Off-the-Shelf CAR T Shows 58.3% MRD Clearance in Pretreated LBCL Group

Patients treated with the investigational allogeneic anti-CD19 CAR T-cell therapy cemacabtagene ansegedleucel (cema-cel) for large B-cell lymphoma (LBCL) who tested positive for molecular residual disease (MRD) following first-line therapy experienced reductions in plasma ctDNA levels and MRD clearance, according to a news release from the developer, Natera.¹

Specifically, according to findings from an interim analysis of the phase 2 ALPHA3 trial (NCT06500273), 58.3% of patients treated with the “off-the-shelf” CAR T-cell therapy achieved MRD clearance. Additionally, compared with a 26.6% median increase in plasma ctDNA levels among patients who underwent observance at the day 45 MRD assessment, those treated with cema-cel experienced a 97.7% decrease in plasma ctDNA by the time of the analysis.

According to the developers, these findings provide early evidence of cema-cel’s potential to prevent or delay clinical relapse among this MRD-positive LBCL patient population. The study was designed to assess whether the allogenic CAR T product can eliminate residual disease and prevent recurrence.

"MRD status following frontline therapy has emerged as one of the strongest predictors of relapse in LBCL, and the ALPHA3 study and cema-cel could be transformative for patients with lymphoma," David Kurtz, MD, PhD, senior vice president and chief scientific officer of the Hematology Franchise at Natera, stated in the news release.¹ "Pairing our ultra-sensitive phased variant MRD technology with cema-cel, pending the outcome of the ALPHA3 study, creates an actionable solution for patients who test positive for MRD at the end of [frontline] treatment."

Patients 18 years and older in the phase 2 trial across sites in the US and Canade were randomly assigned 1:1 to receive cema-cel following a chemotherapy doublet containing fludarabine and cyclophosphamide for lymphodepletion or observation alone, per standard of care.² MRD testing was performed with the Foresight CLARITY™ IUO MRD test, which is used to identify presence of MRD following first-line LBCL treatment.

Moreover, the developers highlighted prior research by Rochewski, et al, in the Journal of Clinical Oncology highlighting a prognostic advantage with ultrasensitive ctDNA detection vs conventional radiographic response criteria, suggesting a refined definition of remission could improve clinical outcomes for patients with LBCL.³ Specifically, this study found that MRD status by the end of frontline anthracycline-based chemotherapy treatment had an HR of 28.3 vs 3.6 with a positive PET scan.

The primary end point of the study was event-free survival (EFS) per independent review committee (IRC) assessment. Secondary end points included progression-free survival per IRC assessment, overall survival, adverse effects and laboratory toxicities, as well as MRD clearance.

Eligibility criteria for enrollment on the trial included confirmed diagnosis of LBCL per WHO 2017 criteria, and completion of full-course frontline standard therapy, including rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (R-CHOP), rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH-R), or polatuzumab vedotin-piiq (Polivy), rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP). Additionally, eligibility requirements included an observable response at the end of frontline therapy per PET/CT evaluation; a positive MRD test; an ECOG performance status of 0 to 1; and adequate hematologic, renal, hepatic, pulmonary, and cardiac function.

Those ineligible for enrollment included those with central nervous system-involved, transformed, or T-cell/histiocyte rich disease; prior receipt of anti-CD19 targeted therapies; or any anticancer treatment following frontline treatment. Additionally, patients with active or clinically significant autoimmune disease, any active infections requiring systemic treatment, or a history of primary malignancy or bone marrow disorder within 3 years of enrollment were deemed ineligible for trial participation.

References

1. Natera highlights positive interim futility analysis from Allogene Therapeutics’ MRD-guided ALPHA3 trial in large B-cell lymphoma. News release. Natera, Inc. April 13, 2026. Accessed April 13, 2026. https://tinyurl.com/4r3dj4j3
2. Roschewski M, Kurtz DM, Westin JR, et al. Remission assessment by circulating tumor DNA in large B-cell lymphoma. J Clin Oncol. 2025;43(34):3652-3661. doi:10.1200/JCO-25-01534
3. Consolidation of first-line MRD+ remission with cema-cel in patients with LBCL (ALPHA3). ClinicalTrials.gov. Updated March 13, 2026. Accessed April 13, 2026. https://tinyurl.com/5n7dwam6