Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis.

Biosimilars are increasingly available for the treatment of many serious disorders, however some concerns persist about switching a patient to a biosimilar whose condition is stable while on the reference biologic. Randomized controlled studies and extension studies with a switch treatment period (STP) to or from a biosimilar and its reference biologic were identified from publicly available information maintained by the U.S. Food and Drug Administration (FDA). These findings were augmented with data from peer reviewed publications containing information not captured in FDA reviews. Forty-four STPs were identified from 31 unique studies for 21 different biosimilars. Data were extracted and synthesized following PRISMA guidelines. Meta-analysis was conducted to estimate the overall risk difference across studies. A total of 5,252 patients who were switched to or from a biosimilar and its reference biologic were identified. Safety data including deaths, serious adverse events, and treatment discontinuation showed an overall risk difference (95% CI) of -0.00 (-0.00, 0.00), 0.00 (-0.01, 0.01), -0.00 (-0.01, 0.00) across STPs, respectively. Immunogenicity data showed similar incidence of anti-drug antibodies and neutralizing antibodies in patients within a STP who were switched to or from a biosimilar to its reference biologic and patients who were not switched. Immune related adverse events such as anaphylaxis, hypersensitivity reactions, and injections site reactions were similar in switched and non-switched patients. This first systematic review using statistical methods to address the risk of switching patients between reference biologics and biosimilars finds no difference in the safety profiles or immunogenicity rates in patients who were switched and those who remained on a reference biologic or a biosimilar.

U.S. Food and Drug Administration Approval: peginterferon-alfa-2b for the adjuvant treatment of patients with melanoma.

On March 29, 2011, the U.S. Food and Drug Administration approved peginterferon alfa-2b (PEG-IFN) (Sylatron™; Schering Corporation, Kenilworth, NJ) for the adjuvant treatment of melanoma patients with microscopic or gross nodal involvement following definitive surgical resection including complete lymphadenectomy. The approval was based on a single, open-label, multicenter trial enrolling 1,256 patients. After surgical resection, patients were randomized (1:1) to either PEG-IFN or observation for 5 years. PEG-IFN, 6 µg/kg per week, was administered s.c. for eight doses, followed by 3 µg/kg per week for up to 252 weeks. Stratification factors included microscopic or gross nodal involvement, number of positive nodes, Breslow thickness, ulceration, sex, and study center. Patients were assessed for recurrence by the investigators based on physical examination every 3 months for 2 years and every 6 months thereafter. The relapse-free survival (RFS) interval, the primary efficacy endpoint, was significantly longer in PEG-IFN-treated patients. The median RFS times were 34.8 months and 25.5 months, respectively. There was no statistically significant difference in the overall survival time. The most common (>60%) grade 1-4 adverse reactions were fatigue, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions. The most common serious adverse reactions were fatigue, increased ALT and AST, and pyrexia. Thirty-three percent of patients receiving PEG-IFN discontinued treatment as a result of adverse reactions. Five deaths were reported within 30 days of the last treatment dose, two resulting from cardiovascular disease considered as possibly related to treatment.

Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood.

Chronic lymphocytic leukemia (CLL) is a progressive malignancy of mature B-cells that involves the peripheral blood (PB), lymph nodes (LNs) and bone marrow (BM). Although the majority of CLL cells are in a resting state, small populations of proliferating cells exist; however, the anatomical site of active cell proliferation remains to be definitively determined. Based on findings that CLL cells in LNs have increased expression of B-cell activation genes, we tested the hypothesis that the fraction of 'newly born' cells would be highest in the LNs. Using a deuterium oxide (2H) in vivo labeling method in which patients consumed deuterated (heavy) water (2H2O), we determined CLL cell kinetics in concurrently obtained samples from LN, PB and BM. The LN was identified as the anatomical site harboring the largest fraction of newly born cells, compared to PB and BM. In fact, the calculated birth rate in the LN reached as high a 3.3% of the clone per day. Subdivision of the bulk CLL population by flow cytometry identified the subpopulation with the CXCR4dimCD5bright phenotype as containing the highest proportion of newly born cells within each compartment, including the LN, identifying this subclonal population as an important target for novel treatment approaches.

Cold-water immersion in a 22-year-old service member.

Cold-water immersion can include aspects of both hypothermia and near drowning. We present a case of a 22-year-old active duty service member who became a victim of cold-water immersion in Alaska. His rescue by the U.S. Coast Guard and subsequent treatment in a small community emergency room are reviewed using a case management format. Care of the cold-water immersion patient with limited resources is highlighted and the potential complications of cold-water immersion are emphasized. Disturbances in acid base balance, pulmonary function, and cardiac rhythm are discussed. Changes in some of the hematological indices seen in the cold-water immersion patient are reported for the first time.

U.s. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma.

The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m2 on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy.

Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro.

Regulatory T cells (Treg) play important roles in suppressing immune responses and maintaining tolerance. Rabbit antithymocyte globulin (rATG) and horse ATG (hATG) are widely used in the treatment of immune-mediated syndromes, but their effects on Treg are unknown. We show here that in vitro culture of normal human peripheral blood mononuclear cells (PBMCs) with a low-dose rATG resulted in marked expansion of functional Treg by converting CD4+CD25- T cells to CD4+CD25+ T cells. hATG did not expand but rather decreased Treg. Immuno-blot showed increased expression of FOXP3 and NFAT1 in CD4+CD25- and CD4+CD25+ T cells exposed to rATG. PBMCs treated with rATG displayed increased interleukin-10 in culture supernatants than those treated with hATG. Furthermore, rATG and hATG showed differences in their potential to stimulate CD4+ T cells as examined using different activation markers. Microarray revealed that rATG induced markedly different gene-expression patterns in PBMCs, compared with hATG-treated or untreated PBMCs. Our findings indicate that rATG expanded Treg, probably through transcriptional regulation by enhanced NFAT1 expression, in turn conferring CD4+CD25- T cell FOXP3 expression and regulatory activity. The therapeutic effects of rATG may occur not only because of lymphocyte depletion but also enhanced Treg cell number and function.

T cell-to-T cell clustering enhances NF-kappaB activity by a PI3K signal mediated by Cbl-b and Rho.

Full activation of T cells requires the binding of antigen to the T cell receptor and stimulation of the CD28 molecule, a process which typically occurs when T cells bind to an antigen presenting cell. The transcription factor, NF-kappaB, is an integration point for these two signals and its activation is critical for T cell function. Using antibodies to the TCR and CD28 molecules to activate Jurkat T cells, we show that cells that were permitted to aggregate into multi-cellular clusters increased NF-kappaB activity compared to unclustered cells. Inhibition of PI3K signaling with wortmannin decreased the clustering-mediated NF-kappaB signal. Over-expression of a dominant negative form of Cbl-b, an endogenous inhibitor of PI3K, in unclustered cells rescued NF-kappaB activation to the same levels caused by cell clustering. Inhibiting signaling through Rho with dominant negative RhoA abrogated both clustering-mediated and dominant negative Cbl-b-mediated NF-kappaB inactivation, but not TCR/CD28 mediated NF-kappaB activation. Taken together, these results suggest that in addition to pathways stimulated by classical T cell-APC interactions, another signal arising from T cell clustering can enhance activation.

Direct transfer of p65 into T lymphocytes from systemic lupus erythematosus patients leads to increased levels of interleukin-2 promoter activity.

The recent identification of a number of molecular defects in T cells from patients with systemic lupus erythematosus (SLE) has raised expectations for gene replacement therapy as an option in the treatment of these diseases. In this report, we have adapted an electroporation-based technique to transfer successfully DNA to peripheral blood T cells from normal individuals and patients with systemic lupus erythematosus and rheumatoid arthritis. Transfection efficiency, judged by the percentage of live cells expressing green fluorescence after transfection with a pGFP (green fluorescence protein), reached 32 +/- 3% in normal, 13 +/- 3% in SLE, and 17 +/- 13% in RA T cells. The transfection efficiency was slightly higher in CD8+ than in CD4+ cells, and the cells maintained acceptable (75%) viability up to the fourth post-transfection day. SLE T cells have been shown to display low levels of the p65 subunit of the NF-kappaB transcription factor and decreased production of IL-2. Since NF-kappaB contributes to the transcriptional regulation of the IL-2 promoter, the effect of the forced replenishment of p65 on IL-2 transcription was tested. The low level of interleukin-2 promoter activity in SLE T cells increased to normal levels following transfection with cDNA encoding the NF-kappaB p65 subunit. Taken together, these results demonstrate the feasibility of transfection of T cells from SLE patients by electroporation and the reversal of decreased interleukin-2 promoter activity in SLE T cells, and are an early step toward gene therapy as a method of treatment for these individuals.