Interferon Alpha-2a In Patients Research Articles

SAT-194 - The safety and efficacy of hepalatide (L47) treatment combined with pegylated interferon-alpha 2a in patients with chronic hepatitis B: the preliminary data from a double-blind, RCT phase II trial

SAT-194 - The safety and efficacy of hepalatide (L47) treatment combined with pegylated interferon-alpha 2a in patients with chronic hepatitis B: the preliminary data from a double-blind, RCT phase II trial

Comparison of fibrosis regression of entecavir alone or combined with pegylated interferon alpha2a in patients with chronic hepatitis B

Antiviral treatment with necleos(t)ide analogues contributes to histological improvement and virologic response in chronic hepatitis B (CHB) patients. However, whether adding pegylated interferon alpha2a (Peg-IFN-α-2a) can help additional clinical benefit, particularly on fibrosis regression was still unknown. Chronic hepatitis B patients with pre-treatment biopsy-proven Ishak fibrosis score 2, 3 or 4 were randomly assigned to entecavir (ETV) alone or ETV plus Peg-IFN-α-2a (Peg-IFN-α-2a add-on) group (1:2 ratio). Post-treatment liver biopsy was performed at week 78. Fibrosis regression was defined as decrease in Ishak fibrosis score by ≥ 1 stage or predominantly regressive categorized by P-I-R score. Serum HBV DNA levels were assessed at baseline and every 26weeks, while HBsAg and HBeAg were evaluated at baseline and every 52weeks. A total of 218 treatment-naive CHB patients were randomly assigned to ETV alone or Peg-IFN-α-2a add-on group. Totals of 155 patients (ETV alone: Peg-IFN-α-2a add-on, 47:108) were included in statistical analysis. Fibrosis regression rates were 68% (32/47) in the ETV alone and 56% (60/108) in Peg-IFN-α-2a add-on group (p = 0.144). Both groups showed a similar trend of virological suppression during the process of 104-week antiviral therapy (p = 0.132). HBeAg or HBsAg loss or seroconversion rates in the ETV alone group were lower than Peg-IFN-α-2a add-on group though without statistical significance. Peg-IFN-α-2a add-on therapy did not yield additional fibrosis regression and virologic response than ETV alone therapy.

A real-world single-center retrospective study on efficacy and safety of pegylated interferon alpha-2a in patients with myeloproliferative neoplasm.

e19536 Background: Pegylated forms of interferon (PEG-IFN) have a better pharmacologic profile than short-acting interferons, resulting in a more convenient less-frequent schedule of injections, less immunogenicity and possibly less toxicity. Several clinical studies of PEG-IFN-α-2a have reported promising results in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Herein, we present the outcomes of MPN patients treated with PEG-IFN-α-2a seen outside of a clinical trial setting at a single center. Methods: Thirty-five MPN Patients treated with PEG-IFN-α-2a between January 2014 and October 2019 were included this retrospective analyses. Therapeutic responses for ET and PV were calculated by the revised ELN/IWG-MRT criteria. Responses in myelofibrosis (MF) were calculated by both EUMNET and ELN/IWG-MRT criteria. Best responses over all cycles of treatment were assessed. Molecular data was limited to JAK V617F. Results: Twenty patients with ET, 13 with PV and two with MF were enrolled in this study. The median age at diagnosis was 47 years (range; 21-83 years). JAK2 V617F mutation was detected in 16 patients (45.7%). Overall, the majority of patients (62.9%) had received at least one prior cytoreductive therapy for underlying disease. Median starting dose of PEG-IFN-α-2a was 90 mcg/week via self injection (range: 45-135 mcg/w). Treatment duration was pursued for a median duration of 21.4 months (range: 1.2-109.8). In the PV/ET group 33 patients were evaluated and overall best response rate was 87.8% (CR in 15 pts and PR in 14 pts). In the MF group (n = 2); a PR was seen in one patient and CR in one patient. No vascular events occurred within the cohort while on therapy. Of the eight patients receiving at least phelebotomy per month, all patients became phelobotomy independent with therapy. Of the 20 ET patients, 12 patients (60%) had platelet normalization (< 450 x 109/L). Among all patients, fatigue (31.4%), muscle pain (20%) and depression (8.6%) were the most common adverse events (AEs). Any grade of hematological AEs was not seen with PEG-IFN-α-2a. Eleven patients discontinued therapy secondary to: treatment associated severe AEs in 8 patients, lack of response in two patients and pregnancy in one patient. No death was reported during the analyses period. Conclusions: Our results suggest that PEG-IFN-α-2a remains a viable treatment option especially for younger patients who want to avoid prolonged cytotoxic therapy.

Ruxopeg, a Multi-Center Bayesian Phase 1/2 Adaptive Randomized Trial of the Combination of Ruxolitinib and Pegylated Interferon Alpha 2a in Patients with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis

BackgroundMPN-associated myelofibrosis (MF) is a condition characterized by splenomegaly, anemia, bone marrow (BM) fibrosis and debilitating symptoms. About 80% of patients (pts) harbor a driver mutations in JAK2, CALR or MPL genes that can be used as biomarkers for minimal residual disease assessment. Ruxolitinib (Rux) is a JAK inhibitor approved in intermediate or high risk (HR) MF to improve symptoms and splenomegaly but with little impact on the malignant clone and fibrosis. Interferon alpha (IFNa) can reduce mutant allele burden and fibrosis but is often poorly tolerated in highly symptomatic pts. The RUXOPEG study was designed to assess the efficacy and safety of the combination of Rux + IFNa in MF (NCT02742324).MethodsRUXOPEG is a multi-center Bayesian Phase 1/2 adaptive trial. Phase 1 includes up to 9 cohorts of 3 pts with increasing doses of both drugs. Tested doses of Rux and IFNa are 10, 15 and 20 mg BID, and 45, 90 and 135 mcg/week, respectively. Phase 2 will randomize between the 2 best dose combinations selected from phase 1. Primary objective: identify the most efficacious dose combination that also satisfies safety requirements. Primary tolerance criterion is the occurrence of dose limiting toxicities (DLT) within 45 days; primary efficacy criterion is >50% reduction in spleen length within 6 months. Secondary objectives include molecular response, reduction of BM fibrosis, quality of life and symptoms evolution, event-free and overall survival. The planned total enrollment is 42 pts. Key inclusion criteria are: diagnosis of MF (WHO criteria), intermediate or HR (IPSS), need of active therapy, presence of a driver mutation. Key exclusion criteria: prior treatment (or contra-indication) with Rux or IFNa, eligibility for stem cell transplantation, inadequate liver, cardiac or renal function, autoimmune disease, history of depression.Enrolment in 5 cohorts was completed in June 2018, and the last cohort for phase 1 will be opened in August. This abstract reports the current available data for the 5 cohorts who have completed the primary endpoint, but the presentation will provide the detailed analysis of primary and secondary endpoints of phase 1, which will be available in October 2018.ResultsAmong the 15 pts currently enrolled in phase 1, 6 were females, mean age was 60.9 years (range: 38-72), 8 had primary MF, 5 post ET and 2 post PV MF. Median spleen size was 6 cm (range 0 - 18) by palpation and 18 cm (range 10-25) by imaging. Mean (range) blood counts were: hemoglobin 12 g/dL (8.5 - 13.8), WBC 18.3 G/L (8 - 35.5), platelets 457 G/L (157 - 906) and 6 pts had circulating blasts. 12 pts had JAK2V617F and 2 had CALR mutations; karytotype was normal in 9 pts, abnormal in 5 (very HR in 3). In 10 pts analyzed by NGS so far, 8 had additional mutations (1 in 5 pts, 3 in 1, and 4 in 2) in TET2 (n= 5), ASXL1 (4), DNMT3A (2), TP53 (2), SF3B1 (1) and SRSF2 (1) genes.Safety: No DLT was observed in the 5 cohorts (primary safety criterion), the highest tested dose combination being Rux 15 mg BID + IFNa 135 mcg/week. The last cohort will test Rux 20 mg BID + IFNa 135 mcg/week. 4 serious adverse events have been reported: 1 AML transformation (very HR cytogenetics, 3% circulating blasts at baseline), 1 thrombotic event, 1 squamous cell carcinoma and 1 aggravation of Raynaud's phenomenon.Efficacy: preliminary data show a clear decrease in spleen size at 6 months (median 0 cm by palpation, range 0-9; 12.1 cm by imaging, range 10-21) and improvement in blood counts (mean, range): hemoglobin 10.5 g/dL (9.7 - 12.5), WBC 8.6 G/L (5.4 - 11.1), platelets 267 G/L (80 - 486). According to IWG criteria, all the 10 pts evaluable at time of abstract preparation responded (3 partial response, 7 hematological improvement). JAK2V617F allele burden decreased from a mean of 75% (range 43- 96) at baseline to 46% (range 24 - 84) at 6 months. Encouraging results were also found in a patient with 5 mutations (figure1) with a clear decrease in JAK2V617F, ASXL1, DNMT3A and EZH2 mutations after 12 months of treatment.ConclusionRUXOPEG is the first study to formally assess the safety and efficacy of Rux + IFNa combination in MF patients never exposed to either drugs before. The first 5 dose combinations tested showed no DLT, confirming that this combination was generally well tolerated. Preliminary efficacy results are encouraging, including in patients who received very low doses of both drugs. Full results of the 6 cohorts tested in phase 1 and doses selected for phase 2 will be presented. DisclosuresKiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Giraudier:Novartis: Research Funding. Cassinat:Novartis: Research Funding; AOP Orphan: Research Funding.

Histomorphological Responses after Therapy with Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia (ET) and Polycythemia Vera (PV)

Introduction: We previously reported the long-term efficacy and safety of pegylated interferon alpha-2a (PEG-IFN-a-2a) in 83 patients with ET and PV after a median follow-up of 83 months. Here, we present the bone marrow (BM) response assessment according to modified International Working Group for-Myeloproliferative Neoplasms Research and Treatment (IWG-MPN).Objective: To identify histomorphological BM responses in patients with ET and PV treated with PEG-IFN-a-2a as part of a prospective phase II study.Methods: All patients had BM assessment done prior to their enrollment, and then every 6-12 months while on study if possible, and in some patients after treatment discontinuation. Complete BM remission (BM-CR) required absence of > grade 1 reticulin fibrosis and disappearance of megakaryocyte hyperplasia in ET or trilinear hyperplasia with age-adjusted normocellularity in PV. An incomplete, partial response (BM-PR), was defined when fibrosis grading had consistently improved by at least one grade level on at least 2 consecutive samples > 12 months apart, yet with persistent MPN morphological features. Hematologic (HR) and molecular response (MR) assessments were previously reported (ASH 2015, abstract #60).Results: Among 83 enrolled patients (43 PV, 40 ET), 58 patients (70%) had evaluable BM samples for histomorphological response assessment, with median number of 8 samples per patient (range, 3-12). Among the remaining 25 patients, 18 were treated ≤12 months, and 7 did not have representative samples. Median age was 52 years (range, 19-75), and 29% (n=17) were males. Median disease duration prior to enrollment was 31 months (range, 1-350), and the median exposure to PEG-IFN-a-2a was 80 months (range, 15-107). After a median follow-up of 84 months (range, 36-107), 32 patients are on study. Forty-two patients were JAK2 positive, 6 CALR positive, 2 MPL positive and 8 triple negative (TN). Hematologic and molecular (JAK2V617F mutation only) responses were seen in 54 (93%) and 29 (69% of JAK2V617F positive) patients, including complete HR and complete MR in 52 (90%) and 9 (31%) patients, respectively.In total, 29 evaluable patients (50%) had BM response, including 13 patients (22%) with BM-CR (MF-0 in 11, example in Figure 1). Among 16 patients with BM-PR, 3 had resolution of dense collagen bundles as well as decreased reticulin fibrosis. Except for increased platelets in those with BM-PR (p<0.001), likely due to the higher proportion of ET patients in that group, no other differences in basic demographic or clinical parameters were present among different response groups (Table 1). Patients with BM response (PR & CR) had lower discontinuation rate, higher duration of response (HR & MR) with longer time on therapy; 13 patients with BM-CR had higher probability of complete MR (Table 1). Median time to BM-CR was 48 months (range, 30-72), median duration was 30 months (24-52), and has been maintained in 9 patients (69%). Two patients who lost their BM-CR are still on active therapy with persistent complete MR. Interestingly, 4 patients achieved BM-CR after being off therapy for a median of 18 months (range, 2-30), and 3 of them have sustained the BM-CR for 24, 50 and 52 months.Conclusions: Histomorphological BM responses (including complete response) can occur in ET/PV patients treated with PEG-IFN-a-2a, and generally correlate with more durable treatment benefit. Complete BM responses may be sustained even after treatment discontinuation, or be seen after therapy discontinuation. Despite this, we could not identify a uniform correlation between hematologic, histomorphological and molecular response. [Display omitted] [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

Efficacy and Safety of Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia and Polycythemia Vera: Results after a Median 7-Year Follow-up of a Phase 2 Study

Introduction: It has been previously reported that pegylated interferon alpha-2a can induce hematologic and molecular responses in patients with essential thrombocythemia "ET" and polycythemia vera "PV", but the follow up in these studies were relatively short.Objective: We present longer-term efficacy and safety results of a prospective phase II study of pegylated interferon alpha-2a in patients with ET and PV after a median follow up of 82.5 months (range, 8-107).Methods: Patients with a diagnosis of ET or PV, in a need of therapy, either newly diagnosed or previously treated, were eligible for this study. Median interferon starting dose of 180 mcg/week SQ (range, 450-90; 39% started on 90mcg/week) was modified in majority of the patients based on toxicity or lack of efficacy. Clinical and molecular responses were assessed every 3 to 6 months.Results: Among 83 enrolled patients (43 PV, 40 ET), 32 patients (39%) are still on study (but in 8 therapy is on hold: 5 due to toxicity, and 3 for financial reasons). Median age was 53 years (range, 19-78). Overall 37% of patients did not receive prior cytoreductive treatment. The overall median exposure to therapy was 87 months (range, 58-107) and was no different for patients still enrolled on the study and those who stopped study participation. Nine (28%) patients still on study are currently on a dose equal or higher than 90 mcg/week and 15 (47%) are on dose equal or smaller than 45mcg/week. JAK2 status or allele burden had no impact on achievement of response (clinical or molecular), time to response or duration of therapy. 55 of 59 (71%) JAK2V617F positive patients were evaluable for molecular response (Figure); 8 patients carried CARL mutation, 3 carried MPL and in 13 were triple negative. Median duration of hematologic and molecular response was 66 and 53 months, respectively; and directly correlated with treatment length and type of response (CMR had the longest duration of response). Overall yearly discontinuation rate were gradually decreasing for first 5 years, from 17% to 5%, and slowly increasing afterward to 10%. Of the 51 patients not on the study anymore, 27 (35% of the total) discontinued therapy primarily due to treatment toxicity. New late (≥24 months from start of therapy) G3/4 toxicity occurred in 17% of patients. Among patients in complete hematologic response treatment failure due to vascular adverse event or disease transformation was seen in 5 patients each. Three patients died on study (not related to therapy or disease), and 8 after stopping participation. Mean changes in allele burden over time in JAK2 positive patients are depicted in figure.Conclusions: Although pegylated interferon alpha-2a can induce significant hematologic and molecular responses; toxicity still limits its use over longer period of time and loss of response or transformation is encountered. TableResponseCharacteristicsFirst responseLast responseHem Resp, N. of patients (No), (%)CHR62 (76)25 (40)aPHR4 (5)1 (25)ORR66 (79)26 (39)aMol Resp, No, (%)CMR10 (18)9 (90)PMR20 (36)5 (25)*mMR5 (9)2 (40)ORR35 (74)16 (46)SafetyAny gradeGrade≥3Overall Adverse Events (AE), No, (%)any AE83 (100)57 (67)recurrent AE74 (89)13 (16)AE subtypes, No, (%)musculoskeletal73 (88)6 (8)neurological53 (64)2 (4)psychiatric38 (46)4 (11)gastrointestinal54 (65)11 (20)LFT elevation27 (33)5 (18)skin18 (22)2 (11)infection/fever26 (31)3 (12)respiratory23 (28)2 (9)cardiovascular13 (16)3 (23)metabolic16 (19)2 (13)neutropenia37 (45)21 (57)thrombocytopenia18 (22)a1 (6)anemia36 (43)1 (3)Autoimmune toxicity, No, (%)hepatitis1 (2.5)CNS vasculitis1 (2.5)lupus nephritis1 (2.3)Sjogren sy & dermatitis1 (2.5)Vascular AE (TEE/bleeding),Unprovoked6 (7)5 (83)No, (%)Provoked4 (5)3 (75)Disease transformation, No, (%)Myelofibrosis6 (7)AML1 (1)Safety over ≥24 months**Any gradeGrade≥3New AE, No (%)3th year10 (17)4 (40)4th year6 (11)4 (67)5th year5 (10)1 (20)≥ 6th year10 (24)1 (10)**Effective sample size for patients on therapy/year: Initial number of patients at risk at the beginning of period minus half of patients censored during that period*% calculated from 19 patientsastatistically significant differences by Fisher's exact testAbbr. CMR= complete molecular remission (undetectable JAK2 allele burden), PMR= partial molecular remission (>50% decrease in allele burden), mMR= minor molecular remission (20-49% decrease in allele burden) [Display omitted] DisclosuresOff Label Use: Pegylated Interferon alfa-2a used for patients with essential thrombocythemia and polycythemia vera. Cortes:Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Pegylated interferon alpha-2a in patients with myeloproliferative neoplasms (MPN): international experience in 115 cases

Abstract 2818[][1] Background: Pegylated interferon alpha-2a (Peg INF2a) has been demonstrated to be active therapy for high-risk essential thrombocythemia (ET) and polycythemia vera (PV), as well as treatment for early myelofibrosis (MF). We retrospectively analyzed the outcomes of Peg INF2a therapy in MPN patients treated outside the constraints of a clinical trial in the USA and EU. Methods: Clinical records of MPN patients treated at the participating centers, receiving Peg INF2a outside of the context of a clinical trial, were analyzed for response (ET and PV by ELN criteria; MF by EUNMET and IWG-MRT criteria), toxicity, and duration of response. Results: Patients: 115 patients were identified (54 PV (47%), 44 ET (38%), 17 MF (15%)) with a median age at diagnosis (48) and gender distribution (59% females) typical for the disorders. The patients had been diagnosed with the MPN a median of 44 months (0.0–312 months) prior to initiation of the Peg IFN2a and 64% harbored the JAK2-V617F mutation. The majority of patients (81%) had received at least one prior cytoreductive therapy for their disease (73 hydroxyurea, 39 anagrelide, 37 aspirin, 21 prior interferon (non pegylated), 3 phlebotomy alone). Therapy: Median starting dose of Peg INF2a was 45 micrograms/week (range: 22.5–180) with peak starting doses ranging from 30 to 300 micrograms/week. A total of 84 patients (73%) remain on Peg IFN2a with median duration of treatment of 17 months (range: 1.0–92). Toxicity: Overall the Peg INF2a was well tolerated. Hematological toxicity was Gr 3 or lower. There were 6 cases with anemia (5%), 10 with thrombocytopenia (9%) and 8 had leukopenia (7%). Most common non-hematologic toxicities were Gr 1–3 fatigue in 27 (23%), Gr 1 LFT elevation in 6 (5%), Gr 2–3 skin/allergic reaction in 6 (5%), Gr 1–2 nausea in 5 (4%), and Gr 2 mood disorder in 5 (4%) patients. Twenty patients (17%) discontinued therapy secondary to toxicity. Response: ET-PV: By ELN criteria, 30 PV patients achieved CR (55%), 17 achieved PR (31%), 4 achieved NR (7%), and 3 patients (5%) were lost to follow up or were too early to evaluate for response. In ET, the responses were CR in 27 (61%), PR in 7 (16%), NR in 4 (9%), and 6 patients (14%) were lost to follow up or were too early to evaluate for response. MF: The responses by IWG criteria were 1 CR (6%), 2 PR (12%), 2 CI (12%) and 9 SD (53%). By EUNMET, there were 2 CR (12%), 4 major responses (24%), 4 moderate responses (24%), 1 minor response (6%), 2 no response (12%), and 3 patients (17%) were lost to follow up or were too early to evaluate for response. Conclusions: Peg INF2a used at doses consistent with published clinical trials is active and well-tolerated when administered in a clinical setting outside of the support of a clinical trial. Given the majority of patients had previously failed cytoreductive therapy these results substantiate prior reports of efficacy of Peg INF2a in MPNs. Upcoming randomized clinical trials through the Myeloproliferative Disorders Research Consortium will help further define the role of Peg INF2a as first line therapy in high-risk MPNs. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. [1]: #fn-2

7123 First-line bevacizumab + reduced-dose interferon-alpha2a in patients (pts) with metastatic renal cell carcinoma (mRCC): an update on overall survival

7123 First-line bevacizumab + reduced-dose interferon-alpha2a in patients (pts) with metastatic renal cell carcinoma (mRCC): an update on overall survival

883 POSTER Phase I trial of sorafenib (BAY 43–9006) in combination with interferon alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma and malignant melanoma

883 POSTER Phase I trial of sorafenib (BAY 43–9006) in combination with interferon alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma and malignant melanoma

Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial

Less than half of patients with melanoma that has spread to local draining regional lymph nodes (stage III melanoma) live with no disease for 5 years or longer after surgery. We aimed to see whether interferon alpha-2a increased survival prospects in these patients. 444 patients from 23 centres in the WHO Melanoma Programme had complete lymphadenectomy for pathologically proven regional nodal spread of melanoma and were randomly assigned to receive either 3 MU subcutaneously of recombinant interferon alpha-2a three times a week for 3 years, or to observation alone after surgery. Patients were stratified by centre, nodes with macroscopic or microscopic melanoma, number of affected nodes, and nodal metastatic spread. Treatment was continued for 3 years or until first sign of relapse. 424 patients entered the study. 5-year disease-free survival of those who had surgery plus interferon alpha-2a was 27.5% (95% CI 21.7-33.6); for those who received surgery alone, survival was 28.4% (22.5-34.6) (p=0.50). Neither Kaplan-Meier cumulative survival rates, nor multivariate analysis of survival, showed a difference between those who had surgery and interferon alpha-2a (35%, 95% CI 29-42) and those who had surgery alone (37%, 31-44). Patients with melanoma that has spread to the local draining regional lymph nodes tolerate well 3 MU of interferon alpha-2a given subcutaneously three times a week for 3 years, but this treatment does not improve either disease-free or overall survival.