While most pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) are curable with modern risk-adapted therapy, survival following relapse remains poor. For children in first relapse treated with salvage chemotherapy, the five-year overall survival (OS) has been approximately 40 to 50 percent, with early timing of medullary relapses and second or greater relapses conferring increasingly worse prognoses.1,2 The recent success of CD19-directed antibody-based or cellular immunotherapies has led to improved clinical outcomes for some patients with relapsed/refractory B-ALL and U.S. Food and Drug Administration (FDA) approval of several products,3–5 but also engendered CD19 antigen-loss relapses that are challenging to cure.6,7
The CD22 antibody-drug conjugate inotuzumab ozogamicin has independently demonstrated robust remission reinduction in adults with relapsed/refractory B-ALL,8 leading to its FDA approval in 2017. During the past several years, pediatric-specific studies have investigated the safety and tolerability of inotuzumab administered as monotherapy or in combination with multiagent chemotherapy for children with relapsed/refractory B-ALL, including detailed assessment of potential hepatic sinusoidal obstruction syndrome (SOS) toxicity. In addition to these trials, recent case series reports have noted promising clinical activity in children with relapsed ALL previously treated with CD19-targeting immunotherapies.9,10
Dr. Erica Brivio and colleagues recently reported results from the European Innovative Therapies for Children with Cancer (ITCC) consortium phase I study ITCC-059 (EUDRA-CT 2016-000227-71), which investigated two dose levels of single-agent inotuzumab in 25 children and adolescents (1-17 years old) with CD22+ multiply-relapsed/refractory B-ALL. A maximally tolerated dose of 1.8 mg/m2/cycle administered weekly for three doses at 0.8, 0.5, and 0.5 mg/m2 (DL2) was identified. Importantly, an overall response rate of 80 percent (20/25 patients) was observed with 84 percent (16/19 patients with available data) of responders achieving deep remission with negative flow cytometric minimal residual disease (MRD).11 SOS was not seen in any subject during inotuzumab therapy but did occur in two of five non-responding patients treated with subsequent high-dose chemotherapy. Surprisingly, seven children with inotuzumab-induced remission who received subsequent allogeneic hematopoietic stem cell transplantation (HSCT) did not experience SOS, though prophylactic defibrotide was used in one patient.11 The ITCC-059 trial is now accruing in a part 2 phase with inotuzumab in combination with multiagent chemotherapy.
Concurrently, Dr. Maureen O'Brien and colleagues evaluated inotuzumab monotherapy in 48 children and adolescents/young adults (AYAs) aged one to 21 years with second or greater relapsed/refractory CD22+ B-ALL via the Children's Oncology Group (COG) AALL1621 phase II trial (NCT02981628). A complete response (CR) rate of 58.3 percent (28/48 patients) was observed after one cycle of inotuzumab given at the same 1.8 mg/m2/cycle dosing with 66.7 percent (18/27) achieving MRD negativity. Three additional patients (6.3%) achieved MRD-negative remission after a second cycle. As in the ITCC-0659 trial, SOS was not observed during inotuzumab therapy. However, six of 21 subjects (28.6%) who underwent subsequent allogeneic HSCT experienced grade 3 SOS, which was successfully managed in all patients with early administration of defibrotide. AALL1621 is also currently evaluating inotuzumab in combination with multiagent chemotherapy in children with relapsed/refractory B-ALL.
In Brief
Both the ITCC-059 and AALL1621 clinical trials independently established that single-agent inotuzumab dosed at 1.8 mg/m2/cycle was tolerable and efficacious in heavily pretreated pediatric patients with multiply relapsed B-ALL. Differences in MRD-negative response rates between the studies may be attributable to relatively small sample sizes. It is also posited that inclusion of AYA patients 18 to 21 years of age (8/48; 22.9%) in the COG study may have contributed to lower CR rates, as better responses were seen in patients aged 17 years or younger. While SOS rates during HSCT differed between the two studies, it is reassuring that affected patients were responsive to medical interventions. Given the demonstrated success in pediatric patients with relapsed ALL, inotuzumab is now under clinical investigation in children and AYAs with newly diagnosed National Cancer Institute high-risk CD22+ B-ALL through the COG AALL1732 phase III trial led by Drs. Maureen O'Brien and Jennifer McNeer (NCT03959085), which is randomizing patients to best-available multiagent chemotherapy versus chemotherapy with two intercalated cycles of inotuzumab.
Competing Interests
Dr. Pariury and Dr. Tasian indicated no relevant conflicts of interest.
