Peginterferon Alfa-2b Research Articles

Melanoma: tumor microenvironment and new treatments.

In the recent past years, many discoveries in the tumor microenvironment have led to changes in the management of melanoma and it is rising up hopes, specially, to those in advanced stages. FDA approved seven new drugs from 2011 to 2014. They are: Vemurafenib, Dabrafenib and Trametinib, kinases inhibitors used for patients that have BRAFV600E mutation; Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-1), monoclonal antibodies that stimulate the immune system; and Peginterferon alfa-2b, an anti-proliferative cytokine used as adjuvant therapy. In this article, we will review the molecular bases for these new metastatic melanoma therapeutic agents cited above and also analyze new molecular discoveries in melanoma study, as Cancer-Testis antigens (CT). They are capable of induce humoral and cellular immune responses in cancer patients and because of this immunogenicity and their restrict expression in normal tissues, they are considered an ideal candidate for vaccine development against cancer. Among CT antigens, NY-ESO-1 is the best characterized in terms of expression patterns and immunogenicity. It is expressed in 20-40% of all melanomas, more in metastatic lesions than in primary ones, and it is very heterogeneous inter and intratumoral. Breslow index is associate with NY-ESO-1 expression in primary cutaneous melanomas, but its relation to patient survival remains controversial.

Pembrolizumab (pembro) plus low-dose ipilimumab (ipi) for patients (pts) with advanced renal cell carcinoma (RCC): Phase 1 KEYNOTE-029 study.

510 Background: The CTLA-4 antibody ipi and the PD-1 antibody pembro have demonstrated efficacy in pts with advanced malignancies. While these immune checkpoint inhibitors have shown robust activity as monotherapy, combination therapy may further improve outcomes. KEYNOTE-029 (NCT02089685) is a phase 1/2 study designed to assess the safety and efficacy of pembro + ipi or pegylated interferon alfa-2b (IFN-α) in pts with advanced melanoma or RCC. Here we report data from the phase 1 portion of the study in pts with RCC treated with pembro + ipi. Methods: Pts ≥18 years with advanced/unresectable or metastatic clear cell RCC who received ≥1 prior therapy for metastatic disease, had ≥1 measurable lesion per RECIST v1.1, and ECOG PS 0-1 were enrolled. Pts received pembro 2 mg/kg Q3W + low-dose ipi (1 mg/kg Q3W for 4 doses) until disease progression, unacceptable toxicity, investigator/patient decision, or 2 years of pembro treatment. AEs were monitored throughout treatment and for 30 days thereafter and graded per NCI CTCAE v4.0. Primary end point was safety; primary efficacy end point was ORR assessed per RECIST v1.1 by independent central imaging vendor review. Results: As of the March 17, 2016, data cutoff, 10 pts with RCC received pembro + low-dose ipi. 60% were male, 70% were white, median age was 61 years (range, 48-70 years), 40% received 2 prior lines of therapy, and 40% received prior immunotherapy. With a median follow-up of 17.4 months (0.9-23.5 months), 70% of pts experienced treatment-related AEs (TRAEs) of any grade, most commonly fatigue (30%); and 50% experienced grade 3/4 TRAEs, most commonly increased lipase (20%). 50% of pts discontinued pembro because of TRAEs, most commonly increased lipase (40%). There were no treatment-related deaths. ORR was 20% (2 partial responses); median duration of response was not reached (14.1+-17.1 months+). An additional 3 pts had stable disease; disease control rate was 50%. Conclusions: The combination of pembro + low-dose ipi for 4 doses, followed by pembro monotherapy, demonstrates a manageable toxicity profile and preliminary antitumor activity in pts with advanced RCC. Clinical trial information: NCT02089685.

Efficacy and safety profile of boceprevir- or telaprevir-based triple therapy or dual peginterferon alfa-2a or alfa-2b plus ribavirin therapy in chronic hepatitis C: the real-world PegBase observational study.

BackgroundThe aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice.MethodsPegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naïve and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12).ResultsSVR12 rates in treatment-naïve genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naïve patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports.ConclusionThe efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies.

A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma

BackgroundIpilimumab and peginterferon alfa-2b are established systemic treatment options for melanoma that have distinct mechanisms of action. Given the need for improved therapies for advanced melanoma, we conducted an open-label,...

HBsAg and HBeAg in the prediction of a clinical response to peginterferon α-2b therapy in Chinese HBeAg-positive patients

BackgroundThis study aimed to evaluate the predictive values of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) levels in 171 Chinese patients with chronic hepatitis B who received a 48-week course of pegylated interferon alfa-2b therapy at 1.5 mcg/kg.MethodsHBsAg, HBeAg, and hepatitis B virus (HBV) DNA levels were measured at baseline and weeks 12, 24, 48, and 72. Clinical responses were defined as a combined response (CR, HBeAg seroconversion [sustained response, SR] combined with HBV DNA level <2,000 IU/mL at week 72). The positive predictive value and negative predictive value were calculated for HBsAg alone and/or combined with HBeAg and HBV DNA at weeks 12 and 24.ResultsOf 171 patients included, 58 (33.9 %) achieved a SR. Of patients who achieved a SR, 33 (56.9 %) achieved a CR. Totally 19.3 % (33/171) patients achieved CR and 80.7 % (138/171) patients did not. Patients with HBsAg <1500 IU/mL at week 12 had a 47.4 % chance of achieving an off-treatment SR and patients with a HBsAg decrease >1.5 logIU/mL at week 12 had a 54.5 % chance. Patients with HBsAg >20,000 IU/mL at weeks 12 and 24 had a 93.8 and 100.0 % chance, respectively, of not achieving a CR. An HBsAg level or changes at weeks 12 and 24, combined with HBeAg or HBV DNA, increased the chance for a SR and CR.ConclusionsOn-treatment HBsAg quantification, alone or in combination with HBeAg or HBV DNA, predicted off-treatment SR and CR after 48 weeks of PEG-IFNα-2b therapy, and thus, may guide clinicians in making a therapeutic decision to continue or terminate the therapy.

Safety and Efficacy of Pegylated Interferon Alpha-2b Monotherapy in Hepatitis C Virus-Infected Children with End-Stage Renal Disease on Hemodialysis.

Treatment of hepatitis C virus (HCV) in end-stage renal disease (ESRD) patients is an important issue before kidney transplantation (KT). The aim of the study is to assess the efficacy and tolerability of HCV treatment with pegylated interferon (PEG IFN)-α 2b in children with ESRD. The study included 17 children, aged 3-18 years with ESRD on hemodialysis (HD), with chronic HCV. They received 40 μg/m2 of PEG IFN-α 2b once-weekly subcutaneous injections for 48 weeks. Early virological response (EVR) was achieved in 76.5%. At week 24, 8 patients had negative HCV RNA. Six patients received KT during therapy. Treatment was discontinued in 2 patients: one for anemia and another for retinopathy. Two patients completed 48 weeks of therapy and both achieved end-of-treatment response and sustained virological response (SVR). Constitutional symptoms were the most frequently reported side effects. Neutropenia occurred in 10 patients (58.8%), drop in hemoglobin in 10, and thrombocytopenia in 9. HCV-infected children with ESRD on HD have high EVR (76.5%) on IFN monotherapy. SVR could not be assessed due to the high dropout rate related mainly to early transplantation. Constitutional symptoms and hematological side effects were the most frequently reported side effects.

Interrelation between endogenous intoxication indicators and nitric oxide metabolites in the infectious process in chronic viral hepatitis C

Aim. To study dynamics and interrelation between final nitric oxide metabolites (nitrites) and endogenous intoxication index (medium mass molecules) in patients with chronic hepatitis C with the effect of antiviral therapy on them.Methods. The study included 99 patients with chronic hepatitis C. The combination therapy for 48 weeks in patients with genotype 1 chronic hepatitis C with pegylated interferon (peginterferon alfa-2a and alfa-2b) in combination with ribavirin and for 24 weeks with daily standard interferon alfa-2b administration in patients with virus genotypes 2 and 3 was conducted. The nitric oxide level was estimated by the content of the nearest metabolite (nitrite) in blood serum using the P.P. Golikov method. Medium mass molecules in the blood serum were determined by the N.I. Gabrielyan method.Results.In patients with chronic hepatitis C high values of nitrogen oxide metabolites and the medium mass molecules in the blood serum were revealed, whereas the level of nitroxidemia and endogenous intoxication by the values of medium mass molecules was associated with the viral replicative capacity value and alanine aminotransferase serum levels. Amid the combination antiviral therapy the nature of nitroxidergy changed with the normalization of nitrogen oxide indicators by 24 weeks and an increase to 48 weeks of treatment. There were significantly positive correlative relations between pronouncement of levels of nitric oxide metabolites and the medium mass molecules before the start of antiviral therapy (R=0.292629, pConclusion. Chronic hepatitis C promotes increase in nitrite ion content and medium mass molecules in the blood serum, their level is associated with virus replication activity and cytolysis severity; antiviral therapy has an effect on the level of endogenous intoxication with the normalization of content of the nitrite ions and medium mass molecules in blood serum by 24th week of treatment.

Immunotherapy with imiquimod and interferon alfa for metastasized Merkel cell carcinoma.

Merkel cell carcinoma (mcc) is a highly aggressive neuroendocrine tumour of the skin. Remission rates are high with chemotherapy in patients with metastasis, but without any improvement in overall survival. We present the case of a 90-year-old woman with facial mcc. After radiation and surgery, the mcc recurred with widespread cutaneous and regional lymph node metastases. The metastases were treated with weekly intralesional injections of 1-2×10(6) IU interferon alfa-2a, accompanied by topical imiquimod 5% cream 3 times weekly. After partial regression, subcutaneous pegylated interferon alfa-2b was added at a dose of 30 μg weekly, which was then increased to 50 μg weekly. At 4 months after the start of immunotherapy, all cutaneous metastases and the intralesionally treated lymph node metastases receded. Interruption or reduction of systemic interferon application resulted in locoregional relapses that were successfully treated with surgery or intralesional interferon injections. The patient remains alive 30 months after initiation of immunotherapy, suggesting that locally metastasized mcc might be able to be controlled with local and systemic immunotherapy.

Influence of insulin resistance on the development of hepatocellular carcinoma after antiviral treatment for non-cirrhotic patients with chronic hepatitis C.

BackgroundInsulin resistance is considered to be an important factor in the progression of fibrosis and the enhancement of the risk of hepatocellular carcinoma (HCC) for chronic hepatitis C patients. The aim of this study was to assess the effect of insulin resistance on the development of HCC by non-cirrhotic chronic hepatitis C patients treated with pegylated interferon alpha-2b (PEG-IFNα2b) and ribavirin.MethodsThis retrospective study consisted of 474 Japanese non-cirrhotic patients with chronic hepatitis C. The cumulative incidence of HCC was estimated using the Kaplan-Meier method, according to insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR) and treatment outcome.ResultsThe overall sustained virological response (SVR) rate was 45.1 % (214/474, genotype 1: 35.4 % [129/364] and genotype 2: 77.3 % [85/110]). Twenty-one (4.4 %) patients developed HCC during the follow-up period. The 5-year cumulative incidence of HCC of the SVR group (2.6 %) was significantly lower than that of the non-SVR group (9.7 %) (log-rank test: P = 0.025). In multivariable logistic regression analysis, HOMA-IR (≥2.5) (hazard ratio [HR] 12.8, P = 0.0006), fibrosis status (F3) (HR 8.85, P < 0.0001), and post-treatment alanine aminotransferase (ALT) level (≥40 U/L) (HR 4.33, P = 0.036) were independently correlated to the development of HCC. Receiver operating characteristic analysis to determine the optimal threshold value of HOMA-IR for predicting the development of HCC in the non-SVR group showed that the areas under the curve was high (0.80, cutoff value: 3.0). Only three patients (1.4 %) who achieved SVR developed HCC. Two of them had severe insulin resistance and did not show improvement in HOMA-IR after achieving SVR.ConclusionsInsulin resistance has a strong impact on the development of HCC by non-cirrhotic patients who have PEG-IFNα2b and ribavirin treatment failure.

Predictors of Virological Response in 3,235 Chronic HCV Egyptian Patients Treated with Peginterferon Alpha-2a Compared with Peginterferon Alpha-2b Using Statistical Methods and Data Mining Techniques

Despite the appearance of new oral antiviral drugs, pegylated interferon (PEG-IFN)/RBV may remain the standard of care therapy for some time, and several viral and host factors are reported to be correlated with therapeutic effects. This study aimed to reveal the independent variables associated with failure of sustained virological response (SVR) to PEG-IFN alpha-2a versus PEG-IFN alpha-2b in treatment of naive chronic hepatitis C virus (HCV) Egyptian patients using both statistical methods and data mining techniques. This retrospective cohort study included 3,235 chronic hepatitis C patients enrolled in a large Egyptian medical center: 1,728 patients had been treated with PEG-IFN alpha-2a plus ribavirin (RBV) and 1,507 patients with PEG-IFN alpha-2b plus RBV between 2007 and 2011. Both multivariate analysis and Reduced Error Pruning Tree (REPTree)-based model were used to reveal the independent variables associated with treatment response. In both treatment types, alpha-fetoprotein (AFP) >10 ng/mL and HCV viremia >600 × 10(3) IU/mL were the independent baseline variables associated with failure of SVR, while male gender, decreased hemoglobin, and thyroid-stimulating hormone were the independent variables associated with good response (P < 0.05). Using REPTree-based model showed that low AFP was the factor of initial split (best predictor) of response for either PEG-IFN alpha-2a or PEG-IFN alpha-2b (cutoff value 8.53, 4.89 ng/mL, AUROC = 0.68 and 0.61, P = 0.05). Serum AFP >10 ng/mL and viral load >600 × 10(3) IU/mL are variables associated with failure of response in both treatment types. REPTree-based model could be used to assess predictors of response.

Alopecia Universalis- An Unpleasant Reality with Interferon Alfa-2b and Ribavirin Treatment for Hepatitis C

Numerous cutaneous side effects of combination Pegylated interferon alfa-2b (PEG-IFN) and ribavirin (RBV) therapy have been reported. Although cases alopecia areata (AA) associated with PEG-IFN/RBV therapy have been reported in the literature, but alopecia universalis is uncommon entity. We have treated up till now around 3500 patients suffering from this disease with Pegylated Interferon-2b and ribavirin, as oral directly acting antivirals has been recently launched in India. Out of these 3500 patients, 1470 (42%) patients developed alopecia during various stages of treatment, some even after stopping of treatment. Five patients developed Alopecia Universalis (AU) while undergoing the treatment which makes prevalence rate of 14% in total of 3500 but if we calculate prevalence of Alopecia Universalis in patients who developed alopecia on treatment, it increases to 34%. Now the good thing is that we have already entered the phase of Interferon free treatment in India, thus patients will get rid of these frustrating side effects like AA and AU which undermines the importance of successful treatment after achievement of sustained virological response.

Peg-Interferon Alfa 2-b Related Cellulitis in a 40 Years Man

Background: Pegylated interferon and ribavirin are currently one of the accepted treatment for chronic Hepatitis C. Dermatologic complications of interferon have been reported, but to date a few cases of bacterial cellulitis; a rare and severe complication, have been published. Cellulitis is a common infectious process affecting the skin and subcutaneous tissues which results in significant morbidity and holds considerable healthcare costs. Cases Report : Herein, we report a case of chronic hepatitis C genotype 1a who was on medication since 8 weeks prior to developing leg cellulitis, an uncommon pegylated interferon injection site. Considering no other possible risk factors were found to be in favor of bacterial cellulitis, our case is unique in its kind. Some reports reveal necrotizing vasculitis as basis for cutaneous lesions, which could be due to the high concentrations of drug at the injection site, a toxic effect of the diluents, or an immunological reaction. C onclusion: According to the latter mechanism patients could develop bacterial cellulitis in their different organs. Conclusively, we propose the hypothesis of a possible association between cellulitis to occur at any site as the complication of pegylated interferon Alfa 2b and would highlight the role of a careful skin examination that could be an asset in preventing local skin infections.

MicroRNA expression in chronic Hepatitis C patients treated with combined pegylated interferon alpha and ribavirin therapy

The role of microRNAs (miRNA) in many diseases, including chronic hepatitis, represents an interesting research field. The current work aimed to study the effect of combination therapy (pegylated interferon alpha-2b plus ribavirin) on microRNA-128 (miR-128) and microRNA-296 (miR-296-5p) expression in patients with chronic hepatitis C. Also, we aimed to investigate the potential value of both types of microRNAs in differentiation between responders and non-responders either in the pre-treatment or post-treatment groups. Sixteen patients with chronic hepatitis C were compared to 10 healthy, age and sex matched controls. Venous blood samples were withdrawn before initiation of combination therapy and 12 weeks later and qPCR was used for gene expression assays. Comparison of pre-treatment group to the control group showed significant miR-128 down-regulation, while miR-296-5p showed a non-significant downregulation. Regarding post-treatment group, there was non-significant upregulation of miR-128, while miR-296-5p was significantly downregulated compared to either pre-treatment group or the control group. Comparative studies of miR-128 and miR-296-5p in responders versus non-responders showed non-significant fold change either in the pre- or post-treatment groups. It could be concluded that chronic hepatitis C as well as the combination therapy modulate miR-128/296 expression. Until now, miRNAs studied were not useful indicators to differentiate between responders and non-responders to combination therapy either in pre- or post-treatment group.

Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study.

Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naïve. A multicenter, retrospective observational study. The study was conducted retrospectively on 1214 treatment naïve-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients' data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient's demographic characteristics, baseline viral load, genotype, and fibrosis scores. The mean age of the patients was 50.74 (±0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2/3, age less than 45 years, low fibrosis stage, low baseline viral load and presence of early virological response. SVR rates to each peginterferon were found to be similar in genotype 1/4 although SVR rates were found to be higher for peginterferon alpha-2b in patients with genotype 2/3. The number of patients who failed to complete treatment due to adverse effects was 33 (2.7%). The number of patients failed to complete treatment due to adverse effects was 33 (2.7%). Our findings showed that the rate of SVR to dual therapy was higher in treatment-naïve Turkish patients than that reported in randomized controlled trials. Also peginterferon alpha-2a and alpha-2b were found to be similar in terms of SVR in genotype 1 patients.

Polymers in Drug Delivery

Polymers are being used extensively in drug delivery due to their surface and bulk properties. They are being used in drug formulations and in drug delivery devices. These drug delivery devices may be in the form of implants for controlled drug delivery. Polymers used in colloidal drug carrier systems, consisting of small particles, show great advantage in drug delivery systems because of optimized drug loading and releasing property. Polymeric nano particulate systems are available in wide variety and have established chemistry. Non toxic, biodegradable and biocompatible polymers are available. Some nano particulate polymeric systems possess ability to cross blood brain barrier. They offer protection against chemical degradation. Smart polymers are responsive to atmospheric stimulus like change in temperature; pressure, pH etc. thus are extremely beneficial for targeted drug delivery. Some polymeric systems conjugated with antibodies/specific biomarkers help in detecting molecular targets specifically in cancers. Surface coating with thiolated PEG, Silica-PEG improves water solubility and photo stability. Surface modification of drug carriers e.g. attachment with PEG or dextran to the lipid bilayer increases their blood circulation time. Polymer drug conjugates such as Zoladex, Lupron Depot, On Caspar PEG intron are used in treatment of prostate cancer and lymphoblastic leukemia. Polymeric Drug Delivery systems are being utilized for controlled drug delivery assuring patient compliance.

Combination of Dasatinib and Peg-Interferon Alpha 2b in Chronic Phase Chronic Myeloid Leukemia (CP-CML) First Line: Preliminary Results of a Phase II Trial, from the French Intergroup of CML (Fi-LMC)

Background: Combination of Pegylated-Interferon alpha (Peg-IFNa) 2a and imatinib (IM) has been reported to significantly induce higher rates of molecular responses (including undetectable BCR-ABL transcript) over IM alone, as frontline therapy for CP-CML patients (pts) in a randomized phase 3 trial (SPIRIT, Preudhomme et al, NEJM 2010). Second generation TKIs such as dasatinib (DASISION, Kantarjian et al, NEJM 2010) enhance the speed and depth of molecular response (MR) in comparison to IM. Phase II trial using nilotinib and PegIFNa2a has recently reported high rates of deep molecular response (MR4.5) within 24 months (Nicolini FE et al, Lancet Haematology 2015). Aims: To determine the efficacy and safety of the combination of dasatinib and Peg-IFNa2b in CP-CML frontline. (EUDRACT Number: 2012-003389-42, Dasa-PegIFN trial). Methods: Newly diagnosed Ph+ CP-CML pts less than 65-year-old started dasatinib 100 mg/day. At 3 months, they were assigned to receive Peg-IFNa2b associated to dasatinib when platelets (plt) > 100 X 109/L, Neutrophils (ANC) > 1.5 X 109/L) and lymphocytes Results: 81 pts were enrolled between October 2013 and July 2014. All pts will have completed the 12 months follow-up time-point in August 2015. 79/81pts were included in the analysis (1 pt died of a CML-related haemorrhage before receiving dasatinib, 1 screening failure (masked Ph)). Median age was 48 (20-65) years. 54% of pts were male. Sokal scores were low, intermediate and high in 51%, 32% and 17% of pts respectively. After the first 3 months of therapy (M3), sixty-one patients (77%) started Peg-IFNa2b at the dose of 30 microg/week in association with dasatinib. For these pts after M3, reported hematologic adverse events (AE) were neutropenia (G3/4 n=11; G1/2 n=17), thrombocytopenia (G3/4 n=0; G1/2 n=7), anemia (G3/4 n=0; G1/2 n=7). Extra-hematologic AE were essentially of low grade (overall, G3/4 n=3; G1/2 n=113). According to NCI CTCAE V4.0, most frequent AE were infections (16%), general symptoms (15%), skin lesions (10%), hepato-biliary abnormalities (7.7%), nervous system/headache (7.7%) musculoskeletal pain (7%), psychiatric (7%), GI (6%) disorders. Eight serious AE (SAE) were reported after Peg-IFNa2b initiation: G4 neutropenia n=2, dysthyroitidis n=1, dyspnea n=1, pleural effusion n=1, lymphoid hyperplasia n=1, hemorrhoids n=1, rectal fistula (SUSAR) n=1. Efficacy was analysed according to the intention-to-treat principle (ITT), and considering missing data as no response to avoid inflated results. Overall at M3, 85% of pts had a BCR-ABL1/ABL1 ratio ≤10%. For eligible patients who received combined therapy (n=61), rates of MMR were 16%, 51%, 70%, and 70% (pending n=5) at M3, M6, M9 and M12, including MR4.5 rates 10%, 20%, 30% at M6, M9 and M12 respectively. Eighteen pts (22.7%) were not eligible to receive Peg-IFNa2b. Reasons, according to protocol criteria, were ANC 4.0 X 109/L (n=1), absence of complete hematologic response (n=1), non compliance (n=1). Rates of MMR for these pts were 27% at M6, 50 % at M9 (missing n=2), pending data for n=6 at M12. Conclusion: Peg-IFNa2b combined to dasatinib therapy in first line CP-CML induces a high rate of deep molecular response (ie MR4.5) during the first year of therapy. Despite few pending data, results at 12 months are already in line with previous data combining Peg-IFNa and TKI, expecting a potential for an increased rate in therapy cessation attempt. Preliminary data of this phase II trial indicate a manageable toxicity profile for this combination, despite an increased rate of neutropenia. Updated analyses (ITT and per protocol) will be presented for all the pts with at least 12 months follow-up. Disclosures ROY:BMS: Other: CongressTravels/Accomodations, Research Funding, Speakers Bureau; Novartis: Other: Congress Travels/Accomodations, Research Funding, Speakers Bureau; Merck: Other: Peg-Interferon provided in the trial. Guerci-Bresler:Novartis: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau; PFIZER: Speakers Bureau. Giraudier:BMS: Speakers Bureau; Novartis: Other: Congress Travel/Accomodation, Speakers Bureau. Johnson-Ansah:Hybrigenics SA: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Ame:Novartis: Speakers Bureau; BMS: Speakers Bureau. Etienne:BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau. Nicolini:BMS: Other: Travel/Accommodations/Expenses; Novartis: Other: Travel, Accommodations, Expenses; ARIAD: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Consulting or Advisory Role, Speakers Bureau; Novartis: Honoraria, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Ianotto:Novartis: Other: Congress Travel/ Accomodations. Legros:ARIAD: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Coiteux:BMS: Speakers Bureau. Hermet:BMS: Speakers Bureau; Novartis: Speakers Bureau. Mahon:BMS: Speakers Bureau; Novartis: Speakers Bureau. Rousselot:ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau.

Safety and Efficacy of Addition of Pegylated Interferon alpha2b to Standard Dose Dasatinib in Newly Diagnosed Chronic Phase CML Patients

▪Rationale: Dasatinib (DAS) and interferon have different modes of action and may have synergistic activity in CML, due to both antineoplastic and immunostimulatory mechanisms. Addition of pegylated interferon (PegIFN) to imatinib therapy in CP-CML has in previous clinical trials (French SPIRIT and NordCML002) resulted in deeper molecular responses. Thus, an optimal combination of DAS and PegIFN may increase the proportion of patients who reach deep molecular response with potential for treatment-free remission (TFR).Design: Newly diagnosed CP-CML patients were treated with DAS (Sprycel, BMS) 100 mg OD as single drug for three months. Thereafter weekly subcutaneous injections of Peg-IFN α2b (PegIntron, MSD) were added to DAS; from end of month 3 (M3) to M6, 15µg/week, thereafter 25µg/week until M15. Primary end points were safety and the rate of MMR at M12. The doses of PegIFN were lower than in the SPIRIT and NordCML002 studies to increase adherence.Population: Forty patients were included at 14 university centers. One patient was lost to follow-up after M6. All patients were included in analysis up to M12. Mean and median age was 48 years (range 19-71). The proportions of high risk patients were 25% (Sokal), 15% (Hasford), and 15% (EUTOS).Safety and dosing: Treatment was well tolerated with expected DAS and PegIFN related side effects. Six patients had seven serious adverse events (AEs), all hospitalizations. 1 episode each of bradycardia/atrial fibrillation (possibly PegIFN-related), headache (DAS), fever (PegIFN), anaphylaxis-like reaction (PegIFN), fever/malaise/headache (PegIFN), pneumonia and a knee effusion (both unrelated). One pleural effusion occurred (grade 2, 3%). Grade 3-4 neutropenia and thrombocytopenia occurred in 6 and 9 patients respectively. Prolonged hematological toxicity (>2 months) occurred in 8 patients, causing dosing problems in 5. One patient suffered grade 3 depression. Grade 3 flu-like symptoms occurred in 2 patients. One patient had lipase elevation grade 3 and one patient developed hypothyroidism attributed to PegIFN. Grade 2 dermal AEs like rash and acne occurred in about 20%, attributable to both drugs. 94% (DAS) and 76% (PegIFN) of assigned dose was given. Dose reductions occurred in 19 patients for DAS and 20 patients for PegIFN. Two patients discontinued DAS and switched to nilotinib, 1 for headache at M3 and 1 at M12 for lack of efficacy/hematological toxicity. Two patients could not start PegIFN for hematological toxicity (one lost to follow-up after M6). PegIFN was discontinued because of bradycardia/atrial fibrillation (1 patient), anaphylaxis (1 patient), flu-like syndrome (2 patients) and long-term hematological toxicity (2 patients). At 12 months 31/38 pats (82%) were still on PegIFN, a higher proportion than in the French Spirit or NordCML002 studies.Efficacy: We have used the DAS arm of the Dasision study (Kantarjian NEJM 2010) as a historical control. Early response at M3 was very similar between studies. In the present and the Dasision cohorts respectively, 18% vs 16% missed the 10% BCR-ABLIS landmark, 66% vs 56% achieved a CCyR and 8% vs 8% achieved MMR. At M6, three months after introduction of PegIFN, a steep increase in MMR rate was observed compared with Dasision. This was also reflected in deep responses, MR4.0 (see tables) and MR4.5 at M12, 18% vs 5%. The primary efficacy endpoint was MMR at M12, 82% vs 46%. Table 1MMRDAS+PegIFN (%)DAS (Dasision)(%)Difference (%)M3880M6532726M9663927M12824636Table 2MR4.0DAS+PegIFN (%)DAS (Dasision) (%)Difference (%)M3303M620614M938830M12481236Progressions and treatment failure defined by ELN 2013: Failures: No progression was noted. At M3, 2 patients still had >95% Ph+ metaphases (MF). At M6, four patients (11%) had > 35% Ph+MF or >10% BCR-ABL levels. At M12, one patient failed CCgR and two more patients failed <1% BCR-ABL. No BCR-ABL mutations were detected in "failure" patients.Conclusion: The combination of DAS and low dose PegIFN could be safely administered in newly diagnosed CP CML. No unexpected autoimmune phenomena were observed, and pleural effusions were rare. Efficacy appears very promising with high early MMR rates and deep molecular responses. A randomized comparison DAS +/- PegIFN is warranted.Support: Study drug from BMS and MSD. Grant from BMS. [Display omitted] DisclosuresHjorth-Hansen:Ariad: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Off Label Use: Dasatinib and Pegylated IFN combination in CML. Richter:Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding.

USP18 downregulation in peripheral blood mononuclear cells predicts nonresponse to interferon-based triple therapy in patients with chronic hepatitis C, genotype 1: a pilot study.

Background and aimsPatients with advanced liver fibrosis owing to chronic hepatitis C virus genotype 1 represent a difficult-to-treat group even if a protease inhibitor is added to pegylated interferon alpha and ribavirin. Therefore, only patients with a high chance of cure should be treated with interferon-based treatment.Patients and methodsExpression of IFNG, IFNLR1, and interferon-sensitive genes CXCL9, IFI16, IFI27, ISG15, and USP18 in peripheral blood mononuclear cells was assessed before and during the initial 12 weeks of treatment. The studied group consisted of 26 treatment-experienced patients of average age of 50 years with advanced liver fibrosis compared to seven healthy volunteers. Fourteen patients were treated with pegylated interferon alpha 2b, ribavirin, and boceprevir and 12 patients with telaprevir. The overall sustained virological response (SVR) rate was 69% (18/26).ResultsA significant difference in the initial expression (median, interquartile range [IQR]) of CXCL9 2.9×, IQR: 1.7–12.4 vs 1.2×, IQR: 0.5–1.8; (P=0.01) IFNG 7.3×, IQR: 1.7–32.6 vs 0.7×, IQR: 0.4–1.3; P=0.002 and USP18 3.7×, IQR: 2.1–7.7 vs 1.4×, IQR: 0.9–1.6; (P=0.03) was found between the SVR and non-SVR groups. Expression of all analyzed genes was progressively increasing during the first 12 weeks of therapy, but a significant difference between SVR and non-SVR group was found only in USP18 expression at week 12 (P=0.001). Initial expression of four genes predicted SVR in univariate analysis (CXCL9 [OR: 12.00, 95% CI: 1.21–118.89], IFI27 [OR: 12.00, 95% CI: 1.21–118.89], IFNG [OR: 10.50, 95% CI: 1.50–73.67], USP18 [OR: 21.00, 95% CI: 2.05–215.18]). In multivariate analysis, only the initial expression of USP18 was identified as a predictor of SVR (P=0.047).ConclusionInitial expression of USP18 and the course of its activation could be a reliable predictor of SVR achievement.

345PD A phase I study of pegylated interferon alfa-2b as an adjuvant therapy in Japanese patients with malignant melanoma

345PD A phase I study of pegylated interferon alfa-2b as an adjuvant therapy in Japanese patients with malignant melanoma

Efficacy and Tolerability of Peginterferon alpha-2a and Peginterferon alpha-2b in Iranian Patients With Chronic Hepatitis C.

Background:Nearly 0.5% of Iranians are infected with HCV. Peginterferon-alpha-2a and Peginterferon-alpha-2b are the two available types of interferon for the treatment of hepatitis C. Comparing the results of these two treatments is still a challenge.Objectives:The aim of this study was to compare the results of Peginterferon-alpha-2a and Peginterferon-alpha-2b in Iranian patients with chronic hepatitis C.Patients and Methods:289 patients with chronic hepatitis C attending Tehran Hepatitis Center (THC) and Hepatitis Clinic of Tehran Blood Transfusion Organization (TBTO) from January 2008 to April 2013 and treated with combination of Peginterferon-alpha-2a or Peginterferon-alpha-2b plus Ribavirin were enrolled in this retrospective cross-sectional study. Treatment response and side effects were compared.Results:Among all naive patients, 82.0% achieved SVR, 5.4% were resistant to therapy and 11.0% withdrew the treatment. Relapse was seen in 12.2% of naive patients who finished the course of treatment. RVR and EVR were seen in 67.7% and 90.6% of naive patients, respectively. Patients divided into two groups. Group A consists of 247 patients treated with Peginterferon-alpha-2a and group B 42 patients treated with Peginterferon-alpha-2b. No significant difference in treatment response was observed between naive patients of the two groups. The rates of arthralgia/myalgia, alopecia, pruritus, insomnia, dyspnea and anorexia were higher in group A and the rates of dermal problems, coryza and bleeding were higher in group B. In a subgroup analysis, the two kinds of Peginterferon-alpha-2a available in Iran were compared. Rapid and early viral responses and relapse rates were lower in the one made in Iran and the long-term responses were not different. The rates of arthralgia/myalgia, fever, alopecia, pruritus, insomnia, dyspnea, anorexia, cough, headache and abdominal pain were higher and the rates of irritability and coryza were lower in the one made in Iran.Conclusions:There was no significant difference in the efficacy of Peginterferon-alpha-2a and Peginterferon-alpha-2b in Iranian patients. Physicians might choose the treatment regimen for every individual concerning the differences in side effects of Peginterferons.