Inotuzumab Ozogamicin–Based Bridging Therapy Boosts Obe-Cel Outcomes in B-Cell ALL

Inotuzumab Ozogamicin in Obe-Cel Recipients

With B-ALL | Image credit: © Nittaya

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Bridging therapy, when paired with inotuzumab ozogamicin (Besponsa), demonstrated prolonged event-free survival (EFS) and overall survival (OS) in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) who received obecabtagene autoleucel (obe-cel; Aucatzyl) as part of the phase 1/2 FELIX trial (NCT04404660), according to data presented at the 51st Annual EBMT Meeting.1

At a median follow-up of 21.5 months (range, 8.6-41.4), the bone marrow blast percentage was 81.5% at screening and 2.0% at lymphodepletion in the inotuzumab arm (n = 18). In the patient cohort that did not receive inotuzumab (n = 100), the bone marrow blast percentage rates were 40.0% and 52.0% at screening and lymphodepletion, respectively. In the population of patients who did not receive any bridging therapy (n = 9), the respective rates were 20.0% and 30.0%.

“Bridging with inotuzumab ozogamicin was employed in patients with the highest disease burden and had the greatest reduction in pre-lymphodepletion bone marrow blast percentage,” coauthor Deborah Yallop, MBBS, of King’s College Hospital in London, United Kingdom, said during a presentation of the data.

The objective response rates in the inotuzumab, no inotuzumab, and no bridging therapy groups were 83.3% (95% CI, 58.6%-96.4%), 75.0% (95% CI, 65.3%-83.1%), and 100% (95% CI, 66.4%-100%), respectively. The complete response (CR) rates were 38.9%, 58.0%, and 88.9%, respectively. The CR with incomplete hematologic recovery rates were 44.4%, 17.0%, and 11.1%, respectively.

The median duration of response was 21.2 months (95% CI, 5.1-not evaluable [NE]) in the inotuzumab arm, 14.2 months (95% CI, 8.2-NE) in the arm that didn’t receive inotuzumab, and NE in the arm that received no bridging therapy.

“Longer EFS and OS was observed in patients who received bridging therapy with inotuzumab compared with those who received bridging therapy without inotuzumab,” Yallop stated.

The median EFS was 22.1 months (95% CI, 4.1-NE), 9.0 months (95% CI, 6.0-15.0), and NE in the inotuzumab, no inotuzumab, and no bridging therapy arms, respectively. The median OS was 23.8 months (95% CI, 4.8-NE), 14.1 months (95% CI, 11.5-NE), and NE, respectively.

Taking a Deeper Dive Into the Present Analysis

Bridging therapy is often employed prior to CAR T-cell therapy to manage and reduce disease burden in patients with hematologic malignancies. However, the effects of bridging therapy on CAR T-cell efficacy have not been fully elucidated.

Obe-cel is an autologous CAR T-cell therapy designed with a fast off-rate CD19 binder meant to enhance immunotoxicity and persistence. In 2024, obe-cel received approval from the FDA for the treatment of patients with relapsed or refractory B-cell precursor ALL based on earlier findings from FELIX.2 The study enrolled patients with relapsed or refractory CD19-positive B-cell ALL. Enrolled patients were required to have relapsed following a remission lasting 12 months or less, relapsed or refractory ALL following two or more prior lines of systemic therapy, or disease that was relapsed or refractory 3 or more months after allogeneic stem cell transplantation (ASCT).

To better understand the effects of bridging therapy on obe-cel’s activity, investigators conducted the present analysis.1 Per the study’s design, patients underwent leukapheresis upon enrollment and optional bridging therapy within 7 days prior to initiating lymphodepletion, which consisted of 4 x 30 mg/m2 of fludarabine plus 2 x 500 mg/m2 of cyclophosphamide. Tumor burden–guided dosing was administered on days 1 and 10, after which patients entered a period of safety and efficacy follow-up.

Bridging therapy was administered according to physician’s choice and was given with inotuzumab ozogamicin with or without chemotherapy; or without inotuzumab ozogamicin, with chemotherapy, a TKI, chemotherapy with a TKI, steroids, or rituximab (Rituxan). No bridging therapy was also an option.

The median number of doses of inotuzumab was 1 in the bridging therapy group. Within the population of patients who received inotuzumab (n = 18), bridging therapy consisted of chemotherapy with inotuzumab (n = 9) and inotuzumab alone (n = 9). The median duration of treatment exposure was 14.5 days (range, 1-40). In the population of patients who didn’t receive inotuzumab (n = 100), bridging therapy consisted of chemotherapy (n = 80), or chemotherapy plus a TKI (n = 10). Other regimens included a TKI alone (n = 7), steroids (n = 2), and other (n = 1). The median duration of treatment exposure was 12.0 days (range, 1-151).

Additional notable baseline characteristics indicated that Philadelphia chromosome–positive patients represented 27.8%, 27.0%, and 44.4% of those in the inotuzumab, no inotuzumab, and no bridging therapy arms, respectively. Most patients were refractory to their last prior line of therapy in the bridging therapy cohorts, at 61.1% and 52.0% with and without inotuzumab, respectively; only 33.3% of patients who didn’t receive bridging therapy were refractory to their last line of therapy. Prior inotuzumab was administered in 27.8%, 34.0%, and 11.1% of cases across the three respective arms. Prior ASCT was performed on 55.6%, 39.0%, and 77.8% of patients who received inotuzumab, did not receive inotuzumab, or received no bridging therapy at all, respectively.

Examining Additional Findings

“CAR T-cell expansion was high in all groups, including [the group of patients who received] bridging therapy with inotuzumab despite the substantial reduction in disease burden in this group at lymphodepletion,” Yallop said. In total, across the three groups, the Cmax geographic mean was 110,896 copies/μg DNA (coefficient of variation [CV], 253.8%). The geographic mean for area under the curve (AUC)0-28 days was 1,105,176 days x copies/μg DNA (CV, 211.8%). The median Tmax was 14 days (range, 2-55).

“Compared with the bridging therapy with inotuzumab group, both the bridging therapy without inotuzumab and no bridging therapy groups had notably higher post-infusion Cmax and AUC0-28 values, potentially due to higher disease burden at lymphodepletion,” Yallop explained.

Safety Spotlight

With respect to safety, Yallop noted a higher rate of grade 3 or greater cytokine release syndrome in the inotuzumab group, at 5.6% vs 2.0% in the group without inotuzumab and 0% in the population that didn’t receive any bridging therapy. The respective rates of grade 3 or greater immune effector cell–associated neurotoxicity syndrome were 11.1%, 7.0%, and 0%. Grade 3 or greater hepatobiliary disorders occurred in 5.6%, 6.0%, and 11.1% of patients who received inotuzumab, no inotuzumab, and no bridging therapy, respectively.

“High expansion and long-term persistence of obe-cel was observed in all the bridging therapy groups evaluated, with excellent outcomes,” Yallop concluded.

Disclosures: Yallop has acted in a consulting or advisory role for Amgen, Autolus Therapeutics, Clinigen, Gilead Sciences, Pfizer, and Servier.

References

1. Park JH, Tholouli E, Sandhu KS, et al. Obecabtagene autoleucel (obe-cel) for relapsed/refractory adult B-cell acute lymphoblastic leukemia (R/R B-ALL): the impact of inotuzumab-containing bridging therapy on treatment outcomes. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025. Florence, Italy. Abstract OS8-02.
2. FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed April 1, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute#:~:text=On%20November%208%2C%202024%2C%20the,acute%20lymphoblastic%20leukemia%20(ALL)