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Clinical

Andre H. Goy, MD; Sandra M. Swain, MD, FACP, FASCO Associate Dean for Research; Carolina Bernabe Ramirez, MD; Jonathan E. Rosenberg, MD; David H. Vesole, MD, PhD, FACP Director, Myeloma Program; Isabel Preeshagul, DO, MBS  
 

Community Practice Connections™: 5th Annual Precision Medicine Symposium – An Illustrated Tumor Board

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

PHA-22-TTD0588 - /clinical/mcl

In an interview, Craig A. Portell, MD, offered an in-depth look at sequencing therapies in relapsed/refractory mantle cell lymphoma. 

Sequencing Therapies in Relapsed/Refractory Mantle Cell Lymphoma

Zanubrutinib, obinutuzumab, and venetoclax delivered promising response and survival data for the treatment of patients with mantle cell lymphoma harboring a TP53 mutation.

BOVen Regimen Appears Effective in High-Risk MCL

Acalabrutinib, a BTK inhibitor, has shown promising results in treating mantle cell lymphoma, with the FDA granting it priority review.

Acalabrutinib Receives FDA Priority Review in Frontline MCL

The ready-to-use formulation of bortezomib is now an FDA-approved option for patients with multiple myeloma and mantle cell lymphoma. 

FDA Approves Ready-to-Use Subcutaneous Bortezomib Formulation 

Acalabrutinib plus bendamustine and rituximab led to a 27% reduction in the risk of disease progression or death in the frontline setting for older patients with mantle cell lymphoma.

Frontline Acalabrutinib/BR Regimen Improves PFS in MCL

Portell on the Changing Landscape of Mantle Cell Lymphoma

Craig A. Portell, MD, associate professor of medicine at University of Virginia, discusses the current standard of care for patients with relapsed/refractory mantle cell lymphoma and how sequencing therapies changed the landscape of mantle cell lymphoma (MCL) treatment.

Several Bruton's tyrosine kinase (BTK) inhibitors have been approved for the treatment of mantle cell lymphoma (MCL). The main ones include:

 – This was the first BTK inhibitor approved for MCL by the FDA in 2013. It is used as a treatment for both newly diagnosed and relapsed/refractory MCL.

 – Approved in 2017, acalabrutinib is a second-generation BTK inhibitor. It was developed to be more selective for BTK and has a potentially better adverse-effect profile compared with ibrutinib.

 – Approved in 2019, zanubrutinib is another second-generation BTK inhibitor. It is designed to offer greater potency and selectivity for BTK, with potentially fewer off-target effects than ibrutinib.

Portell highlights that covalent BTK inhibitors are the current standard of care for patients who have not received them as part of first-line therapy. However, as more patients relapse after initial BTK inhibitor treatment, managing their care becomes challenging, especially with the growing complexity of BTK inhibitor resistance.

Chimeric antigen receptor (CAR) T-cell therapy has been beneficial in these cases, and emerging therapies like bispecific antibodies, covalent BTK inhibitors, and venetoclax (Venclexta) offer hope. The sequencing of these treatments depends on individual patient factors.

 As we are seeing more and more relapsed disease after first-line covalent BTK inhibitors, it is often probably a CAR T-cell therapy, but most patients will have not seen a covalent BTK inhibitor in the first-line relapsed setting. I think covalent BTK inhibitors are the standard of care for that patient population.

 It has become more complicated as we have learned more about BTK inhibitor resistance, it is hard to know what to do afterwards. The CAR T-cell space has been helpful, [and] we are hopeful to see some interesting data with bispecific antibodies and other new therapies, including covalent BTK inhibitors and venetoclax. These are all therapies that can be hard to know how to sequence, and sometimes it [really depends on the individual] patient.

Videos

Craig A. Portell, MD, discusses the current standard of care for patients with relapsed/refractory mantle cell lymphoma and how sequencing therapies changed the landscape of mantle cell lymphoma treatment.

News

​​Sequencing Therapies in R/R Mantle Cell Lymphoma

Craig A. Portell, MD, associate professor of medicine at University of Virginia, previews his session on sequencing therapies in relapsed/refractory mantle cell lymphoma being presented at the 2024 Society of Hematologic Oncology (SOHO) Annual Meeting.

According to Portell, as more is learned about Bruton’s tyrosine kinase (BTK) inhibitor resistance, it can be a challenge to know what to do afterwards. He adds that the chimeric antigen receptor (CAR) T-cell therapy space has been very helpful with this.

He also remains hopeful that more data on bispecific antibodies, covalent BTK inhibitors, venetoclax (Venclexta), etc., all of which are hard to know how to sequence, will continue to help address challenges in the field of relapsed/refractory mantle cell lymphoma.

Further, Portell offers some insights on what one can expect from this session at SOHO, as well as additional sessions that are of particular interest to him and colleagues.

 So, today I am going to be talking about sequencing therapies in relapsed mantle cell lymphoma. [We are] starting first with patients, whether they have been exposed to BTK inhibitors or not, and how that may impact the decision making, and then, after exposure to BTK inhibitors, how to fit CAR T-cell therapy in vs a non covalent BTK inhibitor, and [we will] talk about some special scenarios, particularly with 

 [We will be] really going through the pathways of when a patient would relapse in various different scenarios. So, hopefully that will be informative and give some suggestions about how to manage patients in certain scenarios after progression with various different disease characteristics.

[Overall], the lymphoma sessions, I think, in general, are going to be very well reviewed and thoughtful. So, I am looking forward to hearing what my colleagues have to say.

Craig A. Portell, MD, previews his session on sequencing therapies in relapsed/refractory mantle cell lymphoma being presented at the 2024 Society of Hematologic Oncology Annual Meeting. 


Conference News

Moving Forward With Ibrutinib Plus Venetoclax in MCL

Matthew Matasar, MD, chief of the division of blood disorders at the Rutgers Cancer Institute and professor at the Rutgers Robert Wood Johnson Medical School, discusses the next steps for the development of ibrutinib (Imbruvica) given in combination with venetoclax (Venclexta) and potential challenges with using the combination.

Ibrutinib with venetoclax was compared with ibrutinib and placebo for the treatment of patients with relapsed/refractory mantle cell lymphoma in the phase 3 SYMPATICO study (NCT03112174). The combination therapy appears well-tolerated, opening possibilities for exploring other combinations, particularly in relapse settings, and potentially moving them to first-line treatment.

Here, Matasar emphasizes the importance of ongoing data analysis and patient follow-up in treating MCL, suggesting that understanding long-term outcomes and responses to various therapies will help clarify the efficacy of combining different treatments, such as the doublet mentioned.

 Most importantly, we need to continue to follow these data and watch them mature. Mantle cell lymphoma is sometimes a marathon and not a sprint and following these patients to learn their subsequent outcomes, impact of the next line of therapy, and responses to the next line of therapy will better clarify the impact of having a doublet in this clinical context. The combination was very well-tolerated with no new safety signal outside of that which is expected from its constituent components. That certainly does give us an opportunity to think about other combinations both in relapse setting as well as whether they're optimal partners. to enhance their activity and enable it to move to the first-line setting.

 One challenge in this field is that we have a number of [Bruton’s tyrosine kinase (BTK)] inhibitors that are available currently. When SYMPATICO was designed, it leveraged ibrutinib, which was an even more relevant consideration because of a relative paucity of alternatives. Now, we find the therapeutic landscape with multiple approved BTK inhibitors, both covalent and noncovalent. It remains an interesting question for us in the community of lymphoma doctors, whether ibrutinib or other BTK inhibiting approaches may be the optimal partner for venetoclax.

Matthew Matasar, MD, discusses the next steps for the development of ibrutinib given in combination with venetoclax for patients with mantle cell lymphoma, and potential challenges with using the combination. 

Potential Implications of Using Ibrutinib With Venetoclax in MCL

Matthew Matasar, MD, chief of the division of blood disorders at the Rutgers Cancer Institute and professor at the Rutgers Robert Wood Johnson Medical School, discusses how ibrutinib (Imbruvica) given in combination with venetoclax (Venclexta) compares with ibrutinib and placebo for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL).

The combination was evaluated in the phase 3 SYMPATICO study (NCT03112174), a 

patients with relapsed/refractory MCL who received 1 to 5 prior therapies for MCL. Once enrolled, patients were randomly assigned in a 1:1 fashion to receive ibrutinib 560 mg once daily for 24 months in combination with venetoclax or placebo.

A total of 134 patients were treated with ibrutinib plus venetoclax. Investigators evaluated the primary end point of median investigator-assessed PFS with global censoring, which was 31.9 months in the ibrutinib arm vs 22.1 months among the 133 patients in the ibrutinib plus placebo arm.

 We see an improvement in clinical end points with the combination treatment both in terms of overall response rate, progression-free survival, and depth of response. We hope to continue to follow these patients over time and see whether this combination translates to improvements in overall outcomes and overall survival. Due to setting, relapsed/refractory mantle cell lymphoma is a moving target. We have other drugs emerging in the space, but the availability of a potent and well-tolerated oral combination approach is very attractive.

 The potential implications are that we may see a new option emerging for patients with a higher-risk of relapsed/refractory mantle cell lymphoma where we may be able to get more benefit out of our line of [Bruton's tyrosine kinase] inhibiting therapy with this combination approach, deferring the potential toxicities of other later live interventions, such as CAR [chimeric antigen receptor] T-cell therapy and allogeneic stem cell transplantation.

Matthew Matasar, MD, discusses how ibrutinib given in combination with venetoclax compares with ibrutinib and placebo for the treatment of patients with relapsed/refractory mantle cell lymphoma.

Matasar Discusses Phase 3 Data on Venetoclax and Ibrutinib for MCL

Matthew Matasar, MD, chief of the division of blood disorders at the Rutgers Cancer Institute and professor at the Rutgers Robert Wood Johnson Medical School, discusses the phase 3 SYMPATICO study (NCT03112174) of ibrutinib (Imbruvica) given in combination with venetoclax (Venclexta) vs ibrutinib and placebo for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL).

The standard-of-care for patients with relapsed mantle cell lymphoma continues to evolve. Ibrutinib or BTK monotherapy has been a long-standing standard-of-care in these patients. The question is whether we can do better than monotherapy at providing deeper and more durable responses. This has been our goal, to develop combination therapy in this context. To that end, we see data from SYMPATICO, which was a randomized trial of ibrutinib continuously, with or without the addition of 2 years of venetoclax at initiation, with an attempt to improve these very clinical end points.

We see the results are favorable. In terms of activity, we see definite improvements in response and progression-free survival for the patients treated with the doublet. What we do not yet know is whether this is going to translate to improvements in survival. We do not yet have a full and clear picture about the incremental impact of combination therapy.

| I would say that ibrutinib plus venetoclax, or IV, which is confusing for our nurses, is an attractive combination because it is a dual oral program. That's important both for the patient journey, as well as for logistics and operational considerations when we take care of our patients in a variety of health care contexts.

Matthew Matasar, MD, discusses the phase 3 SYMPATICO study of ibrutinib given in combination with venetoclax vs ibrutinib and placebo for the treatment of patients with relapsed/refractory mantle cell lymphoma.

Novel Approaches in MCL Treatment and Predictive Insights as discussed by Julie Chang, MD.

Novel Approaches in MCL Treatment and Predictive Insights

Julie Chang, MD, associate professor of medicine at the University of Wisconsin School of Medicine and Public Health, discusses the reasoning behind the development of a minimal residual disease (MRD)-adapted study in patients with previously untreated mantle cell lymphoma (MCL).

In the trial, clonoSEQ assessed MRD status in peripheral blood was used to establish a link between early response and outcomes. Additionally, it guided maintenance therapy decisions in patients with previously untreated MCL.

The study included 21 patients. Patients with a complete response (CR) who were MRD-negative by clonoSEQ following induction and consolidation therapy were treated with maintenance. Patients who did not have a CR or persistent MRD positivity received maintenance with obinutuzumab for a total of 8 cycles. Further, the study followed patients for ≥2 years from therapy completion.

According to Chang, the study focuses on providing more tolerable frontline therapy options for older patients ineligible for intensive treatments, using a combination of the novel monoclonal antibody obinutuzumab and bendamustine. The study also aims to investigate whether MRD testing can serve as a predictor for the need of maintenance therapy.

 We know that patients who are older and not eligible for intensive therapies can have limited options for frontline therapy that's tolerable. We were very interested in using the novel monoclonal antibody, obinutuzumab [Gazyva] and combining it with bendamustine [Bendeka]. We know that from the results of the GALLIUM study [NCT01332968] in other types of low-grade non-Hodgkin lymphomas that resulted in better progression-free survival compared with bendamustine and rituximab [Rituxan]. We were hoping to capitalize on that same benefit in [patients with] mantle cell lymphoma.

 We are also interested in seeing if minimal residual disease testing could predict the need for maintenance therapy. Maintenance therapy has been very controversial, or there's been mixed data about the benefit of that modality, so we are very interested in seeing if there was some biological predictor for benefit.

Julie Chang, MD, discusses the reasoning behind the development of a minimal residual disease-adapted study in patients with previously untreated mantle cell lymphoma.


The targeted therapy combination of obinutuzumab (Gazvya), zanubrutinib (Brukinsa), and venetoclax (Venclexta; BOVen) showed promising results in treating 

-mutant mantle cell lymphoma (MCL), a difficult-to-cure form of cancer. Patients receiving BOVen achieved high rates of survival and disease-free status after 2 years, exceeding expectations for this aggressive subtype. Moreover, those who completed therapy demonstrated near-complete remission, with over 80% achieving undetectable levels of cancer cells. These findings suggest that BOVen could be a game-changer for patients with

-mutant MCL, offering significantly improved outcomes compared to standard treatments. Further investigation is needed, but this study provides strong evidence for the potential of BOVen as a powerful new treatment option.

American Society of Hematology 2023 Annual Meeting

, Anita Kumar, MD, associate attending physician and lymphoma specialist at Memorial Sloan Kettering Cancer Center, discusses findings from the phase 2 trial (NCT03824483) evaluating BOVen in 

utant mantle cell lymphoma is a high-risk entity. Unfortunately, patients with this subtype of mantle cell lymphoma have poor outcomes with standard chemo-immunotherapy. The idea for this study was to develop a combination of biologically targeted therapies. The obinutuzumab, zanubrutinib, and venetoclax [BOVen] combination was used to treat this high-risk subgroup of patients. And we hypothesized that this combination would be more efficacious than standard chemo-immunotherapy. 

Two-year progression-free survival associated with the BOVen treatment regimen for 

mutant mantle cell lymphoma was 72%. And the 2-year overall survival was 75%. The disease-free survival at 2 years was 88%. The disease-free survival is superior to the progression-free survival because we did observe some deaths that were not related to disease, reflected some excess deaths related to COVID-19 because this study took place during the context of the COVID-19 pandemic. We found that at 2 years, there were 11 patients who were progression-free and so therefore, the primary endpoint of the study was met. 

We look at the patients who completed 24 cycles of therapy, the 11 patients, all of these patients achieved a complete remission. Of the 11 patients, 1 we could not assess the minimal residual disease [MRD] status because they didn't have a baseline tumor specimen available for analysis. But in the remaining 10 patients, 80% or 8 patients achieved an undetectable MRD status and stopped therapy and then 2 of the patients were a CR but had detectable minimal residual disease. And those patients continued on the oral drugs of the zanubrutinib and obinutuzumab. 

Anita Kumar, MD, discusses findings from the phase 2 study of zanubrutinib, obinutuzumab, and venetoclax in TP53-mutant mantle cell lymphoma presented at ASH 2023. 

New Treatment Potential for TP53-Mutated MCL

Pirtobrutinib Produces Durable Responses in Pretreated MCL

Nirav Shah, MD, associate professor at the Medical College of Wisconsin, discusses long-term data from the phase 1/2 BRUIN study (NCT03740529) which evaluated pirtobrutinib (Jemperli) in mantle cell lymphoma (MCL) and next steps for evaluating the agent.

FDA previously granted approval to pirtobrutinib in January 2023

 for the treatment of adult patients with relapsed/refractory MCL who had received at least 2 prior lines of systemic therapy, including a Bruton’s tyrosine kinase (BTK) inhibitor. This approval was supported by findings from the phase 1/2 BRUIN study.

In the study, pre-treated patients with relapsed/refractory MCL given pirtobrutinib, a highly selective kinase inhibitor, achieved an overall response rate of 50%, and 13% of patients had a complete response at time of analysis.

Shah further discussed data from the study

, highlighting the durable responses observed with pirtobrutinib in this patient population.

Nirav Shah, MD, discusses long-term data from the phase 1/2 BRUIN study which evaluated pirtobrutinib in mantle cell lymphoma, and next steps for evaluating the agent.


Mantle Cell Lymphoma

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