Community Oncologists Critical to Success of CAR T-cell Therapy in R/R Large B-Cell Lymphoma

Caron A. Jacobson, MD

Axicabtagene ciloleucel (Yescarta) can result in meaningful long-term responses in patients with relapsed or refractory large B-cell lymphoma who have received at least 2 prior systemic therapies, but successful treatment is heavily influenced by the active involvement of community oncologists, according to a new paper.

The article, published in The Oncologist,¹ outlines the practical implications of new research into axicabtagene ciloleucel, the first FDA-approved autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for this group of patients. Though the therapy can only be administered at authorized treatment centers, corresponding author Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues, suggest that community oncologists can serve key functions on the path to successful treatment. 

“The community oncologist plays a fundamental role in the CAR T-cell treatment journey, first by referring patients to an academic center that is an authorized treatment center for CAR T-cell therapy at an appropriate point in their disease course and then by providing long-term support of patients through management of prolonged AEs [adverse events] and disease monitoring,” Jacobson and colleagues wrote.

Patients who are diagnosed with aggressive B-cell lymphomas are typically treated first with immunochemotherapy, but an estimated 20% to 40% of these patients will see their treatment fail or will experience a relapse.^2-4

Salvage chemotherapy is typically the next step for patients eligible for intensive therapy, but again, the success rate is only moderate, with only 40% to 60% of patients responding.^2,3 Those who are refractory to immunotherapy or see relapse within a year of their initial diagnosis tend to have a poor prognosis, Jacobson and colleagues wrote.

The phase I/II ZUMA-1 study, published last year in The Lancet Oncology,⁵ attempted to fill the unmet therapeutic need by investigating the autologous anti-CD19 CAR T-cell therapy axicabtagene ciloleucel. The study of 108 patients with refractory large B-cell lymphoma showed an objective response rate of 83% and a complete response rate of 58%. After 27.1 months, 39% of patients had ongoing responses.

Though the therapy shows promise for a group of patients that might otherwise have few options, Jacobson and colleagues noted that the role of the community oncologist is critical. First and foremost, the investigators said it is important for community oncologists to identify patients who are candidates for the therapy as quickly as possible, in part because the process of initiating treatment can be lengthy.

“From the time a patient is referred to an authorized treatment center for CAR T-cell therapy to the time of CAR T-cell infusion, the process can take 4-6 weeks,” the authors wrote.

Early identification is most feasible if local oncologists are vigilant about monitoring patients for treatment failure or relapse, they said.

Although patients on any round of therapy could theoretically benefit from the CAR T-cell therapy, Jacobson and colleagues said that frailty becomes a bigger concern with each round of treatment, thus it is better for academic medical centers to see patients earlier on in the process. They wrote that patients whose disease progresses during their first line of therapy should be referred to academic medical centers, given the significant likelihood of relapse with second-line therapies.

“Academic centers are equipped to facilitate a smooth and rapid transition to the next line of therapy, especially CAR T-cell therapy, if patients are already receiving treatment there, which may be particularly important for patients with rapidly progressing disease,” Jacobson and colleagues wrote.

On the other end of the treatment spectrum, the investigators said that community oncologists are “critical partners” in the monitoring of patients after treatment. The authors note that a patient who is responding to treatment without signs of adverse events can typically return home after 4 to 8 weeks of staying near the treatment center. However, once home, their local doctor needs to keep an eye out for a number of potential conditions, such as prolonged hypogammaglobulinemia and B-cell aplasia. Some patients experience prolonged cytopenias, and the authors said that blood counts should be monitored. The patients are also at an ongoing risk of serious infections as a result of treatment-related immunosuppression.

“Immunotherapies have been shown to modulate CAR T-cell activity,⁶ and for a patient who may have some level of persistent CAR T cells even after relapse, subsequent treatments must be carefully considered and their effects monitored,” Jacobson and colleagues said.

Overall, though, ZUMA-1 showed a rate of treatment-related mortality of less than 2%. Thus, the investigators wrote that the therapy is an exciting opportunity for this particular subset of patients with large B-cell lymphomas, but that success is predicated upon their community oncologists having the information and initiative to promptly link such patients to the right care.

“With appropriate management of common AEs, axicabtagene ciloleucel offers the potential for long-term durable responses in patients who otherwise lack curative treatment options,” the study authors concluded.

_References

1. _{Jacobson, C.A., Farooq, U. and Ghobadi, A. (2020), Axicabtagene Ciloleucel, an Anti‐CD19 Chimeric Antigen Receptor T‐Cell Therapy for Relapsed or Refractory Large B‐Cell Lymphoma: Practical Implications for the Community Oncologist. The Oncol. 2020;25(1):e138-e146. doi: 10.1634/theoncologist.2019-0395.}
2. _{Crump M, Kuruvilla J, Couban S et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTGLY.12. J Clin Oncol. 2014;32(31):3490-3496. doi: 10.1200/JCO.2013.53.9593.}
3. _{Gisselbrecht C, Glass B, Mounier N et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184-4190. doi: 10.1200/JCO.2010.28.1618.}
4. _{Vitolo U, Trněný M, Belada D et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017;35(31):3529-3537. doi: 10.1200/JCO.2017.73.3402.}
5. _{Locke FL, Ghobadi A, Jacobson CA et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7.}
6. _{Jacobson CA, Locke FL, Miklos DB et al. End of phase 1 results from ZUMA-6: Axicabtagene ciloleucel (axi-cel) in combination with atezolizumab for the treatment of patients with refractory diffuse large B cell lymphoma. Biol Blood Marrow Transplant. 2019;25(suppl; abstr 239). doi: 10.1016/j.bbmt.2018.12.314.}