Dr Moustafa on the Evolving Use of Bispecific Antibodies in DLBCL

Muhamad Alhaj Moustafa, MD, MS, hematologist, medical oncologist, Departments of Hematology and Oncology (Medical), Mayo Clinic, discusses currently available bispecific antibodies for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The use of bispecific antibodies in relapsed/refractory DLBCL has increased in the last few years, with several agents receiving FDA approval.

On June 15, 2023, the bispecific antibody therapy, glofitamab-gxbm (Columvi) 

received accelerated approval from the FDA

 for the treatment of adult patients with relapsed/refractory DLBCL not otherwise specified or large B-cell lymphoma arising from follicular lymphoma who received 2 or more prior lines of systemic therapy. This approval was supported by findings from the phase 1/2 NP30179 trial (NCT03075696), in which patients who received glofitamab achieved an objective response rate of 56% and a complete response rate of 43%.

The addition of agents such as glofitamab to the DLBCL arsenal addresses the lack of effective options for patients who progressed on prior CAR T-cell therapy, Moustafa begins. These antibodies have a novel mechanism of agent, targeting specific cell surface markers and augmenting the immune response against cancer cells. Clinical trials leading to the approval of bispecific antibodies have demonstrated efficacy in providing additional lines of therapy for patients with DLBCL, he adds.

Moustafa explains that prior to the availability of bispecific antibodies, options for patients with DLBCL were somewhat limited. Although the addition of CAR T-cell therapy to the treatment arsenal helped improve patient outcomes in this space, there were few effective alternatives to this therapeutic class. Bispecific antibodies have further expanded the treatment armamentarium in DLBCL, thereby potentially improving patient outcomes, helping to address this unmet need.

Overall, the emergence of bispecific antibodies represents a key advancement in the approach to DLBCL management and underscores the significance of ongoing research and innovation in this disease space, particularly related to the development of targeted immunotherapies. Further investigations are warranted to elucidate the long-term efficacy and safety profile of bispecific antibodies across diverse patient populations.

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Muhamad Alhaj Moustafa, MD, MS, discusses the evolution of bispecific antibodies in diffuse large B-cell lymphoma.

Dr Moustafa on Standard Treatment Approaches in MCL

Muhamad Alhaj Moustafa, MD, MS, hematologist, medical oncologist, Departments of Hematology and Oncology (Medical), Mayo Clinic, discusses standard treatments for transplant-eligible and transplant-ineligible patients with mantle cell lymphoma (MCL).

The standard first-line treatment approach for transplant-eligible patients with MCL typically consists of a chemoimmunotherapy combination, such as rituximab (Rituxan) plus chemotherapy, Moustafa says. Other potential treatment regimens for patients in this population include bendamustine-rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD), Moustafa notes. If these patients achieve a complete response (CR) with initial induction therapy, they will often receive subsequent autologous stem cell transplant (ASCT), Moustafa explains. Patients who continue to experience CR with ASCT will then receive maintenance therapy with rituximab for approximately 3 years, according to Moustafa.

Conversely, transplant-ineligible patients with MCL typically receive chemoimmunotherapy, which may be followed by maintenance rituximab, Moustafa emphasizes. Transplant-ineligible patients who cannot tolerate chemoimmunotherapy, including elderly patients or those with comorbidities, may benefit from off-label treatment with BTK inhibitors, Moustafa concludes. 

The current arsenal of FDA-approved BTK inhibitors for patients with pretreated MCL includes acalabrutinib (Calquence), zanubrutinib (Brukinsa), and pirtobrutinib (Jaypirca). 

Acalabrutinib received accelerated approval in 2017

Zanubrutinib was granted accelerated approval in 2019

. Both approvals were for the treatment of adult patients with MCL who have received at least 1 prior therapy.

Acalabrutinib and zanubrutinib are covalent BTK inhibitors. Ibrutinib (Imbruvica), another covalent BTK inhibitor, 

 for patients with MCL who had received at least 1 prior therapy. However, in 2023, 

this indication was voluntarily withdrawn

The first noncovalent BTK inhibitor to gain approval for adult patients with previously treated MCL was pirtobrutinib, 

which received accelerated approval in 2023

 for the treatment of adult patients with disease that is relapsed/refractory to at least 2 lines of systemic therapy, including a prior BTK inhibitor.

Muhamad Alhaj Moustafa, MD, MS, discusses standard treatments for transplant-eligible and transplant-ineligible patients with mantle cell lymphoma.

Muhamad Alhaj Moustafa, MD, MS, hematologist/medical oncologist, Mayo Clinic, assistant professor, Mayo Clinic School of Medicine, discusses the evolution of treatment options for patients with mantle cell lymphoma (MCL). 

The treatment armamentariums for patients with lymphomas such as MCL are transformingwith the evolution of immune system manipulation, which is at the forefront of future therapies, Moustafa begins. This shift in the treatment paradigms encompasses a wide array of therapeutic approaches, ranging from bispecific antibodies to CAR T-cell therapies, BTK inhibitors, combinations of immunomodulators, and the introduction of novel agents, he states. The diversity of these therapeutic options presents a spectrum of opportunities for improving the care and treatment outcomes of patients with lymphomas, including those with MCL, Moustafa explains.

This treatment trajectory is marked by a sense of optimism regarding the future managementof MCL and other lymphomas. The synergy between traditional treatments and innovative immunotherapies enhances the effectiveness of standard regimens and significantly improves patients’ quality of life. The prospect of chemotherapy-free treatment approaches is particularly interesting, as these regimens may spare patients from the harsh adverse effects associated with conventional chemotherapeutic agents, Moustafa continues. However, despite the progress made, the treatment of patients with MCL continues to pose significant challenges.

Despite treatment advances, including the advent of novel agents and therapies, a definitive cure for MCL remains elusive, Moustafa continues. Currently, allogeneic stem cell transplantation is the most viable option for patients who have experienced relapses or refractory cases of MCL, he emphasizes. Unfortunately, this approach is typically reserved for patients who have exhausted other avenues of treatment, Moustafa says.

With the combined efforts of researchers and clinicians, as well as the collective work of the medical community, oncologists continue to investigate treatment options for patients with MCL, with the ultimate goal of a cure, he concludes.

Muhamad Alhaj Moustafa, MD, MS, discusses the evolution of treatment options for patients with mantle cell lymphoma. 

Dr Moustafa on the Evolution of Treatment Options for Patients With MCL

Muhamad Alhaj Moustafa, MD, MS, hematologist/medical oncologist, Mayo Clinic, assistant professor, Mayo Clinic School of Medicine, discusses the phase 3 SHINE trial (NCT01776840), which evaluated ibrutinib (Imbruvica) given with bendamustine (Treanda) and rituximab (Rituxan; BR) in patients with mantle cell lymphoma (MCL).

The SHINE trial aimed to address the needs of patients with MCL 65 years of age and older who are ineligible for autologous stem cell transplantation, Moustafa begins. Investigators compared the efficacy and safety of ibrutinib given in combination with BRvs BR alone in in this population, he states. The findings from the SHINE trial have illuminated a substantial progression-free survival (PFS) benefit with ibrutinib plus BR vs BR alone, Moustafa says, adding that the investigational treatment approach extended the median PFS by 27.7 months. These results underscore the potential of incorporating ibrutinib as a therapeutic strategy for patients with MCL, particularly in the first-line setting, he notes.

However, this favorable outcome with ibrutinib plus BR was associated with an increase in the incidence of grade 3/4 adverse effects (AEs), and oncologists should evaluate the nuances of the risk-benefit profile of the SHINE regimen when contemplating this treatment approach, Moustafa expands.

Questions remain regarding the sequencing of BR with rituximab maintenance therapyand ibrutinib, he notes. For instance, it is unknown whether administering these therapies sequentially could lead to a PFS similar to that achieved with concurrent administration while mitigating the elevated toxicity that might result from concurrent administration.

A dearth of comprehensive data in this area persists, leaving room for further investigation and consideration. However, there is still promise with the use of these therapies, Moustafa continues. Furthermore, the SHINE trial contributes significantly to the growing body of evidence that informs treatment decisions for patients with MCL, highlighting potential pathways for more tailored and effective treatment strategies in the future, Moustafa concludes.

Muhamad Alhaj Moustafa, MD, MS, discusses the phase 3 SHINE trial, which evaluated ibrutinib given with bendamustine and rituximab in patients with mantle cell lymphoma.


Dr Moustafa on the Influence of the SHINE Trial in MCL

Muhamad Alhaj Moustafa, MD, MS, hematologist/medical oncologist, Mayo Clinic, assistant professor, Mayo Clinic School of Medicine, discusses how the approval of pirtobrutinib (Jayprica) has improved the treatment of patients with mantle cell lymphoma (MCL), and the role that this agent has in the current treatment landscape.

Patients with relapsed/refractory MCL are historically characterized as having poor prognosis, and are not likely to experience responses with chemoimmunotherapy regimens, Moustafa begins. Although the introduction of first-generation BTK inhibitors marked the beginning of a transformation in the management of patients with MCL, treatment options were limited for those whose disease relapsed on prior BTK inhibitor therapy, he states. The recent approval of CAR T-cell therapies in MCL serves as a viable option in the third-line setting, Moustafa notes, but these patient still lack effective alternatives once they experience disease progression on CAR T-cell therapy.

In January 2023, pirtobrutinib gained FDA approval for patients with relapsed/refractory MCL

who had been previously exposed to at least 2 prior lines of systemic therapy, including a BTK inhibitor. This regulatory decision was supported by efficacy data from the phase 1/2 BRUIN trial (NCT03740529).

Updated results from the trial have demonstrated that pirtobrutinib produced an overall response rate (ORR) of 56.7% in a subset of 90 patients with MCL, Moustafa reports. This consisted of a 18.9% complete response rate and a 37.8% partial response rate, he adds. Moreover, the median duration of response was 17.6 months at a median follow-up of 12.7 months. Additional analysis of survival outcomes revealed that pirtobrutinib produced a median progression-free survival of 7.4 months and a median overall survival of 23.5 months.

Overall, pirtobrutinib is a vital addition to the treatment armamentarium for patients with MCL in the third line and beyond, Moustafa concludes.

Muhamad Alhaj Moustafa, MD, MS, has improved the treatment of patients with mantle cell lymphoma, and the role that this agent has in the current treatment landscape.

Muhamad Alhaj Moustafa, MD, MS

Articles

Dr Moustafa on the Evolving Use of Bispecific Antibodies in DLBCL

Dr Moustafa on Standard Treatment Approaches in MCL

Dr Moustafa on the Evolution of Treatment Options for Patients With MCL

Dr Moustafa on the Influence of the SHINE Trial in MCL

Dr. Moustafa on Clinical Implications of the BRUIN Trial of Pirtobrutinib in MCL