The Concept of Biosimilars: From Characterization to Evolution-A Narrative Review.

Biologic agents are currently the fastest emerging segment of drug expenditure. Unlike chemically synthesized small-molecule drugs, biologics are more complex, medicinal products produced by a living organism. They have become part of the standard of care in the treatment of a large variety of diseases, such as growth disorders, autoimmune diseases, cancer, cardiovascular illnesses, hemophilia, and rare genetic conditions, to name a few. Biosimilars, which are copies of biologics that are highly similar, were introduced in the market with an aim to offer efficacy that is not clinically different from the originator or reference product, at lower prices. We aim to clarify the concept of biosimilar, from definitions, history, market entry, challenges faced, and future evolution. For that purpose, we performed a literature search on the sites of the medicines regulatory agencies and PubMed from 1990 to 2014 with the keywords "biosimilars," "market," and "regulatory." In 2006, the first biosimilar, somatropin [rDNA origin], was marketed and led the way for biosimilar drug manufacturing. As a result, manufacturers have entered a diversified competition, facing challenges in manufacturing these complex agents, such as immunogenicity and efficiency. Biosimilars are set to evolve differently in various markets, namely the U.S., Japan, the European Union, and the "pharmerging" economies. IMPLICATIONS FOR PRACTICE: This article highlights the importance of biosimilars, as a cost-cutting strategy, in the delivery of state-of-the-art health care in developing countries, at a fraction of what a reference biological agent would cost.

Factors associated with risk of central nervous system relapse in patients with non-core binding factor acute myeloid leukemia.

Central nervous system (CNS) relapse is uncommon in patients with acute myeloid leukemia (AML) with the use of high-dose cytarabine containing chemotherapy regimens. The clinical and molecular features associated with a higher risk of CNS relapse are not well defined. We assessed the incidence and outcome of CNS relapses among 1245 patients with relapsed/refractory AML referred to our institution between 2000 and 2014. CNS leukemia relapse was observed in 51 patients (4.1%). Using a multivariate regression model and after adjusting for age, FLT3-ITD mutation (OR = 2.33; P = .02) and elevated LDH (>1000 IU/L, OR = 1.99; P = .04) were independent predictive factors for CNS relapse. Patients under 64 years of age with 0, 1, or 2 baseline adverse features had a probability of 3.8%, 7.0%-8.0%, and 13.9% for developing CNS disease, respectively. Our study identifies patients with AML at higher risk for CNS relapse in whom prophylactic CNS therapy may be warranted.

Impact of achievement of complete cytogenetic response on outcome in patients with myelodysplastic syndromes treated with hypomethylating agents.

Two hundred and sixteen consecutive patients with MDS and abnormal karyotype treated with hypomethylating agents between 4/04 and 10/12 were reviewed. Median follow-up was 17 months. Using IWG criteria, best responses were complete response (CR) in 79 patients (37%), partial response (PR) in 4 (2%), and hematologic improvement (HI) in 10 (5%). Cytogenetic response (CyR) was achieved in 78 patients (36%): complete (CCyR) in 62 (29%) and partial in 16 (7%). CyR was achieved in 48 of 79 patients (61%) with CR, 1 of 14 (7%) with PR/HI, and in 29 of the 123 (24%) with no morphologic response. Median overall survival (OS) and leukemia-free survival (LFS) for patients with and without CCyR were 21 and 13 months (P = .007), and 16 and 9 months (P = .001), respectively. By multivariate analysis, the achievement of CCyR was predictive for better OS (HR = 2.1; P < .001). In conclusion, CyR occurs at a rate of 36% (complete in 29%) in patients with MDS treated with HMA and is not always associated with morphological response. The achievement of CCyR is associated with survival improvement and constitutes a major predictive factor for outcome particularly in patients without morphologic response. Therefore, the achievement of CCyR should be considered a milestone in the management of patients with MDS.

Outcome of acute limb ischemia in cancer patients.

The optimal management strategy for acute limb ischemia (ALI) in patients with a concomitant malignancy is not well established. A very high mortality rate (83-100%) at 1 year has been reported in those who are treated surgically. Accordingly, a conservative management approach has been suggested as the main therapeutic modality. Our aim was to evaluate the survival outcomes of cancer patients treated for ALI at our cancer center. Cancer patients treated for ALI at the MD Anderson Cancer Center from 2001 to 2011 were included in this study. Overall survival and amputation-free survival rates were calculated. A total of 74 cancer patients with concomitant ALI were included in the study. Surgery was the most common therapy (36 patients; 49%). Percutaneous catheter-based interventions were used in 21 patients (28%). Eighteen patients (24%) received anticoagulation therapy only, and six patients (8%) received no therapy. The 30-day, 6-month, and 1-year overall survival rates were 80% (95% confidence interval [CI], 69% to 87%), 59% (95% CI, 47% to 69%), and 48% (95% CI, 36% to 59%), respectively. Eight patients (11%) underwent amputation. The 1-year amputation-free survival rate was 47% (95% CI, 35% to 58%). In conclusion, we did not find an invasive approach for the treatment of ALI in cancer patients to be associated with the very high mortality rates previously reported. In our opinion, the indications for surgery or catheter-based intervention in these patients should not differ from patients without cancer.

Targeting the anterior superior iliac spine yields significantly longer bone marrow cores.

Pathologists and haematologists generally agree that the length of the biopsy core is a good surrogate for the diagnostic quality of the bone marrow. Previous studies suggested that the angulation of the biopsy needle from the posterior superior iliac spine (PSIS) could influence the length of the biopsy cores, targeting the anterior superior iliac spine (ASIS) from the PSIS would yield longer specimens than the traditional angulation technique (TAT), where the biopsy needle is directed straight in, perpendicular to the plane of the back. Twenty five adult haematology patients were prospectively recruited by haematologists-in-training (HITs), who were trained to target the ASIS using a lateral angulationtechnique (LAT). The mean length of biopsy cores was 16 mm and that was significantly longer (p=0.003) than a comparable group of bone marrow biopsies previously obtained by HITs using the TAT approach. These results support the LAT as a new standard of haematology practice. TRIAL REGISTRATION NUMBER: NCT 02524613.

Hypertension induced by chemotherapeutic and immunosuppresive agents: a new challenge.

BACKGROUND: Hypertension is a common adverse effect of certain anti neoplastic therapy. The incidence and severity of hypertension are dependent mainly on the type and the dose of the drug. METHODS: We reviewed the literature for studies that reported the effect of anti neoplastic agents on blood pressure in patients with malignancies. The medical databases of PubMed, MEDLINE and EMBASE were searched for articles published in English between 1955 and June 2012. The effects of specific agents on blood pressure were analyzed. RESULTS AND CONCLUSIONS: Hypertension is a prevalent adverse effect of many of the new chemotherapy agents such as VEGF inhibitors. Approximately 30% of patients treated for cancer will have concomitant hypertension, and crucial chemotherapy can sometimes be stopped due to new onset or worsening severe hypertension. The importance of a timely diagnosis and optimal management of HTN in this group of patients is related to the facts that HTN is a well established risk factor for chemotherapy-induced cardiotoxicity and if left untreated, can alter cancer management and result in dose reductions or termination of anti-cancer treatments as well as life-threatening end organ damage.