Inotuzumab ozogamicin combined with chemotherapy in pediatric B-cell precursor CD22+ acute lymphoblastic leukemia: results of the phase IB ITCC-059 trial

Abstract

Inotuzumab ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin. The phase IB of the ITCC-059 trial tested InO combined with chemotherapy in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Relapsed /refractory CD22+ BCP-ALL pediatric patients were enrolled. The primary objective was to establish the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy and tolerability. InO was combined with 1.5 mg/m2 of vincristine (days 3, 10, 17, 24), 20 mg/m2 of dexamethasone (2 5-day blocks, then amended), and intrathecal therapy. A rolling-6 design was used testing InO from 0.8 to 1.8 mg/m2/cycle. Between May 2020 and April 2022, 30 patients were treated, and 29 were evaluable for dose limiting toxicities (DLT). At 1.1 mg/m2/cycle, two of four patients had DLT (liver toxicity). InO was de-escalated to 0.8 mg/m2/cycle (N=6) without DLT while awaiting a protocol amendment to reduce dexamethasone dose to 10 mg/m2. Post amendment, InO was re-escalated to 1.1 mg/m2/cycle (N=6, 1 DLT), then to 1.4 mg/m2/ cycle (N=3, no DLT), and finally to 1.8 mg/m2/cycle (N=7, 1 DLT). Three additional patients were treated in an expansion cohort. The pooled response rate was 80% (24/30; 95% confidence interval [CI]: 61.4-92.3) and, among responders, 66.7% achieved minimal residual disease negativity. The RP2D of InO combined with vincristine, dexamethasone and intrathecal therapy was declared at 1.8 mg/m2/cycle (1.5 mg/m2/cycle after remission) in a fractioned schedule. This combination showed a response rate similar to the single agent cohorts of this trial, with liver toxicity issues at the initial higher dexamethasone dose (clinicaltrials gov. Identifier: NTR5736).

Figure 1.

Proportions of non-responders, responders and minimal residual disease negativity. Responders are defined as those with <5% of bone marrow blasts regardless the recovery of the neutrophil count and platelets. Minimal residual disease (MRD) negativity is defined as <10^-4. CR: complete remission; SD/PD: stable disease/progressive disease.

Figure 2.

Swimmer plot of patients’ treatment and response. Each bar starts at day 1 of cycle 1. Yellow shaded areas represent the study treatment period. Green shaded areas represent the duration of response. Inotuzumab ozogamicin (InO) dose levels (DL): DL-1: 1.1 mg/m/cycle; DL-2: 0.8 mg/m/cycle; DL2: 1.8 mg/m/cycle; DL-1_amd: 1.1 mg/m/cycle (reduced dexamethasone); DL1_amd: 1.8 mg/m/cycle (reduced dexamethasone); DL2_amd: 1.8 mg/m/cycle (reduced dexamethasone); 16 patients received only 1 cycle (combination), 10 patients 1 combination cycle + 1 single agent cycle, 3 patients 2 combination cycles, 1 patient received 3 cycles (1 combination cycle + 2 single agent cycles). CR: complete remission; CCR: continuous complete remission achieved on InO therapy; PD: progressive disease/relapse; CAR T: chimeric antigen receptor T-cell therapy; HSCT: hematopoietic stem cell transplantation; SOS: sinusoidal obstruction syndrome; NA: not applicable; FU: follow-up.

Figure 3.

Overall survival and event-free survival. Probabilities were estimated using the Kaplan-Meier method. Events were defined as non-response (not achieving complete remission [CR], CR with insufficient platelet recovery [CRi] or CR without recovery of counts [CRp], considered as event at day 0), relapse after remission achieved as a result of inotuzumab ozogamicin (InO) treatment, death from any cause, or secondary malignancies. Crosses represent censored subjects. Shaded areas represent the 95% confidence interval. OS: overall survival; EFS: event-free survival.

Figure 4.

Cumulative incidence of relapses and non-relapse death. Probabilities were estimated using the Kaplan-Meier method. Patients not achieving remission were counted as event at time zero for the cumulative incidence of relapse (blue line). Patients dying while in remission achieved as a result of inotuzumab ozogamicin (InO) treatment were counted as event in the non-relapse death curve (red line).