Introduction

Inotuzumab ozogamicin (Ino) is an anti-CD22 immuno-conjugated monoclonal antibody, which has improved the clinical outcome of relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). The use of Ino in the clinical practice is well consolidated, while data on retreatment in patients previously exposed to the drug are very limited (Alban J, et al; JCO Precis Oncol. 2022).

Methods

Within the framework of the Campus ALL network in Italy, we retrospectively analyzed the clinical outcomes of a population of adult patients with R/R ALL who underwent retreatment with Ino. The studied population must have previously received treatment with Ino, intended as the first exposure to the drug, either for hematologic relapse of ALL or for minimal residual disease (MRD) positivity, and a second exposure, Ino retreatment, in a subsequent line of therapy. We included patients receiving Ino either as a single agent or in combination with other treatments (radiotherapy, chemotherapy, tyrosine kinase inhibitors, etc.), regardless of the dosage. This criterion applied to both first treatment and retreatment with Ino. Patients could have received a retreatment with Ino to bridge to another therapy, such as allogeneic transplant (alloHSCT), CAR-T, or no further therapy. The outcomes included in the analysis were the complete remission rate (CR and CR with incomplete hematological recovery, CRi), incidence of hematologic and extra-hematologic toxicity (graded according to CTCAE V. 5.0), cumulative incidence of relapse (CIR), progression-free survival (PFS), and overall survival (OS).

Results

We included 26 patients for this analysis, of which 20 had Philadelphia-negative (Ph-) ALL and 6 Philadelphia-positive (Ph+) ALL. The median age of the study population was 39 years (range 16-66), and the median follow-up was 5 months (range 0.3-26). According to the GIMEMA LAL1913 baseline risk stratification (Bassan R. et al, Blood Advances 2023), 11/20 Ph- ALL patients had a high risk or a very high-risk profile, including 6 Ph-like ALL cases. Regarding the first Ino exposure, 24 of 26 patients received Ino for hematologic relapse, and the remaining 2 for MRD positivity. Among the 24 patients receiving Ino for R/R disease, a CR/CRi rate of 79% was observed. Both patients receiving Ino for MRD positivity had a logarithmic reduction of MRD levels. At the time of retreatment with Ino, the median number of previous lines of treatment was 3 (range 2-7). Concerning disease characteristics at retreatment, 15 patients (58%) had more than 50% of blasts and 7 (27%) had extramedullary disease (EMD). The median number of Ino cycles was 1 (range 1-4), with 6 cases of dose reduction primarily due to medical decisions. The CR rate was 61.5%, with 31% of patients achieving a MRD negativity, similar to what observed during their first exposure to the drug. Factors, such as high burden disease, EMD, or the number of previous lines of therapy (> or < 3) did not significantly affect the CR rate. All patients achieving a CR/CRi were successfully bridged to the planned subsequent treatment, either alloHSCT or CAR-T cell therapy. Of these patients 28.5% subsequently relapsed. After a median follow-up of 5 months, the 1-year OS and PFS for responders vs non-responders to retreatment were 51% (95%CI, 29%-91%) vs 11% (95%CI, 2%-70%, p 0.0015) and 42% (95%CI, 22%-79%) vs 0% (p <0.001), respectively. Among the 10 patients who responded to retreatment with Ino followed by CAR-T cell therapy, the 1-year OS and PFS were 71% (95%CI 45%-100%) and 56% (95%CI, 31%-100%), respectively. Among the responders who underwent consolidation with alloHSCT, which was a second transplantation in 4 out of 5 patients, the OS and PFS were 40% (95%CI 45%-100%) and 20% (95%CI, 31%-100%), respectively. In terms of grade 2-4 toxicities, we observed 15% of self-limiting transaminitis (no cases of veno-occlusive disease), 23% of infectious complications (including 1 fatal event), and 46% of hematologic toxicities. Notably, the incidence of these toxicities was not significantly higher than those reported during the first Ino exposure.

Conclusions

This study indicates that retreatment with Ino is a valuable option associated with a high CR rate and acceptable safety, even in heavily pretreated relapsed patients. Notably, the clinical outcomes for patients who responded to Ino retreatment and were subsequently bridged to CAR-T therapy were particularly encouraging.

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2025
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