Axicabtagene Ciloleucel for Follicular Lymphoma: Julio Chavez, MD

Julio Chavez, MD.

Recently, the FDA approved axicabtagene ciloleucel (Yescarta®, Kite Pharma, Inc.) for adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. The approval was based on results from ZUMA-5, a phase 2 trial in which axicabtagene ciloleucel demonstrated a high rate of efficacy. In this interview, one of the study investigators, Julio Chavez, MD, of the Moffitt Cancer Center, speaks with Oncology Data Advisor about challenges in the management of FL and the significance of the approval of axicabtagene ciloleucel.

What are some of the challenges of managing FL?

Julio Chavez, MD: The first challenge is to determine whether the patient will need treatment. Unlike diffuse large B-cell lymphoma (DLBCL), FL can be asymptomatic, and patients may not need treatment right away. Some patients can be observed and hence spared from potentially toxic treatment, especially if we consider chimeric antigen receptor (CAR) T-cell therapy. The second challenge is to choose the right treatment for patients. Some patients with minimally symptomatic disease and low burden FL may not need cytotoxic therapy; sometimes single agent anti-CD20 monoclonal antibodies could be enough. In higher-risk patients, such as those with high tumor burden relapse, early relapse, or post-autologous transplant relapse, there are several treatment options, and clinicians should choose based on clinical characteristics such as age, comorbidities, patient preference, and efficacy of the treatment options available.

Can you comment on the significance of your results?

Dr. Chavez: Axicabtagene ciloleucel was studied in patients with indolent non-Hodgkin’s lymphoma, including FL and marginal zone lymphoma (MZL) in the ZUMA-5 clinical trial. Axicabtagene ciloleucel is currently approved for relapsed/refractory DLBCL after two lines of therapy. ZUMA-5 is a phase 2 clinical trial that included patients with relapsed/refractory FL and MZL after two lines of therapy, including at least one regimen containing an anthracycline and an anti-CD20 monoclonal antibody. We enrolled 151 patients and treated 146 patients. The trial included high-risk patients such as those with early relapse (progression of disease within 24 months), those who had undergone autologous transplantation, heavily pretreated patients (median of 3 prior lines), patients who previously received phosphoinositide kinase 3-kinase (Pi3K) inhibitors, and patients whose disease was refractory to the last line of therapy. Axicabtagene ciloleucel showed high response rates, with an objective response rate of 92% and a complete response rate of 76%. The median progression-free survival and duration of response were not reached. The median follow up was relatively short (about 18 months).

These results are very significant. With the current treatment options (such as Pi3K inhibitors), the complete response rates are less than 10% and progression-free survival is between 10 to 12 months. Thus, axicabtagene ciloleucel emerges as an important treatment option. In addition, small sets of long-term data on patients with FL from the University of Pennsylvania, Fred Hutchinson Cancer Research Center, and the National Cancer Institute show long-term remission in an important proportion of patients who have received axicabtagene ciloleucel. It is too early to say that CAR T-cell therapy could be curative for FL, but early results seem encouraging.

What additional research is underway for axicabtagene ciloleucel?

Dr. Chavez: Axicabtagene ciloleucel is being studied in the ZUMA-7 clinical trial, which is a randomized phase 3 clinical trial of axicabtagene ciloleucel versus standard of care in patients with DLBCL at first relapse (early relapse of less than 12 months). Accrual has been completed, and we are eagerly waiting for results. Axicabtagene ciloleucel is also being studied as a frontline therapy for high-risk patients in the ZUMA-12 study (high International Prognostic Index score and/or double hit lymphoma) with residual disease after two cycles of chemotherapy. Preliminary results were presented already. Investigators are also studying axicabtagene ciloleucel in primary central nervous system lymphoma (NCT04608487). There are studies with the aim of reducing toxicities (cytokine release syndrome and neurotoxicity) from axicabtagene ciloleucel, such as the ZUMA-19, in which an anti-granulocyte-macrophage colony-stimulating factor antagonist is used. Cytokine release syndrome and neurotoxicity remain challenging toxicities from axicabtagene ciloleucel.

What advice would you give clinicians who are managing patients with FL?

Dr Chavez: The most important thing is to discuss all available treatment options. Given that there are several, many patients could feel overwhelmed; thus, physician guidance is key. One consideration is to determine whether the patient requires treatment. An observation period is reasonable in asymptomatic patients. Another consideration is the patient’s wishes. Some patients may not want or be ready for CAR T-cell therapy due to potential toxicities and logistics, and they might prefer a less aggressive approach. Given the potential for long-term remission with CAR T-cell therapy, some patients may prefer that route. Finally, clinicians should consider performance status and comorbidities in order to consider this therapy. If the clinician has any questions or concerns about CAR T-cell therapy, he or she should refer the patient to a specialized center with experience in CAR T-cell therapy in order to discuss the pros and cons of the treatment.

About Dr. Chavez

Julio Chavez, MD, is an Associate Member in the Lymphoma Section of the Department of Malignant Hematology at the Moffitt Cancer Center in Tampa, Florida. He is board certified in both medical oncology and internal medicine. Dr. Chavez is the principal investigator of several ongoing clinical trials involving targeted therapies and immunotherapy, and he is an author on numerous publications. His areas of interest include lymphoblastic leukemia in the elderly, as well as lymphoid malignancies, specifically aggressive lymphomas, chronic lymphocytic leukemia, and virally-related lymphoid malignancies.

For More Information

Jacobson C, Chavez JC, Sehgal AR, et al (2020). Primary analysis of Zuma-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood (ASH Annual Meeting Abstracts), 136(suppl_1):40-41. DOI:10.1182/blood-2020-136834

Clinicaltrials.gov (2021). A phase 2 multicenter study of axicabtagene ciloleucel in subjects with relapsed/refractory indolent non-Hodgkin lymphoma (Zuma-5). NLM identifier: NCT03105336.

Clinicaltrials.gov (2021). Efficacy of axicabtagene ciloleucel compared to standard of care therapy in subjects with relapsed/refractory diffuse large B-cell lymphoma (Zuma-7). NLM identifier: NCT03391466.

Clinicaltrials.gov (2020). Efficacy and safety of axicabtagene ciloleucel as first-line therapy in participants with high-risk large B-cell lymphoma (Zuma-12). NLM identifier: NCT03761056.

Clinicaltrials.gov (2021). Axi-cel in CNS Lymphoma. NLM identifier: NCT04608487.

Clinicaltrials.gov (2021). Study of lenzilumab and axicabtagene ciloleucel in participants with relapsed or refractory large B-cell lymphoma (Zuma-19). NLM identifier: NCT04314843.

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. 


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