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1.
Blood ; 138:2174, 2021.
Article in English | EMBASE | ID: covidwho-1582375

ABSTRACT

Background: Severe aplastic anemia (SAA) is a rare bone marrow failure disorder associated with significant morbidity and mortality. SAA is characterized by severe pancytopenia and a hypocellular (<25%) bone marrow. The standard of care treatment is hemopoietic stem cell transplant or immunosuppressive therapy (IST) for patients (pts) who are ineligible for transplant. IST usually comprises an antithymocyte globulin (ATG) derived from horse or rabbit, and cyclosporine A (CsA). Although IST can be an effective treatment, individual intolerance, insufficient response, relapse, and clonal evolution remain significant limitations. The lack of global availability of the more effective horse ATG also leaves many pts with limited treatment options and poorer outcomes. In addition, pts with SAA often require transfusions which can be burdensome and negatively impact their quality of life. Eltrombopag (ETB) is indicated for use in pts with SAA who have had an insufficient response to IST (FDA PI, 2014) or are refractory to IST (EMA SmPC, 2015). More recently in the USA, ETB may also be used in combination with IST as first-line (1L) treatment (FDA PI, 2018). Aims: To assess the efficacy and safety of ETB + CsA (without ATG) as 1L therapy in adult pts with SAA. Methods: SOAR (NCT02998645) is a Phase 2, single-arm, multicenter, open-label study. Treatment-naive pts with SAA received ETB + CsA for 6 months;responders continued CsA therapy for an additional 24 months (later reduced to 18 months). The primary efficacy endpoint was overall response rate (ORR) by 6 months. ORR was defined as the proportion of pts with complete response ([CR] = absolute neutrophil count [ANC] ≥1000/μL AND platelet count ≥100,000/μL AND hemoglobin ≥10 g/dL) plus the proportion of pts with partial response ([PR] = any 2 of the following counts: ANC ≥500/μL;platelet count ≥20,000/μL;automated reticulocyte count ≥60,000/μL, but not sufficient for a CR). CR and PR were confirmed by 2 assessments ≥7 days apart;transfusion restrictions were also applied. For the primary endpoint to be considered ‘clinically meaningful’ at least 17/54 pts treated were required to have a response. Other endpoints included ORR by 3 months, ORR at 6 months (ie, confirmed response at the 6-month visit), and transfusion independence, which was defined as transfusion not being required in a period of ≥28 days for platelet transfusions and ≥56 days for red blood cell (RBC) transfusions. Results: Pts (N=54) had a median (interquartile range [IQR]) age of 55.0 (40.0-67.0) years and 63.0% were male. The majority of pts were White (40.7%) or Asian (40.7%). The median (IQR) duration of exposure to ETB and CsA was 5.7 (2.5-5.8) months and 5.7 (2.4-8.1) months, respectively, and the median (IQR) daily ETB dose was 150.0 (100.0-150.0) mg/day. In the full analysis set, the primary endpoint was met, with 25/54 pts having a CR or PR by 6 months (ORR 46.3%;95% confidence interval [CI], 32.6-60.4%). Of the 25 responders, 2 (3.7%) achieved a CR by 6 months. ORR by 3 months was 40.7% (95% CI, 27.6-55.0%;n=22/54), and ORR at 6 months was 37.0% (95% CI, 24.3-51.3%;n=20/54). 70.4% of all pts qualified for ≥1 period of RBC and/or platelet transfusion independence by 6 months, including all 25 (100%) responders and 13/29 (44.8%) non-responders (Fig. 1). 40.7% of all pts (responders: 68.0%;non-responders: 17.2%) qualified for ≥1 period of RBC transfusion independence (corresponding percentages for platelet transfusion independence were the same as for the combined RBC and/or platelet endpoint). Adverse events (AEs) occurred in 52/54 (96.3%) pts;45 (83.3%) pts experienced treatment-related AEs (TAEs), 23 (42.6%) of whom had a grade ≥3 TAE. The most common all-grade AEs were increased blood bilirubin (40.7%), nausea (29.6%), increased alanine aminotransferase (22.2%), and diarrhea (22.2%). Seven (13.0%) pts discontinued treatment due to grade ≥3 AEs. There were 8 on-treatment deaths (aplastic anemia [n=3];COVID-19, hemorrhage, multi-organ dysfunction syndrom , pyrexia, and thrombosis [all n=1]);no deaths were considered treatment-related. Conclusion: Data from the SOAR study indicate that ETB + CsA may be beneficial for pts with SAA ineligible for transplant who cannot access or tolerate ATG. All responders and almost half of non-responders qualified for ≥1 period of transfusion independence by 6 months, suggestive of a decreased transfusion burden. No new safety signals were identified. [Formula presented] Disclosures: Vallejo: Novartis: Honoraria;Sanofi: Honoraria;Pfizer: Honoraria. Finelli: Takeda: Consultancy;Celgene BMS: Consultancy, Research Funding, Speakers Bureau;Novartis: Consultancy, Speakers Bureau. Calado: Agios: Membership on an entity's Board of Directors or advisory committees;AA&MDS International Foundation: Research Funding;Alexion Brasil: Consultancy;Instituto Butantan: Consultancy;Novartis Brasil: Honoraria;Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees. Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria, Research Funding;Amgen: Research Funding;Alexion: Consultancy, Honoraria, Research Funding;Apellis Pharmaceuticals Inc: Consultancy, Honoraria;Swedish Orphan Biovitrum AB: Consultancy, Honoraria. Kriemler-Krahn: Novartis: Current Employment. Haenig: Novartis: Current Employment. Maier: Novartis: Current Employment. Scheinberg: Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;BioCryst Pharmaceuticals: Consultancy;Roche: Consultancy;Abbvie: Consultancy. OffLabel Disclosure: In the United States, eltrombopag is a thrombopoietin receptor agonist indicated in combination with standard immunosuppressive therapy (ATG + CsA) for the first-line treatment of adult and pediatric patients aged 2 years and older with severe aplastic anemia (SAA). It is also indicated for the treatment of patients with SAA who have had an insufficient response to immunosuppressive therapy. The SOAR trial aims to assess the efficacy and safety of eltrombopag + CsA (without ATG) as first-line therapy in adult patients with SAA.

2.
HemaSphere ; 5(SUPPL 2):42-43, 2021.
Article in English | EMBASE | ID: covidwho-1393439

ABSTRACT

Background: Pegcetacoplan (PEG), a PEGylated peptide targeting proximal complement protein C3, can control both intravascular and extravascular hemolysis. In the PEGASUS trial (NCT03500549), a phase 3, randomized, open-label, active-comparator controlled study, PEG was shown to be superior to eculizumab (ECU) after 16 weeks in improving hemoglobin levels (Hb) and clinical outcomes in patients with paroxysmal nocturnal hemoglobinuria (PNH) (Hillmen P et al, EHA 2020). Aims: We report on the efficacy and safety of PEG through 48 weeks of treatment. Methods: This study is a continuation of the PEGASUS trial. Eighty patients ≥18 years with PNH, and Hb levels <10.5 g/dL despite stable ECU treatment for ≥3 months, were enrolled. Patients completed a 4-week run-in period with both ECU and PEG before 1:1 randomization to PEG (n=41;1080 mg subcutaneously twice weekly) or ECU monotherapy (n=39;continued dosing regimen). The primary endpoint was the change from baseline (CFB) in Hb levels to Week 16. After the randomized control period (RCP), patients could continue to an open-label period (OLP), which included a 4-week run-in period for ECU patients (ECU-to-PEG), followed by PEG monotherapy (same dosage as in RCP) for all patients for a 48-week total study period. Key secondary endpoints included blood transfusion avoidance, CFB in absolute reticulocyte count (ARC), CFB in lactate dehydrogenase (LDH), CFB in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and adverse events (AEs). Results: Three patients discontinued PEG during the 16-Week RCP due to hemolysis;the remaining 77 patients entered the OLP. PEG demonstrated superiority to ECU with a mean Hb level improvement of 2.7 g/dL at Week 16, which was sustained throughout the OLP in all patients receiving PEG monotherapy. ECU-to-PEG patients demonstrated Hb improvement with mean Hb levels of 11.6 g/dL at Week 48 (CFB: 2.9 g/dL), while PEG-to-PEG patients maintained high Hb levels through the OLP with a mean Hb level of 11.3 g/dL at Week 48 (CFB: 2.6 g/dL) (Figure A). Seventy-three percent of PEG-to-PEG patients remained transfusion free for the 48-week study, and 72% of the ECU-to-PEG patients were transfusion free during the OLP through Week 48. Improvements in ARC (PEG-to- PEG: 80.0×109 cells/L;ECU-to-PEG: 94.0×109 cells/L), LDH (PEG-to-PEG: 222.7U/L;ECU-to-PEG: 224.1 U/L), and FACIT-fatigue score (PEG-to- PEG: 40.6;ECU-to-PEG: 42.5) were also observed at Week 48 (Figure B). The most common AEs by physician-reported preferred term throughout the study for all patients who received PEG were injection site reactions (36%), hemolysis (24%), and diarrhea (21%). Of all study patients, 30% experienced serious AEs with 6% possibly related to PEG. No cases of meningitis were reported. One death was reported due to COVID-19, unrelated to study treatment. Six patients discontinued due to hemolytic events: 5 classified by the treating physician as "hemolysis" and 1 as "hemolytic anemia." Overall, 12 patients (15%) discontinued PEG: 3 in RCP, 8 in OLP due to TEAEs (6 in ECU-to-PEG, 2 in PEG-to-PEG), and one during follow-up;one patient withdrew due to physician decision. Summary/Conclusion: Adult patients with PNH with suboptimal response on prior ECU treatment received PEG in this continuation of the PEGASUS trial and experienced durable treatment effect in all efficacy parameters at Week 48. The safety profile of PEG was consistent with previously reported data. The results suggest that PEG represents a new effective therapeutic option for patients with PNH.

3.
HemaSphere ; 5(SUPPL 2):41-42, 2021.
Article in English | EMBASE | ID: covidwho-1393433

ABSTRACT

Background: Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. The standard of care for patients that are ineligible for hemopoietic stem cell transplant is immunosuppressive therapy (IST), comprising antithymocyte globulin (ATG) and cyclosporine A (CsA). Horse (h-) ATG is considered more effective than rabbit ATG;however, lack of response, relapse, and clonal evolution remain significant limitations. Expense, individual intolerance, and a lack of global availability of h-ATG also leave many patients (pts) with more limited treatment options and poorer outcomes. Eltrombopag (ETB) is indicated for use in patients with SAA who have had an insufficient response to IST (FDA PI, 2014) or are refractory to IST (EMA SmPC, 2015). More recently in the USA, ETB may also be used in combination with IST as first-line treatment (FDA PI, 2018). Aims: To assess the efficacy and safety of an ATG-free regimen (ETB + CsA) in treatment-na.ve pts with SAA. Methods: SOAR (NCT02998645) is a Ph2, single-arm, multicenter, open-label study. Adult pts with SAA received ETB + CsA as first-line therapy for 6 months;responders continued CsA therapy for an additional 24 months (subsequently reduced to 18 months). The primary efficacy endpoint was overall response rate (ORR) by 6 months. ORR was defined as the proportion of pts with complete response ([CR] = absolute neutrophil count [ANC] ≥1000/μL AND platelet count ≥100,000/μL AND hemoglobin ≥10 g/dL) plus the proportion of pts with partial response ([PR] = any 2 of the following counts: ANC ≥500/μL;platelet count ≥20,000/μL;automated reticulocyte count ≥60,000/μL, but not sufficient for a CR). CR and PR were confirmed by 2 assessments ≥7 days apart;transfusion restrictions were applied. Based on historical data, an ORR of ≥30% was considered clinically meaningful. Results: A total of 54 pts were enrolled. The median (interquartile range [IQR]) age was 55.0 (40.0-67.0) years, 63.0% were male, and the majority of pts were White (40.7%) or Asian (40.7%). The median (IQR) duration of exposure to ETB and CsA were 5.7 (2.5-5.8) months and 5.7 (2.4-8.1) months, respectively, and the median (IQR) daily ETB dose was 150.0 (100.0-150.0) mg/day. In the full analysis set, the primary endpoint was met with an ORR by 6 months of 46.3% (25/54);95% CI, 32.6-60.4% (Fig. 1). Of the 25 responders, 2 (3.7%) achieved CR by 6 months. ORR by 6 months is also shown by age group (<65 and ≥65 years) (Fig. 1). Secondary endpoints included ORR by 3 months (40.7% [22/54];95% CI, 27.6-55.0%), and ORR at 6 months (ie, patients with confirmed response at 6-month visit: 37.0% [20/54];95% CI, 24.3- 51.3%). Adverse events (AEs) occurred in 52/54 pts;45 (83.3%) pts experienced treatment-related AEs (TAEs), 23 (42.6%) of whom had a grade ≥3 TAE. The most common all-grade AEs were increased blood bilirubin (40.7%), nausea (29.6%), increased alanine aminotransferase (22.2%), and diarrhea (22.2%). Seven (13.0%) pts discontinued study due to AEs. There were 8 on-treatment deaths (aplastic anemia [n=3];COVID-19, hemorrhage, multi-organ dysfunction syndrome, pyrexia, and thrombosis [all n=1]);no deaths were considered treatment-related. Summary/Conclusion: Data from the SOAR study indicate that ETB + CsA therapy may be beneficial as first-line treatment for SAA pts who cannot use ATG. The ORR is particularly notable, given the median age of this pt cohort (55.0 years). No new safety signals were identified.

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