Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial

Abstract

Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1-18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m². Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9-93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49-20.07). One year Event Free Survival was 36.7% (95% CI: 22.2-60.4%), and Overall Survival was 55.1% (95% CI: 39.1-77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT.

Fig. 1. Event Free Survival and Overall Survival of patients treated in phase II.

Blue line: Event Free Survival (EFS); Yellow Line: Overall Survival (OS). CI Confidence Interval.

Fig. 2. Dose-response curves for calicheamicin based on MTT assays.

Each color represents a different patient. The intersection with the black line at 50% represents the IC50 value. IC50: concentration of drug required for 50% inhibition; MRD neg: minimal residual disease <10⁻⁴; CR: complete response; poor responders: no CR and/or MRD ≥ 10⁻⁴. The median IC50 value for all patients was 0.75 ng/ml (range 0.035–27.27; n = 10), median 0.26 ng/ml (range 0.035–1.05; n = 5) in the good responders (left panel) and median 3.12 ng/ml (range 0.34–27.27; n = 5) in the poor responders (right panel) (p = 0.032). From the literature, the median calicheamicin sensitivity in AML cells was 4.8 ng/ml, ranging between 0.1–1000 ng/ml (de Vries JF, et al.; 2012).

Fig. 3. CD22 expression on BM blasts at baseline, saturation and InO internalization on leukemic PB blasts post infusion on day one.

Presented as Mean Fluorescence Intensity (MFI) (A), percentage CD22-positive cells (B), saturation (C) and internalization (D). Grey horizontal lines represent the median value per group. In all four parameters, there were no statistically significant differences between the response groups as defined in the statistical methods for the PD analysis. Triangles represent patients with PCR-MRD quantitative range >10⁻⁴.