Hypoparathyroidism is one of the few remaining hormonal insufficiency states for which replacement therapy is unavailable. Previous short-term controlled trials have shown PTH to be a safe and effective treatment of hypoparathyroidism. In this randomized, parallel group, open-label trial, we compared synthetic human PTH-(1-34) (PTH) with conventional therapy, calcitriol and calcium, over a 3-yr period. Twenty-seven patients with confirmed hypoparathyroidism, aged 18-70 yr, were randomized to either twice daily sc PTH or oral calcitriol and calcium. The primary end points were calcium levels in serum and urine. Secondary end points were creatinine clearance, markers of bone turnover, and bone mineral density. Throughout the 3-yr study period, serum calcium levels were similar in both treatment groups within or just below the normal range. Mean urinary calcium excretion was within the normal range from 1-3 yr in PTH-treated patients, but remained above normal in the calcitriol group. Bone mineral content and bone mineral density showed no significant between-group differences over the 3-yr study period. We conclude that treatment with twice daily sc PTH provides a safe and effective alternative to calcitriol therapy and is able to maintain normal serum calcium levels without hypercalciuria for at least 3 yr in patients with hypoparathyroidism.

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit. Clin Cancer Res; 21(18); 4035-9. Ó2015 AACR. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships: J.L. Abbruzzese is a consultant/advisory board member for Celgene and Halozyme. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose. Learning ObjectivesUpon completion of this activity, the participant should have a better understanding of the mechanism of action of blinatumomab, how the toxicities of blinatumomab reflect the mechanism of action, and the level of evidence supporting use of blinatumomab for the treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia.

Purpose: To describe the Food and Drug Administration review and marketing approval considerations for bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma. Experimental Design: Food and Drug Administration reviewed a multicenter study of bortezomib in 155 patients with progressive mantle cell lymphoma after at least one prior therapy. Results: Seventy-seven percent were stage IV, and 75% had one or more extranodal sites of disease. Prior therapy included an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. Median age was 65 years. All received bortezomib 1.3 mg/m 2 i.v. on days 1, 4, 8, and 11 of each 3-week cycle. The primary end point was response. Response and progression were determined by independent review of serial computed tomography scans using International Lymphoma Workshop Response Criteria. The overall response rate was 31%, including complete response (CR) plus CR unconfirmed (CRu) plus partial response; median response duration was 9.3 months. The CR plus CRu response rate was 8% with a median duration of 15.4 months. Adverse events were similar to those observed previously for bortezomib. The most commonly reported treatment-emergent adverse events were asthenia (72%), peripheral neuropathies (55%), constipation (50%), diarrhea (47%), nausea (44%), and anorexia (39%). The most common adverse event leading to discontinuation was neuropathy. Conclusions: Bortezomib received regular approval for the treatment of patients with mantle cell lymphoma in relapse after prior therapy.On December 8, 2006, bortezomib (Velcade for injection) received marketing approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy for their disease. This drug approval is the first for the specific indication of mantle cell lymphoma, a subtype of nonHodgkin's lymphoma characterized by unique pathologic, cytogenetic, and clinical features (1).Bortezomib, a modified dipeptidyl boronic acid derived from leucine and phenylalanine, is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, a large protein complex that degrades most intracellular proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins. Inhibition of the 26S proteasome prevents this targeted proteolysis, which then may alter multiple signaling cascades within the cell.Bortezomib had received accelerated approval in 2003 for multiple myeloma after two prior therapies and in 2005 received regular approval for the treatment of multiple myeloma after one prior therapy (2). The sponsor, Millennium Pharmaceuticals, Inc., in conjunction with Johnson and Johnson Research and Pharmaceutical Development, met with FDA during the design of this registration study and during the conduct and analysis phases to assure agreement on the study design, end points, adjudication plan for assessing the end points, and the analysis plan in...