Minimal residual disease negativity key to durable remissions after CAR-T for CLL
Click Here to Manage Email Alerts
Minimal residual disease status appeared to influence outcomes after chimeric antigen receptor T-cell therapy for high-risk chronic lymphocytic leukemia, according to study results.
Patients who achieved minimal residual disease-negative complete response to a CD19-directed CAR T-cell therapy experienced significantly longer PFS, long-term follow-up data from a phase 1/phase 2 study presented at ASH Annual Meeting and Exposition showed.
“Our analysis shows that patients with CLL who achieved initial deep remissions after CAR T-cell therapy had a more durable response,” Alexandre V. Hirayama, MD, physician-researcher at Fred Hutchinson Cancer Research Center, told Healio. “Those who had deep remissions and no detectable clones by next-generation sequencing had durable remissions.”
Hirayama and colleagues presented long-term follow-up data from a trial that evaluated a CD19-targeted CAR-T cell therapy for patients with relapsed or refractory CLL.
The investigators also performed single-cell sequencing analyses of the CAR-T infusion products produced during the study with the aim of identifying outcomes associated with certain T-cell characteristics.
Researchers divided study participants into two cohorts. Patients in one group had discontinued ibrutinib (Imbruvica; Janssen, Pharmacyclics) therapy prior to apheresis or lymphodepletion, and patients in the other group received concurrent ibrutinib 420 mg daily during the CAR-T process and into the follow-up period.
At median follow-up of 23.5 months (interquartile range, 11-33.8), PFS could not be estimated (95% CI, 22.2-not reached) for 18 patients who achieved a minimal residual disease (MRD)-negative complete response as determined by flow cytometry with undetectable post-treatment malignant IGH clones. Conversely, researchers reported median PFS of 8.5 months (95% CI, 2.9-not reached) for 11 patients with an MRD-negative complete response by flow cytometry but detectable malignant IGH clones after therapy.
Of the 47 patients treated in the study, 68% had achieved a bone marrow flow cytometry MRD-negative response to CAR T-cell therapy.
Hirayama and colleagues also performed single-cell multiomics analysis of CAR-T infusion products.
Fred Hutch manufactured the CAR-T used in the study using a point-of-care process. The CAR-T construct is identical to that used in the FDA-approved therapy lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) developed by scientists at Fred Hutch and licensed for commercial development.
“Our group wanted to look at the characteristics of infusion CAR T cells and correlate these with patient outcomes,” Hirayama said. “We already have plenty of data suggesting that CAR T-cell quality and expansion are associated with outcomes, so we are continuing that process of trying to understand how the intrinsic characteristics of these products are associated with responses among patients treated.”
Researchers completed multiomic profiling for 25 patients (median age 61 years; range 55-67; 80% male), all of whom underwent lymphodepletion followed by a single infusion of 2 × 106 CAR T cells/kg. The heavily pretreated group received a median five (range, 4-7) previous therapies and 96% had high-risk cytogenetics. Fifty-six percent of patients achieved a flow cytometry MRD-negative complete response to therapy.
“There were some signatures — especially related to the quality of CAR T cells —associated with deeper remissions,” Hirayama said.
The multiomic analysis so far suggests that CAR T cells within the infusion products of patients who achieved an MRD-negative complete response to therapy have lower interferon-signaling genes, Hirayama said.
Patients with high-risk CLL typically have a poor prognosis and outcome, and no commercially available CAR T-cell therapies exist for these patients despite multiple ongoing clinical trials, Hirayama said.
“This is a patient population with unmet medical needs,” Hirayama told Healio. “We are waiting for a commercial CAR T-cell option for patients with CLL, especially for those who have high-risk features.”
Collapse
Hirayama AV, et al. Abstract 1749. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021.
Click Here to Manage Email Alerts