Inotuzumab Ozogamicin Administration in First Remission Results in Profound and Safe Minimal Residual Disease Eradication in Adult Patients with Ph-Negative Acute Lymphoblastic Leukemia: Findings from a Phase 2, Single-Arm Trial

Background: Effective eradication of minimal residual disease (MRD) is crucial in maintaining clinical response among patients with B-cell acute lymphoblastic leukemia (B-cell ALL). This study aims to investigate the effectiveness of early administration of Inotuzumab Ozogamicin (InO) in achieving minimal residual disease (MRD) clearance in first remission and to assess the change in MRD levels from baseline to InO administration.

Methods: This trial focuses on Ph-negative B-cell lymphoblastic leukemia patients in first remission (CR1) who did not achieve MRD negativity or experienced MRD-positive relapse (≥0.01% by flow cytometry) after initial therapy. Patients received InO at 1.5 mg/m² per cycle (28 days), administered as 0.5 mg/m² on days 1, 8, and 15. Treatment was continued for up to 2 cycles unless there was disease progression or unacceptable toxicity. The primary outcome was MRD negativity within the first cycle, defined as no detectable leukemic cells assessed by flow cytometry.

Results: Between May 2023 and July 2024, 17 patients participated in the trial, and all of them were included in the evaluation for efficacy and safety. Their median age was 36 years (range: 17-69 years). 16 patients had persistent MRD, while 1 experienced MRD recurrence. Among them, 3 patients were classified as Ph-like disease, 6 had ZNF384 fusion, 4 had IKZF1 alteration, and 1 had TP53 mutation. Except for 1 patient who experienced MRD recurrence, the remaining 16 patients received 1-2 cycles of chemotherapy before the initiation of InO.

After one cycle of InO, 82.3% (14/17) of patients achieved MRD negativity as assessed by flow cytometry. All patients with detectable fusion genes (7/7) also achieved molecular MRD-negative remission confirmed by PCR testing. Among the 3 patients who remained MRD-positive after the first cycle of InO, one patient received only 1 dose of InO, achieving flow-MRD levels below 0.01%. She voluntarily withdrew from this trial to undergo HSCT. Two underwent a second cycle of InO treatment (3 doses) and had undetectable MRD levels. The overall MRD clearance rate for all patients is 94.1% (16/17) , and for those who completed InO treatment according to the trial design (n=16; 14 patients received 1 cycle, 2 patients finished 2 cycles) reached 100%.

As of the cutoff date in July 2024, 15 patients remained in remission, while 2 experienced relapses. One patient received only one round of chemotherapy after achieving MRD clearance due to chemotherapy intolerance, and subsequently relapsed five months after exiting the trial. The other patient who initially experienced an MRD-positive relapse, despite achieving MRD negativity after the first cycle of InO treatment, later experienced a morphological relapse. Following an additional cycle of InO treatment, this patient has remained in persistent remission.

In terms of toxicity, no patients experienced grade 3 or higher non-hematologic adverse events. Liver function abnormalities were noted in 5 of 17 patients (3 grade 1, 2 grade 2). Thrombocytopenia and neutropenia were the most common hematologic adverse reactions as expected, each occurring in 7 patients, with 3 experiencing grade 3 neutropenia. It is noteworthy that no cases of veno-occlusive disease (VOD) or deaths was observed in any patients, despite 8 cases undergoing bridged allo-transplantation after InO treatment.

Conclusion: The early administration of InO in CR1, even with a single course, can effectively eradicate MRD to a deep level. Moreover, early use of InO exhibits a favorable safety profile and did not significantly increase the risk of post-transplant VOD occurrence, making it a safe and effective treatment option for patients with B-ALL.