Monoclonal antibody therapy

Blinatumomab. Blinatumomab is a bispecific monoclonal antibody with one site for CD3 (T cells) and the other site for CD19 (present on most B-ALL cells). Thus, blinatumomab promotes the binding of the patient’s own cytotoxic T cells to B lymphoblasts, resulting in the tumor being killed. In a phase I/II trial of children younger than 18 years with relapsed/refractory B-ALL, 27 of 70 patients (39%) treated at the recommended phase II dose achieved a CR with single-agent blinatumomab; 52% of those achieving CR were MRD negative.[162]In a pooled analysis of five trials that included 166 pediatric and 517 adult patients, those with less than 50% bone marrow blasts at the start of treatment had better responses to blinatumomab. Among pediatric patients, CR rates (including CR with partial hematologic recovery [CRh] and CR with incomplete hematologic recovery [CRi]) were 65.3% for patients with less than 50% baseline bone marrow blast percentage, compared with 38.3% for patients with 50% or more baseline bone marrow blast percentage. Similarly, MRD responses were more frequent in patients with less than 50% baseline bone marrow blast percentage than in those who had 50% or more bone marrow blast percentage (51.4% vs. 25.5%). There was no significant difference in these end points when comparing patients with 5% to <25% blasts and 25% to <50% blasts at the start of blinatumomab treatment.[163]

Inotuzumab. Inotuzumab is an anti-CD22 monoclonal antibody that is conjugated to calicheamicin. In trials of adult patients with relapsed/refractory B-ALL, CR was achieved in approximately 80% of patients.[164,165] There have been two phase II trials of single-agent inotuzumab (both trials used 1.8 mg/m2 total dose in the first course and 1.5 mg/m2 in subsequent courses) used in the treatment of pediatric patients with relapsed (second or greater relapse) or refractory ALL.[87]Expert panel recommendations for the prevention of SOS associated with HSCT after inotuzumab include limiting inotuzumab to two courses, avoiding dual-alkylator HSCT regimens, avoiding hepatotoxic agents, and considering SOS prophylactic agents.[167]

Inotuzumab. Inotuzumab is an anti-CD22 monoclonal antibody that is conjugated to calicheamicin. In trials of adult patients with relapsed/refractory B-ALL, CR was achieved in approximately 80% of patients.[164,165] There have been two phase II trials of single-agent inotuzumab (both trials used 1.8 mg/m2 total dose in the first course and 1.5 mg/m2 in subsequent courses) used in the treatment of pediatric patients with relapsed (second or greater relapse) or refractory ALL.[87]Expert panel recommendations for the prevention of SOS associated with HSCT after inotuzumab include limiting inotuzumab to two courses, avoiding dual-alkylator HSCT regimens, avoiding hepatotoxic agents, and considering SOS prophylactic agents.[167]

In the COG phase II trial (N = 48), the overall response rate (ORR) (CR + CRi) was 58.3% after the first course, and 62.5% after two courses. Of those achieving complete response or complete response with incomplete count recovery, 70% were MRD negative (<0.01%). Overall, inotuzumab was well tolerated, without any significant hepatoxicity or sinusoidal obstructive syndrome (SOS) during treatment. However, of 21 patients who subsequently went on to receive HSCT, 6 (28.6%) developed SOS.[87]

Inotuzumab. Inotuzumab is an anti-CD22 monoclonal antibody that is conjugated to calicheamicin. In trials of adult patients with relapsed/refractory B-ALL, CR was achieved in approximately 80% of patients.[164,165] There have been two phase II trials of single-agent inotuzumab (both trials used 1.8 mg/m2 total dose in the first course and 1.5 mg/m2 in subsequent courses) used in the treatment of pediatric patients with relapsed (second or greater relapse) or refractory ALL.[87]Expert panel recommendations for the prevention of SOS associated with HSCT after inotuzumab include limiting inotuzumab to two courses, avoiding dual-alkylator HSCT regimens, avoiding hepatotoxic agents, and considering SOS prophylactic agents.[167]

On a phase II trial conducted by the Innovative Therapies for Children With Cancer group (N = 28), the ORR was 81.5% (all responses occurring after the first cycle). Of the patients achieving a response, 81.8% achieved MRD negativity (<0.01%), 59.1% after the first course, and the remaining patients after the second course. SOS was observed in seven (28%) patients, six after subsequent HSCT and one during inotuzumab therapy. There was no correlation between the extent of CD22 expression (mean fluorescence index or percentage of CD22 positive cells) and response. In a post-hoc analysis, combining patients from the phase I and phase II trials, the authors found that having a shorter interval between last dose of inotuzumab and undergoing HSCT was associated with a higher risk of developing SOS.[166]

Rituximab or ofatumumab. These monoclonal antibodies target CD20, which is poorly expressed in younger children with ALL, but more common in teenagers and young adults. A number of studies have suggested benefit when adding one of these agents to reinduction chemotherapy in adults,[168,169] but very little data have been published in children.