Dr Mehta on Risks of CAR T-cell Therapy in Heavily Pretreated Lymphoma Patients

Amitkumar Mehta, MD, associate professor of medicine, associate director, Hematology and Oncology Fellowship Program, director, Phase I Program, co-director, CAR-T Program, University of Alabama at Birmingham (UAB) Bone Marrow Transplant Program, co-director, Cutaneous T Cell Lymphoma Clinic, The Kirkin Clinic, director and principal investigator, Lymphoma Tissue Bank, director, UAB Lymphoma Working Group, UAB Medicine, discusses the risks associated with CAR T-cell therapy in patients with lymphoma who have undergone multiple lines of prior chemotherapy.

Patients receiving CAR T-cell therapy later in their treatment course often face an elevated risk of secondary malignancies due exposure to prior lines of cytotoxic chemotherapy, Mehta explains. This can predispose patients to myeloid malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

Additionally, there is emerging evidence suggesting that CAR T-cell therapy itself may contribute to the development of secondary T-cell lymphomas, he continues. Mehta notes that cases like this have demonstrated a potential clonal relationship between the CAR-modified T-cells and the newly developed lymphomas, though further research is required to confirm this risk.

Infections are another significant concern for patients undergoing CAR T-cell therapy, he states. Many of these patients have received rituximab (Rituxan) and other chemotherapy agents, which can result in hypogammaglobulinemia and increase the risk of infections, including severe viral infections like COVID-19. For example, infections occurred in approximately 75% of patients receiving the treatment, with 35% experiencing grade 3/4 infections which required interventions such as intravenous antibiotics or hospitalization. Notably, infection rates were higher during the first 3 months of treatment but declined over time.

Mehta emphasizes that cytopenia’s, particularly neutropenia, are well-defined risks following CAR T-cell therapy, further heightening the risk for bacterial infections. Given the complexity of these risks, it is essential to discuss the benefits and potential complications of CAR T-cell therapy with patients.

Ongoing research will help clarify the long-term risks, particularly the potential for secondary malignancies in this heavily pretreated patient population, Mehta concludes.

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Amitkumar Mehta, MD, discusses CAR T-cell therapy-associated risks in patients with lymphoma who have undergone multiple lines of prior chemotherapy.

Dr Mehta on FDA-Approved Treatment Options in Later-Line Hematologic Malignancies

Amitkumar Mehta, MD, associate professor of medicine, associate director, Hematology and Oncology Fellowship Program, director, Phase I Program, co-director, CAR-T Program, University of Alabama at Birmingham (UAB) Bone Marrow Transplant Program, co-director, Cutaneous T Cell Lymphoma Clinic, The Kirkin Clinic, director and principal investigator, Lymphoma Tissue Bank, and director, UAB Lymphoma Working Group, UAB Medicine, discusses FDA-approved treatment options for patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma in later lines.

There are 2 FDA-approved agents for diffuse large B-cell lymphoma (DLBCL) in the third-line setting

 Mehta begins. Both therapies have shown efficacy for patients who have progressed after 2 prior lines of treatment, he explains. In follicular lymphoma, both 

 received FDA approval for use in later-line treatment settings, Mehta notes. Historically, patients who have progressed on at least 2 lines of conventional chemoimmunotherapy face poor outcomes. Retrospective studies, such as the SCHOLAR-1 study, provide a benchmark for evaluating new therapies in these populations, he reports. Mehta adds that both glofitamab and epcoritamab have demonstrated promising efficacy when compared with historical standards.

CAR T-cell therapies have not yet been directly compared with bispecific antibodies like glofitamab or epcoritamab in head-to-head clinical trials, Mehta continues. However, both CAR T-cell therapies and bispecific antibodies have significantly improved patient outcomes compared with conventional chemoimmunotherapy.

In follicular lymphoma, the third-line treatment paradigm has undergone several shifts, he expands. PI3K inhibitors, which were once considered a viable option in this setting, have since been withdrawn due to their associated adverse effects, particularly infections. Consequently, CAR T-cell therapies and mosunetuzumab have become critical treatment alternatives for patients with this disease, generating high overall response rates and progression-free survival benefit, Mehta emphasizes.

Notable differences between these agents exist. CAR T-cell therapy typically requires inpatient admission due to its complexity and cost, whereas bispecific antibodies are often administered in an outpatient setting, he states. Despite these distinctions, both approaches have led to significant improvements in patient outcomes compared to the historical benchmarks in later-line settings, Mehta concludes.

Amitkumar Mehta, MD, discusses FDA-approved treatment options for patients with diffuse large B-cell lymphoma and follicular lymphoma in later lines.

Dr Mehta on the Sequencing of CAR T-Cell Therapy and Bispecific Antibodies in Lymphoma

Amitkumar Mehta, MD, associate professor of medicine, associate director, Hematology and Oncology Fellowship Program, director, Phase I Program, co-director, CAR-T Program, University of Alabama at Birmingham (UAB) Bone Marrow Transplant Program, co-director, Cutaneous T Cell Lymphoma Clinic, The Kirkin Clinic, director and principal investigator, Lymphoma Tissue Bank, and director, UAB Lymphoma Working Group, UAB Medicine, discusses the complexities and considerations surrounding the sequencing of CAR T-cell therapies and bispecific antibodies in the treatment of patients with non-Hodgkin lymphoma.

The introduction of new agents into the therapeutic landscape for any oncologic or hematologic malignancy presents new challenges, particularly in determining the optimal order in which available treatments should be administered, Mehta says. Currently, the best sequence for CAR T-cell therapies and bispecific antibodies for patients with relapsed/refractory non-Hodgkin lymphoma remains unclear, Mehta explains

A collaborative approach between academic institutions and community health care providers is needed to address questions regarding the sequencing of these agents, Mehta says. Given the increasing number of therapeutic options, it is essential for clinicians to develop comprehensive treatment plans tailored to each patient's specific needs, he adds. Collaboration between sites ensures that patients receive timely access to advanced therapies, such as CAR T-cell therapy or bispecific antibodies, and maintains continuity of care with local physicians, Mehta notes

In Mehta's practice, he explains that enhanced communication between academic centers and community practitioners has proven to be effective. Regular discussions and consultations enable the coordination of complex treatment strategies, allowing for the efficient processing of CAR T-cell therapy or the initiation of a bispecific antibody . This approach ensures that patients receive the most appropriate therapy and facilitates a smooth transition back to community care, where ongoing management can continue under the guidance of local providers, he explains.

Collaborative efforts such as these are the cornerstone of effective lymphoma management as the treatment landscape continues to evolve, Mehta continues. Academic and community providers can optimize treatment sequencing and ensure that patients receive the best care tailored to their individual circumstances, he concludes.

Amitkumar Mehta, MD, discusses complexities and considerations around sequencing CAR T-cell therapies and bispecific antibodies in lymphoma. 

Amitkumar Mehta, MD, an associate professor for the University of Alabama at Birmingham, discusses the rationale behind utilizing parsaclisib (INCB050465) in relapsed or refractory mantle cell lymphoma (MCL) as part of the phase 2 CITADEL-205 study.

Numerous developments have been made in the treatment of patients with MCL, including the emergence of BTK inhibitors, which have made their mark due to the responses they elicit in the relapsed/refractory setting, according to Mehta. However, the frontline setting is still challenging because of the number of available treatments, Mehta says. Although CAR T-cell therapy and BTK inhibitors have had a great impact on the paradigm, the latter are associated with several adverse effects, including atrial fibrillation and bleeding issues, adds Mehta.

Due to this, there is a need for novel, highly-active agents with more tolerable safety profiles. This formed the rationale for evaluating parsaclisib in relapsed/refractory MCL, as PI3K inhibitors have proven to be highly effective in this disease, explains Mehta. Additionally, the agent has demonstrated activity in other B-cell lymphomas, such as follicular lymphoma and marginal zone lymphoma, Mehta concludes.

Amitkumar Mehta, MD, discusses the rationale behind utilizing parsaclisib in relapsed or refractory mantle cell lymphoma as part of the phase 2 CITADEL-205 study.

Amitkumar Mehta, MD

Articles

Dr Mehta on Risks of CAR T-cell Therapy in Heavily Pretreated Lymphoma Patients

Dr Mehta on FDA-Approved Treatment Options in Later-Line Hematologic Malignancies

Dr Mehta on the Sequencing of CAR T-Cell Therapy and Bispecific Antibodies in Lymphoma

Dr. Mehta on the Rationale for Utilizing Parsaclisib in Relapsed or Refractory MCL