Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children's Oncology Group Protocol AALL1621

Abstract

PURPOSE Children's Oncology Group trial AALL1621 was conducted to prospectively determine the safety and efficacy of inotuzumab ozogamicin (InO) in pediatric and adolescent patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS This single-arm phase II trial enrolled patients age 1-21 years with R/R CD22-positive B-ALL. In cycle 1, InO dosing was 0.8 mg/m2 intravenously on day 1 and 0.5 mg/m2 on days 8 and 15 of a 28-day cycle with response evaluation at day 28. Using a two-stage design, the trial was continuously monitored for dose-limiting toxicities and sinusoidal obstruction syndrome (SOS). CD22 expression was retrospectively evaluated by central flow cytometry. RESULTS Forty-eight patients were evaluable for response and toxicity; 19 had complete response (CR) and nine CR with incomplete count recovery (CRi) after cycle 1 (CR/CRi rate: 58.3%; two-sided 90% CI, 46.5 to 69.3). Twenty-seven of 28 patients with CR or CRi had minimal residual disease measured by flow cytometry; 18 (66.7%) had minimal residual disease < 0.01%. Seven of 28 patients (25%) with CR or CRi had delayed count recovery past day 42 in cycle 1. Three (6.3%) patients had grade 3 ALT elevation and one patient had grade 3 hyperbilirubinemia in cycle 1. Of 21 patients undergoing hematopoietic stem-cell transplantation after InO, 6 (28.6%) developed grade 3 SOS. Partial CD22 expression and lower CD22 site density were associated with lower likelihood of response to InO. CONCLUSION InO is effective and well tolerated in heavily pretreated children and adolescents with R/R CD22-positive B-ALL. SOS after hematopoietic stem-cell transplantation and prolonged cytopenias were notable. CD22 modulation was identified as a mechanism of resistance. Expanded study of InO combined with chemotherapy is underway.

Outcomes After Nonresponse and Relapse Post-Tisagenlecleucel in Children, Adolescents, and Young Adults With B-Cell Acute Lymphoblastic Leukemia

“…Inotuzumab, a CD22-specific antibody-calicheamicin conjugate, achieved a 58% CR rate in CAYAs with B-ALL (phase II; n = 48). 9 CD22-specific CAR T cells achieved a 70% CR rate (phase I; n = 58) in CAYAs with B-ALL. 10 To our knowledge, this is the first CAR targeting an alternative antigen to CD19 to successfully achieve comparable efficacy.…”

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas

“…Grade ≥3 febrile neutropenia was recorded in 21.4–32% of the patients and neutropenia was ubiquitous (92.9%; 18.8–56% grade ≥3). Likewise, B-cell depletion was universal, but there was no significant decrease in peripheral T-cells post-InO regardless of response [ 179 , 180 , 181 , 182 , 183 ].…”

Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against <i>FLT3</i>- mutant acute myeloid leukemia and <i>KMT2A</i>-rearranged acute lymphoblastic leukemia

“…We similarly detected no increase in IFN-ߛ or IL-2 production nor alteration in the viability of CD34+/CD38+ or CD34+/CD38-hematopoietic progenitors with co-culture with FLT3CART (Supplemental Bispecific CD19xFLT3CART also has potent in vitro and in vivo activity against KMT2A-R ALL Modulation of target antigen surface expression is another well-recognized mechanism of leukemia relapse in clinical experience to date with CD19-and CD22-targeting CAR T cells and antibody-based immunotherapies. 14,31 As a strategy potentially to augment anti-leukemia activity and perhaps also to diminish risk of antigen escape specifically in KMT2A-R ALL, we generated bicistronic CD19xFLT3-directed CAR constructs using a single vector. Each dualtargeting construct contained the above-described same FLT3 scFv with 4-1BB/CD3ζ costimulatory domains (Supplemental Figure 1A) and an FMC63-derived CD19 scFv with 4- 5A and Supplemental Methods).…”