Clinical utilization of blinatumomab and inotuzumab immunotherapy in children with relapsed or refractory B-acute lymphoblastic leukemia.

BACKGROUND: The treatment paradigm for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (rrALL) has been revolutionized given recent clinical trials demonstrating remarkable success of immunotherapies and leading to drug approvals by United States and European agencies. We report experience with commercial blinatumomab and inotuzumab use at two North American pediatric oncology centers in children and adolescents/young adults with B-ALL. PROCEDURE: Patients 0-25 years old treated with the CD19 × CD3 bispecific T cell-engaging antibody blinatumomab and/or the CD22 antibody-drug conjugate inotuzumab from January 1, 2010, to June 1, 2018, were eligible. Disease status included relapsed B-ALL in second or greater relapse, primary chemotherapy-refractory B-ALL, or B-ALL complicated by severe infection precluding delivery of conventional chemotherapy. RESULTS: We identified 27 patients who received blinatumomab and/or inotuzumab outside of clinical trials during the study period. Four of the 13 patients (31%) with relapsed disease achieved minimal residual disease (MRD)-negative remission, and five patients (39%) underwent hematopoietic stem cell transplant (HSCT). In the 12 patients with primary chemorefractory B-ALL treated with immunotherapy, 11 (92%) achieved MRD-negative remission as assessed by flow cytometry; 10 patients (83%) underwent subsequent HSCT. Two patients with B-ALL in MRD-negative remission received blinatumomab due to severe infection and remained in remission after chemotherapy continuation. CONCLUSIONS: Blinatumomab and inotuzumab can induce deep remissions in patients with rrALL and facilitate subsequent HSCT or other cellular therapies. Blinatumomab can also serve as an effective bridging therapy during severe infection. The optimal timing, choice of immunotherapeutic agent(s), and duration of responses require further investigation via larger-scale clinical trials.

Extranodal diffuse large B-cell lymphoma presenting with extensive organ involvement.

Extranodal involvement in diffuse large B-cell lymphoma (DLBCL) is defined as disease outside of the lymph nodes and occurs in up to one-third of patients, though multiorgan extranodal involvement is rare. Here, we describe a case of a patient presenting with widely metastatic lesions, including involvement of the lung, parotid gland, breast, pancreas, femur and multiple soft tissue masses, with initial concern for primary breast malignancy. Breast pathology and imaging were consistent with triple-expressor, double-hit stage IV high-grade B-cell lymphoma with extensive extranodal involvement. Extranodal involvement is a poor prognostic factor associated with high rates of treatment failure, and novel therapies targeting CD19 are currently being studied for relapsed and refractory DLBCL. Extranodal disease is a complex entity that can involve virtually any organ system and should be considered for new presentations of malignancy.

Miliary coccidioidomycosis mimicking tuberculosis: Case report and review of literature.

Miliary coccidioidomycosis is a severe manifestation of diseases caused by Coccidioides immitis and Coccidioides posadasii that is endemic to the southwestern United States as well as Central and South America. While most cases of coccidioidomycosis present with pulmonary disease, certain risk factors increase the risk for disseminated disease. We present a case of miliary coccidioidomycosis in a 46-year-old patient with uncontrolled diabetes. Additionally, we review the features of thirty-seven cases of patients with miliary coccidioidomycosis.

Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of ABT-199 observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199-induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL. SIGNIFICANCE: These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.