A Phase 2 Trial of Inotuzumab Ozogamicin (InO) in Children and Young Adults with Relapsed or Refractory (R/R) CD22+ B-Acute Lymphoblastic Leukemia (B-ALL): Results from Children's Oncology Group Protocol AALL1621
Authors: O'Brien Maureen M , Ji Lingyun , Shah Nirali N. , Rheingold Susan R. , Bhojwani Deepa , Yi Joanna S. , Yuan Constance M. , Harris Andrew C , Brown Patrick A. , Borowitz Michael J. , Militano Olga , Devidas Meenakshi , Raetz Elizabeth A. , Gore Lia , Loh Mignon L. 
Published: February 2020

Background: Approximately 10-20% of children and young adults with B-cell acute lymphoblastic leukemia (B-ALL) will relapse. Therapies that can bridge patients (pts) to hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor (CAR)-T cell therapy are critical to improving outcomes. Inotuzumab ozogamicin (InO) is a CD22-targeted antibody-drug conjugate linked to calicheamicin that is FDA-approved for adults with R/R refractory B-ALL. Prospective data on the efficacy and safety of InO in pediatric pts is lacking.
Methods: This single arm phase 2 trial enrolled pts age 1-21 years with CD22-positive B-ALL in &gt;2nd relapse, refractory to 2 prior induction regimens, any relapse after HSCT, or 1st relapse with Down syndrome (DS). The primary aim was rate of complete response (CR) or CR with incomplete count recovery (CRi) following cycle 1. Secondary aims included adverse events, incidence of sinusoidal obstruction syndrome (SOS), and level of minimal residual disease (MRD) measured by multiparameter flow cytometry in responders. Eligibility included ≥5% marrow blasts, direct bilirubin ≤1.5x upper limit of normal, and no prior SOS. Pts received one cycle of InO at the FDA-approved adult dose of 1.8mg/m2 (0.8mg/m2 on day 1, 0.5mg/m2 on days 8 and 15). Central nervous system (CNS) status dictated intrathecal therapy. Based on response at day 28, pts with at least stable disease (SD) could receive a 2nd cycle; those with CR/CRi received InO 0.5mg/m2 on days 1, 8, and 15 in cycle 2, while those without CR/CRi received the same fractionated dose as cycle 1. Pts with CR/CRi after 2 cycles were eligible to receive up to 6 total cycles. The trial used an admissible two-stage design (α=0.05, β=0.20) testing the null hypothesis of CR/CRi rate of 30% vs. alternative of 48%, requiring a minimum of 9/24 (response/enrolled) for stage 1 and 20/48 total. The trial was continuously monitored for dose-limiting toxicities (DLT) and SOS. Results herein are based on data cutoff of June 30, 2019.
Results: Forty-eight pts received InO and were evaluable for response/toxicity. Median age was 9 years (range 1-21). Three pts had DS. 67% were in &gt;2nd relapse, 21% were in 1st relapse but refractory to reinduction, 23% had prior HSCT, 23% had prior CD19 CAR-T, and 29% had prior blinatumomab. Median marrow blasts were 81% (range 6-100), with 81% of pts having M3 marrow. 19 pts achieved CR and 9 achieved CRi after cycle 1 (CR/CRi rate: 58.3%, 95%CI 43.2-72.4%). Three pts had partial response (PR), 9 SD, and 8 progressive disease (PD); 2 pts (1 PR, 1 SD) had CR/CRi with cycle 2. Two pts with PD in cycle 1 had marrow CR (MRD 0.02% and &lt;0.01% in 1 case each) but progression in the CNS. MRD was reported for 26 of the 28 pts with CR/CRi; of these, 17 (65.4%) had MRD &lt;0.01% and 4 (15.4%) had MRD 0.01-0.099%. The most common adverse events (AE) in cycle 1 were febrile neutropenia (27%) and infection (18.8%). No treatment related toxic deaths were reported. DLTs were reported in 9 pts in cycle 1; the most common DLT was hematologic [absolute neutrophils &lt;500/µL or platelets &lt;20,000/µL beyond 42 days from the start of cycle 1 (n = 7)], but DLT stopping bounds were not crossed. One pt was not evaluable for hematologic DLT. Four (8.3%) pts had ALT elevation, 6 (12.5%) had AST elevation (maximum grade 3), and 1 had grade 3 bilirubin in cycle 1. No pt required dose modification for hepatic toxicity. Thirteen pts had subsequent HCST and 4 (30.7%) developed SOS. All SOS cases were grade 3 (CTCAE v 5.0) and treated with defibrotide; 3 resolved quickly while one was more severe but resolving at the time of death from other HSCT complications. There were no cases of SOS without subsequent HSCT. Limited samples showed that alteration in surface CD22 expression is a likely mechanism for non-response. Peripheral B cell aplasia was nearly universal in evaluated pts.
Conclusions: InO demonstrated a CR/CRi rate of 58% in these heavily pretreated children and young adults with R/R CD22-positive B-ALL. In responders, 65.4% achieved MRD &lt;0.01%. Minimal hepatic toxicity was observed during InO therapy. SOS occurred in 30.7% of pts who underwent subsequent HSCT (8.3% of pts overall), and all but 1 case resolved quickly with supportive care and defibrotide. The most common DLT was prolonged marrow aplasia. Given the observed efficacy, InO will be incorporated into a randomized phase 3 trial for newly diagnosed pediatric pts with high-risk B-ALL.

Disclosures
O'Brien: Pfizer: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; BMS: Research Funding; BTG: Research Funding. Rheingold:Pfizer: Research Funding; Novartis: Consultancy. Borowitz:Beckman Coulter: Honoraria. Raetz:Pfizer: Research Funding. Gore:Amgen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Novartis: Consultancy, Other: Service on Data Safety Monitoring Committee; travel, accommodations, expenses; Roche/Genentech: Consultancy, Honoraria, Other: travel expenses; Anchiano: Equity Ownership, Other: spouse employment and company leadership; Blueprint Medicines: Equity Ownership; Celgene: Equity Ownership, Other: DSMC member; Clovis: Equity Ownership; Mirati: Equity Ownership; Sanofi Paris: Equity Ownership. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Inotuzumab ozogamicin is FDA-approved for adults with relapsed B-ALL but is not approved for children. Its use in a pediatric population with relapsed B-ALL will be presented