Axi-Cel Induces Durable Remissions in Relapsed CLL, B-Cell Lymphoma

Patients with relapsed chronic lymphocytic leukemia (CLL) and B-cell lymphoma who received the anti-CD19 CAR T-cell therapy FMC63-28Z, which was later developed as axicabtagene ciloleucel (axi-cel; Yescarta), experienced highly durable rates of remission, according to long-term data from a phase 1/2 study (NCT00924326).

Results from the study, which were presented at the 2020 ASCO Virtual Scientific Program, showed that 58% of the CD19-directed CAR T-cell product treatments (n = 25/43) led to a best response of complete remission (CR), while 23% (n = 10/43) resulted in a best response of partial remission (PR). No patients who achieved a best response of PR or stable disease experienced a durable response. Furthermore, 60% of the CRs were determined to still be evaluable and ongoing at the time of the last follow-up. For the ongoing CRs, the duration of response (DOR) ranged from 42 months to 113 months.

The median event-free survival (EFS) in the 45 evaluable patients was 55 months. The median overall survival (OS) with this approach in these patients had not yet been reached at the time of the presentation. Notably, the median EFS and OS did not differ between lymphoma types or cohorts examined on the study.

T cells that express anti-CD19 CARs have historically been shown to result in the CR of patients with relapsed lymphoma. While approved anti-CD19 CAR T-cell products yield a CR remission rate ranging between 40% to 54%, investigators had yet to fully explore the long-term durability of these responses, as well as the long-term adverse effects (AEs) of this approach.

“Our group conducted the first study of anti-CD19 CAR T cells to show success in treating B-cell lymphoma. This trial used the CAR FMC63-28Z, which was later commercially developed as axicabtagene ciloleucel,” lead study author Kathryn Cappell, MD, PhD, of the National Cancer Institute, said in a poster presentation during the meeting. “[In the study,] we [examined] the outcomes in long-term AEs in these first [patients with] lymphoma treated with anti-CD19 CAR T cells.”

Over the course of the study, which was conducted between 2009 and 2015, 43 patients—3 of whom received repeat CAR T cell infusions—were treated with a conditioning chemotherapy regimen comprised of cyclophosphamide plus fludarabine followed by anti-CD19 CAR T cells. Of the patients treated, 28 had aggressive diffuse large B-cell lymphoma or aggressive primary mediastinal B cell lymphoma, 7 had CLL, and 8 had low-grade lymphoma.

The patient population was treated in 3 cohorts that varied the dose of lymphodepleting chemotherapy and administration of interleukin-2 (IL-2). In the first cohort, patients received 60 mg/kg of cyclophosphamide, and then 25 mg/m2 of fludarabine, followed by CAR T cells; IL-2 followed cell infusion. Meanwhile, patients in the second cohort were treated with 30 mg/kg or 60 mg/kg of cyclophosphamide, followed by 25 mg/m2 of fludarabine, and then CAR T-cell infusion. The third cohort of patients received 300 mg/m2 or 500 mg/m2 of cyclophosphamide with 30 mg/m2 of fludarabine simultaneously, followed by a CAR T-cell infusion.

“We also examined the correlation of CAR levels and response, and we found that patients who achieved a CR had higher peak CAR level as compared with those who did not,” said Cappell. “Similarly, patient who achieved a DOR of greater than 3 years, also had higher peak CAR levels. All except 4 patients achieved peak CAR levels between days 6 and 17. The 4 patients who did not, experienced later peaks between days 26 and 55.”

When examining the association of CAR T-cell persistence with response, investigators found that CAR T-cell persistence at day 28 to day 56 was not linked with either response or DOR.

Although AEs associated this therapy were rare, according to Cappell, several were reported. The most common toxicities observed with treatment included B-cell depletion and hypogammaglobulinemia, although these events were observed to improve over time. Seven of 43 patients went on to develop a second malignancy following treatment, and only 1 patient experienced an autoimmune diagnosis of hypothyroidism. Furthermore, investigators reported that infections requiring hospitalization that occurred in greater than 6 months after CAR infusion occurred in 4 of the 43 patients.

When examining B-cell and immunoglobulin recovery over time in 24 evaluable patients who achieved CR, investigators noted that 38% were unable to recover normal B-cell levels. Additionally, 75% of patients were found to have a longstanding abnormality in 1 or more immunoglobulin.

“The take-home points from our study are that anti-CD19 CAR T cells can lead to highly durable remissions in B-cell lymphoma. These are the longest reported responses in [this disease], and they range from 97 months for DLBCL or PMBCL to 113 months for follicular lymphoma,” said Cappell. “We show that response and durability of response is associated with higher peak CAR levels, but not persistence of the CAR levels at a later time point.”

These findings indicate that anti-CD19 CAR T cells may be curative in regard to certain types of lymphoma, though this has yet to be proven, Cappell concluded.

Reference

1. Cappell KM, Sherry RM, Yang JC, et al. Long-term follow-up of anti-CD19 CAR T-cell therapy for B-cell lymphoma and chronic lymphocytic leukemia. J Clin Oncol. 2020;38(suppl 15):3012. doi:10.1200/JCO.2020.38.15_suppl.3012