Lori A. Leslie, MD, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, and Andre H. Goy, MD, physician in chief of the Hackensack Meridian Health Oncology Care Transformation Services, chairman and chief physician officer at John Theurer Cancer Center at Hackensack University Medical Center, and Lymphoma Division Chief at the John Theurer Cancer Center, share strategies for when CAR T-cell therapy is not an option.

The patient population that is ineligible for CAR T-cell therapy is shrinking because of improved toxicity management and intervention, Leslie says. Now, referring providers may be surprised by which patients are eligible for CAR T-cell therapy. As such, it is important to evaluate patients at a CAR T-cell therapy center. However, for patients who are not eligible for CAR T-cell therapy, more options have become available. For example, in diffuse large B-cell lymphoma, agents such as tafasitamab-cxix (Monjuvi), selinexor (Xpovio), and loncastuximab tesirine-lpyl (Zynlonta) are approved for use. Currently, these agents are not curative, although they have shown high response rates, Goy says.

For patients who are eligible for both CAR T-cell therapy and novel agents, treatment is typically sequenced such that novel agents are used following CAR T-cell therapy failure, Leslie says. However, regimens that incorporate novel agents into up-front treatment are also being explored. For example, the phase 3 POLARIX trial (NCT03274492) evaluated the addition of the antibody-drug conjugate polatuzumab vedotin-piiq (Polivy) to rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone. These agents are also being incorporated into existing treatment regimens as a bridge to CAR T-cell therapy, Leslie says.

In terms of investigational therapeutics, bispecific T-cell engagers have garnered significant excitement and have shown encouraging responses post CAR T-cell therapy, Leslie says. However, because these agents are more easily administered than CAR T-cell therapy, a key question is whether these agents will replace CAR T-cell therapy in certain scenarios, Leslie concludes.

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Lori A. Leslie, MD, and Andre H. Goy, MD, share strategies for when CAR T-cell therapy is not an option.  

Inside the Clinic: JTCC Experts Share Strategies for When CAR T-Cell Therapy Is Not an Option

Lori A. Leslie, MD, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, and Andre H. Goy, MD, physician in chief of the Hackensack Meridian Health Oncology Care Transformation Services, chairman and chief physician officer at John Theurer Cancer Center at Hackensack University Medical Center, and Lymphoma Division Chief at the John Theurer Cancer Center, discuss approaches to CAR T-cell therapy.

Indications for CAR T-cell therapy are expanding, which has been exciting to see, Leslie says. Moreover, real-world data sets are showing encouraging efficacy with these therapies. In diffuse large B-cell lymphoma (DLBCL), axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi) are approved for patients who have received at least 2 lines of therapy. For eligible patients with DLBCL in need of third-line treatment, CAR T-cell therapy is a preferred option, Leslie says. Notably, axi-cel is expected to become a second-line standard for patients with relapsed/refractory large B-cell lymphoma based on the results from the phase 3 ZUMA-7 trial (NCT03391466), which showed improved event-free survival with the therapy vs standard-of-care chemotherapy, Goy says.

In mantle cell lymphoma (MCL), the current setting for the use of CAR T-cell therapy is evolving, Leslie explains. Currently, brexucabtagene autoleucel (Tecartus) is approved for any patient with relapsed/refractory MCL. However, the NCCN guidelines recommend that patients be previously exposed to chemotherapy and a BTK inhibitor.

In follicular lymphoma, axi-cel is approved for patients who have received at least 2 lines of therapy. However, because of the variation in disease biology, not all patients with follicular lymphoma will need CAR T-cell therapy in the third-line setting, Leslie says. For example, patients with indolent disease may be better served with alternative therapies, such as PI3K inhibitors or EZH2 inhibitors, Leslie adds. It will be important to sort out the optimal sequence of treatment given the implications on patient care and treatment costs, Goy concludes.

Lori A. Leslie, MD, and Andre H. Goy, MD, discuss approaches to CAR T-cell therapy.

Inside the Clinic: JTCC Experts Discuss Approaches to CAR T-Cell Therapy

Lori A. Leslie, MD, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, and Andre H. Goy, MD, physician in chief of the Hackensack Meridian Health Oncology Care Transformation Services, chairman and chief physician officer at John Theurer Cancer Center at Hackensack University Medical Center, and Lymphoma Division Chief at the John Theurer Cancer Center, discuss optimal strategies for CAR T-cell–related adverse effects (AEs).

Preemptive strategies with tocilizumab (Actemra) and steroids can help mitigate acute AEs associated with CAR T-cell therapy. Following CAR T-cell therapy infusion, important long-term AEs to be aware of include cytopenias, immunoglobulin (Ig) recovery, immune system recovery, and hypogammaglobulinemia, Goy and Leslie say. Currently, with supportive care, approximately 75% of patients recover their CD4 counts and Ig levels 2 years after infusion. 

Short-term AEs to be aware of are cytokine release syndrome (CRS) and neurotoxicity, Leslie says. Notably, neurotoxicity, which can be a concerning early-onset toxicity, generally resolves completely, Goy says. In early-phase studies with CAR T-cell therapy, intervention was more common in the event of grade 3 CRS or neurotoxicity. Now, earlier intervention strategies are recommended, which has led to milder presentations of these AEs, such as fever and blood pressure changes, Leslie says. Notably, such interventions have not negatively affected efficacy outcomes, Leslie adds. Ultimately, close monitoring during the first period following infusion is necessary, when CRS and neurotoxicity are most common, because neurotoxicity, for example, can present as something as subtle as a change in writing or something as severe as encephalopathy, Leslie concludes.

Lori A. Leslie, MD, and Andre H. Goy, MD, discuss optimal strategies for CAR T-cell–related adverse effects. 

Inside the Clinic: JTCC Experts Highlight Optimal Strategies for CAR T-Cell–Related AEs

Lori A. Leslie, MD, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, and Andre H. Goy, MD, physician in chief of the Hackensack Meridian Health Oncology Care Transformation Services, chairman and chief physician officer at John Theurer Cancer Center at Hackensack University Medical Center, and Lymphoma Division Chief at the John Theurer Cancer Center, discuss retreatment with CAR T-cell therapy.

Data regarding retreatment with CAR T-cell therapy is limited, Goy says. Anecdotal evidence has shown that responses are generally shorter with retreatment than with the first infusion, prompting questions about the mechanism of resistance to CAR T-cell therapy. In acute lymphoblastic leukemia, the loss of CD19 has been shown to be a primary mechanism of resistance, whereas its relevance in large B-cell lymphoma (LBCL) is less clear, Goy says. In LBCL, it is more likely that T-cell exhaustion and a suppressive microenvironment have a greater effect on responses. Similarly, in follicular lymphoma, responses with retreatment are high, suggesting loss of CD19 may not be a primary resistance mechanism, Leslie adds. 

Early retreatment may be an approach worth exploring because approximately 30% of patients who experience a partial response or stable disease following first infusion can convert to a long-term complete remission, Goy says. However, he adds that retreatment may be futile if there is minimal T-cell amplification following infusion and the underlying resistance mechanism is not addressed. An alternative approach that has been studied to elicit a more durable response is adding a checkpoint inhibitor to CAR T-cell therapy, Goy says. Alternatively, data have shown that the administration of ibrutinib (Imbruvica) prior to CAR T-cell therapy enhances T-cell fitness, Leslie adds.

For patients who cannot be retreated with CAR T-cell therapy, bispecifics such as mosunetuzumab have shown promise as salvage therapy, Goy says.

Another important question is: At what point should retreatment be considered? To that end, research is evaluating longitudinal cell-free DNA persistence to see whether there is an opportunity for early treatment escalation strategies to augment T-cell responses, Goy says. Ultimately, the emergence of allogeneic and bispecific CAR T-cell therapies may affect how retreatment is thought about entirely. As more is understood about the biology of CAR T-cell therapy, the field will be better equipped to answer whether retreatment is a strategy worth pursuing, Leslie concludes.

Lori A. Leslie, MD, and Andre H. Goy, MD, discuss retreatment with CAR T-cell therapy.

Inside the Clinic: JTCC Experts Discuss Retreatment With CAR T-Cell Therapy

Lori A. Leslie, MD, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, and Andre H. Goy, MD, physician in chief of the Hackensack Meridian Health Oncology Care Transformation Services, chairman and chief physician officer, John Theurer Cancer Center at Hackensack University Medical Center, and Lymphoma Division Chief, John Theurer Cancer Center, discuss next steps with CAR T-cell therapy.

CAR T-cell therapy has had a significant effect on treatment paradigms throughout lymphoma and leukemia, but its development is still in its infancy, Goy explains. Finding ways to make CAR T-cell therapy more effective and induce more durable, minimal residual disease–negative responses is a key research area, Leslie says. Although toxicity management has improved since the initial approvals of these agents, further reducing toxicity so that these therapies can be safely administered in an outpatient setting is also an area of focus. 

In terms of its placement throughout treatment paradigms, CAR T-cell therapy is currently indicated for more heavily pretreated patients. However, it is being moved into earlier lines of treatment throughout B-cell malignancies and is being expanded to other hematologic malignancies and solid tumors, Leslie adds. CAR T-cell therapy is undoubtedly a game-changer in the relapsed/refractory setting and will likely become an up-front consolidation therapy for high-risk patients, such as those with double-hit lymphoma and mantle cell lymphoma, Goy says.

Ultimately, future treatment throughout oncology will likely place a heavy focus on cellular therapy and T-cell engaging therapy, Goy concludes.

Lori A. Leslie, MD, and Andre H. Goy, MD, discuss next steps with CAR T-cell therapy.

Inside the Clinic: JTCC Experts Highlight Next Steps With CAR T-Cell Therapy

Andre H. Goy, MD, physician in chief, Hackensack Meridian Health Oncology Care Transformation Service; chairman & chief physician officer, John Theurer Cancer Center; Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology, Hackensack Meridian School of Medicine; and professor of medicine, Georgetown University, discusses the clinical data reported with axicabtagene ciloleucel (axi-cel; Yescarta) in patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL) and real-world findings with brexucabtagene autoleucel (brexu-cel; Tecartus) in mantle cell lymphoma (MCL).

The data from extended follow-up of the phase 2 ZUMA-5 trial (NCT03105336) showed that axi-cel elicited an overall response rate (ORR) of 94% and a complete response (CR) rate of 79% in patients with follicular lymphoma. The CAR T-cell therapy also induced an ORR of 83% and a CR rate of 63% in those with marginal zone lymphoma. Among all patients with indolent NHL, the ORR with axi-cel was 92%, with a CR rate of 75%. These responses were maintained over time, Goy says.

Furthermore, a real-world analysis investigated the use of brexu-cel in patients with MCL. This analysis added to the data from the ZUMA-5 trial by examining a different CAR T-cell therapy, brexu-cel, which is significant according to Goy, because patients who are put onto clinical trials are selected to a certain degree. 

Patients with MCL are generally older, and they typically present with more comorbidities and more aggressive disease, Goy says. The real-world data reported with brexu-cel, showed a similar ORR, CR rate, duration of response, durability, and toxicity compared with what has been observed in clinical trials, Goy adds. These data are encouraging for expanding the platform of cell therapy, Goy concludes.

Andre H. Goy, MD, discusses the clinical data reported with axicabtagene ciloleucel in patients with relapsed or refractory indolent non-Hodgkin lymphoma and real-world findings with brexucabtagene autoleucel in mantle cell lymphoma.

Dr. Goy on the Utility of Axi-Cel and Brexu-Cel in Relapsed/Refractory Non-Hodgkin Lymphoma

Andre Goy, MD, Physician in Chief Hackensack Meridian 

 Oncology Care Transformation Service, Chairman & Chief Physician Officer - John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology - Hackensack Meridian School of Medicine, Professor of Medicine – Georgetown University, Hackensack, NJ, discusses the clinical implications of CAR T-cell therapy in mantle cell lymphoma (MCL). 

In July 2020, initial results of the phase 2 ZUMA-2 trial led to the FDA approval of brexucabtagene autoleucel (Tecartus) for the treatment of patients with relapsed/refractory MCL. Updated results from the study, which were presented during the 2021 Transplantation & Cellular Therapy Meetings, showed that at a median follow-up of 17.5 months, the overall response rate was 92%, with a complete response rate of 67%. 

Taken collectively, these data highlight the importance of referring patients who fail on standard therapy to clinical trials involving CAR T-cell therapy, says Goy. Currently, patients with MCL who progress on standard treatment options have poor outcomes, says Goy. CAR T-cell therapy has demonstrated high response rates that appear durable, Goy explains.

Additionally, many patients with MCL are too old for an allogeneic stem cell transplant, and the risk of developing chronic graft-versus-host disease with transplant is high, says Goy. As such, the integration of CAR T-cell therapy for this patient population with MCL that has a high risk of relapse is critical, concludes Goy. 

Andre Goy, MD, discusses the clinical implications of CAR T-cell therapy in mantle cell lymphoma.  



Dr. Goy on the Clinical Implications of CAR T-Cell Therapy in MCL 

Andre H. Goy, MD, physician in chief, Hackensack Meridian Health Oncology Care Transformation Service, chairman and chief physician officer, John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, academic chairman oncology, Hackensack Meridian School of Medicine at Seton Hall University, and professor of medicine, Georgetown University, discusses the potential utility of BTK inhibitors as maintenance therapy in mantle cell lymphoma (MCL).

Though the data is early, BTK inhibitors appear to have activity as maintenance therapy in MCL, explains Goy.

A study from the European MCL Intergroup is evaluating ibrutinib (Imbruvica) as maintenance therapy in patients who had an autologous stem cell transplant after rituximab (Rituxan), with cyclophosphamide, doxorubicin, vincristine, and prednisone, R-BAC (rituximab, bendamustine, and cytarabine), and transplant induction, concludes Goy.

Andre H. Goy, MD, discusses the potential utility of BTK inhibitors as maintenance therapy in mantle cell lymphoma. 


Andre H. Goy, MD

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