups, Seymour notes.

Although it was not a prospective objective of the trial, local labs completed 4-color flow cytometry. Overall, 8 patients tested negative for minimal residual disease. In the context of a single agent in relapsed and refractory CLL, this agent has demonstrated very encouraging efficacy, Seymour believes.

John F. Seymour, MBBS, FRACP, PhD, discusses the efficacy of single-agent ABT-199 (GDC-0199), a novel Bcl-2 inhibitor, in high-risk relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.

John F. Seymour, MBBS, FRACP, PhD

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