CME
Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™
Released: August 18, 2023
Expiration: August 17, 2024
Introduction
In this module, Catherine C. Coombs, MD, MS, and Toby Eyre, MBChB, MD, review key data from the 17th International Conference on Malignant Lymphoma (ICML) on the use of BTK inhibitors in mantle cell lymphoma (MCL).
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset that can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
Clinical Care Options plans to measure the educational impact of this activity. Several questions will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Before continuing with this educational activity, please take a moment to answer the following questions.
Mantle Cell Lymphoma: Treatment Overview
Catherine C. Coombs, MD, MS:
Dr Eyre, before we get into the data, what is your general approach to treating MCL in 2023 and what factors do you consider?
Toby Eyre, MBChB, MD:
When determining the treatment plan for patients with MCL, healthcare professionals must consider certain factors, such as the patient’s age, physical fitness, and goals of care. We are currently still in an era where patients are generally divided according to their physical fitness to determine feasibility for autologous stem cell transplant.
Although there are recent data challenging this approach to care, it remains the standard. So immunochemotherapy is the general approach, but the intensity and consolidation strategies differ according to patients’ age and physical fitness. Typically, those aged 65 years and younger are prescribed a cytarabine- and rituximab-based induction regimen, followed by autologous stem cell transplant and rituximab maintenance.1
For older patients, there is a variety of immunochemotherapy regimes that can be used: rituximab, cyclophosphamide, doxorubicin, bortezomib, and prednisolone (VR-CAP); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP); and bendamustine plus rituximab (BR). Each of these regimens is often followed by maintenance therapy.2 These are the current standard approaches to MCL treatment that are available.3,4
Phase II IMCL-2015 GELTAMO: 5-Year Update of First-line Ibrutinib Plus Rituximab for Indolent MCL
Catherine C. Coombs, MD, MS:
The first study that we will discuss that was presented at 2023 ICML is GELTAMO, a multicenter, single-arm, open-label phase II clinical trial. Researchers provided a 5-year update on first-line treatment with ibrutinib plus rituximab for patients with indolent MCL.
Toby Eyre, MBChB, MD:
There is broad consensus among healthcare professionals that patients with indolent MCL who are asymptomatic, without high tumor burden, and with a low Ki-67 score can be observed in routine clinical practice.5 However, there is sparsity in data regarding how these patients perform long term.
The GELTAMO study looked at the introduction of ibrutinib, given at the standard MCL dose of 560 mg daily, plus 8 doses of rituximab. This is essentially an early intervention study in indolent MCL. Now, one of the interesting things about this study is that patients could stop treatment if they sustained undetectable minimal residual disease (MRD) after 2 years.
The primary endpoint was complete response after 12 cycles, and the median follow-up was 59 months.6,7
IMCL-2015 GELTAMO: Baseline Characteristics
Toby Eyre, MBChB, MD:
The patients included in this study were generally younger in age and had lower risk features, which is to be expected given the patient profile.
Conceptually, this study is interesting. The nonrandomized data include patients who might not otherwise, one could argue, need treatment, which really needs to be considered.6
IMCL-2015 GELTAMO: Baseline Pathology, Genetic, and Molecular Features
Catherine C. Coombs, MD, MS:
We use MRD testing frequently in chronic lymphocytic leukemia. In GELTAMO, a significant portion of the patients enrolled were leukemic with nonnodal disease, so there is disease in the blood. Yet for the portion of patients who did not have a leukemic presentation, MRD testing was also done via peripheral blood. Is that typically done in MCL and is it always helpful?
Toby Eyre, MBChB, MD:
That is a great question. EuroClonality MRD was used, which is an ASO-PCR method. Next-generation sequencing was also permitted if needed. In MCL, there is no consensus on how best to assess MRD. There are different techniques like flow cytometry, next-generation sequencing, or polymerase chain reaction–based technology, but it remains to be determined which method is optimal.6-8
IMCL-2015 GELTAMO: Long-term Safety (Select Events)
Toby Eyre, MBChB, MD:
One of the issues this study brings to light is that patients experienced toxicity with ibrutinib. Thirteen patients (26%) stopped treatment because of adverse events. Seven patients (14%) stopped treatment because of ibrutinib-related adverse events, and a small number required dose reductions (12%).6
IMCL-2015 GELTAMO: Response Rates and Undetectable MRD
Toby Eyre, MBChB, MD:
The long-term data suggest that response rates were very good, and of more importance, approximately two thirds (64%) of patients were able to discontinue ibrutinib because of undetectable MRD attainment at 2 years.6
IMCL-2015 GELTAMO: Survival Outcomes
Toby Eyre, MBChB, MD:
Finally, early events occurred for some patients with particularly high-risk disease. For example, those with TP53 mutations that were found at a later point did not experience a particularly durable response. In addition, those with high-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) also experienced progression-free survival (PFS) events.6
Phase II ICML-2015 GELTAMO: Impact on Practice
Toby Eyre, MBChB, MD:
These data show that first-line ibrutinib plus rituximab is an interesting theoretical option. Treatment could be stopped in approximately two thirds of patients at 2 years, and the long-term median PFS of 72 months and 5-year PFS rate of 80% looks good. But do take note that these data represent low-risk patients.6 So we really need randomized data in this setting. In summary, this approach is not routine practice and needs further evaluation, ideally in the randomized setting vs observation.
First-line Acalabrutinib Plus Rituximab in Older Patients With MCL
Catherine C. Coombs, MD, MS:
The next abstract we will discuss is by the group at MD Anderson Cancer Center—a single-institution, single-arm phase II trial looking at the first-line treatment of acalabrutinib with rituximab for older adults with MCL.
Toby Eyre, MBChB, MD:
We have previously seen phase II data from MD Anderson on the combination of ibrutinib and rituximab in 50 patients with MCL. Although the response rates were very good, there were concerning signals of cardiac toxicity, particularly with atrial fibrillation and hypertension. Quite a few patients (42%) had to discontinue treatment because of toxicity.9
Conceptually, the idea for this trial is to replace ibrutinib with a well-tolerated, second-generation BTK inhibitor—acalabrutinib—that has shown more favorable safety profiles in other malignancies such as chronic lymphocytic leukemia. Patients received IV rituximab and continuous acalabrutinib delivered at the standard dose (100 mg orally twice daily) for up to 2 years, after which acalabrutinib monotherapy could be continued until progression of disease or another reason to discontinue.10
First-line Acalabrutinib Plus Rituximab in Older Patients With MCL: Baseline Characteristics
Toby Eyre, MBChB, MD:
This study included older patients (aged 65 years or older) with good performance status (≤2). They received what was described as ‘”cardiology clearance,” which means that patients completed cardiac tests to confirm their cardiac function before admission into the clinical trial.
These patients were a relatively low-risk group; they were not meant to be indolent, for example, as discussed in the previous study. Few patients were found to have blastoid (n = 3) or pleomorphic (n = 1) disease, and 12 patients had a TP53 aberrancy.10
First-line Acalabrutinib Plus Rituximab in Older Patients With MCL: Response
Toby Eyre, MBChB, MD:
Results show that this combination was very well tolerated by patients, with high response rates.10
First-line Acalabrutinib Plus Rituximab in Older Patients With MCL: Survival
Toby Eyre, MBChB, MD:
With a medium follow-up of 17 months, the 2-year PFS was 92%. These are really excellent results.10
First-line Acalabrutinib Plus Rituximab in Older Patients With MCL: AEs and Patient Disposition
Toby Eyre, MBChB, MD:
The combination of acalabrutinib plus rituximab was well tolerated with no new or concerning safety signals.
First-line Acalabrutinib Plus Rituximab in Older Patients With MCL: Impact on Practice
Toby Eyre, MBChB, MD:
Now, of course, this is a fairly selected phase II study with a modest-sized patient population from a single center.10 We need to see the applicability of this combination in a larger patient population across a number of institutions to better understand its safety and efficacy in clinical practice. Although the results of this study are encouraging, these are early data that are not practice-changing at present.
BRUIN: Updated Results and Subgroup Analysis With Pirtobrutinib for Previously Treated MCL
Catherine C. Coombs, MD, MS:
The final study we will discuss is BRUIN, a phase I/II dose-escalation and expansion study of pirtobrutinib in patients with covalent BTK inhibitor–pretreated relapsed or refractory MCL. The abstract shared at the 2023 ICML provided an update on a subgroup analysis, with at least 3-years of follow-up from start of enrollment.11
As of January 2023, the FDA approved pirtobrutinib for the treatment of adult patients with relapsed or refractory MCL after ≥2 lines of systemic therapy, including a BTK inhibitor.12
BRUIN MCL: Baseline Characteristics
Toby Eyre, MBChB, MD:
Ninety patients who had received a median of 3 previous lines of therapy, including a covalent BTK inhibitor, were included in the study, so this is a heavily pretreated group of patients. Among those who had received a previous covalent BTK inhibitor, 55.6% had an intermediate-risk simplified MIPI score and 22.2% had a high-risk score.11 Results from this primary analysis set have also been published in the Journal of Clinical Oncology.13
BRUIN MCL: Response
Toby Eyre, MBChB, MD:
Among the 90 patients included in this analysis, the ORR was approximately 57%. Also included were a small subset of BTK naive patients (n = 14) who had a higher ORR of 85.7%.11,13
BRUIN: DoR, PFS, and OS in Pretreated Patients With MCL per IRC Assessment
Toby Eyre, MBChB, MD:
The median PFS across the cohort was 7.4 months. One of the intriguing aspects of this study is that patients who respond to pirtobrutinib have durable responses, considering where this agent is used in the treatment of MCL. These are heavily pretreated patients, but the median duration of response was 17.6 months, which is an intriguing finding. I think we need to better understand why that is the case.11
BRUIN: DoR, PFS, and OS in High-Risk MCL Subgroups per IRC Assessment
Toby Eyre, MBChB, MD:
Another important finding from the BRUIN update at the 2023 ICML was that patients responded to treatment whether or not they had a TP53 deletion or a high Ki-67 score. Thirty percent was the parameter for determining Ki-67 in this study, and we have seen strong adverse prognostic features with both TP53 and Ki-67 in pooled analyses with covalent BTK inhibitors in patients who have previously received ibrutinib.14 These subanalyses were certainly interesting.11,13
BRUIN: Safety in MCL
Toby Eyre, MBChB, MD:
The final thing to discuss about the BRUIN study is the safety data. The safety of pirtobrutinib in the MCL population appears very favorable. There were very low rates of hypertension, atrial fibrillation, and discontinuations because of drug-related toxicity. So pirtobrutinib certainly looks like a promising agent to potentially move forward within the MCL treatment pathway.13 It is currently being evaluated in a randomized phase III clinical trial (BRUIN MCL-321/ NCT04662255), which is comparing pirtobrutinib to investigator’s choice of acalabrutinib, ibrutinib, or zanubrutinib in pretreated, BTK inhibitor–naive patients with MCL, and is also being studied in combination with other therapies for the treatment of MCL and other diseases.15
BRUIN: Impact on Practice
Toby Eyre, MBChB, MD:
As mentioned previously, pirtobrutinib is now approved by the FDA as a third-line therapy and beyond.12 In April, the European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion of pirtobrutinib and recommended the agency grant conditional marketing approval to it for a similar indication.16 This may lead to a formal approval later in the year. It will be important to see if that anticipated approval is also going to be in the third-line setting and beyond.
Catherine C. Coombs, MD, MS:
Although the majority of patients in this analysis had received previous covalent BTK inhibitor therapy, 14 patients had not—and it was striking to see how excellent their responses were. This gives me confidence in the ongoing phase III BRUIN MCL-321 trial, of which I eagerly await the results. The safety profile is certainly very attractive, and hopefully, the efficacy will be favorable as well.
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