scholarly journals Long-Term Efficacy and Safety of Ropeginterferon Alfa-2b in Patients with Polycythemia Vera — Final Phase I/II Peginvera Study Results

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3030-3030 ◽  
Author(s):  
Heinz Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
Josef Thaler ◽  
Ernst Forjan ◽  
Ella Willenbacher ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
First Year ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Dosing Regimen ◽  
Advisory Committees ◽  
Hematological Response

Abstract Background: Ropeginterferon alfa-2b (Ropeg) is a novel long-acting monopegylated IFN-alpha-2b. Due to reduced dosing frequencies, better tolerability and improved compliance, Ropeg may be a favorable treatment option for long-term therapy in patients with polycythemia vera (PV). Study design: PEGINVERA phase I/II (NCT: 2010-018768-18), a prospective, open-label, multicenter study, investigated the efficacy and safety of Ropeg for long-term treatment in 51 patients aged ≥18 years with a confirmed diagnosis of PV, regardless of prior cytoreductive therapy. Following ≥1 year of 2-weekly treatment, patients who responded well to Ropeg were permitted to switch to a 4-weekly dosing regimen. Results: Baseline characteristics of the study cohort and interim safety and efficacy data were presented previously (Gisslinger et al., Blood, 2015). Fifty-one patients were treated: Median exposure to Ropeg was approximately 5.1 years (61 months; range: 0 to 87 months). Patients were treated for a median of approximately 2 years (98.9 weeks; (Q1-Q3: 69.0 - 117.4 weeks) on the 2-weekly regimen and 4 years (207.1 weeks; Q1-Q3: 158.6 - 242.0 weeks) on the 4-weekly regimen. The best observed individual hematological response for patients in the efficacy analysis set (FAS) was a complete hematological response for 27/42 (64.3%) and a partial response for 14/42 (33.3%) patients. Patients required a median of 34 weeks (Q1-Q3: 10-96 weeks) treatment to achieve a complete hematological response, and 10 weeks (Q1-Q3: 10-20 weeks) to achieve any hematological response. Switch from 2 to 4-week dosing regimen had no apparent effect on maintenance of response. With respect to JAK-2 allele burden, the best observed individual molecular response was a complete response for 12/42 (28.6%) patients and a partial response for 19/42 (45.2%) patients. Lowest JAK-2 values relative to baseline are presented by patient in Figure 1. Patients required a median of 82 weeks (Q1-Q3: 44-115 weeks) treatment to achieve a complete molecular response and 34 weeks (Q1-Q3: 18-55 weeks) treatment to achieve any molecular response. Irrespective of dosing regimen, molecular responses tended to increase over time. Most patients reported at least one adverse reaction (AR) to treatment (409 ARs in 48/51 [94.1%]); however, the majority (296 in 44 [86.3%] patients) were mild; 102 (in 34 [66.7%] patients) were moderate and 11 (in 10 [19.6%] patients) were severe. The most frequently reported ARs (frequency >20%) were arthralgia, influenza-like illness and fatigue. Twelve serious treatment emergent adverse events (TEAE) reported by 8/51 patients (15.7%) were considered to be treatment related: 2 events of depression, 2 of positive anti-thyroid antibodies, and one each of acute stress disorder, increased antinuclear antibodies, arthralgia, atrial fibrillation, fatigue, influenza-like illness, pyrexia, and increased transaminases. 25 patients completed the trial. The majority of discontinuation due to TEAE (13/21 patients) occurred in the first year, when the recommended slow up-titration of Ropeg could not be applied because of the maximum-tolerated-dose design. After the first year, only 8 additional patients discontinued because of TEAE. Conclusions: The final results of this phase I/II study of Ropeg in patients with PV support the findings of the pivotal phase III clinical trial (Gisslinger et al., Blood 2015) with respect to safety and efficacy as determined by hematological, clinical and molecular parameters. In addition, these data provide evidence that treatment with Ropeginterferon alfa-2b for up to 7 years is efficacious, well-tolerated and disease-modifying at both the 2 week and 4 week maintenance treatment regimens. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Kralovics:MyeloPro Diagnostics and Research GmbH: Equity Ownership. Krauth:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Greil:MSD: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zoerer:AOP Orphan Pharmaceuticals: Employment. Empson:AOP Orphan Pharmaceuticals: Employment. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment.

Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2823-2823 ◽  
Author(s):  
Catriona HM Jamieson ◽  
Robert P Hasserjian ◽  
Jason Gotlib ◽  
Jorge E. Cortes ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Selective Inhibitor ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 92-92 ◽  
Author(s):  
Giuseppe Saglio ◽  
Andreas Hochhaus ◽  
Timothy P. Hughes ◽  
Richard E. Clark ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Eligibility Criterion ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Vascular Events ◽  
Advisory Committees ◽  
The Impact

Abstract Introduction Frontline NIL continues to show benefit over IM in pts with Philadelphia chromosome-positive (Ph+) CML-CP, with higher rates of major molecular response (MMR; BCR-ABLIS ≤ 0.1%) and MR4.5 (BCR-ABLIS ≤ 0.0032%), lower rates of progression to accelerated phase (AP)/blast crisis (BC) and fewer new BCR-ABL mutations on treatment in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts (ENESTnd) trial. Here, we report data with a minimum follow-up (f/u) of 4 y; updated data based on 5 y of f/u will be presented. Methods Adults with newly diagnosed Ph+ CML-CP (N = 846) were randomized to NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Progression and overall survival (OS) events were collected prospectively during study f/u, including after discontinuation of study treatment. Efficacy in the NIL 300 mg BID and IM arms was evaluated based on achievement of EMR (BCR-ABLIS ≤ 10% at 3 mo). Results At 4 y, ≥ 87% of pts remained on study in each arm and 57%-69% remained on core treatment (Table). Rates of MMR and MR4.5 by 4 y were significantly higher with NIL vs IM. Significantly fewer pts progressed to AP/BC on NIL vs IM (on core treatment: 0.7%, 1.1%, and 4.2%; on study: 3.2%, 2.1%, and 6.7% [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Of 17 pts across the 3 arms who progressed on core treatment, 11 (65%) had never achieved complete cytogenetic response and none had achieved MR4.5. Fewer mutations have emerged in the NIL arms vs the IM arm; in y 4, mutations emerged in 2 pts (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM). More pts achieved EMR in the NIL 300 mg BID arm vs the IM arm (91% vs 67%). Pts with EMR had significantly higher rates of progression-free survival (PFS) and OS at 4 y vs pts with BCR-ABL > 10% at 3 mo. Among pts with BCR-ABL > 10% at 3 mo, more progressions to AP/BC occurred in the IM arm (n = 14) vs the NIL 300 mg BID arm (n = 2); half of these pts progressed between 3 and 6 mo. In pts with intermediate or high Sokal risk, PFS and OS at 4 y were higher in both NIL arms vs the IM arm. No new safety signals were detected. Selected cardiac and vascular events were more common on NIL vs IM (by 4 y, peripheral arterial occlusive disease [PAOD] in 4 [1.4%], 5 [1.8%], and 0 pts; ischemic heart disease [IHD] in 11 [3.9%], 14 [5.1%,] and 3 [1.1%] pts; and ischemic cerebrovascular events in 3 [1.1%], 5 [1.8%], and 1 [0.4%] pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively). In the NIL 300 mg BID arm, 2 of 11 IHD events occurred between 3 and 4 y (all 4 PAOD events occurred in the first 2 y). In the NIL 400 mg BID arm, 2 of 5 PAOD events and 3 of 14 IHD events occurred between 3 and 4 y. Most pts (7 of 9) with a PAOD event on NIL were at high risk due to a combination of baseline risk factors. Conclusions NIL, a standard-of-care frontline therapy option for newly diagnosed CML-CP pts, affords superior efficacy compared with IM, including higher rates of EMR (which is associated with improved long-term outcomes), higher rates of MR4.5 (a key eligibility criterion for many studies of treatment-free remission), and a lower risk of disease progression. NIL continues to show good tolerability with long-term f/u. While selected cardiac and vascular events (including PAOD) are slightly more frequent on NIL vs IM, no increase in annual incidence of these events over time has been observed. Disclosures: Saglio: ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hochhaus:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL: Research Funding. Clark:Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Nakamae:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau, travel/ accomodations/ meeting expenses Other. Kim:BMS, Novartis,IL-Yang: Honoraria; Pfizer: Consultancy, Research Funding. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Flinn:Novartis: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Fan:Novartis: Employment. Menssen:Novartis: Employment. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; ARIAD: Research Funding. Larson:Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy.

scholarly journals Outcomes with Interferon in Essential Thrombocythemia: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3147-3147
Author(s):  
Moazzam Shahzad ◽  
Mamoon Ahmed ◽  
Sakina Abbas ◽  
Muhammad Arslan ◽  
Tooba Kashif ◽  
...  
Keyword(s):  
Systematic Review ◽  
Board Of Directors ◽  
Interferon Alpha ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Meta Analysis ◽  
Molecular Response ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Hematological Response

Abstract Introduction Essential thrombocythemia (ET) is a BCR-ABL negative myeloproliferative disorder characterized by high burden of symptoms, thrombocytosis, increased risk of thrombosis and bleeding, and risk of progression to Myelofibrosis. Interferon alpha (IFN-α) is a potent immunomodulation agent proposed to be capable of inducing complete hematological remission in patients with myeloproliferative disorders. Many INF- α have been studied for treatment of patients with ET. We present a systematic review and meta-analysis assessing the efficacy of IFN-α therapy in patients with ET. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for " Thrombocythemia, Essential " AND " Interferons " in April 2021. We did not place any time constraints. Our search produced a total of 825 records and duplicates were removed. After screening and removing irrelevant and review articles, we included 21 original articles reporting IFN-α as the only treatment for ET in adult patients. The data were collected for baseline characteristics of the participants and efficacy and safety of the intervention. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results A total of 388 patients from 21 articles were evaluated. The median age of participants was 54 (35-62) years and 31% (n=64/205) were males. The type of IFN used were Interferon-alpha in 4 studies, pegylated (PEG)IFN-α-2a in 2 studies, IFN-α-2b in 6 studies, recombinant IFN-α-2C in 3 studies, recombinant IFN-y in 1 study, PEG-IFN-2b in 1 study, recombinant IFN-2b in 2 studies, and PEG-IFN in 1 study. The pooled overall hematological response (OHR) was 86.4% (95% Cl 0.67-0.98, I 2= 65%, p=0.02, n=73) with complete hematological response (CHR) of 70.6% (95% Cl 0.54-0.84, I 2=34%, p=0.21, n=65) and partial hematological response (PHR) of 13% (95% Cl 0.02-0.27, I 2=42%, p=0.16, n=65). The pooled overall molecular response (OMR) was 84% (95% Cl 0.72-0.93, I 2=13%, p=<0.01, n=81) with complete molecular response (CMR) of 64.2% (95% Cl 0.41-0.84, I 2=68%, p=<0.01, n=81) and partial molecular response (PMR) of 35% (95% Cl 0.16-0.56, I 2=33%, p=0.01, n=43). Side effects reported were nausea, allergic reactions, liver dysfunction, dose dependent mild myalgia, fever, malaise, itching, persistent fever, headache, and flu like symptoms. Conclusion Interferon alpha, in different formulations shows consistent and high activity in patients with essential thrombocythemia. It resulted in clinical responses, as well as molecular responses. Side effect profiles were consistent among different reports and were reasonable tolerated. There is a large body of evidence supporting actively and safety of this approach in a diverse ET patient population. Figure 1 Figure 1. Disclosures McGuirk: Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company.

scholarly journals Hepatobiliary and Thromboembolic Events during Long-Term E.X.T.E.N.Ded Treatment with Eltrombopag in Adult Patients with Chronic Immune Thrombocytopenia (ITP)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1368-1368
Author(s):  
Mansoor N. Saleh ◽  
James B Bussel ◽  
Raymond SM Wong ◽  
Balkis Meddeb ◽  
Abdulgabar Salama ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Adult Patients ◽  
Phase Iii ◽  
First Year ◽  
Thromboembolic Events ◽  
Advisory Committees ◽  
Platelet Counts

Abstract Introduction: ITP, characterized by a reduction in platelets leading to thrombocytopenia, which persists for >12 months is considered chronic (cITP). Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of patients with cITP aged ≥1 year refractory to other treatments (eg corticosteroids, immunoglobulins). The recently completed Phase III EXTEND (Eltrombopag eXTENded Dosing) study was a global, open-label, extension study of patients with cITP, who received eltrombopag or placebo in prior eltrombopag clinical studies. The primary objective of EXTEND was to describe the long-term safety and tolerability of eltrombopag treatment in these patients. Here, we examine the occurrence of hepatobiliary and thromboembolic events (TEEs) as adverse events (AEs) of special interest in this study. Methods :Adult patients (≥18 years old) diagnosed with cITP according to ASH/BCSH guidelines were enrolled and received eltrombopag starting at 50 mg/day. Dose was titrated to 25-75 mg per day or less often as required, based on individual platelet count responses (targeted range ≥50-200x109/L). Patients who received 2 years of treatment and transitioned off eltrombopag due to commercial availability of eltrombopag were considered to have completed the study, whether or not they continued treatment with eltrombopag. The primary endpoint included detection and documentation of investigator-reported AEs, which included hepatobiliary AEs and TEEs. Analyses were conducted using the safety population, defined as all subjects who entered the study and had taken at least one dose of the study medication. Results:302 patients were enrolled and received at least one dose of eltrombopag: 67% were female; 38% splenectomized; 49% aged 18-49 years. Median duration of exposure was 2.4 years (range, 2 days to 8.8 years) and mean average daily dose was 50.2 (range, 1-75) mg/day. Overall, 259/302 (86%) achieved platelet counts of ≥50×109/L at least once during the study and 126/248 (51%) patients maintained continuous platelet counts ≥50×109/L for at least 31 weeks. Incidence of bleeding symptoms (WHO grades 1-4) generally decreased over time in patients with available data, from 57% (n=171/302) at baseline to 16% at 1 year (n=13/80), and 21% (12/58) at 2 years. 45 (15%) patients experienced at least one hepatobiliary AE, with the highest incidence within the first year of treatment (Figure A). AEs of increased ALT or AST led to the discontinuation of five and three patients, respectively and four patients discontinued due to an AE of increased blood bilirubin. Nine patients experienced ALT and/or AST >3 x upper limit of normal (ULN) and total bilirubin >1.5xULN. 19 (6.3%) patients experienced a total of 23 TEEs. Most events occurred in the first year (Figure B), and none after year 4. TEEs included deep vein thrombosis (n=6), cerebral infarction (stroke) [n=3], myocardial infarction (n=4), transient ischemic attack (n=2), others (n=8, 1 occurrence of each). A clear association with elevated platelet counts was not observed. Platelets >200x109/L at the time of the TEE were recorded in 8/19 patients; 6/19 experienced the TEE at or shortly after achieving their maximum platelet count. In total, 10 patients discontinued because of TEEs. Conclusions: Long-term treatment with eltrombopag in patients with cITP led to sustained platelet increases and reduced bleeding symptoms. The highest incidences of hepatobiliary AEs and TEEs occurred during the first year of treatment, though several events were recorded after 3 years of therapy. Long-term eltrombopag therapy was well-tolerated with a positive benefit-risk relationship in adults with cITP, with decreasing events after the first year of treatment. Disclosures Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. Bussel:Amgen, Novartis & GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingleheim, Prophylix Pharma, Protalex, Rigel Pharmaceuticals: Research Funding; Momenta Pharmaceuticals, Novartis, Prophylix Pharma, Protalex, Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; UptoDate: Patents & Royalties; Physicians Education Resource: Speakers Bureau. Wong:Bayer, Biogen-Idec and Novartis: Consultancy; Bayer, Biogen-Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and Roche: Research Funding; Biogen-Idec and Novartis: Membership on an entity's Board of Directors or advisory committees. El-Ali:Novartis: Employment. Quebe-Fehling:Novartis: Employment.

scholarly journals Meta-Analysis of Long-Term Risk of Recurrent Venous Thromboembolism after Stopping Anticoagulation in Men and Women with First Unprovoked Venous Thromboembolism

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2527-2527 ◽  
Author(s):  
Faizan Khan ◽  
Alvi Rahman ◽  
Marc Carrier ◽  
Clive Kearon ◽  
Jeffrey I. Weitz ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Anticoagulant Therapy ◽  
Research Funding ◽  
Meta Analysis ◽  
First Year ◽  
Advisory Committees ◽  
Men And Women ◽  
Second Year ◽  
Recurrent Vte

Abstract Background: The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) is uncertain. Anticoagulant therapy is highly effective at reducing the risk of recurrent VTE, but this clinical benefit is not maintained once anticoagulation is stopped. Current guidelines suggest considering indefinite anticoagulation in all patients with unprovoked who have a non-high bleeding risk. However, this is a weak recommendation based on limited evidence. Deciding whether patients with a first unprovoked VTE should be considered for indefinite anticoagulant therapy requires estimation of the long-term risk of recurrent VTE after stopping anticoagulation. This risk however, is poorly established, hindering decision making. Methods: We performed a systematic review and meta-analysis of randomized clinical trials and prospective observational studies to determine the rate of recurrent VTE in the first year, in the second year, between years 2 and 5, and years 5 and 10; and the cumulative incidence for recurrent VTE at 2, 5 and 10 years after stopping anticoagulation in men and women with first unprovoked VTE, who had completed at least 3 months of initial treatment. Studies were identified through a comprehensive literature search using MEDLINE, EMBASE and the Cochrane CENTRAL databases. Data clarifications were requested from authors of eligible studies. Rates of recurrent VTE were calculated for each study from the total number of recurrent VTE events divided by the person-years of follow-up, and then pooled using random-effects meta-analysis. Results: Fourteen studies involving 6, 446 patients were included in the analysis. Among men with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 11.2 events (95% CI, 9.0-13.6) in the first year; 7.4 events (95% CI, 5.5-9.5) in the second year; 4.4 events/year (95% CI, 3.2-5.7) between years 2 and 5, and 3.8 events/year (95% CI, 1.6-6.9) between years 5 and 10 [Table 1]. Among women with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 8.6 events (95% CI, 6.5-11.0) within the first year; 5.2 events (95% CI, 3.5-7.2) in the second year; 3.0 events/year (95% CI, 1.6-4.7) between years 2 and 5, and 2.0 events/year (95% CI, 1.3-2.9) between years 5 and 10 [Table 1]. In men and women respectively, the cumulative incidence for recurrent VTE was 17.8% (95% CI, 14.0%-21.9%) and 13.4% (95% CI, 9.8%-17.4%) at 2 years, 28.2% (95% CI, 22.0%-34.4%) and 20.9% (95% CI, 14.0%-28.5%) at 5 years, and 40.8% (95% CI, 28.0%-53.9%) and 28.5% (95% CI, 19.5%-38.3%) at 10 years after stopping anticoagulant therapy [Table 2]. Conclusions: Among patients with a first unprovoked VTE who have completed at least 3 months of initial treatment, men have a higher long-term risk of recurrent VTE after stopping anticoagulation, and may be given greater consideration for indefinite anticoagulant therapy. Our findings affirm the importance of considering patient's sex in deciding the optimal duration of anticoagulation, and as such, emphasize the need for individualized, patient-centered approach for the long-term management of unprovoked VTE. Disclosures Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Research Funding; Pfizer: Honoraria; Bayer: Honoraria. Weitz:Bristol-Myers Squibb: Honoraria; Daiichi-Sankyo: Honoraria; Ionis: Consultancy, Honoraria; Janssen: Honoraria; Servier: Honoraria; Novartis: Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding. Schulman:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Sanofi: Honoraria; Bayer: Honoraria. Couturaud:Pfizer: Research Funding; Bayer: Honoraria, Other: Travel Support; AstraZeneca: Honoraria; Actelion: Other: Travel Support; Intermune: Other: Travel Support; Leo Pharma: Other: Travel Support; Daiichi Sankyo: Other: Travel Support. Becattini:Bayer HealthCare: Other: Lecture Fees; Boehringer Ingelheim: Other: Lecture Fees; Bristol Meyer Squibb: Other: Lecture Fees. Agnelli:Daiichi Sankyo: Other: Personal Fees; Boehringer Ingelheim: Other: Personal Fees; Bayer Healthcare: Other: Personal Fees; Pfizer: Other: Personal Fees; Bristol-Myers-Squibb: Other: Personal Fees. Brighton:Glaxo Smith Klein: Other: Personal Fees; Novo Nordisk: Other: Personal Fees; Bayer: Other: Personal Fees. Lensing:Bayer: Employment. Prins:Pfizer: Consultancy; Daiichi Sankyo: Consultancy. Hutton:Cornerstone Research Group: Honoraria. Palareti:Roche: Membership on an entity's Board of Directors or advisory committees; Werfen: Speakers Bureau; Alfa-Wassermann: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Prandoni:Pfizer: Consultancy; Daiichi-Sankyo: Consultancy; Sanofi: Consultancy; Bayer: Consultancy. Büller:Pfizer: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Thrombogenics: Consultancy, Research Funding; Isis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding. Rodger:Biomerieux: Research Funding.

The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Monotherapy Demonstrates Long-Term Safety and Durability Of Response In Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Patients In An Open-Label Extension Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4163-4163 ◽  
Author(s):  
Susan O'Brien ◽  
Richard R. Furman ◽  
Nathan Fowler ◽  
Steven E. Coutre ◽  
Jeff P. Sharman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Extension Study ◽  
First Year ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Background Bruton’s Tyrosine Kinase (BTK) plays a critical role in chronic lymphocytic leukemia (CLL) cell survival by modulating B-cell receptor signaling. Ibrutinib (PCI-32765), a first-in-class oral inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells. A total of 148 patients with CLL/SLL received ibrutinib monotherapy in a Phase 1 multiple ascending dose study (PCYC-04753) or Phase 1b/2 continuous dosing study (PCYC-1102-CA), after which a long-term extension study was available for continued follow-up for safety and efficacy with daily orally-administered ibrutinib monotherapy. The studies included patients with treatment-naïve (TN) and relapsed or refractory (RR) CLL/SLL. The aims of the present analysis were to evaluate safety based on time on ibrutinib therapy (≤ 1 year and > 1 year), summarize safety findings in the TN and RR patient populations, and assess duration of response (DOR). Methods Demographics and baseline characteristics were summarized according to parent study, comprising either TN patients or RR CLL/SLL patients who had received at least one dose of ibrutinib monotherapy. Patient disposition, treatment-emergent adverse events (AEs), best response, overall response rate (ORR), and DOR were determined for the time treated (beginning in the parent studies and extending into the long-term extension study). Results At a median treatment duration of 21.5 months, 109 out of 148 patients continued treatment with ibrutinib for over a year. The percentage of patients who had a grade 3 or higher serious adverse event (SAE) declined over time from 43% within the first year of study treatment to 32% after the first year of treatment. With respect to side effects determined to be related to study drug, the number of grade 3 AEs and SAEs also declined from within the first year of treatment (24% and 8%, respectively) to after the first year of treatment (7% and 0%, respectively). AEs leading to ibrutinib discontinuation occurred in 12 patients within the first year of treatment for all 148 patients and in 6 out of 109 patients after the first year of treatment. Overall, the most frequent AEs grade 3 or higher were pneumonia (16.9%), hypertension (13.5%), neutropenia (11.5%), thrombocytopenia (7.4%), and diarrhea (5.4%), regardless of relationship to study drug. Grade 3 or higher SAEs were reported in RR patients at 62% compared to TN patients at 29%. Pneumonia was reported in TN patients at 6.5% and in RR patients at 19.7%. Within the efficacy population (n = 140), the ORR was 86.2% for TN patients and 88.3% for RR patients who achieved a partial response (PR) or better. The ORR combined with PR with lymphocytosis suggests that 93.1% of TN patients and 93.7% of RR patients achieved an objective response to ibrutinib therapy based on Cheson JCO 2012. After a median follow up of 27.2 months (range 1.9-42 months) for TN and RR responders who achieved PR or better, the median DOR has not been reached. At landmark 30 months, 76.1% of the responders were alive without progression. Conclusions Ibrutinib as a single agent demonstrates long-term safety, tolerability, and durability of response in patients with TN and RR CLL/SLL. Indeed, a decrease in the number of patients experiencing SAEs or AEs grade 3 or higher after 1 year of treatment with ibrutinib resulted in low rates of treatment-related discontinuation after that time point. Grade 3 or higher SAEs were reported at a two-fold higher rate in patients who had received prior therapies, which may be reflective of disease state rather than relationship to ibrutinib. A majority of patients remain on ibrutinib monotherapy with the median DOR not yet reached in the ongoing extension study. Disclosures: O'Brien: Pharmacyclics: Research Funding. Furman:Genentech: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Gilead: Consultancy. Fowler:Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Coutre:Pharmacyclics: Consultancy, Research Funding. Burger:Pharmacyclics: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Jones:Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wierda:Abbott Laboratories: Research Funding; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, DSMB, DSMB Other, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Merck: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Tragara: Research Funding. Flinn:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding; Janssen: Research Funding. Kolibaba:Pharmacyclics: Research Funding. Shaw:Pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. James:Pharmacyclics: Employment, Equity Ownership. Chu:Pharmacyclics: Employment, Equity Ownership. Byrd:Celgene: Consultancy; Johnson and Johnson: Consultancy; Pharmacyclics: Research Funding.

scholarly journals Four Weeks Administration Schedule of Ropeginterferon Alfa-2b (AOP2014/P1101) in Polycythemia Very Patients Allows Maintaining of Efficacy with Favorable Toxicity Profile in the Phase I/II Peginvera Stud

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1603-1603 ◽  
Author(s):  
Veronika Buxhofer-Ausch ◽  
Heinz Gisslinger ◽  
Josef Thaler ◽  
Ernst Schlögl ◽  
Gunther Gastl ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Exposure Duration ◽  
Research Funding ◽  
Blood Parameters ◽  
Phase Iii ◽  
Advisory Committees ◽  
One Year ◽  
Monthly Dose

Abstract Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, consisting predominantly of only one isoform, leading to longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design The PEGINVERA study (NCT01193699) is the phase I/II single arm dose escalation study with cohort extension after defining the MTD. 51 patients with PV who could be either cytoreduction therapy naive or pre-treated were included. Ropeginterferon alfa-2b was administered subcutaneously in a dose range of 50-540 µg every two weeks. Main objectives were definition of the maximum tolerated dose as well as observation long term safety and efficacy in terms of normalization of blood parameters and molecular abnormalities. The option to switch to an "once every four weeks" schedule has been implemented by the amended protocol for patients who responded well to the treatment and participated in the study for longer than one year. The dose of the study drug had to remain unchanged after the switch, resulting in a decrease of the overall exposure to the drug. Outcomes of this switch are presented here. Results 44 patients (period A, median exposure duration 37 weeks, mean monthly dose 505 µg), eligible for the analysis, i.e. being treated in the maintenance setting, were dosed every two weeks based on the Phase II dosing rules prior the amendment. 33 patients (period B, median exposure duration 12 weeks, mean monthly dose 432 µg) were dosed every two weeks beyond the first year and, showing benefit from treatment, have been assessed as eligible for the switch. 28 patients (period C, median exposure duration 93 weeks) were then switched to dosing once every four weeks (mean monthly dose 203 µg). Blood parameters were normalized and remained stable following one year of treatment and could be maintained after the switch (hematocrit, median in % - period A: 42.7, period B: 42.9, period C: 42.8; WBC, median in G/l - period A: 5.6, period B: 5.3, period C: 5.8; platelets, median in G/l - period A: 252, period B: 217, period C: 210). Spleen length stayed stable within the normal range following the switch in the majority of patients (mean, in cm - period A: 11.6, period B: 8.8, period C: 11.1). Complete hematological response could be maintained in 57% of patients in period A, in 38% of patients in period B and in 50% of patients in period C, while for partial hematological responders the results were 71%, 54% and 57%, respectively. Molecular response improved continuously over time, being maintained at the best individual level in 38% of period A patients, compared to 53% of period B and 69% of period C patients. Comparison of patient discontinuations between the arms revealed the following rates: 5(11%) in the period A, 5(15%) in the period B and 3(11%) in the period C, while the mean numbers of adverse events per patient treatment week was 0.15, 0.27 and 0.09 respectively. There were no new drug-related SAEs occurring in the period C. Conclusions This explorative data re-confirm the feasibility to administer ropeginterferon alfa-2b once every four weeks, while efficacy was maintained compared to the biweekly application schedule. Reduced injection frequency is not associated with a lack or loss of response, but clearly improves tolerability. Finally, continuous reduction of the JAK2 allelic burden indicates that duration of interferon treatment rather than the absolute dose level is an important variable inducing molecular responses. The here presented findings support the idea that interferon alpha effects in PV are pleiotropic, such as induction of immune-surveillance, which may be sufficiently maintained also at lower ropeginterferon alfa-2b levels. Disclosures Buxhofer-Ausch: AOP Orphan: Research Funding. Gisslinger:Geron: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Sanofi Aventis: Consultancy. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:AOP Orphan: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria; Novartis: Honoraria; AOP Orphan Pharmaceuticals: Honoraria, Research Funding. Willenbacher:AOP Orphan: Research Funding. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Celgene: Consultancy; Pfizer: Honoraria, Research Funding; Roche, Celgene: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Ratiopharm: Research Funding; AOP Orphan: Research Funding.

scholarly journals Outcomes with Interferon in Polycythemia Vera: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3659-3659
Author(s):  
Moazzam Shahzad ◽  
Mamoon Ahmed ◽  
Muhammad Arslan ◽  
Sakina Abbas ◽  
Tooba Kashif ◽  
...  
Keyword(s):  
Systematic Review ◽  
Side Effects ◽  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Meta Analysis ◽  
Molecular Response ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Hematological Response

Abstract Introduction Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm that presents with increase proliferation of red cells as well as variable presence of thrombocytosis & leukocytosis. Currently treatment options for PV are phlebotomy, low-dose aspirin or cytoreductive therapy. Interferon (IFN) is a biological response modifier that exerts myelosuppressive action on excessively proliferative cell lineages and is also a non-leukemogenic drug. We conducted a systematic review and meta-analysis on the efficacy of Interferon for the treatment of PV. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for " Polycythemia Vera " AND " Interferons ". A total of 577 records were discovered using database searching. All search results were imported into the Endnote X9.0 reference manager, and duplicates were removed. After screening and excluding review and irrelevant articles, 22 original articles reporting IFN as treatment for PV in adult patients were included. The data were collected for baseline characteristics of the participants and efficacy and safety of the intervention. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results A total of 1123 patients were evaluated from 22 studies. The median age was 54.5 (47.5-67) years and median follow-up time was 24 (9-146) months. The median prior number of phlebotomies was 4.55 (2-18). The type of IFN used were recombinant IFN-alpha-2a in 2 studies, IFN-a2b in 5 studies, recombinant IFN-a in 6 studies, and Pegylated-recombinant IFN-α2a in 7 studies. The pooled overall hematological response (OHR) was 86% (95% Cl 0.76-0.93, I 2= 84%, p=<0.01, n=460) with pooled complete hematological response (CHR) of 63% (95% Cl 0.50-0.76, I 2=85%, p=<0.01, n=409) and pooled partial hematological response (PHR) of 22% (95% Cl 0.12-0.34, I 2=81%, p=<0.01, n=361). Pooled overall molecular response (OMR) was 64% (95% Cl 0.56-0.71, I 2=0%, p=0.6, n=190) with pooled complete molecular response (CMR) of 24% (95% Cl 0.14-0.35, I 2=75%, p=<0.01, n=276) and pooled partial molecular response (PMR) of 38% (95% Cl 0.31-0.45, I 2=0%, p=0.5, n=191). Side effects reported were nausea, allergic reactions, liver dysfunction, dose dependent mild myalgia, fever, malaise, itching, persistent fever, headache, and flu like symptoms [Table 1]. Conclusion Interferon shows promising results when used for the treatment of polycythemia vera with a durable hematologic and molecular response and has an acceptable side effects profile. However, large randomized clinical trials are needed to confirm these findings and to explore the dose and combination of interferon with other drugs.. Figure 1 Figure 1. Disclosures Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Bellicum Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company.

scholarly journals Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 4 Years Following AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2059-2059 ◽  
Author(s):  
Wolfgang Miesbach ◽  
Karina Meijer ◽  
Michiel Coppens ◽  
Peter Kampmann ◽  
Dr. Klamroth ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Factor Ix ◽  
First Year ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
The Mean ◽  
Second Year

Background: The aim of gene therapy is to provide long-term therapeutic effect from a single administration, yet information on response durability is currently limited. AMT-060 is an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human factor IX (FIX) gene and liver-specific promoter. AMT-060 is being analyzed in an ongoing study of 10 participants with severe/moderate-severe hemophilia B (Phase 1/2 study, NCT02396342). Aim: To describe efficacy and safety outcomes from a planned interim analysis at up to 4-years post-AMT-060. Methods: Adult males with FIX activity ≤2% and a severe bleeding phenotype received a single intravenous infusion of AMT-060 (5x1012gc/kg, Cohort 1, n=5) or (2×1013 gc/kg, Cohort 2, n=5). Assessments included FIX activity, FIX replacement use, annualized bleeding rate (ABR), treatment-related adverse events (TRAE), immunological and inflammatory biomarkers up to 4 years (Cohort 1) and 3.5 years (Cohort 2). Results: As of 8 May 2019, for Cohort 1 the mean yearly FIX activity (annualized to 4 years) was 6.0 as compared to 4.4% in the first year, 6.8% in the second year and 7.3% in the third year. Mean yearly FIX activity for Cohort 2 at 3 years was 7.9% as compared to 7.1% in the first year and 8.4% in the second year. Factor IX activity for each patient over the length of follow up is shown in Figure 1. Eight of 9 participants using prophylaxis at baseline were able to discontinue use. During the last 12 months of observation, the mean annualized bleed rate (ABR) was 1.7 for Cohort 1 and 0.7 for Cohort 2. Respectively, these represent a reduction in mean ABR to the year prior to treatment of 88% and 83%. During this same period the consumption of FIX replacement therapy declined 93% and 96% relative to pre-treatment respectively for Cohort 1 and Cohort 2. No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. TRAE were mainly reported in the first 3.5-months after treatment, including three participants who experienced transient mild elevations in alanine aminotransferase as previously described. One new TRAE (joint swelling post-exercise) was observed during the last 12 months of observation post-treatment. Updated data, up to 4-years of observation, will be presented for the first time. Conclusions: Long-term stable endogenous FIX activity and reductions in ABR and FIX replacement use were observed following a single treatment with AMT-060. There were no additional safety concerns with longer term follow-up. These findings support the ongoing Phase III study of the enhanced construct, AMT-061, which encodes the highly active Padua FIX variant. Figure 1 Disclosures Miesbach: Bayer, BioMarin, CSL Behring, Chugai, Freeline, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda/Shire, UniQure: Consultancy; Bayer, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire: Research Funding; Bayer, Chugai, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire, UniQure: Speakers Bureau. Meijer:Pfizer, Sanquin, Uniqure: Research Funding; Uniqure, BMS, Aspen, Boehringer Ingelheim, Sanquin, Bayer: Consultancy, Honoraria; Sanquin: Research Funding; Bayer: Research Funding. Coppens:Pfizer: Honoraria; Portola Pharmaceuticals, Inc: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Uniqure: Research Funding; Boehringer Ingelheim: Research Funding; Sanquin Blood Supply: Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Kampmann:Uniqure BV: Research Funding. Klamroth:Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, Takeda: Consultancy; Bayer, Novo Nordisk, SOBI: Research Funding. Schutgens:Baxalta Shire, Novo Nordisk, Bayer, CSL Behring, Pfizer, UniQure BV: Research Funding. Castaman:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Seifried:Medac: Other: BSD owns IP and is contract manufacturer; Uniqure BV: Research Funding. Schwaeble:Uniqure BV: Research Funding. Bönig:Celgene, Novartis, Sandoz Hexal: Consultancy; Kiadis Pharma: Other: Contract manufacturing of ATIR101; Sandoz Hexal, Uniqure: Research Funding; Miletenyi: Speakers Bureau. Sawyer:Uniqure BV: Employment. Leebeek:CSL Behring: Research Funding; UniQure: Consultancy; Shire/Takeda: Research Funding; Novo Nordisk: Consultancy; Sobi: Other: Travel grant; Shire/Takeda: Consultancy.

scholarly journals Integration of Multiple Bioassays Using Machine Learning to Identify High-Risk CP-CML Patients Treated with Frontline Imatinib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1728-1728
Author(s):  
Chung Hoow Kok ◽  
Sakrapee Paisitkriangkrai ◽  
David T Yeung ◽  
Liu Liu ◽  
Verity A Saunders ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Board Of Directors ◽  
Predictive Value ◽  
Research Funding ◽  
Molecular Response ◽  
Advisory Committees ◽  
Term Survival ◽  
Long Term Survival

Abstract Introduction. Imatinib has revolutionised the treatment of chronic phase-chronic myeloid leukemia (CP-CML), with up to 70% of patients (pts) achieving major molecular response (MMR, BCR-ABL1 < 0.1% IS). Achievement of MMR by 2 years (yrs) is associated with an excellent prospect of long term survival. Currently, three baseline prognostic scoring systems - the Sokal, Hasford (Euro) and EUTOS risk scores - have all been used to identify pts with a poor response and/or an adverse prognosis in CP-CML. Recently, the EUTOS long-term survival (ELTS) score is shown to have strong predictive power for overall survival in CML pts. We have previously reported bioassays that have significant value for predicting MMR. Combinations of these biomarkers, together with clinical risk score, may provide a better indicator of high risk pts at the time of diagnosis. Aim. To identify high-risk pts by combining selected predictive bioassay, determine whether the ELTS score is more discriminating, and determine whether it provides additional predictive value when combined with the biomarker score. Methods. Bioassays including CRKL IC50 imatinib (White, Blood, 2005), OCT-1 Activity (OA)(White, JCO, 2010), leves of 39 plasma cytokines (Nievergall, Leukemia, 2016), expression of 20 most prognostic gene by qPCR TLDA (Kok, ASH abstract, 2015), ABCB1 gene expression (Eadie, Leukemia, 2016), KIR2DL5B genotype (Yeung, Blood, 2015), BIM and ASXL1 polymorphisms (Marum, Blood advances, 2017) were used in this study. High-risk by biomarker score (HR) was defined as pts who did not achieve MMR by 2 yrs. 210 TIDEL-II pts (frontline imatinib with early switch to nilotinib for failure to meet optimal time-dependent molecular targets) were used in this study (Yeung, Blood, 2015). Only 201 pts had ELTS scores. The Recursive Partitioning and Regression Trees (rpart) algorithm was used to identify important bioassays in predicting high-risk pts. Fisher's-exact test was used for statistical analysis. Results. In the TIDEL-II cohort, there were 21 high ELTS and 180 low/intermediate ELTS pts. Pts with high ELTS had significantly lower rates of MMR by 2 yrs compared to those pts with low/intermediate ELTS (57% vs 81%, p=0.02). We constructed a predictive model using multiple different bioassays as variables to predict high-risk pts. The rpart based model used in this analysis yielded four variables (IGFBP2 gene expression, KIR2DL5B genotype, OA, and MCP-1 cytokine plasma level) as most important for predicting high-risk pts. The accuracy of the model was 84%. Pts predicted as high-risk (HR, n=27) had significantly lower MMR achievement rate compared to those predicted as low-risk (LR), (26% vs 86%, n=183, p<0.0001, OR:17.3). Importantly, pts with HR had significantly higher rate of blast-crisis progression (15%, n=4/27) compared to those with LR (1.6%, n=3/183, p=0.006, OR:10.4) and pts with high ELTS (5%, n=1/21). Interestingly, there were two categories of HR patient groups based on the model: 1) Patient with high IGFBP2 gene expression and low OA, and 2) pts with low IGFBP2, KIR2DL5B positive genotype and high MCP-1 cytokine level. When combined with ELTS, the bioassays model improved ELTS performance in predicting HR pts. For instance, within the low/intermediate ELTS pts group, our assays could futher distinguish HR pts with inferior MMR (n=20, 2 yrs MMR of 30%) versus LR pts (n=160, 2 yrs MMR 87%). Similarly, pts with high ELTS in combination with HR also had lower MMR rate (n=1/5, 20%) compared to pts with high ELTS in combination with LR (n=11/16, 69%, p=0.11, OR:8.8). Conclusion. We developed a combined bioassays model that is predictive of MMR failure and adverse clinical outcomes for pts who receive optimised frontline imatinib therapy. This model performs well even without adding clinical parameters. Our model has additional predictive value when used together with the ELTS score, and can distinuguish HR pts within the low/intermediate ELTS group, as well as LR patients within the high ELTS category. Further confirmation of the predictive performance of this model, using a large independent patient cohort is now indicated. We postulate that this bioassay-based model could be used, in combination with ELTS, for identifying HR pts who would benefit from intensified therapeutic approaches to obtain optimal clinical outcome. Disclosures Yeung: Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Specialised Therapeutics Australia: Honoraria. Yong:Celgene: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:BMS: Research Funding; Novartis: Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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