Interferon Alpha-2a Research Articles

Modern etiotropic therapy of chronic viral hepatitis B

Chronic viral hepatitis B (CHB) is a significant global health problem. The biological characteristics of the hepatitis B virus, which causes this disease, significantly impede the achievement of complete virus elimination in most patients. In this regard, the rational choice of drugs and antiviral therapy regimens is crucial for increasing life expectancy and improving the quality of life in patients with CHB. The purpose of this literature review is to identify current approaches and trends in etiotropic therapy for CHB.Materials and methods. The review uses data published in domestic and foreign scientific journals, clinical guidelines, regulatory documents, and Internet resources.Results. Currently, the most effective means of etiotropic therapy for CHB are interferons (standard interferon alpha, pegylated interferons alpha-2a and alpha-2b), as well as first-line nucleoside/nucleotide analogs (entecavir, tenofovir) and second-line analogs (lamivudine, telbivudine, adefovir). The choice of a specific drug is determined by the patient's clinical condition, preferences, availability, and cost of treatment. Despite certain limitations of current etiotropic therapies for CHB, their use can significantly increase patients' life expectancy and improve their quality of life.

Association of serum interferon alpha-2a levels with disease severity and prognosis in systemic sclerosis.

To determine serum type I interferon IFN-α2a concentrations in systemic sclerosis (SSc) patients, explore its association with cytokine/chemokine expressions, and evaluate correlation with the phenotype including the predictive value for interstitial lung disease (ILD) progression. Serum samples were obtained from 200 SSc patients and 29 healthy controls. IFN-α2a levels were measured by ultrasensitive electrochemiluminescence assay. Pro-inflammatory and chemokine panels were determined by Luminex® Discovery Assay multiplex kit. Baseline SSc disease characteristics were recorded together with longitudinal data for determining ILD progression after 2 years. IFN-α2a concentrations were higher in SSc patients compared with controls, although not reaching significance (means ± SD of 49.20 ± 156.8 pg/ml vs 9.606 ± 4.399 pg/ml, respectively; (p = 0.158)). Using the cut-off of 15.9 pg/ml, we identified 62 patients as having a type 1 (T1) IFN signature in their circulation. Patients with an IFN signature had significantly higher levels of chemokines (CCL8, CCL19, CXCL10, CXCL11), and the cytokine IL-1α compared with those without an IFN signature. IFN-α2a concentrations strongly correlated with a T1 IFN related chemokine score supporting activation of this pathway. Phenotyping association queries revealed association between IFN values and both skin and ILD involvements at baseline. Longitudinal data did not identify IFN as a predictive marker for ILD progression. Using serum determinations, the activation of the T1 IFN pathway showed strong correlations with inflammatory mediators and associations with clinical manifestations, especially skin fibrosis and ILD in SSc patients. However, activated IFN pathway was not predictive of ILD progression.

Combination therapy with ruxolitinib and pegylated interferon alfa-2a in newly diagnosed patients with polycythemia vera

AbstractWe report the 2-year end-of-study results from the phase 2 COMBI II clinical trial investigating the combination treatment of ruxolitinib and low-dose pegylated interferon alfa-2a in patients with newly diagnosed polycythemia vera (PV). The primary outcome was safety and key secondary endpoints were efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF). We used the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria. The remission criteria included remissions in symptoms, splenomegaly, peripheral blood counts, and bone marrow. We included 25 patients with PV with a median age of 70 years; 5 of those had prior thromboembolic events and 3 had computed tomography–verified splenomegaly. Two patients stopped both study drugs; 1 of these due to progression to post-PV myelofibrosis, the only one with a grade 3 infection. No events of herpes zoster infections were observed. None of the patients discontinued treatment due to psychiatric symptoms. The peripheral blood cell count remission rate was 92% at 24 months. Using the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria, 14 (56%) achieved remission at 24 months; 3 (12%) achieved complete remission and 11 (44%) achieved partial remission. The following items from the Myeloproliferative Neoplasm Symptom Total Symptom Score were significantly reduced: abdominal discomfort, night sweats, itching, and bone pain. The median JAK2V617F VAF decreased from 47% (95% confidence interval [CI], 35-59) to 7% (95% CI, 3-15), and 60% of patients achieved molecular remission. In conclusion, combination treatment improved cell counts; bone marrow cellularity, and fibrosis; and decreased JAK2V617F VAF; with acceptable toxicity in patients with PV. The trial was registered at www.clinicaltrialsregister.eu as #EudraCT2018-004150-13.

Feasibility, tolerability, and first experience of intracystic treatment with peginterferon alfa-2a in patients with cystic craniopharyngioma.

Children with craniopharyngiomas (CPs) typically suffer from a life-long chronic disease. The younger the child, the more vulnerable the maturing brain is to invasive therapies such as surgery or radiotherapy. Therefore, treatment modalities facilitating avoidance or delay of invasive therapies are beneficial for these patients. In the last decade, intracystic injection of interferon alfa-2a or alfa-2b evolved as a treatment of choice based on efficacy and minor toxicity. However, the drug is no longer available internationally. After an extensive pharmacological review, peginterferon alfa-2a was identified as the agent with closest similarity. A retrospective case series is described, including five patients treated with intracystic peginterferon alfa-2a for cystic CP according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI. Patients' age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage. Intracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic CP. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes.

CP-07. FEASIBILITY, TOLERABILITY AND FIRST EXPERIENCE OF INTRACYSTIC TREATMENT WITH PEGINTERFERON ALFA-2A IN PATIENTS WITH CYSTIC CRANIOPHARYNGIOMA

Abstract BACKGROUND Craniopharyngiomas (CP) is a life-long chronic disease predominantly affecting young children. Consequently, the developing brain is particularly sensitive to therapies such as surgery or radiotherapy. Hence, therapies allowing to avoid or delay intensive therapies provide substantial benefit. Intracystic injection of interferon alfa-2a or -2 has emerged as frequently applied treatment based on advantageous risk-benefit ratio with good effects leading to cyst shrinkage. Unfortunately, the original drug is worldwide no longer available. To overcome this shortage we performed an elaborate pharmacological review, identifying peginterferon alfa-2a (Pegasys®) as best currently available alternative drug for intracystic treatment of CP patients. METHODS Within an international collaboration we set up a novel protocol for intracystic peginterferon treatment. Based on the protocol five patients were treated with intracystic peginterferon alfa-2a for cystic CP. After initial CP cyst-aspiration peginterferon alfa-2a was injected once per week via an Ommaya reservoir. One treatment course was six weeks accompanied by regular response assessment with MRI (3-6 weeks). Side effect, safety and therapeutic effects were analyzed. RESULTS Age of patients ranged from 4 to 54 years (4 pediatric patients &amp;lt;12 years, 1 adult patient). Intracystic therapy with peginterferon alfa-2a was generally well tolerated throughout the treatment course and resulted in cyst shrinkage in all cases. Cyst leakage was observed in one case highlighting the importance of testing cyst permeability before starting intracystic treatment courses. CONCLUSIONS Taken together, intracystic treatment with peginterferon alfa-2a was feasible and effective being comparable to prior intracystic interferon protocols for cystic CP being of potential clinical benefit for this severely affected patient cohort. Our experience in this small cohort indicated the potential of this treatment modality, which should be further investigated within a larger trial cohort.

Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D

BackgroundIn a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear.MethodsIn this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 μg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.ResultsA total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity.ConclusionsThe combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.)

GS-002 48-week off-therapy efficacy and safety of bulevirtide in combination with pegylated interferon alfa-2a in patients with chronic hepatitis delta: final results from the phase 2b, open-label, randomised, multicentre study MYR204

GS-002 48-week off-therapy efficacy and safety of bulevirtide in combination with pegylated interferon alfa-2a in patients with chronic hepatitis delta: final results from the phase 2b, open-label, randomised, multicentre study MYR204

Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules.

Some drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian Immunodeficiency Virus (SIV), but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses. To investigate this hypothesis, drugs were tested ex vivo on peripheral blood mononuclear cells (PBMC) from nine antiretroviral therapy (ART)-suppressed individuals. We tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant [inhibitor of apoptosis proteins (IAP) inhibitor], bortezomib (proteasome inhibitor), and INK128/sapanisertib [mammalian target of rapamycin mTOR] [c]1/2 inhibitor). After 6 days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay). Obatoclax reduced intact HIV DNA [median = 27-30% of dimethyl sulfoxide control (DMSO)] but not defective or total HIV DNA. Other drugs showed no statistically significant effects. Obatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.

Results of Response-Guided Therapy with Pegylated Interferon Alpha 2a in Chronic Hepatitis B and D.

Pegylated interferon alpha 2a continues to be used for the treatment of chronic hepatitis D. The reported on-treatment virologic response varies between 17 and 47%, with relapses in more than 50% of these patients. No stopping rules have been defined, and the duration of the treatment is not clearly established, but it should be between 48 and 96 weeks. In total, 76 patients with compensated liver disease treated with peg-interferon according to the Romanian National protocol for the treatment of hepatitis D were retrospectively included. The duration of treatment was up to 96 weeks, with the following stopping rules: less than a 2 log HDV RNA decrease by week 24 and less than a 1 log decrease every 6 months afterwards. Six months after stopping the treatment, it can be restarted for unlimited cycles. The inclusion criteria were aged above 18, HBs Ag-positive, HDV RNA detectable, ALT above ULN and/or liver fibrosis at least F1 at liver biopsy, or Fibrotest and/or Fibroscan higher than 7 KPa and/or inflammation at least A1 at liver biopsy or Fibrotest. We monitored our patients for a total period of 4 years (including those that repeated the cycle). After the first 6 months of treatment, 27 patients (35.5%) had a greater than 2 log HDV RNA decrease, 19 of them achieving undetectable HDV RNA. Seventeen patients (22.3%) had undetectable HDV RNA 24 weeks after stopping 96 weeks of treatment, and none relapsed in the following 2 years. Of these 17 patients, 6 were cirrhotic, and 4 had F3. Undetectable HDV RNA at 24 weeks was the only parameter that predicted a long-term suppression of HDV RNA. In 49 patients, the treatment was stopped after 6 months according to protocol, but it was restarted 6 months later. Five of these patients finished a 48-week course of treatment; none achieved undetectable HDV RNA. During the first course of therapy, 45 patients had at least one moderate adverse reaction to treatment. In one patient, the treatment was stopped due to a serious adverse event (osteomyelitis). Treatment doses had to be reduced in 29 patients. The virologic response at week 24 can select the patients who will benefit from continuing the treatment from those who should be changed to another type of medication when available.

Treatment results of our patients with acute viral hepatitis C

Aim: The diagnosis of acute hepatitis C virus (HCV) infection can be made during follow-up in patients with a generally known risk contact, as it is mostly asymptomatic. The earliest indicator of acute HCV infection is increased HCV-RNA. Anti-HCV seroconversion is also the strongest evidence of acute infection. The risk of chronicity is at least 80%. Treatment of acute HCV infection is recommended because of the high rate of chronicity. Spontaneous recovery can be seen after 8-12 weeks in acute viral hepatitis C. Therefore, 8-12 weeks should be waited to start specific treatment. The aim of this study is to evaluate the data of the patients we follow up with the diagnosis of acute HCV in our clinic, to determine the most appropriate time to start treatment in acute viral hepatitis C and to evaluate the effectiveness of Peg-interferon alfa 2a treatment.&#x0D; Materials and Methods: The data of patients diagnosed with acute viral hepatitis C in our clinic between 2005 and 2015 were evaluated.&#x0D; Results: Twelve patients with acute viral hepatitis C were followed in our clinic. Twelve of the cases were male, and the mean age was 38.83 ± 6.75 (range, 25-50) years. Spontaneous clearance was observed in three patients at the third month. Three months after the acute diagnosis of HCV, pegylated-interferon alpha 2a 180 mcg (1x1 / week sc) was started in nine patients without spontaneous improvement and treatment was performed for six months. Treatment response was 100% at 6-month and 2-year follow-ups.&#x0D; Conclusion: Acute viral hepatitis C is a disease that should not be overlooked.&#x0D; After diagnosis, 8-12 weeks should be waited for spontaneous viral clearance. Patients who do not develop spontaneous viral clearance after 8-12 weeks can be largely treated with interferon alfa 2a therapy.&#x0D; Spontaneous recovery was observed in three of our patients after 8-12 weeks of follow-up (HCV-RNA was negative by PCR, AST-ALT values were normal).

Subcutaneous panniculitic-like T-cell lymphoma localized to a site of peginterferon alfa-2a administration

T cell dyscrasias that demonstrate a proclivity for the subcutaneous fat include atypical lymphocytic lobular panniculitis, lupus profundus, and primary subcutaneous T cell lymphoma, including subcutaneous panniculitis-like T cell lymphoma (SPTCL). We encountered two patients who developed fever and indurated abdominal erythema at their peginterferon alfa-2a injection sites. Biopsies showed an atypical CD8 positive, granzyme positive, CD5 negative, MXA negative lymphocytic lobular panniculitis, diagnostic of SPTCL. Peginterferon alfa-2a was held in both patients. One patient received chemotherapy with an excellent response, while the other continued to have progressive disease. Peginterferon alfa-2a is known to significantly elevate serum MXA, which may induce high levels of MXA expression at the injection site, creating a microenvironment for the development of lupus profundus, which may eventuate into SPTCL. In summation, a potential risk of peginterferon alfa-2a injections is the development of SPTCL potentially arising in a background of an exogenous interferon triggered lymphocytic panniculitis.

Interferons in the treatment of myeloproliferative neoplasms.

Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferon-based therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.

Comparing Common Therapies in Polycythemia Vera (PV): A Disproportionality Analysis in the FDA Adverse Event Reporting System (FAERS) Database

Background: Prior to the approval of ropeginterferon alfa-2b-njft (ropeginterferon) in November 2021, the alternatives to hydroxyurea for the treatment of polycythemia vera (PV) included Janus Kinase inhibitors (JAKi) and older versions of recombinant interferon-alpha (rIFNα). As ropeginterferon and the JAKi ruxolitinib are the only FDA approved medications for the treatment of PV, we conducted a safety review of the FDA's Adverse Event Reporting System (FAERS) to assess reporting rates for adverse events (AEs) of both FDA-approved and non-FDA approved rIFNα and JAKi agents. Methods: AE data for ropeginterferon, peginterferon alfa-2a, ruxolitinib, and pacritinib in PV-treated patients were obtained from FAERS reports from November 1, 2021, through March 31, 2023. AEs were recorded using preferred terms (PTs) and primary system organ classes (SOCs) from the Medical Dictionary for Regulatory Activities (MedDRA). Serious non-fatal AEs (SAEs) were defined as AEs requiring hospitalization, life-threatening, resulting in disability, congenital anomaly, or otherwise medically significant. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated using R v4.2.3 Statistical Software. The RORs were used to detect disproportional reporting rates for non-serious AEs, SAEs, and fatal AEs as well as SOC-specific reporting rates. A reporting signal was considered significant when the ROR 95% CI lower limit was greater than one. Results: SOC-specific RORs for the assessed treatments are summarized in Table 1. RORs by AE seriousness are displayed in Figure 1. Ropeginterferon had the only non-serious AE significant ROR (ROR = 5.37; 95% CI: 3.63 - 7.94). The two highest SOC-specific RORs for ropeginterferon were “Medical and Surgical Procedures” (ROR = 15.32; 95% CI: 1.88 - 124.67) and “Social Circumstances” (ROR = 6.30; 95% CI: 2.66 - 14.94). Peginterferon alfa-2a had the highest SAE reporting odds (ROR = 5.68; 95% CI: 3.03 - 10.6). The highest SOC RORs for peginterferon alfa-2a were “Hepatobiliary Disorders” (ROR = 16.35; 95% CI: 4.86 - 55.01) and “Immune System Disorders” (ROR = 5.11; 95% CI: 1.49 - 17.48). Ruxolitinib was the only agent assessed to have significant reporting signals for both SAEs (ROR = 1.93; 95% CI: 1.43 - 2.61) and fatal AEs (ROR = 9.86; 95% CI: 3.62 - 26.82) The highest SOC RORs for ruxolitinib were “Neoplasms Benign, Malignant, and Unspecified” (ROR = 7.96; 95% CI = 3.47 - 18.27) and “Product Issues” (ROR = 3.85; 95% CI: 2.42 - 6.12). Conclusions: This study examined FAERS reports to detect disproportional reporting odds of drug-associated AEs severity and SOCs in four PV treatments: ropeginterferon, ruxolitinib, interferon alfa-2a, and pacritinib. Ropeginterferon had a significant ROR for non-serious AEs. Peginterferon alfa-2a demonstrated a significant ROR for SAEs. Ruxolitinib had both significant SAE and fatal AE RORs. The highest SOC-specific RORs for ropeginterferon were in the non-specific categories of “Medical and Surgical Procedures” and “Social Circumstances.” Peginterferon alfa-2a had significant SOC signals for “Hepatobiliary Disorders” and “Immune System Disorders,” which are AE categories also reported in the prescribing information for peginterferon alfa-2a. “Neoplasms Benign, Malignant, and Unspecified” was the highest SOC ROR for ruxolitinib and may potentially relate to the association of treatment with secondary malignancies. Limitations include a lack of adjustments for multiplicity due to the exploratory nature of the analysis. AEs reports to FAERS may not be treatment related. In addition, publicity or FDA approvals may disproportionately affect reporting rates for ropeginterferon (FDA-approved in 2021) or ruxolitinib (approved for PV in 2014). FAERS may also not include representative AE reports as healthcare provider and patient submissions are both postmarketing and voluntary. Fatal events during clinical trials were reported to the FDA (including ropeginterferon) but are not reflected in FAERS. Therefore, FAERS data may not represent the true incidence of AEs. Reporting signals for any treatments or any causal relationship should be confirmed by assessing future AE reporting trends, electronic health records analysis, or prospective clinical trials.

Protein profiles in the transfected oviductal secreting cells of laying hen (Gallus gallus domesticus)

Due to the intensive development of novel biopharming applications, there is a need for the in vitro verification models prior to in vivo testing. Laying hen has been already applied as an animal bioreactor to produce the therapeutical enzyme in a rare disease called lysosomal acid lipase deficiency. In this study, we aimed to verify how the proteome of the transfected oviduct epithelial cells would be affected by genetic nonviral modification with the human exogene. The study was based on a previously developed method to cultivate chicken oviduct epithelial cells (COEC). The typical characteristics of the COEC epithelial cells were retained across the experiments. The mean efficiency of nucleofection ranged from 2.6 to 19.7% depending on the cells' isolation and location in the oviduct (upper, infundibulum site, or magnum). The PCR confirmed the incorporation of human interferon alpha2a (hIFNα2a) exogene into the nucleofected COEC but, the production of hIFNα2a protein did not exceed the detection level in this study. The ovalbumin protein was detected in the nontransfected and transfected COEC, which confirmed the normal secreting functions of the cells subject to modification. Proteomic analysis revealed an increase in abundance of the cell adhesion molecules and collagen molecules after introducing gene under ovalbumin promoter. According to the bioinformatic analyses there was a limited negative impact of transfection on cells, and the normal biochemical pathways were not severely disordered. In conclusion, the observations provide new knowledge about the proteomic profile of the manipulated COEC with regard to the retained normal functionality of the cells, which can be informative for avian biopharma research.

Efficacy of Pegylated Interferon Alpha-2a in Uveitic Macular Edema Refractory to Biologic Agents

ABSTRACT Purpose To report the efficacy of pegylated interferon alpha-2a (Roferon, Hoffmann-La Roche brands, Switzerland) in uveitic macular edema refractory to biologic agents. Methods Herein, we present two cases of non-infectious uveitis with cystoid macular edema (CME) who were unresponsive to immunosuppressant treatment, and whose uveitis and macular edema recurrences were prevented with subcutaneous injections of pegylated interferon α-2a. Results Two young males (27- and 30-year-old) diagnosed with non-infectious uveitis and CME were on immunosuppressive treatment. Although both received systemic steroids and biologic agents, macular edema persists. After initiation of pegylated interferon alpha-2a (Pegasys, Genentech, USA) CME regressed significantly and did not occur during their follow-ups of 14 and 12 months. Conclusion Pegylated interferon-alpha-2a can be used as an effective alternative to interferon alpha-2a in uveitic macular edema cases, resistant to other immunosuppressive agents.

Mogamulizumab for Refractory CD3-CD4+ Lymphocytic-Variant Hypereosinophilic Syndrome

OCS Introduction. Lymphocytic hypereosinophilic syndrome (L-HES) is an indolent T-cell lymphoproliferative disorder characterized by chronic blood hypereosinophilia and eosinophil-related organ damage secondary to the production of eosinophilopoietic cytokines (including interleukin-5) by clonal T cells, among which CD3-CD4+ T cells are the most frequent subset. Both high exposure to oral corticosteroids (OCS), failure and/or toxicity of OCS-sparing therapies and the risk of progression to AITL (up to 5 - 10% of patients) underscore the unmet need for novel treatments targeting the clonal T-cells (and not only eosinophils). We previously reported that peripheral CD3-CD4+ T cells express C-C chemokine receptor 4 (CCR4). We hypothesized that mogamulizumab, an afucosylated monoclonal antibody targeting CCR4-positive cells through antibody-dependent cellular cytotoxicity, could be beneficial for refractory L-HES patients. Methods. We assessed both the expression of CCR4 by clonal CD3-CD4+ T cells in the skin and lymph nodes as well as theability of mogamulizumab to induce ADCC in vitro on sorted CD3-CD4+ T cells from two L-HES patients, using homologous sorted NK cells as effector cells. We then set up a compassionate use program of intravenous mogamulizumab (1.0 mg/kg weekly for the first 28-day cycle, then on days 1 and 15 from subsequent cycles) for refractory L-HES patients despite treatment with immunosuppressants and/or biologics targeting the IL-5 pathway. Complete blood response was defined as complete if the subset of CD3-CD4+ T cells was &amp;lt;0.5% of all lymphocytes, or as partial if the number of CD3-CD4+ T cells decreased by &amp;gt;50% without reaching complete response at the time of the last perfusion. Results. Significant CCR4 expression on tissue CD4+ T cells was evidenced, and NK cells indeed led to the lysis of CD3-CD4+ T-cells coated with mogamulizumab (10 μg/ml). Four patients with refractory L-HES (despite treatment with high-dose OCS, n=4; pegylated interferon alpha 2a; n=3; or mepolizumab, a single patient) and active disease entered the compassionate use program (Table 1). Despite substantial tapering in OCS doses, all cases showed clinical response. Blood responses (either partial or complete, two patients each) and sharp decrease in absolute eosinophil counts (AEC) were reported in all patients ( Figure 1). Both patients with lymph node enlargement rapidly improved. Although prolonged blood and clinical responses have been observed after discontinuation of mogamulizumab, relapses still occurred preceded by an increase in T-cell clone size and absolute eosinophil count (AEC). Rechallenging a relapse with a short course of mogamulizumab resulted in a complete remission for a further 12 months in case #1. In terms of safety, mogamulizumab was discontinued in two patients due to adverse events: one for recurrent infusion-related reactions and one for infectious events. Lymphopenia was reported in 3/4 cases but was preexisting in the 3 cases. Case #4 reported a serious adverse event related to a tumor lysis syndrome leading to the massive release of IL-5 and subsequent rebound of AEC. Hence lower doses of mogamulizumab, transient use of OCS and/or mepolizumab should be considered in patients with very high number of CD3-CD4+ T cells who are about to start mogamulizumab. Discussion. Mogamulizumab represents a new therapeutic option for L-HES patients with severe refractory HES, T-cell clone related symptoms and/or large or rapidly increasing clonal T-cell counts. In patients who achieve complete remission under mogamulizumab, whether fixed repeated (e.g., every 6 months) infusions could be beneficial to prevent relapses and transformation into high-grade lymphoma remains to be investigated. Figure legend. Hematological responses to mogamulizumab in four refractory lymphocytic HES patients. oral corticosteroids; pINF-α: pegylated interferon alpha; MEPO: mepolizumab; MOGA: mogamulizumab.

Real-World Experience of Ropeginterferon-Alfa Treatment of PV and ET - Two Centers Experience

BACKGROUND AND AIM: Interferon alpha is an effective treatment for Polycythemia Vera (PV) and Essential Thrombocythemia (ET) and is the only treatment known to induce sustained molecular responses by decreasing JAK2 mutation allelic burden. Long-acting pegylated interferons are better tolerated. Ropeginterferon-alfa is a monopegylated interferon with a longer half-life and is the first interferon to be FDA-approved for the treatment of PV. It is not yet approved for ET, but clinical trials are ongoing. Given the similar disease biology between PV and ET and the efficacy of pegylated interferon-alfa in both PV and ET, this study aims to look at a real-world experience of treating PV and ET with ropeginterferon-alfa since its approval. METHODS: We conducted a retrospective chart review of all our PV and ET patients treated with ropeginterferon-alfa at Huntsman Cancer Institute, University of Utah (SLC cohort), and at the University of North Carolina at Chapel Hill (UNC cohort), since the drug's approval for PV from November 2021 through June 2023. The complete hematologic response (CHR) was defined as the normalization of blood counts within the reference range of the local lab standards. Prior to ropeginterferon-alfa, the participants were managed with therapeutic phlebotomies, or cytoreduced with either hydroxyurea, pegylated interferon-alpha 2a ( Pegasys), JAK2 inhibitors, or were newly diagnosed and previously untreated. RESULTS: A total of 120 patients (76 in SLC cohort and 44 in UNC cohort) were included in this study. Of those, 75 (62.5%) were diagnosed with PV, 37 (31%) with ET, and 1 with congenital polycythemia due to germline JAK2 mutation. Twenty-three (19%) patients had a prior history of thrombosis. JAK2 mutation was present in 100 (83%) patients, while 9 (7.5%) were CALR mutated, 1 with MPL mutation, and 1 with triple-negative ET. Extended myeloid gene panel sequencing was available in 64 (53.3%) patients and 35 of them (54.6%) patients had additional somatic mutations. Most common somatic mutations include TET2 (11 patients) and DNMT3A (8 patients) and CBL (3 patients), among others. Of the cohort, 15 (12%) patients discontinued ropeginterferon-alfa due to various adverse events, which included: fatigue, joint aches, skin rash, and increased anxiety and depression. Of the 105 patients who are on ropeginterferon-alfa, 9 patients were previously untreated patients while 96 (91.4%) were pretreated with other therapies and switched to ropeginterferon-alfa. In many patients, the switch to ropeginterferon-alfa was done because of the increased frequency and aggressivity of squamous cell skin cancers while on hydroxyurea treatment. All of them started ropeginterferon-alfa at a dose of either 50 mcg or 100 mcg every two weeks and were increased at an increment of 50 mcg to achieve a goal of CHR. As most of the patients were switching from prior therapies, 51 (49%) were already in CHR at the time of initiating ropeginterferon-alfa. The median ropeginterferon-alfa dose to maintain CHR was 50mcg in the SLC cohort and 100mcg in the UNC cohort. (See table for more details). We have 6 patients with DNMT3A mutation, 4 (66.6%) have achieved CHR at a median ropeginterferon-alfa dose of 100 mcg (range 50 mcg - 150 mcg), and 2 patients are undergoing dose titration. Of the 11 patients with TET2 mutation, 7 (63.3%) achieved CHR at a median ropeginterferon-alfa dose of 150 mcg (range 50 mcg - 500 mcg). The analysis of JAK2 V617F and CALR allelic burden, transcripts of inflammatory, prothrombotic, and hypoxia-regulated (HIFs) genes, and evaluation of females for reversal of clonal to polyclonal myelopoiesis is ongoing. CONCLUSION: Ropeginterferon-alfa is effective in PV and ET, however, the dose that achieves CHR is highly individualized, necessitating an incremental titration approach. The patients already in CHR from prior therapy needed relatively lower doses of ropeginterferon-alfa to maintain CHR. Clinical trials are ongoing with an alternate accelerated dosing scheme and results are awaited.

Hematopoietic stem cell transplantation in primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: A case report

Primary Cutaneous Aggressive Epidermotropic CD8+ T-Cell Lymphoma (PCAETCL), a rare subtype of Primary Cutaneous Lymphoma (PCL), is known for its aggressive clinical course and refractoriness to standard treatments. Clinically, PCAETCL often presents with skin lesions that rapidly disseminate to various extracutaneous sites, resulting in a grim prognosis with a 5-year survival rate of less than 40%. This article presents a case of a 43-year-old male patient initially diagnosed with CD8+ cytotoxic Mycosis Fungoides (MF). The patient’s treatment course involved multiple therapeutic modalities, including methotrexate, bexarotene, gemcitabine, peginterferon alfa 2a, and radiation therapy. Despite several lines of treatment, disease progression persisted. Eventually, the patient underwent allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) from his sister, marking a turning point in his therapeutic approach. The case underscores the diagnostic and therapeutic challenges associated with PCAETCL. It shows the heterogeneous responses found in literature, ranging from brief remissions to unfavorable outcomes, including severe infections. This highlights the lack of standardized treatment protocols for PCAETCL, with HSCT, both allogeneic and autologous, emerging as potential options for achieving prolonged responses. In conclusion, PCAETCL remains a rare and aggressive clinical entity with no established standard treatment. This case report illustrates the aggressive nature of the disease and the importance of individualized treatment approaches, including transplantation. Collaborative research efforts are crucial to enhance our understanding of PCAETCL, identify prognostic factors, and develop more effective therapeutic strategies to improve patient outcomes. Keywords: Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma Lymphoma; T-Cell; Cutaneous; Allogeneic hematopoietic stem cell transplantation Mycosis Fungoides; Extracutaneous manifestation Central nervous system involvement Multiple lines of therapy.

Five-year follow-up of 96 weeks peginterferon plus tenofovir disoproxil fumarate in hepatitis D.

Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown. In the HIDIT-II study patients (including 40% with liver cirrhosis) received 180 μg PEG-IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 μg PEG-IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy). Until the end of follow-up, 16 (13%) patients developed liver-related complications (PEG-IFNa + TDF, n = 5 vs PEG-IFNa + placebo, n = 11; p = .179). Achieving HDV suppression at week 96 was associated with decreased long-term risk for the development of hepatocellular carcinoma (p = .04) and hepatic decompensation (p = .009). Including complications irrespective of PEG-IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG-IFNa (16/102, p > .999) but was associated with a higher chance of HDV-RNA suppression (p = .024, odds ratio 3.9 [1.3-12]). Liver-related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG-IFNa treatment. PEG-IFNa treatment should be recommended to HDV-infected patients until alternative therapies become available. Retreatment with PEG-IFNa should be considered for patients with inadequate response to the first course of treatment. NCT00932971.

MPN-119 Retrospective Evaluation of BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) Treated With Pegylated Interferon Alfa-2A at a Single Center

MPN-119 Retrospective Evaluation of BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) Treated With Pegylated Interferon Alfa-2A at a Single Center