February 8, 2021 - Prior exposure to anti-CD19 therapy did not impact response to the CAR T-cell therapy lisocabtagene maraleucel in patients with relapsed/refractory large B-cell lymphoma.
Prior exposure to anti-CD19 therapy did not impact response to lisocabtagene maraleucel (liso-cel; Breyanzi) in patients with relapsed/refractory large B-cell lymphoma (LBCL), according to results from a post-hoc analysis of the phase 1 TRANSCEND NHL 001 trial (NCT02631044) presented during the 2021 Transplantation & Cellular Therapy Meeting.1
Among 12 patients who had previously received anti-CD19 therapy, 2 patients achieved a complete response (CR) as their best response to that treatment, 3 patients reported a partial response (PR), and 1 achieved stable disease. Five patients experienced disease progression, while 1 patient’s response status was unknown.
Results from the analysis showed that 92% (n = 11/12) experienced an objective response to liso-cel per independent review committee (IRC) assessment and Lugano criteria; this included 6 CRs (50%) and 5 PRs with the CAR T-cell therapy. Moreover, 5 patients experienced a duration of response (DOR) to liso-cel of 9 months or longer (range, 0.8-27.4), with 4 patients continuing to respond at the time of data cutoff.
The response rates reported in this subgroup proved to be comparable to those observed in the overall TRANSCEND NHL 001 study population. Of the 256 patients determined to be efficacy evaluable, which included those who were given at least 1 dose of liso-cel and had PET-positive disease per IRC, the objective response rate was 73% (95% CI, 66.8%-78.0%), with a CR rate of 53% (95% CI, 46.8%-59.4%).2 The median DOR had not been reached (95% CI, 8.6–not reached [NR]). Moreover, the median progression-free survival (PFS) was 6.8 months in this population (95% CI, 3.3-14.1) and the median overall survival (OS) was 21.1 months (95% CI, 13.3-NR).
“In this post-hoc analysis of a small subset of patients from TRANSCEND, patient response to liso-cel and liso-cel pharmacokinetics were not impacted by prior exposure to anti-CD19 therapy,” Scott R. Solomon, MD, of the Blood and Marrow Transplant Program, Leukemia and Cellular Immunotherapy Program at the Northside Hospital Cancer Institute, and colleagues, wrote in a poster highlighting the data. “Additional analyses on a larger number of patients with prior anti-CD19 therapy are warranted to confirm these findings.”
An investigational, CD19-targeted, defined composition, 4-1BB CAR T-cell product, liso-cel is given at equal target doses of CD8 and CD4 T cells; the product has showcased safety and efficacy in patients with aggressive, relapsed/refractory LBCL in the TRANSCEND NHL 001 trial. Data from the trial led to the February 2021 FDA approval of the CAR T-cell product for use in adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.
The multicenter, pivotal, phase 1 trial enrolled adult patients aged 18 years or older with relapsed/refractory LBCL; this included those with diffuse large B-cell lymphoma (DLBCL); high-grade B-cell lymphoma with rearrangements of MYC and either BCL-2, BCL-6, or both; DLBCL transformed from an indolent lymphoma; primary mediastinal B-cell lymphoma; and follicular lymphoma. To be eligible for enrollment, patients had to have an ECOG performance status of 0-2, creatinine clearance of greater than 30 mL/min/1.73 m2, and a left ventricular ejection fraction of at least 40%.
Those who underwent prior hematopoietic stem cell transplantation and those with secondary central nervous system lymphoma were permitted. Notably, no lower threshold for absolute lymphocyte count, absolute neutrophil count, platelets, or hemoglobin, were established.
In the trial, patients were screened and then underwent leukapheresis where bridging therapy was permitted while the product was being manufactured. Once disease was reconfirmed via PET imaging, patients went on to receive lymphodepleting chemotherapy with fludarabine at 30 mg/m2 and cytarabine at 300 mg/m2, delivered over the course of 3 days. Two to 7 days after the chemotherapy, patients received liso-cel.
A total of 269 participants were assigned to 1 of 3 target dose levels of the CAR T-cell product: 50 × 106 CAR T cells (1 or 2 doses), 100 × 106, and 150 × 106; this was given as a sequential infusion of 2 components, CD8 and CD4 CAR T cells, at equal target doses.
The co-primary end points of the trial included adverse effects (AEs), dose-limiting toxicities, and ORR per Lugano criteria and IRC. Key secondary end points comprised CR rate by IRC, DOR, PFS, OS, and cellular kinetics.
For the post-hoc analysis, investigators looked at a subset of patients from the trial who had previously received CD19-targeted therapy before liso-cel to evaluate impact of the CAR T-cell product on safety and efficacy outcomes, as well as cellular kinetics.
The median age of the 12 patients in the subgroup of interest was 60.5 years, and 83% were male. Half of the patients had an ECOG performance status of 0, while the remainder had a status of 1. The median number of previous lines of treatment was 4. Fifty-eight percent of patients previously underwent transplantation and 67% were refractory to chemotherapy. Regarding histology, 58% had DLBCL not otherwise specified, 33% had DLBCL that was transformed from follicular lymphoma, and 8% had high-grade B-cell lymphoma.
Additional data showed that previous anti-CD19 therapy did not impact cellular kinetic parameters. Liso-cel demonstrated long-term persistence at 3 months in the majority, or 83% (n = 5/6), of those who received prior CD19-targeted treatment; persistence at 1 year was observed in 50% of patients (n = 2/4), which was comparable to those who did not receive previous CD19-targeted treatment.
Regarding safety, all patients in this subgroup experienced treatment-emergent AEs (TEAEs), 58% (n = 7) of which were grade 3 or higher. The most reported grade 3 or higher TEAEs included neutropenia (58%), thrombocytopenia (42%), and anemia (33%). Sixty-seven percent of patients reported all-grade cytokine release syndrome (CRS) and 42% experienced all-grade neurological effects with liso-cel. However, all toxicity rates proved to be comparable to those experienced by the overall study population and all CRS or neurological effects were either grade 1 or 2.
“These findings suggest that liso-cel can be considered for the treatment of patients who have received prior anti-CD19 therapies,” concluded Solomon.