The following article features coverage from the American Society of Hematology 2021 meeting. Click here to read more of Hematology Advisor‘s conference coverage.

A starting dose of 1.2 mg/m2/cycle of the antibody-drug conjugate inotuzumab ozogamicin (InO) demonstrated acceptable efficacy and no new safety signals in an ongoing phase 4 study in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL), according to the results of an interim analysis presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“In previous studies, InO showed good efficacy. However, patients receiving InO had an increased risk of [hepatic] sinusoidal obstruction syndrome, or SOS, following hematopoietic stem cell transplantation,” said Muhit Özcan, MD, of Ankara University Cebeci Hospital in Ankara, Turkey, who presented the findings.

InO is approved in the US and the European Union for R/R ALL. The approved starting dose is 1.8 mg/m2/cycle (in 3 divided doses). The investigators of the phase 4 study ( Identifier: NCT03677596), which is a post-marketing requirement of the US Food and Drug Administration, are evaluating whether a lower dose of InO (1.2 mg/m2/cycle) will improve safety, reducing the likelihood of post-hematopoietic stem cell transplantation (HCT) SOS, relative to the approved dose, and impact efficacy in adults with R/R ALL who are eligible for HCT and have a higher risk of post-HCT SOS.

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The study will include a total of approximately 102 patients with R/R ALL who are eligible for HCT and who have a higher risk of post-HCT SOS. The first phase of the study, the run-in phase, included 22 patients divided among 2 stages (stage 1, n=7; stage 2, n=15). All patients received a starting dose of 1.2 mg/m2/cycle, and the interim analysis reported the efficacy and safety of InO at this dose level (data cut-off date, July 29, 2021).

“If InO shows sufficient efficacy in the run-in phase, the study will proceed to the randomized phase, where [approximately] 80 patients will be randomized to receive InO either at this low dose or at the currently approved dose,” explained Dr Özcan.

To proceed to the randomized phase, ≥3 of 7 patients in stage 1, and ≥10 of 22 patient by the end of stage 2, must achieve complete remission (CR)/CR with incomplete hematologic recovery (CRi), with ≥7 of 22 patients achieving minimal residual disease (MRD) negativity. Study outcomes are overall survival, disease status, subsequent treatments and adverse events (AEs) for ≥2 years after randomization.

Overall, 22 patients (median age, 46 years; range, 21-67) received InO at a starting dose of 1.2 mg/m2/cycle. The cohort was 54.5% male and 77.3% White. Patients received a median of 2 (range, 1-6) treatment cycles over a median duration of 6 weeks (range, 0.1-22.7). Baseline risk factors for post-HCT SOS included previous HCT (31.8%), salvage ≥2 (68.2%), age ≥55 (22.7%), and prior or ongoing hepatic disease (27.3%).

In stage 1 of the run-in phase, 3 of 7 patients achieved CR/CRi (CR, n=2; CRi, n=1). By the end of stage 2, 11 of 22 patients achieved CR/CRi (CR, n=5; CRi, n=6), with 8 of 22 (72.7%) of CR/CRi patients achieving MRD negativity. The median duration of remission was 4.5 months (95% confidence interval, 1.9-not reached). Overall, 10 of 22 (45.5%) patients proceeded to HCT.

Overall, 3 patients died during treatment; causes of death were disease progression

(n=2) and an AE not related to the study treatment (n=1). After treatment, 13 died, 8 after disease progression and 5 after treatment discontinuation without disease progression; causes of death were disease progression (n=5), AEs not related to study treatment (n=6), hepatic SOS (n=1), and kidney complications (n=1).

Treatment was discontinued by half of patients (11/22). Reasons for discontinuation were death (n=3), progressive disease (n=6), relapse (n=1), and participant withdrawal (n=1). Treatment-emergent AEs (TEAEs, any grade) occurred in 90.9% of patients, and treatment-related AEs occurred in 59.1% of patients. The most common grade ≥3 TEAEs included hematologic disorders (31.8%) and infections (36.4%).

Of patients who proceeded to HCT, 20% (2/7) had post-HCT SOS (grade 5, n=1; grade 2, n=1). Grade 5 AEs occurred in 8 additional patients; causes of death were disease progression (n=3), and infections (n=5). AEs led to discontinuation in 2 patients (n=1 each; tumor lysis syndrome and fungal infection) and dose interruption in 3 patients (n=1 each; catheter-related infection, pyrexia, and megaloblastic anemia). No dose reductions were made due to AEs.

“In conclusion, InO showed good efficacy at a starting dose of 1.2 mg/m2/cycle. Half of patients achieving remission, and more than 70% of those in remission achieved MRD negativity,” said Dr Özcan.

As of October 2021, 80 patients have been randomized in the next phase of the trial.

Disclosure: This research was supported by Pfizer. Please see the original reference for a full list of disclosures.

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Özcan M, Cassaday R, Singh P, et al. The efficacy and safety of low-dose inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia: interim results of a phase 4 study. Presented at ASH 2021; December 11-14, 2021. Abstract 1208.