Interferon Alfa-2b Research Articles

Efficacy of Ropeginterferon Alpha 2b in Inducing Treatment Free Remission in Chronic Myeloid Leukemia - an International, Randomized Phase III Trial (ENDURE, CML-IX) of the German CML-Study Group

Background: Only a minority of chronic myeloid leukemia (CML) patients can eventually successfully discontinue tyrosine kinase inhibitor (TKI) therapy after achieving a stable deep molecular remission. Mechanisms underlying a durable treatment free remission (TFR) are not well understood but supposedly involve restoration of anti-CML immunity. It was therefore hypothesized that interferon alpha (IFN) - a potent inducer of Th1-immunity and prior standard therapy in CML - might improve the TFR probability. Randomized trials to improve TFR rates in CML are currently lacking. ENDURE, CML-IX (NCT03117816) is a multicenter, international phase III trial evaluating the role of a novel form of pegylated proline interferon-alpha 2b (ropeg-interferon-alpha, ropeg-IFN) in inducing TFR. Patients and Methods: CML patients in stable deep molecular remission (MR4 or better for at least 12 months prior to screening) and with history of at least 3 years of TKI exposure were eligible to participate in this study. Patients in stable molecular remission could also be included if they had failed a former TKI discontinuation attempt (2nd stopper). Patients were randomized 1:1 to receive either ropeg-IFN 100μg s.c. every 2 weeks for 15 months (ropeg-IFN arm) or no further treatment after TKI stop treatment (no treatment arm). The primary efficacy endpoint of the trial was molecular relapse free survival (MRFS) with molecular relapse being defined as loss of major molecular remission (MMR), which is any increase of the BCR::ABL1 transcript level to >0.1% according to the international scale (IS). Time to relapse is defined as the time from randomization to relapse. Secondary endpoints were MRFS at month 6, 12 and 24 after TKI discontinuation. BCR::ABL1 measurable residual disease (MRD) was monitored from peripheral blood and centrally assessed for all centers in Germany and locally at the French centers. There was a post study follow up to collect clinical and molecular data. Results: Between May 2017 and June 2021, 203 evaluable patients (68 female, 135 male) with a median age of 55 years were randomized at 24 centers in Germany and 3 centers in France to receive ropeg-IFN (n=95) or no treatment (n=108) after TKI stop. For 77 patients in the ropeg-IFN arm (81%) and 86 patients in the no treatment arms (80%) it was their first TKI discontinuation attempt. At the time of data cut off in June 2022, the median observation time for all patients was 36 months. The hazard ratio (HR) of molecular relapse for the ropeg-IFN cohort versus the no treatment cohort was 1.03 (95% CI, 0.68 to 0.1.55; log-rank P=0.89). The Kaplan-Meier probabilities of molecular relapse free survival (MRFS) by 6, 12, and 24 months after TKI discontinuation were 73% (95%-CI: 62-81%), 64% (95-CI: 53-73%) and 56% (95%-CI: 45-66%) for the ropeg-IFN versus 67% (95-CI: 57-75%), 60% (95-CI: 50-69%) and 59% (95%-CI: 49-68%) for no treatment (Figure 1). The MRFS at months 6 and 12 after TKI stop (secondary endpoints) were 70% (95%-CI: 60-79%) and 64% (95%-CI: 53-73%) in 91 patients for ropeg-IFN group versus 65% (95-CI: 56-74%) and 59% (95-CI: 49-68%) in 107 and 104 patients for the no treatment group. Of 90 patients who were candidates for restarting TKI due to MMR loss, 82 patients were actually evaluable for TKI restart. Of those, 77 patients re-achieved at least MMR within 12 months (median time to reestablishing MMR was three months). Of the 5 patients who did not regain MMR, one patient withdrew consent and others were treated for only 1, 3, 4, and 11 months after TKI restart. Ropeg-IFN was well tolerated. Hematological and non-hematological WHO grade 3/4 toxicity occurred in 23 patients in the ropeg-IFN (31 adverse events) and in 20 patients in the no treatment arm (26 adverse events). Three deaths were reported on study which were unrelated to CML (cardiac arrest, fall from stairs, unknown). A detailed safety analysis will be presented at the meeting. Conclusion: Ropeg-IFN maintenance after discontinuing TKI-monotherapy does not increase the proportion of patients, who persistently maintain at least an MMR. The German CML-V (TIGER) trial currently explores the impact of IFN maintenance on TFR when patients receive a combination of TKI plus IFN before TKI stop. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Ropeginterferon Alfa-2b for Pre-Fibrotic Primary Myelofibrosis and DIPSS Low/Intermediate-1 Risk Myelofibrosis

Most patients with early/pre-fibrotic primary myelofibrosis (pre-PMF) and dynamic international prognostic scoring system (DIPSS) low or intermediate-1 risk myelofibrosis (MF) progress to overt PMF or higher risk MF. There is currently no consensus on the optimal treatment strategies in these patients. Ropeginterferon alfa 2b (P1101) is a next generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN). The P1101MF study is a multicenter phase 2 study of P1101 for patients with pre-PMF and DIPSS low/intermediate-1 risk MF (NCT04988815). Key eligibility included the need for cytoreduction, morphologically confirmed pre-PMF, overt PMF, post-polycythemia vera MF (PPV-MF) or post-essential thrombocythemia MF (PET-MF), and DIPSS low/intermediate-1 risk category. The primary outcome was the clinicohematologic complete response (CHCR) rate at 24 and 48 weeks. Secondary outcomes included adverse events (AEs), changes in allele burden of driver genes and other non-driver mutations, changes in quality-of-life (QOL), changes in cytokine profiles and changes in bone marrow morphology. Patients received P1101 at a starting dose of 250mcg followed by 350mcg at week 2 and 500mcg every 2 weeks from week 4 onwards. At the data cut-off of 28 July 2022, 56 patients (33 men, 23 women) with a median age of 58 (range: 30-87) were enrolled. Thirty eight patients (68%) had pre-PMF, 5 (9%) had overt PMF, 3 (5%) had PPV-MF and 10 (18%) had PET-MF. Next-generation sequencing (NGS) in 53 patients showed JAK2V617F in 39 patients (74%), CALR mutations in 13 patients (25%) and MPL mutation in 1 patient (2%). On day 1, the mean white blood cell (WBC) count, hemoglobin concentration, platelet count, and lactate dehydrogenase (LDH) level were 9.4 x 109/L (range: 3.3-33.95), 12.5 g/dL (range: 7.1-15.9), 520 x 109/L (range: 113-1038) and 359 IU/L (range: 136-1146) respectively. The median duration of follow-up was 24 (2-28) weeks. Forty-six and 30 patients completed 12 and 24 weeks of treatment respectively. At 12 and 24 weeks the CHCR rate was 74% and 67%, respectively. At 24 weeks, 36 (92%) of 39 JAK2V617F mutated patients had stable or improved JAK2V617F allele burden by droplet digital polymerase reaction (ddPCR). Three patients (8%) had >50% reduction in the JAK2V617F allele burden with one patient achieving undetectable JAK2V617F from week 16 onwards. Disease progression or blastic transformation were not observed during the study. The most common AEs were malaise (N=22, 39%; Grade 1-2, N=21; Grade 3-4, N=1), anemia (N=12, 21%; Grade 1-2, N=8; Grade 3-4, N=4), muscle pain (N=11, 20%; Grade 1-2, N=11; Grade 3-4, N=0) and hair loss (N=10, 18%; Grade 1-2, N=10; Grade 3-4; N=0) . There were no treatment discontinuations, safety signals or deaths related to treatment. In summary, P1101 was well-tolerated, effective in cytoreduction and induced molecular responses. The recruitment of patients is ongoing.

ODP080 Bisphosphonate treatment for osteoporosis in children with Gorham-Stout syndrome: a case report

Abstract Background Gorham-Stout disease (GSD) is a rare disease defined by progressive bone disappearance due to massive unicentric or multicentric osteolysis with proliferation of vascular structures. Symptoms and signs vary depending on the site of invasion. Including some self-limiting GSD, most treatments are palliative and limited to symptom management. Various treatments have been tried for GSD, but there are no standardized treatment protocols. Treatment includes radiological treatment, surgery, and medications such as bone absorption inhibitors (calcitonin, bisphosphonate (BP)), vitamin D and immune modulators (interferon alpha-2b, Sirolimus) Case presentation: A 4-year-old female patient presented with prolonged back pain after a fall. Pathologic compression fracture in T9, L1 vertebrae identified in simple spine image, and GSD was confirmed by MRI and biopsy finding as hemangioma in vertebrae. This patient has been treated with a combination therapy of Sirolimus and BP for 1 year. BP treatment consist with oral BP (Alendronate) between 3 intravenous BP (Pamidronate) every 4 months. After a year of treatment, BMD improved from initial -1.3 TBLH (z-score) to -0.5/0.4/0.6 Spine/Both femur (z-score), but MRI findings suggest mild aggravation of multiple compression fractures of spines of T9-L5. After 1-year of treatment, at present, the girl is alive and staying with tolerable condition. Conclusions Combination treatment with bisphosphonate and Sirolimus for childhood GSD can be helpful in slowing the demineralization of GSD without any significant adverse effect. Presentation: No date and time listed

Real-life data of adjuvant IFN-α2b and MMC in conjunctival melanocytic lesions

PurposeWe herein compare topical interferon alpha 2b (IFN-α2b) to topical mitomycin C (MMC) in the adjuvant management after excision of primary acquired melanosis with atypia (PAM) and melanoma of the conjunctiva/cornea (CM).MethodsWe included 25 tumors from 25 patients (six with PAM and 19 with CM). After surgical excision, four patients started with adjuvant IFN-α2b (two in combination with radiotherapy), 19 with MMC, and two with radiotherapy alone. Five patients were switched from initial MMC/radiotherapy to IFN-α2b during follow-up. Efficacy was assessed via time to tumor recurrence and initial therapy response.ResultsWith initial IFN-α2b, three patients (3/4, two with additional radiotherapy) showed complete remission (follow-up: 1478–1750 days) and one recurrence (1/4) was noted after 492 days. With initial MMC, no recurrence was recorded in 15 of the 19 patients (follow-up: 99–4732 days). Five patients were switched from MMC or radiotherapy to IFN-α2b: two patients showed complete remission (2/5), while another two (2/5) experienced recurrences and remained without recurrence after repeated courses of IFN-α2b (follow-up: 1798 and 1973 days). Only one patient showed incomplete response. Adverse effects were recorded in five patients, all received MMC.ConclusionTopical IFN-α2b (arguably together with radiotherapy) may be a viable alternative to MMC in PAM and CM. We observed fewer side effects at similar response rates. However, when response to MMC was poor, IFN-α2b may also be of limited utility.

Deployment of metabolic heat rate based soft sensor for estimation and control of specific growth rate in glycoengineered Pichia pastoris for human interferon alpha 2b production

Lack of appropriate process models, reliable online sensors, and process variability in bioprocess systems are poising challenges in real-time monitoring and control of critical process parameters (CPPs). This present investigation deals with the development of a non-invasive soft sensor by utilizing metabolic heat rate as input signal for online estimation of specific growth rate (μest) during the induction phase of glycoengineered Pichia pastoris for human interferon-alpha 2b (huIFNα2b) production. Feedforward strategy employing a predetermined exponential feeding of methanol during the induction phase was dealt at defined setpoint values (μSP). Standard PID controller with predetermined gain values regulated methanol feeding in accordance with the deviation from the μSP value. An adaptive PID (gain scheduling) significantly minimized the deviation of μ from its μSP value, reduced the amplitude of oscillation and achieved long-term controller stability. Robust control of methanol feeding by adaptive PID resulted in a 1.5 and 2.2-fold increase in productivity of huIFNα2b compared to standard PID and feedforward controls respectively. Moreover, adaptive PID control facilitated narrow range control of μ for longer durations (> 20 h) with a low average tracking error (< 6%) enumerating its scope of application in therapeutic protein production in near future.

A Phase 3 clinical trial validating the potency and safety of an innovative, extra-long-acting interferon in chronic hepatitis C.

Ropeginterferon alfa-2b is a novel mono-pegylated, extra-long-acting interferon. It is administered infrequently and showed good tolerability and clinical activity for the chronic hepatitis B or C treatment in our previous Phase 2 clinical trials. This study aims to validate the potency and safety of this novel agent in a Phase 3 chronic viral hepatitis setting. Patients with chronic hepatitis C genotype 2 were randomized to receive subcutaneous injections of ropeginterferon alfa-2b biweekly or the conventional pegylated interferon alfa-2b weekly for 24 weeks, combined with ribavirin. The primary endpoint was to assess the safety and antiviral potency of ropeginterferon alfa-2b by the non-inferiority in sustained virologic response at 12 weeks after treatment. A total of 222 patients were enrolled. Ropeginterferon alfa-2b group showed a favorable safety profile. Side effects that were generally associated with prior interferon therapies, including neutropenia, asthenia, fatigue, alopecia, dizziness, decreased appetite, nausea, flu-like symptoms including myalgia, pyrexia, and headache, and administration site reactions, were notably less in the ropeginterferon alfa-2b group. The cumulative incidence of adverse events of special interest was also notably higher in the control group. The primary endpoint was met and ropeginterferon alfa-2b showed a better SVR12 rate of 79.8% than 71.9% of the control group. Ropeginterferon alfa-2b is efficacious and has a favorable safety profile as compared with the conventional pegylated interferon alfa-2b. This study together with previous Phase 2 data validated ropeginterferon alfa-2b to be a new treatment option for chronic hepatitis C genotype 2.

Mucosal immunity during rehabilitation in the patients after coronavirus infection

Following the coronavirus infection, a variety of symptoms may persist for a long time. Therefore, an important area of further research is to study the state and response of protective immune mechanisms in the post-COVID period. Our aim was to evaluate the dynamics of mucosal immunity by measuring sIgA in the saliva samples and nasal swabs (sIgA, lactoferrin), as well as efficiency of interferon-alpha-2b (IFNa2b) treatment in the patients after coronavirus infection.&#x0D; A study was conducted in the patients aged 18 to 60 years (n = 130) at the terms of 1 to 9 months after a coronavirus infection. A control group consisted of conditionally healthy individuals (n = 15). Diagnosis of post-COVID manifestations was carried out by collecting complaints, anamnestic data, physical examination and questionnaire. The state of mucosal immunity in saliva samples and nasopharyngeal mucosal scrapings was evaluated in dynamics as based on determination of sIgA and lactoferrin concentrations by means of enzyme immunoassay techniques prior to administration of local preventive therapy with recombinant IFNa2b, and 1 month after the treatment (VIFERON gel applied intranasally twice a day for 30 days).&#x0D; The following symptoms of post-COVID syndrome were documented In the study group: joint and muscular pain, shortness of breath, cough, fatigue and weakness, headache and dizziness, anxiety. In the group of patients who received preventive therapy during 1 to 3 months after coronavirus infection, a significantly increased level of saliva sIgA was noted, respectively, 1.840.28 to 5.781.96 mg/mL. As based on the data obtained with scrapings from nasopharyngeal mucosa, a significant increase in the level of sIgA was revealed in the group subjected to therapy up to 3 months after COVID-19 infection, i.e., from 28.613.0 to 39.833.85 mg/mL. In the group of patients devoid of preventive therapy, a stable maintenance of the reduced mucosal immunity parameters was found in all time intervals during the period of convalescence. In all observed patients, regardless of the group, a decreased lactoferrin level was found, being two-fold lower than the normal reference values. The incidence of respiratory viral infections in the group without preventive therapy was statistically significant, being registered in 9.2% of cases.&#x0D; Patients after COVID-19 infection exhibit a persistent decrease in mucosal immunity. Immunological efficacy was observed when using IFNa2b, thus making it possible to recommend it for rehabilitation in this group of patients over the period of convalescence.

Features of the course of COVID-19 in children undergoing outpatient treatment

Objective: to study the clinical and epidemiological features of the course of a new coronavirus infection in children of different ages undergoing outpatient treatment.The study participants were 812 children with COVID-19 aged from 1 month to 17 years, who were on outpatient treatment in the children's polyclinic of the city of Kirov from July to December 2021. The average age of patients with COVID-19 was 5.9 ± 1.1 years. Among the sick young children there were 28%, adolescents — 16%. In 76% of cases, contact with patients with a new coronavirus infection was detected, mainly in the family, as well as in educational institutions. In 70% of cases, an early request for medical help was registered — in the first three days of illness. In most cases (89%), a mild severity of the disease was established with the development of subfebrile fever and pharyngitis. Rhinitis phenomena were recorded in 20% of cases. 7% of children complained of a dry cough. Lung tissue lesion (RG1) was detected in 5% of patients, gastrointestinal tract — 5%. In adolescents, the phenomena of rhinitis, pharyngitis, dry cough were less common than in other age groups. Recombinant interferon alpha-2b and umifenovir were used for etiotropic therapy. All children recovered within 7—10 days from the onset of the disease.

Clinical Study of Chemotherapy Combined with Antivirals for Adult T-cell Leukemia/Lymphoma

To investigate the efficacy of chemotherapy combined with antivirals in adult T-cell leukemia/lymphoma (ATLL) patients and the prognostic factors. Forty nine patients with previously treated or treatment-nave ATLL from January 2018 to January 2021 were included in our study. The patients were divied into two groups according to whether they received antiviral treatment, twenty-seven patients were treated with chemotherapy combined with antivirals, including thirteen patients treated with recombinant interferon alpha-2b and CHOP therapy, eight patients treated with zidovudine combined with CHOP therapy, and 6 patients treated with CHOP regimen combined with interferon and zidovudine. Twenty-two patients were treated with CHOP therapy. The changes of symptom, hematological parameters, lactic dehydrogenase, β2-microglobulin, and the Ki-67 positive rate were compared between the two groups before and after treatments. The clinical efficacy of chemotherapy combined with antiviral therapy for ATLL was evaluated. The antiviral effect was assessed by detecting HTLV-1 virus copy number, and prognostic factors were analyzed. The median follow-up time was 14 months. Compared with the patients treated with chemotherapy alone, the patients treated with chemotherapy combined with antivirals had lower tumor and virus loads, lower white blood cell count, lower lactate dehydrogenase level, lower β2-microglobulin lever, and lower Ki-67 positive rate (all P<0.05). The total effective rate of patients treated with chemotherapy combined with antivirals was significantly higher than those of patients treated with chemotherapy alone (63.0% vs 31.8%, P=0.035). The one-year overall survival (OS) rates of chemotherapy combined with antivirals groups and chemotherapy alone group were (74.1±2.9)％ and (40.9±2.1)％ (P=0.021), respectively. The one-year progress free survival (PFS) rates were (51.9±3.3)％ and (13.6±2.8)％ (P=0.017), respectively. Multivariable Cox regression analysis showed that HTLV-1 virus load (HR=7.518, 95%CI: 2.517-36.192, P=0.013) and antiviral therapy ［HR=5.617 (95%CI 1.803-11.293), P=0.027］ were independent prognostic factors for the long-term efficacy. Addition of antivirals to chemotherapy can prolong PFS and OS in ATLL patients. HTLV-1 virus load and antiviral therapy are independent prognostic factors for ATLL patients.

Efficacy and safety of topical 5-fluorouracil in conjunctival intraepithelial neoplasia refractory to interferon alpha-2b.

To report the efficacy and safety of 5-fluorouracil as the second line of treatment for two cases of conjunctival intraepithelial neoplasia refractive to topical interferon alpha-2b. In the first case, a 77-year-old woman was evaluated because of a fleshy vascularized lesion in the temporal conjunctiva on her right eye with leukoplakia of the corneal epithelium from 10- to 5-o'clock limbus. In the second case, an 81-year-old man, a nodular lesion in the temporal conjunctiva on his RE, with corneal adjacent opalescence, one millimeter in extent, was observed. Both patients were initially treated with excisional surgery, the samples being reported as conjunctival intraepithelial neoplasia with high-grade dysplasia. Co-adjuvant treatment with topical interferon alpha-2b 1 mIU/mL was indicated 4 times/day uninterruptedly. In the first case, there was no response despite 8 months of treatment, while in the second, the corneal lesion progressed in an arboriform pattern after 4 months of topical chemotherapy. In the absence of efficacy, the treatment was then changed to topical 5-fluorouracil (1%), 4 times/day for 7 days with a time-lapse of 21 days off, which constitutes a course. Two and four courses of treatment with 5-fluorouracil 1% were completed in both cases in the absence of important side effects. After the first course, both patients showed complete remission of the lesions. No clinical signs of relapse were noted after 1 year of follow-up. The treatment with 5-fluorouracil is a good option as the second line of treatment for conjunctival intraepithelial neoplasia who are low-responders to interferon alpha-2b, with fewer side effects than other currently available alternatives.

Enhancement the eff ec- tiveness of therapy of the new COVID-19 coronavirus infection using interferon alpha-2b in adults

In order to assess the clinical eff ectiveness of COVID-19 complex therapy in adults, 140 patients with a confi rmed diagnosis of a new coronavirus infection, clinical symptoms and lung damage from 25 to 75 % (mild and moderate form) hospitalized in budgetary healthcare institutions of the Omsk region were included in an open prospective observational study. Patients were evenly divided into two groups: 1 — received standard therapy in accordance with the Temporary Guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" approved by the Ministry of Health of the Russian Federation and interferon alpha-2b preparations (Viferon ® rectal suppositories 3,000,000 IU and Viferon ® gel for external and topical use of 36,000 IU/g); 2 — received only standard therapy. In group 1 patients, elimination of the SARS-CoV-2 antigen from the nasopharyngeal mucosa occurred 2 days earlier than in group 2 patients. Also, patients receiving standard therapy and interferon alpha-2b preparations improved on average 4.5 days earlier, most of the main symptoms of the disease were stopped by the 6th day of therapy. It was noted that in patients receiving complex standard therapy with adding of interferon alpha-2b preparations, a more pronounced regression of lung tissue damage was observed, especially in patients with a high degree of their lesion according to CT data before hospitalization. By the end of treatment in group 1, the proportion of patients with lung tissue lesions of grade CT-3 signifi cantly decreased by 17%, while in group 2, the proportion of patients with CT-3 increased by 13 %. Analysis of the dynamics of laboratory parameters and the main markers of infl ammation in the therapy groups also confi rms the positive eff ect of the inclusion of interferon alpha-2b drugs in the standard therapy. No adverse events associated with the use of interferon alpha-2b preparations were registered. Thus, in patients receiving standard therapy and interferon alpha-2b preparations, recovery occurred in a shorter time. In the end, this contributed to a faster discharge from the hospital and a reduction in the burden on the bed fund and medical staff . The results obtained give grounds to recommend the inclusion of interferon alpha-2b preparations (Viferon ® rectal suppositories 3,000,000 IU and Viferon ® gel for external and topical use 36,000 IU/g) in standard COVID-19 therapy regimens in adult patients with mild and moderate forms of the disease.

Toxicity and bioactivity evaluation of interferon alpha-2b conjugated with solid lipid nanoparticles

Background: Interferon (IFN) are small proteins that belong to the cytokine family and may interfere with viral infections and some cancers. There are many studies focused on the PEGylated interferon’s bioactivity. In this study, we used solid lipid nanoparticles (SLNs) to produce new drug formulations, with the aim of reducing costs, increasing effectiveness, and also reducing side effects, and the biological effects of the formulation and comparing the obtained results with the interferon alpha-2b and PEGylated interferon alpha-2b.

Topical pharmacotherapy for ocular surface squamous neoplasia: systematic review and meta-analysis

Ocular surface squamous neoplasia (OSSN) has different treatment modalities. Although surgical excision has been the gold standard therapeutic option, topical pharmacotherapy agents such as 5-fluorouracil (5-FU), interferon alfa-2b (IFN) and mitomycin-C (MMC) are also commonly used. The protocol was registered (CRD42021224961). Comprehensive literature research was carried out to compare topical pharmacotherapy (5-FU or IFN or MMC) to surgical excision regarding clinical success (tumor resolution), recurrence and complications in patients undergoing treatment for OSSN. From 7859 records, 7 articles were included in the qualitative and 4 in the quantitative synthesis. The outcomes of surgical excision and topical pharmacotherapy were comparable in the included articles. There were no significant differences between surgical excision and topical pharmacotherapy regarding the clinical success [odds ratio (OR): 0.785; confidence interval (CI): 0.130–4.736, P = 0.792)] and tumor recurrence (OR: 0.746; CI: 0.213–2.609; P = 0.646). The most common side effect of the different therapeutic options was dry eye. The highest rate of dry eye symptoms was reported after surgical excision (in 59%). Topical pharmacotherapy with all the 3 agents is as effective and well-tolerable as surgical excision in terms of tumor resolution, recurrence rate and side effects in all OSSN patients suggesting similar long-term clinical benefits.

Topical interferon Alpha-2b in refractory limbal vernal keratoconjunctivitis: a case report

Purpose: To report our experience of managing a steroid resistant limbal vernal keratoconjunctivitis (VKC) by topical interferon alpha-2b (IFN- 2b) eye drops. Methods: Case report Results: A 20-year-old man was referred to our cornea clinic with the chief complaints of itching and photophobia in eyes and foreign body sensation, redness, and ptosis in a both eyes. He had a 10-year history of gradually enlarging limbal gelatinous masses on both eyes, which according to the other signs and impression cytology (IC) was diagnosed as a VKC. As the disease in his left eye was more severe and persistent with maximum topical steroid usage, we started the topical IFN- 2b eye drops, that a rapid therapeutic response was observed. After three months of using the topical IFN- 2b all ocular surface inflammation and other symptoms rapidly disappeared and we continued this drug till another 3 months, at 12-months follow-up, there was no recurrence of the limbal papillary hypertrophic lesions and other signs and symptoms of VKC. Conclusion: In a refractory VKC, topical IFN- 2b can be used and enhance remission in such complex cases and can resolve patient’s complains rapidly.

Intensive topical interferon therapy in uveitic macular edema

To evaluate the efficacy of intensive topical interferon alfa-2b (IFN) therapy in uveitic macular edema (UME). This is a prospective, interventional case study of eyes with UME. Commercially available injection IFN for subcutaneous use was reconstituted to form eye drops and a dose of 6 times/day for 2 weeks, 5 times/day for next 2 weeks, followed by 4, 3, 2, 1 taper per month was prescribed. Optical coherence tomography (OCT) and clinical examination was done at 0, 2, 4, 8 weeks, and further as required. Nine eyes of 9 patients with UME were studied. Mean central macular thickness (CMT) at presentation was 522.2 μm (range: 408-803 μm). At 2-week, 1-month, and 2-month follow-up, mean CMT decreased to 451.6 μm (range: 322-524 μm), 375.8 μm (range: 287-480 μm), and 360.3 μm (range: 260-485 μm), respectively. Four eyes which showed inadequate response to previous topical IFN therapy (4 times/day) showed significant improvement with intensive therapy at 1 month follow-up. In 4 eyes, UME resolved completely with mean CMT 285.5 μm (range: 260-312 μm) at 7.5 weeks (range: 4-12 weeks). Study exit was seen in 2 cases due to inadequate response and relapse of uveitis. Mean follow up was 3.38 months (range: 1-5 months). Intensive topical IFN therapy can be an alternative therapeutic option in the treatment of UME. Study of intraocular penetration, combination with other drugs, and the efficacy of IFN separately for different uveitic entities may explore new avenues in treatment of UME.

Clinicopathological profile, management and clinical outcomes in recurrent cases of ocular surface squamous neoplasia at a tertiary care centre.

This study was taken up to look into the various causes of recurrence, clinicopathological profile and final outcomes in recurrent cases of ocular surface squamous neoplasia (OSSN). A prospective cohort study was conducted and total 18 patients were recruited. All patients were subjected to detailed history, comprehensive eye examination and imaging studies. A treatment plan was formulated based on the size and extent of the lesion. The primary outcome measure was complete response to treatment with no evidence of recurrence after12months and secondary outcome measure was complication associated with each treatment modality. The common cause of recurrence in our study was misdiagnosis of the lesion as in 15 cases it was diagnosed as pterygium and in 03 cases it was actinic keratosis. Excision Biopsy with adjunctive cryotherapy was the preferred treatment modality followed by topical interferon-alpha 2b drop-in our study. We could achieve good outcomes in terms of complete response to the treatment in 16 cases. The complication associated with this treatment was minimal in our study as few patients complained redness and irritation which subsided after application of topical lubricants. There was no sign of recurrence even at 12months of follow-up in all 18 cases. The current study provided clinicopathological characteristics and treatment outcomes in recurrent cases of OSSN. In our study, adopting appropriate treatment strategy, regular follow-up to assess the response to treatment and change over to new treatment plan in cases with inadequate response helped in achieving good outcomes in recurrent cases of OSSN.

Pegylated interferon-α-2b combined with tenofovir disoproxil fumarate, granulocyte-macrophage colony-stimulating factor, and hepatitis B vaccine treatment for naïve HBeAg-positive chronic hepatitis B patients: A prospective, multicenter, randomized controlled study.

Hepatitis B surface antigen (HBsAg) loss or seroconversion is an ideal treatment endpoint for patients with chronic hepatitis B but is rarely achievable inhepatitis B e-antigen(HBeAg)-positive patients using existing treatment strategies. In this study, the effect of pegylated interferon (peg-IFN) alfa-2b plus tenofovir disoproxil fumarate (TDF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and hepatitis B vaccine was evaluated.This randomized controlled trial was conducted at nine liver centers in Chinese university hospitals from May 2018 to July 2020. Patients (n = 303) enrolled were randomly administered peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine (experimental group); peg-IFN-α-2b plus TDF (control group 2); or interferon-α-2b alone (control group 1). The primary efficacy endpoint was HBsAg seroconversion at 48 weeks and the secondary endpoint included safety.No differences in baseline HBsAg levels were observed among the groups. The primary endpoint was achieved in three (3.0%), one (1.03%), and one (1.19%) patient in the experimental group, control group 2, and control group 1, respectively. The incidence of HBsAg seroconversion at week 48 was not significantly different among the three groups (p = 0.629). However, the decrease in serum levels of HBsAg at week 48 was significantly higher in the experimental and control group 2 compared with that in control group 1 (p = 0.008 and 0.006, respectively). No significant difference between the experimental and control group 2 was observed (p = 0.619). Adverse events were not significantly different among the groups except for the lower incidence of neutropenia in the experimental group.Peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine is not superior to peg-IFN-α-2b combined with TDF in HBeAg-positive naïve patients. Clinical Trials Registration:ChiCTR1800016173.

Real-World Treatment Patterns and Recurrence Rates in Cutaneous Melanoma Patients – Single Romanian Center Experience

"Introduction. Cutaneous melanoma is one of the deadliest cancers, and its incidence has dramatically increased over the last 20 years. Its mortality has decreased slightly worldwide over the past 10 years, largely due to new approaches such as sentinel node biopsy and new systemic treatments. Materials and method. This retrospective study comprises 151 cases of cutaneous melanoma (stages 0, I, II, and III) diagnosed between 2003 and 2019 in Romanian patients at a single center. It provides epidemiological information (stage at diagnosis, histological aspects, status of BRAF mutation, pattern of recurrence) and shows survival parameters associated with systemic adjuvant treatments and first and second-line therapies for recurrence. Results. Compared to other European countries, Romanian patients with cutaneous melanomas have different characteristics: younger age (50 years median age at diagnosis), more advanced stages (70% for male and 44% for female patients), and BRAF mutation in 70% of cases. More than 50% of the patients with stages IIB, IIC, and III received adjuvant IFN-α2b after complete resection. However, there were similar outcomes in terms of median disease-free survival (DFS) (33.46 months for the entire cohort) independently of adjuvant systemic treatments administered in the interferon alpha-2b era. The 3-year DFS and OS rates for stages IIB and IIC were similar to those of stage III. The prognosis was worse for BRAF mutated melanoma in terms of DFS and OS, independently of clinical stages. Conclusion. Our study demonstrates that stages IIB and IIC have the same pattern of recurrence and similar outcomes to those of stage III and could benefit from adjuvant systemic treatment as shown in KEYNOTE-716 clinical study."

Effects of Tenofovir Combined with Recombinant Human Interferon α-2b on Negative Conversion Rate, Liver Function, Immune Status, and Drug Safety in Patients with Chronic Hepatitis B: A Systematic Review and Meta-Analysis.

Objective To systematically evaluate the clinical value of tenofovir combined with recombinant human interferon α-2b in the treatment of chronic hepatitis B and to provide evidence-based medicine for its popularization and use. Methods The randomized controlled trials (RCTs) of tenofovir combined with recombinant human interferon α-2b in the online database of PubMed, EMBASE, ScienceDirect, Cochrane Library, China knowledge Network (CNKI), China VIP database, Wanfang database, and China Biomedical Literature Database (CBM) were searched. The data included in this study were extracted by two independent researchers. After extracting the data of the study, the Cochrane manual 5.1.0 standard was used to evaluate the bias risk of all the literature included in this study. RevMan5.4 statistical software was used to analyze the collected data by meta. Results Entecavir combined with recombinant human interferon α-2b can inhibit the activity of HBV polymerase and improve the inflammatory response of the liver. Recombinant human interferon α-2b can regulate immune function by inducing T cell differentiation and maturation and enhancing the production of cytokines. The systematic evaluation showed that entecavir combined with recombinant human interferon α-2b had higher serum HBeAg negative conversion rate, higher drug safety compared with entecavir alone, and improved liver function and immune status. Conclusion Tenofovir combined with recombinant human interferon alpha-2b has a high serum HBeAg negative rate and safety profile for the treatment of chronic hepatitis B. The combination treatment can improve liver function and immune status in patients, but more studies with higher methodological quality and longer duration of intervention are needed for further validation.

S181: MODAKAFUSP ALFA (TAK-573): UPDATED CLINICAL, PHARMACOKINETIC (PK), AND IMMUNOGENICITY RESULTS FROM A PHASE 1/2 STUDY IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM)

Background: Modakafusp alfa (TAK-573) is a first-in-class immunocytokine designed to deliver attenuated interferon alpha-2b to CD38+ cells. In this phase 1/2 study (NCT03215030), the maximum tolerated dose of modakafusp alfa was defined as 3 mg/kg every 4 weeks (Q4W); preliminary data from 29 pts treated at 1.5 mg/kg Q4W (5 in dose escalation, 24 in dose expansion) showed single-agent, anti-myeloma activity with an overall response rate (ORR) of 38% after a median follow-up of 4.2 months (mos) (Vogl ASH 2021, #898). Aims: We present a clinical update on the efficacy and safety of modakafusp alfa 1.5 mg/kg Q4W after a median follow-up of 4.5 mos. We also present PK, immunogenicity, and dose-exposure-response data from the overall study. Methods: Eligible pts had received ≥3 prior lines of treatment. Pts received modakafusp alfa as a 1–4-hour IV infusion at 10 dose levels from 0.001–6 mg/kg at weekly (cycles 1–2 only; 0.001–0.75 mg/kg), every-2-week (0.2–0.3 mg/kg), every-3-week (Q3W; 0.4–0.75 mg/kg), or Q4W (0.75–6 mg/kg) dosing intervals; an expansion cohort was opened at 1.5 mg/kg Q4W after anti-myeloma activity was observed in 3/5 pts in the escalation cohort at that dose. Serum samples prepared from blood were used for PK and anti-modakafusp alfa antibody (ADA) assessments. Modakafusp alfa concentrations were determined via a validated enzyme-linked immunosorbent assay; ADA were detected using a validated bridging electrochemiluminescence assay. Results: As of Oct 2021, 30 pts had received modakafusp alfa 1.5 mg/kg Q4W. The median number of prior lines was 7 (range 3–16); 90% of pts were refractory to an anti-CD38 monoclonal antibody (mAb), while 37% were exposed to an anti-B-cell maturation agent (BCMA). Grade (G) 3–4 treatment-emergent adverse events (TEAEs) were reported in 25 pts (83%); the most frequent G3–4 TEAEs were neutropenia in 19 (63%), thrombocytopenia in 13 (43%), leukopenia in 12 (40%), anemia in 9 (30%), and decreased lymphocyte count in 9 (30%) pts. As reported previously, 1 pt in the 1.5 mg/kg Q4W cohort had a G3 bleeding event, while 3 pts had G3 infections. Among all pts, the ORR was 40% (complete response, 7%; very good partial response, 20%; partial response, 13%); among anti-CD38 mAb-refractory and anti BMCA-exposed pts, the ORR was 37% and 27%, respectively. Median progression-free survival was 6 mos and median duration of response had not been reached (Kaplan-Meier estimate, 91% at 6 mos). Based on pooled available data for the Q3W and Q4W cohorts (all doses) within the escalation and expansion phases, there was a strong trend for a dose-exposure-response relationship for ORR, with the apparent inflection point at 1.5 mg/kg Q4W dosing. No apparent relationship between dose-exposure-response and G3/4 thrombocytopenia or neutropenia was observed across all doses, whereas a correlation between dose-exposure-response and incidence of infusion-related reactions across the 0.4–6 mg/kg Q3W and Q4W dosing cohorts was found. There was an apparent non-linear (more than dose proportional) increase in exposure in the dose range of 0.1–3 mg/kg with a geometric mean terminal half-life of 13 hours in serum for modakafusp alfa 1.5 mg/kg. Based on the available data, 14% and 60% of pts were ADA positive at baseline and post-treatment, respectively. Summary/Conclusion: Modakafusp alfa has a novel mechanism of action and has shown encouraging activity with a manageable safety profile in pts with RRMM. Characterization of the potential clinical impact of immunogenicity is ongoing. The optimal dose for single-agent modakafusp alfa will be further investigated in a phase 2 study.