Inati-Cel Induces High CR and MRD Negativity Rates in CD19+ R/R B-ALL

Acute Lymphoblastic Leukemia
| Image Credit: © Nittaya
– stock.adobe.com

Treatment with inaticabtagene autoleucel (inati-cel), a CD19-directed CAR T-cell therapy, yielded a high complete remission (CR) and measurable residual disease (MRD)–negativity rates in adult patients with CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), according to results from a phase 2 trial (NCT04684147) conducted in China.

Findings published in Blood showed that response-evaluable patients who received inati-cel (n = 48) achieved a 3-month overall response rate (ORR) of 70.8% (95% CI, 55.9%-83.1%; P < .0001 vs historical control rate of 25%). The 3-month CR and CR with incomplete hematologic recovery (CRi) rates were 60.4% and 10.4%, respectively.

The best ORR was 85.4% (95% CI, 72.2%-93.3%), which included a CR rate of 72.9% and a CRi rate of 12.5%. Notably, all 41 any-time responders achieved MRD negativity by flow cytometry; at 3 months, the MRD-negativity rate among responders was 94.1% (95% CI, 80.3%-99.3%).

“The findings from this phase 2 study support the potential of inati-cel as a promising therapeutic option for adult patients with relapsed/refractory B-ALL, demonstrating high rates of 85.4% MRD-negative [best] ORR and durable responses with manageable safety profiles,” lead study author Ying Wang, MD, of the Chinese Academy of Medical Sciences and Peking Union Medical College in Tianjin, China, and colleagues wrote in the publication.

Phase 2 Trial Design

This single-arm, open-label, multicenter trial enrolled patients across 10 centers in China and assessed the safety, efficacy, and pharmacokinetic profile of inati-cel in patients 18 to 65 years of age with relapsed/refractory B-ALL with a morphological bone marrow blast level of at least 5%. Inclusion criteria encompassed patients with primary refractory disease; those with early relapse with first remission lasting less than 12 months; patients with relapse following at least 2 prior lines of systemic therapy; or those with relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with active infections, active central nervous system involvement, or prior exposure to CAR T-cell therapy were excluded.

Of 92 patients screened, 67 underwent leukapheresis for T-cell collection, and inati-cel was successfully manufactured for 66 patients. Following leukapheresis, 12 patients did not receive the CAR T-cell therapy due to active infection (n = 8), disease progression (n = 3), withdrawal (n = 3), ineligibility (n = 1), and physician decision (n = 4).

During manufacturing, patients were allowed to receive bridging therapy. Lymphodepletion consisted of 500 mg/m2 of cyclophosphamide per day on days 5 and 4 plus 30 mg/m2 of fludarabine on days 5 to 2. Inati-cel was administered as a single infusion at a target dose of 0.4 x 106 to 0.6 x 106 CAR-positive T cells.

The primary end point was 3-month ORR. Secondary end points included best ORR, MRD-negativity rate, duration of remission (DOR), relapse-free survival (RFS), overall survival (OS), safety, and pharmacokinetics.

Patients who underwent allo-HSCT in remission were censored at transplant for DOR and OS analyses. Supplementary analyses also evaluated treatment durability in patients receiving subsequent therapies.

Baseline Patient Characteristics

The median age among treated patients was 32 years (range, 18-58), and the majority were male (54.2%). Patients had an ECOG performance status of 0 (41.7%) or 1 (58.3%).

At screening, 9 patients (18.8%) were in early relapse following first remission lasting less than 12 months, and 39 (81.2%) had refractory disease. Primary refractory disease was observed in 12 patients (25.0%), and 8 patients (16.7%) had relapsed or refractory disease following prior allo-HSCT.

The median number of prior therapy lines was 2 (range, 1-4). A total of 13 patients (27.1%) received 1 prior line of therapy, 22 patients (45.8%) received 2 lines, 7 patients (14.6%) received 3 lines, and 6 patients (12.5%) had received 4 or more prior lines.

Bone marrow analysis showed a mean blast percentage of 53.8% (SD, 29.3%) and a median of 62.5%. At the time of screening, 11 patients (22.9%) had blasts between 5% and less than 25%, 8 patients (16.7%) between 25% and less than 50%, 10 patients (20.8%) between 50% and greater 75%, and 19 patients (39.6%) had at least 75% blasts. Extramedullary disease was reported in 2 patients (4.2%).

All patients had CD19-positive disease at enrollment. Cytogenetic alterations included IKZF1 deletions in 11 patients (22.9%), Philadelphia chromosome (Ph) positivity in 10 patients (20.8%), and MLL rearrangements in 7 patients (14.6%). Additionally, TP53 gene deletions or mutations were identified in 4 patients (8.3%), and E2A-PBX1 fusions and Ph-like signatures were each observed in 2 patients (4.2%).

Efficacy and Safety Deep Dive

Additional exploratory analyses showed that the response benefit was observed across baseline risk factors, including primary refractory disease, prior transplant, and high-risk cytogenetic profiles such as KMT2A rearrangements and IKZF1 deletion. Among 9 patients with Ph-positive disease, 8 achieved CR/CRi after inati-cel infusion.

Twelve patients (29.3%) underwent consolidative allo-HSCT while in remission.

At a median follow-up of 23.7 months (interquartile range, 6.2-23.7), the median DOR was 20.7 months (with censoring for allo-HSCT, 95% CI, 6.4-not reached [NR]; without censoring, 95% CI, 9.5-NR).

The median RFS was 12.4 months (95% CI, 5.2-NR), and the estimated 12- and 24-month RFS rates were 54.5% and 35.8%, respectively. The median OS was NR (95% CI, 13.0-NR), and the OS rates at 12 and 24 months were 72.1% and 55.2%, respectively.

The safety profile of inati-cel was consistent with expected toxicities from CD19-directed CAR T-cell therapies. Cytokine release syndrome (CRS) occurred in 87.5% of patients (n = 48), with 12.5% experiencing grade 3 or higher CRS; no grade 5 CRS was reported. The median CRS onset was 4.5 days range, 1-10), and the median duration was 9 days (range, 3-34). Immune effector cell–associated neurotoxicity syndrome of any grade was reported in 8.3% of patients, 6.3% who had grade 3 or higher ICANS.

Hemophagocytic lymphohistiocytosis macrophage activation syndrome (HLH/MAS) occurred in 6.3% of patients, with all instances associated with preceding CRS. Infections were reported in 68.8% of patients, including 2 grade 5 infections (4.2%).

The most frequent grade 3 or higher hematologic adverse effects included neutropenia (95.8%), leukopenia (95.8%), anemia (79.2%), and thrombocytopenia (77.1%).

Reference

Wang Y, Lv L, Song Y, et al. Inaticabtagene autoleucel in adult relapsed or refractory B-cell acute lymphoblastic leukemia. Blood. 2025;9(4):836-843. doi:10.1182/bloodadvances.2024014182