Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, nonmalignant hematologic disease characterized by complement-mediated red blood cell hemolysis. The current standard of care for patients with PNH is C5 inhibition. Anemia persists in up to ~70% of patients receiving eculizumab and is attributed to persistent intravascular hemolysis (IVH) and mostly to C3-mediated extravascular hemolysis (EVH). Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both IVH and EVH. PEGASUS is a phase 3, open-label, active-comparator controlled study of efficacy and safety of pegcetacoplan versus eculizumab. This post hoc analysis of data from PEGASUS categorized the clinical response to pegcetacoplan or ECU in patients with PNH and hemoglobin <10.5 g/dL (despite stable ECU for ≥3 months). METHODS Hematologic response to treatment was categorized (per Risitano AM, et al. Front Immunol. 2019;10:1157) as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count (ARC). Complete response: no transfusions required, stable hemoglobin in the normal range, and no evidence of hemolysis (ie, LDH ≤1.5× upper limit of normal, ARC ≤150,000/µL). Major response: no transfusion, normal hemoglobin, but with evidence of hemolysis (LDH >1.5× upper limit of normal and/or ARC >150,000/µL). Good response: no transfusion, but with chronic mild anemia or evidence of hemolysis. Partial response: chronic moderate anemia and/or occasional transfusions (<3 units/6 months). Minor response: regular transfusions required (3-6 units/6 months). No response: regular and frequent transfusions required (>6 units/6 months). Nine patients (6 from the pegcetacoplan arm and 3 from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16. Although these 9 patients were manually categorized identically by the lead and senior author in a blinded, independent manner, they were not included among these data. RESULTS The intention-to-treat population was comprised of 41 patients randomized to pegcetacoplan and 39 patients randomized to eculizumab. Four patients in the pegcetacoplan arm and 1 patient in the eculizumab arm were not evaluable for analysis due to incomplete data at week 16. Altogether, 61.0% of patients (25/41) in the pegcetacoplan arm have achieved at least a good hematological response, in contrast to 5.1% (2/39) of the eculizumab arm. At week 16, the distribution of response categories was as follows (Figure): in the pegcetacoplan arm and eculizumab arm, respectively, complete responses were 36.6% and 0%, good responses were 24.4% and 5.1%, partial responses were 12.2% and 33.3%, minor responses were 2.4% and 23.1%, and no responses were 0% and 28.2%. The addition of the 9 manually categorized patients did not significantly alter the proportions reported here. Among the factors that may contribute to heterogeneity of hematologic response to treatment are impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure was ruled out, and no difference in LDH was observed, suggesting that the major factor accounting for the difference between the 2 arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells). CONCLUSION In PEGASUS, treatment with pegcetacoplan resulted in a greater proportion of patients with better hematological responses compared to eculizumab. These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematological improvement in the treatment of PNH. Disclosures Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. de Castro:Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Biocryst: Honoraria, Other: Data monitoring committee; Apellis: Consultancy, Honoraria, Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

Download Full-text

Improvements in Fatigue Correlate with Changes in Clinical and Hematological Outcomes: Post Hoc Analyses from the Pegasus Study

Blood ◽

10.1182/blood-2020-142354 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-5

Author(s):

David Cella ◽

William R. Lenderking ◽

Sujata P. Sarda ◽

Scott B. Baver ◽

Mohamed Hamdani ◽

...

Keyword(s):

Board Of Directors ◽

Physical Functioning ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Reticulocyte Count ◽

Hemoglobin Level ◽

Publicly Traded ◽

Advisory Committees ◽

Indirect Bilirubin ◽

Post Hoc

BACKGROUND Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening hematologic disease characterized by complement-mediated hemolysis resulting in anemia, thrombosis, and bone marrow failure. The PEGASUS phase 3 randomized study demonstrated superiority of pegcetacoplan vs. eculizumab on improvements in hemoglobin, and pegcetacoplan improved clinical and hematological outcomes such as fatigue in patients with partial response to eculizumab after treatment for at least 3 months (Hb <10.5 g/dL). The objectives of these post-hoc analyses were to explore relationships among effect modifiers, including fatigue and hemoglobin, reticulocyte count, indirect bilirubin, and physical functioning. Also, this study assessed further detail on the treatment effects of pegcetacoplan on fatigue in patients. METHODS Patients ≥18 years of age with PNH and hemoglobin concentration <10.5 g/dL despite receiving treatment with eculizumab for ≥3 months were eligible for inclusion. Patients entered a 4-week run-in period in which they received eculizumab plus twice-weekly pegcetacoplan (1080 mg, self-administered subcutaneously) and were then randomized 1:1 to monotherapy with pegcetacoplan or eculizumab for 16 weeks. Fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue scale, and a variety of symptoms (including fatigue and physical functioning) were evaluated with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) scale. Convergent validity was assessed using Spearman correlations and known groups validity was assessed using analysis of covariance (ANCOVA), as suggested by the FDA Guidance on patient-reported outcomes (US Food Drug Administration.Fed Regist. 2009;74(235):65132-65133). Subjects were grouped based on hemoglobin level (<10 g/dL, 10 to ≤12 g/dL, >12 g/dL), and by degree of hemoglobin improvement: <1 g/dL, ≥1 to <2 g/dL, and ≥2 g/dL. RESULTS At Week 16, in the overall sample (n = 80; intent-to-treat), the FACIT-Fatigue total score was significantly correlated with hemoglobin (r = 0.47, p < 0.0001; Figure 1), reticulocyte count (r = -0.37, p < 0.01), indirect bilirubin (r = -0.25, p < 0.05), and with multiple EORTC domains including fatigue and physical function (r = -0.88, p < 0.0001 and r = 0.82, p < 0.0001 respectively). In a responsiveness analysis, groups with greater improvement in hemoglobin over 16 weeks showed the most improvement in fatigue (F = 9.03, p < 0.0001), with the largest reduction in fatigue in the group with an increase in hemoglobin of ≥2 g/dL (11.3-point improvement in FACIT-F total score). In contrast, individuals with little to no hemoglobin improvement (<1 g/dL) reported slightly more fatigue (-1.2 worsening in FACIT-F total score). The FACIT-F also distinguished between groups with different levels of hemoglobin (<10 g/dL, 10 to ≤12 g/dL, >12 g/dL) at Week 16 (F = 4.78, p = 0.0019). An analysis of the correlation of change scores indicates a clear separation between pegcetacoplan and eculizumab, showing a greater effect of pegcetacoplan on change in hemoglobin and improvement in fatigue (Figure 2). CONCLUSION In PNH, hemoglobin level and positive change in hemoglobin were significantly related to reduced fatigue. Pegcetacoplan resulted in significantly lower fatigue and hemoglobin scores at Week 16 compared to eculizumab. Disclosures Cella: Novartis:Consultancy;Kiniksa:Consultancy;IDDI:Consultancy;BMS:Consultancy, Research Funding;Oncoquest:Consultancy;ASAHI KASEI PHARMA CORP.:Consultancy;Mei Pharma:Consultancy;Ipsen:Consultancy, Research Funding;Evidera:Consultancy;DSI:Consultancy, Research Funding;BlueNote:Consultancy;Abbvie:Consultancy, Research Funding;Astellas:Consultancy, Honoraria;FACIT.org:Membership on an entity's Board of Directors or advisory committees, Other: President;PROMIS Health Org:Membership on an entity's Board of Directors or advisory committees, Other;Pled Pharma:Research Funding;Janssen:Research Funding;Clovis:Research Funding;Alexion:Research Funding;Apellis:Consultancy;Pfizer:Consultancy, Research Funding.Lenderking:Evidera:Current Employment.Sarda:Apellis:Current Employment, Current equity holder in publicly-traded company.Baver:Apellis:Current Employment, Current equity holder in publicly-traded company.Hamdani:Apellis Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.Hsieh:Evidera/PPD:Current Employment.Shaffer:Evidera:Current Employment.Röth:Sanofi:Consultancy, Honoraria;Roche:Consultancy, Honoraria, Research Funding;Novartis:Consultancy, Honoraria;Biocryst:Consultancy, Honoraria;Apellis:Consultancy, Honoraria;Alexion Pharmaceuticals Inc.:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Download Full-text

Efficacy and Safety of Ravulizumab in Older Patients Aged >65 Years with Paroxysmal Nocturnal Hemoglobinuria in the 301 and 302 Phase 3 Extension Studies

Blood ◽

10.1182/blood-2020-140777 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Regis Peffault De Latour ◽

Jeffrey Szer ◽

Austin Kulasekararaj ◽

Jin Seok Kim ◽

Caroline I. Piatek ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Complement Inhibitor ◽

Efficacy And Safety ◽

Phase 3 ◽

Advisory Committees ◽

Treatment Naïve ◽

Secondary Endpoints

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged >65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged >65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or >65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged >65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (>65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged >65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the >65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (>65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Transfusion Requirements in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria with or without a History of Bone Marrow Disorder Receiving Ravulizumab and Eculizumab: Results from a Phase 3 Non-Inferiority Study Extension

Blood ◽

10.1182/blood-2020-140418 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-33

Author(s):

Antonio Risitano ◽

Jun-Ho Jang ◽

Lee Gyeong-Won ◽

Wanchai Wanachiwanawin ◽

Hubert Schrezenmeier ◽

...

Keyword(s):

Bone Marrow ◽

Sample Size ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Complement Inhibitor ◽

Phase 3 ◽

Advisory Committees ◽

Treatment Groups ◽

History Of

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder leading to hemolytic anemia, which can occur concomitantly with bone marrow disorders (BMD), such as aplastic anemia (AA) and myelodysplastic syndrome (MDS). Accordingly, patients with PNH often require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow failure. After demonstrating a non-inferior efficacy and safety profile in two of the largest clinical trials to date, ravulizumab was approved as a treatment for adults with PNH, including patients with an underlying history of bone marrow disease, who are transfusion dependent or independent. Aims: To assess the efficacy of ravulizumab in patients with PNH with or without an underlying pathology of AA or MDS, and to investigate the impact of ravulizumab on transfusion burden as measured by number of transfusions and total packed RBC (pRBC) units transfused over a 52-week period. Methods: This phase 3 multicenter, randomized, active-controlled, open-label study (study 301, NCT02946463) enrolled complement-inhibitor-naïve patients with PNH. Patients were aged ≥ 18 years with a confirmed diagnosis of PNH by flow cytometry and lactate dehydrogenase (LDH) level ≥ 1.5x the upper limit of normal (ULN; 246 U/L). Patients received either ravulizumab or eculizumab for 26 weeks; after which all patients received ravulizumab from week 26 to week 52. Efficacy outcomes included the proportion of patients achieving transfusion avoidance (TA), number of pRBC units transfused and the number of pRBC or whole blood transfusions (WBT) received from baseline to 26 and 52 weeks of treatment. In this retrospective analysis, outcomes were analysed for the following subgroups: AA, MDS or no BMD (medical history of AA or MDS was determined by the investigator at screening). Descriptive statistics were calculated for continuous (means) and categorical variables (numbers and percentages). Formal hypothesis testing for significance between treatment groups was not performed. Results: Of the 246 patients included in the study, 79 had a history of AA (32.1%) and 13 (5.3%) had a history of MDS. Baseline characteristics were comparable between treatment groups. From baseline to week 26, a comparable proportion of patients with AA achieved TA to those with no BMD; 75.6% for patients with AA and no BMD receiving ravulizumab, and 60.5% and 73.7% for patients with AA and no BMD receiving eculizumab, respectively (Table 1). Importantly, TA was maintained through 52 weeks, with similar proportions of patients with AA (87.1‒91.3%) maintaining TA to patients without BMD (85.7‒91.5%). More specifically, 65.9% of patients with AA and 69.2% of patients without BMD achieved TA through 52 weeks of ravulizumab treatment, and 55.3% and 63.2% of patients with AA and without BMD, respectively, achieved TA on eculizumab followed by ravulizumab. The proportion of patients with MDS who achieved TA appeared numerically lower compared with patients with AA or no BMD, however, this subgroup sample size was small. Furthermore, a lower proportion of patients on ravulizumab with AA or MDS received any transfusion from baseline to weeks 26 and 52 compared with those treated with eculizumab followed by ravulizumab: for week 26, 24.4% and 57.1% for ravulizumab versus 39.5% and 100.0% for eculizumab in patients with AA and MDS, respectively, and for week 52, 29.3% and 57.1% for patients with AA and MDS receiving ravulizumab for 52 weeks versus 44.7% and 100.0% for patients with AA and MDS treated with eculizumab followed by ravulizumab. In addition, ravulizumab-treated patients with AA or MDS had numerally fewer transfusions and units of pRBC/WBT compared with those who received eculizumab followed by ravulizumab. Overall, the exploratory nature of the analysis and small sample size means that interpretation of the data is limited. Conclusions: This analysis demonstrates that majority of patients with PNH and AA who received ravulizumab avoided the need for transfusion up to 52 weeks of treatment. Patients treated with ravulizumab for the 52-week period had numerically fewer transfusions and units of pRBC/WBT transfused compared with patients who received eculizumab followed by ravulizumab. Overall, these findings support the use of ravulizumab in complement-inhibitor-naïve patients with PNH, with or without a history of BMD. Disclosures Risitano: Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; RA pharma: Research Funding; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Yonemura:Alexion Pharmaceuticals: Honoraria, Research Funding. Munir:Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pavani:Alexion Pharmaceuticals: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sicre de Fontbrune:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Röth:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding.

Download Full-text

Efficacy of Mogamulizumab By Prior Systemic Therapy in Patients with Previously Treated Cutaneous T-Cell Lymphoma: Post Hoc Analysis from the Phase 3 Mavoric Study

Blood ◽

10.1182/blood-2018-99-114819 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1619-1619

Author(s):

Pier Luigi Zinzani ◽

Steven M. Horwitz ◽

Youn H. Kim ◽

Alison J. Moskowitz ◽

Pierluigi Porcu ◽

...

Keyword(s):

Board Of Directors ◽

Systemic Therapy ◽

Research Funding ◽

Advisory Committees ◽

Immune Activity ◽

Post Hoc Analysis ◽

Prior Therapy ◽

Prior Systemic Therapy ◽

Post Hoc ◽

Systemic Therapies

Abstract Aims: Patients with the cutaneous T-cell lymphoma subtypes mycosis fungoides (MF) and Sézary syndrome (SS) often require multiple lines and types of systemic therapy. The phase 3 MAVORIC study (NCT01728805) showed that mogamulizumab (MOGA), a monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), is superior to vorinostat (VORI) in median progression-free survival (PFS; 7.7 vs 3.1 months, P<0.0001) and confirmed overall response rate (ORR [complete response plus partial response]; 28% vs 4.8%, P<0.0001) in patients with MF/SS with a median of three prior systemic therapies (range: 1-18). Preclinical studies have suggested that histone deacetylase inhibitors (HDACi) may downregulate CCR4 expression in neoplastic T-cells. Further, romidepsin (an HDACi) has also been shown to suppress NK cell function, which could negatively influence the antibody activity of MOGA. As a result, this post hoc analysis of the MAVORIC study examined the effect of prior systemic therapies, including romidepsin, on response to MOGA. Methods: Patients with MF/SS who had failed ≥1 systemic therapy were randomized to MOGA 1.0 mg/kg intravenously or VORI 400 mg orally daily until disease progression or unacceptable toxicity. Confirmed ORR was based on a global composite response score in each of four disease compartments (skin, blood, lymph nodes, and viscera), achieved at two consecutive visits. PFS, ORR, and the interaction with time from treatment were assessed based on immune activity of last prior regimens, and analyzed using Cox proportional hazards and logistic regression models, respectively. Results: In total, 372 patients (median age: 64 years) were randomized (MOGA, n=186; VORI, n=186). Baseline characteristics, including number and type of prior systemic therapies, were similar between cohorts. The most common last prior systemic therapies in patients randomized to MOGA were oral bexarotene (n=46; 25%), chemotherapy (n=44; 24%), methotrexate (n=20; 11%), interferon alpha (n=17; 9%), extracorporeal photophoresis (ECP; n=16; 9%), and romidepsin (n=16; 9%). Confirmed ORRs in MOGA-treated patients after 1, 3, or ≥6 prior therapies were 25%, 35%, and 30%, respectively. Patients who crossed over to MOGA from VORI, due to progression or intolerance, had an ORR of 30%. ORR and duration of response to MOGA did not vary by last prior systemic therapy (Table). Logistic regression analyses demonstrated that neither the impact of immune activity of the last prior therapy (immune stimulatory or immunosuppressive regimens) nor the time from prior treatment had an effect on PFS or ORR observed in response to MOGA (P>0.05) Conclusions: This post hoc analysis of the MAVORIC study shows no difference in MOGA response by the number of prior systemic therapies, type, or immune activity of last prior therapy. Disclosures Zinzani: MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Horwitz:Spectrum: Research Funding; Innate Pharma: Consultancy; Forty Seven: Consultancy, Research Funding; Trillium: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; Mundipharma: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Corvus: Consultancy. Kim:Medivir: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; miRagen: Research Funding; Neumedicine: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Galderma: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Soligenix: Research Funding; Merck: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Takeda: Honoraria. Porcu:Innate Pharma: Consultancy. Scarisbrick:National Health System, UK: Employment; Kyowa: Consultancy; Takeda: Consultancy; Helsinn: Consultancy; Actellion: Consultancy; Mallinkcrodt: Consultancy; 4SC: Consultancy; Innate Pharma: Consultancy. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Bagot:Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera

Blood ◽

10.1182/blood-2021-149219 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1504-1504

Author(s):

Srdan Verstovsek ◽

Andrew T. Kuykendall ◽

Ronald Hoffman ◽

Yelena Ginzburg ◽

Naveen Pemmaraju ◽

...

Keyword(s):

Iron Deficiency ◽

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Data Safety Monitoring Board ◽

Publicly Traded ◽

Phase 3 ◽

Eligibility Criteria ◽

Advisory Committees ◽

To Receive

Abstract Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per NCCN guidelines. Since patients are seen periodically, PV patients may spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is associated with systemic symptoms with fatigue. These fatigue-related symptoms are found to be the most prevalent and severe as reported in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients have iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018]. The iron deficiency worsens after repeated TP. We have demonstrated in a phase 2 study that rusfertide (PTG-300) has a good tolerability profile and achieves HCT control in PV patients with improvement in iron deficiency. Methods. This is a Phase 3, multicenter, global, randomized trial that compares the efficacy and safety of rusfertide compared to placebo when added on to current therapy for PV (Figure 1). The study population is PV subjects who require frequent phlebotomies to control their hematocrit with or without concurrent therapy. This is a three-part study in subjects with polycythemia vera: - Part 1a: randomized, double-blind, placebo-controlled, add-on parallel-group period for 32 weeks. Subjects will be stratified by their ongoing PV treatment and randomized 1:1 to rusfertide or placebo added-on to their ongoing PV treatment. - Part 1b: open-label treatment phase during which all subjects who complete Part 1a successfully will receive rusfertide for 20 weeks (Week 32 through Week 52). - Part 2: Long term extension (LTE) phase during which all subjects who complete Part 1b will continue to receive rusfertide for 32 weeks (Week 52 to Week 84). Inclusion Criteria: Approximately 250 subjects will be randomized. Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain HCT below 45% in the 6 months prior to enrollment in Part 1. Eligible subjects will continue to receive their therapy at screening for PV (phlebotomy alone (TP) or cytoreductive therapy + TP) and must have a hematocrit <45% at Week 0 prior to randomization. Subjects who meet the eligibility criteria will be stratified by ongoing PV therapy (TP only, TP+hydroxyurea, TP+ruxolitinib, TP+interferon, TP+other) and randomized 1:1 to treatment with rusfertide or placebo added on to the subject's ongoing PV therapy at Week 0. The "add on" design allows subjects to receive standard cytoreductive therapy to control WBC and/or platelets and to receive rusfertide/placebo. The dose of cytoreductive therapy in Part 1a and Part 1b may be decreased for safety but may not be increased for efficacy including control of hematocrit, elevated platelets and/or WBC. Primary endpoint: Proportion of subjects achieving a response starting at Week 20 through Week 32 (inclusive) who receive rusfertide compared to placebo. A response is defined as absence of phlebotomy eligibility defined as either: 1. a confirmed hematocrit ≥45% and that is at least 3% higher than the baseline hematocrit (value immediately prior to randomization at Week 0); confirmation required within 1 to 7 days, or 2. a hematocrit ≥48%. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kuykendall: Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Abbvie: Honoraria; Incyte: Consultancy; Blueprint: Honoraria. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding. Pemmaraju: Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; Sager Strong Foundation: Other; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. O'Connor: Protagonist Therapeutics: Current Employment. Gupta: Protagonist Therapeutics: Current Employment. Kiladjian: Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Categorized Hematologic Response to Pegcetacoplan and Correlations with Quality of Life in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from Phase 1b, Phase 2a, and Phase 3 Trials

Blood ◽

10.1182/blood-2021-147988 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1104-1104

Author(s):

Antonio Risitano ◽

Raymond S Wong ◽

Mohammed Al-Adhami ◽

Crystal Chen ◽

Regis Peffault De Latour

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Research Funding ◽

Response Category ◽

Open Label ◽

Advisory Committees ◽

Hematologic Response ◽

One Year ◽

Post Hoc

Abstract Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a complement-mediated, hematologic disease characterized by hemolysis, anemia, and fatigue that impairs quality of life. Pegcetacoplan (PEG), a C3-inhibitor recently approved by the Food and Drug Administration for treatment of PNH, controls intravascular hemolysis (IVH) and prevents extravascular hemolysis (EVH). The PADDOCK and PALOMINO trials demonstrated PEG's improvement of key hematologic and clinical parameters, including hemoglobin (Hb) level and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The PEGASUS trial demonstrated that PEG was more effective than eculizumab (ECU) in improving these parameters in PNH patients with suboptimal response to prior ECU treatment. Aims: This post hoc analysis categorized hematologic response to PEG in 3 trials: PADDOCK (phase 1b, open-label, two-cohort [NCT02588833]), PALOMINO (phase 2a, open-label, single-cohort [NCT03593200]), and PEGASUS (phase 3, randomized, open-label, active-comparator controlled [NCT03500549]). Methods: PADDOCK and PALOMINO included adult complement inhibitor-naïve patients, while PEGASUS included adult patients with Hb <10.5 g/dL despite ≥3 months of ECU treatment. PADDOCK was a multiple ascending dose pilot study of 2 cohorts: cohort 1 received a suboptimal PEG dose (180 mg/day subcutaneously [SQ]) for 28 days; cohort 2 received a PEG dose of 270-360 mg/day SQ for up to one year. Patients could be enrolled in both cohorts. PALOMINO patients received a PEG dose of 270-360 mg/day SQ for up to one year. PEGASUS comprised a 4-week run-in period where patients received both ECU (continued dosing regimen) and PEG (1080 mg SQ twice-weekly), 16-week randomized controlled period (PEG or ECU monotherapy), and 32-week open-label period (PEG monotherapy) including a 4-week run-in period for the ECU-to-PEG group. Hematologic response category was assessed at Days 113/337 for patients in the combined PADDOCK/PALOMINO trials (N=24) via manual categorization by two independent, blinded observers. Categorization was assessed at Weeks 16/48 for PEGASUS patients (N=80) using SAS 9.4M5. Statistical significance for hematologic response categories within arms at Week 16 vs. 48, and between arms at Week 48, was evaluated using Wilcoxon-Mann-Whitney and Chi-square testing. FACIT-Fatigue scores for PEGASUS patients, summarized using descriptive statistics, were also correlated to hematologic response category. Response categories were defined per the following criteria (Risitano A, et al., Front Immunol, 2019;10:1157): complete- no transfusions required, stable Hb (normal range), no evidence of hemolysis (lactate dehydrogenase [LDH]≤1.5×upper limit of normal [ULN] U/L, absolute reticulocyte count [ARC]≤150,000/µL); major- no transfusion, normal Hb, but with evidence of hemolysis (LDH>1.5×ULN U/L and/or ARC>150,000/µL); good- no transfusions, but with chronic mild anemia or evidence of hemolysis; partial- chronic moderate anemia and/or occasional transfusions (<3 units/6 months); minor- regular transfusions required (3-6 units/6 months); no response- regular and frequent transfusions required (>6 units/6 months). PADDOCK/PALOMINO patients missing data at an assessment timepoint, or PEGASUS patients missing data within 6 weeks prior to an assessment timepoint, were not evaluated. Results: Most PADDOCK/PALOMINO patients achieved at least a good hematologic response at Days 113 and 337 (Table 1). At Week 48, most patients in both PEGASUS arms achieved a good/major/complete hematologic response (inter-arm p=0.4390), with a significant increase in the percent of ECU-to-PEG patients achieving at least a good response after switching to PEG at Week 16 (Week 16 vs. 48: intra-arm p<0.0001; Table 1). In PEGASUS, patients with better response categories had higher FACIT-Fatigue scores when compared to the rest of the cohort (Week 16: p<0.001, Week 48: p=0.028; Table 2). Conclusions: In post hoc analyses of PADDOCK, PALOMINO, and PEGASUS trial data, a substantial proportion of patients achieved and maintained good, major, or complete hematologic responses to PEG, suggesting that PEG can lead to sustained improvements in hematologic parameters. PEGASUS data also demonstrated correlation of improved hematologic response category with clinically meaningful improvements in quality of life, as measured by FACIT-Fatigue. Figure 1 Figure 1. Disclosures Risitano: Jazz: Other: Lecture fees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees; Biocryst: Membership on an entity's Board of Directors or advisory committees; RA Pharma: Research Funding; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Lecture fees, Speakers Bureau; Apellis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Speakers Bureau. Wong: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis Pharmaceuticals: Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Adhami: Apellis Pharmaceuticals: Current Employment. Chen: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour: Swedish Orphan Biovitrum AB: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Download Full-text

Established Prevention of Vaso-Occlusive Crises with Crizanlizumab Is Further Improved in Patients Who Follow the Standard Treatment Regimen: Post-Hoc Analysis of the Phase II Sustain Study

Blood ◽

10.1182/blood-2018-99-112201 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1082-1082

Author(s):

Darla K Liles ◽

Rodolfo Cançado ◽

Julie Kanter ◽

Abdullah Kutlar ◽

Andreas Bruederle ◽

...

Keyword(s):

Board Of Directors ◽

Treatment Regimen ◽

Research Funding ◽

Standard Treatment ◽

Annual Rate ◽

Advisory Committees ◽

Post Hoc Analysis ◽

Number Of Patients ◽

Post Hoc ◽

Standard Treatment Regimen

Abstract Background: In the 52-week SUSTAIN study, which compared the P-selectin inhibitor crizanlizumab with placebo in patients with sickle cell disease (SCD), crizanlizumab 5.0 mg/kg significantly reduced the frequency of vaso-occlusive crises (VOCs) leading to healthcare utilization versus placebo (Ataga KI et al. N Engl J Med 2017;376:429-39). The overall incidences of adverse events and serious adverse events were similar among the patients treated with crizanlizumab and placebo. Aims: This post-hoc analysis from SUSTAIN evaluated key VOC-related endpoints in crizanlizumab 5.0 mg/kg and placebo groups in the per protocol (PP) population, as a way to assess the effect in patients who are able to follow the standard treatment regimen; data from the intention-to-treat (ITT) population will also be shown for context. Methods: The SUSTAIN study was a randomized, double-blind, placebo-controlled, Phase II study (NCT01895361) that enrolled patients aged 16-65 years with SCD who had experienced 2-10 VOC events in the previous 12 months. Patients were randomized 1:1:1 to receive crizanlizumab 5.0 mg/kg, 2.5 mg/kg or placebo 14 times intravenously over 52 weeks; here we focus on the 5.0 mg/kg dose of crizanlizumab versus placebo. The number and time of VOCs leading to healthcare utilization (e.g., hospital admission, emergency department visit) from randomization to end of treatment were measured for each individual patient. Analyses were conducted on the ITT population (i.e., all patients randomized) and PP population (i.e., all patients randomized who received at least 12/14 planned doses of treatment, and completed the study without major protocol violations that impacted the efficacy assessments). Results: In the crizanlizumab 5.0 mg/kg and placebo groups, there were 67 and 65 patients in the ITT population, and 40 and 41 patients in the PP population, respectively; the main reasons for exclusion from the PP population were associated with violations of the visit schedule. As shown previously (Ataga KI et al. N Engl J Med 2017;376:429-39), the median annual rate of VOCs was 1.63 in the crizanlizumab 5.0 mg/kg group versus 2.98 in the placebo group (stratified Wilcoxon Rank-Sum test, P=0.01; Table) in the ITT population. The median time to first on-treatment VOC was 4.07 versus 1.38 months (stratified log-rank test, P=0.001), respectively, in the crizanlizumab 5.0 mg/kg and placebo groups. Overall, 24/67 (35.8%) and 11/65 (16.9%) patients in the crizanlizumab 5.0 mg/kg and placebo groups (stratified Cochran-Mantel-Haenszel test, P=0.013), respectively, did not experience any VOCs during treatment. In the PP population, the median annual rate of VOCs was 1.04 with crizanlizumab 5.0 mg/kg versus 2.18 with placebo (P=0.02; Table). The median time to first on-treatment VOC was 6.55 months with crizanlizumab 5.0 mg/kg and 1.58 months in the placebo group (P<0.001). Overall, 15/40 (37.5%) and 5/41 (12.2%) patients in the crizanlizumab 5.0 mg/kg and placebo groups, respectively, did not experience any VOCs during treatment (P=0.008). The effect of treatment with crizanlizumab 5.0 mg/kg over placebo, as assessed by the three selected endpoints, is visible on the Figure, i.e., reduced frequency of VOCs, delayed first VOC, and increased number of patients with no VOCs during treatment. Conclusions: This post-hoc analysis of SUSTAIN shows that crizanlizumab 5.0 mg/kg provided benefit over placebo: nearly halving the median annual rate of VOCs, doubling the time to first VOC, and doubling the number of patients with no VOCs during treatment in the ITT population. The effect was even more pronounced in the PP population. This suggests that the superior VOC-related treatment outcomes of crizanlizumab 5.0 mg/kg versus placebo are further improved in patients who are able to follow the standard crizanlizumab treatment regimen. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Sancilio: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kutlar:Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding; Sancilio: Other: DSMB Chair; Bluebird Bio: Other: DSMB Member. Bruederle:Novartis: Employment. Shi:Novartis: Employment, Other: Stock owner of Novartis. Campigotto:Novartis: Employment. Ataga:Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Pegcetacoplan Is Superior to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Regardless of Prior Transfusion Requirement

Blood ◽

10.1182/blood-2020-141061 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Regis Peffault De Latour ◽

Carlos M. de Castro ◽

Jeffrey Szer ◽

Kensuke Usuki ◽

Peter Hillmen ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Age Group ◽

Publicly Traded ◽

Advisory Committees ◽

Material Support ◽

Group Sex ◽

Support Research

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by chronic complement-mediated intravascular and extravascular hemolysis. In the phase 3 PEGASUS study (NCT03500549), pegcetacoplan, a C3 inhibitor targeting the proximal complement pathway, was superior to eculizumab (ECU) on the primary endpoint of hemoglobin (Hb) change from baseline at week 16, and improved clinical and hematologic parameters. Additional analyses assessed if any groups of patients might experience further benefit from pegcetacoplan. METHODS Patients ≥18 years old with a diagnosis of PNH and persistent anemia (Hb <10.5 g/dL) at baseline, despite treatment with stable doses of ECU for ≥3 months, entered a 4-week run-in period during which all patients continued their current dose of ECU with the addition of twice-weekly pegcetacoplan (1080 mg, self-administered subcutaneously). On study day 1, patients were stratified based on baseline platelet count and prior transfusion requirements, and randomized 1:1 to monotherapy with pegcetacoplan or ECU for 16 weeks. The primary endpoint of change from baseline (before first dose of pegcetacoplan) at week 16 in Hb and key secondary endpoints (change from baseline at week 16 in absolute reticulocyte count [ARC] and lactate dehydrogenase [LDH]) were analyzed using a mixed-effect model for repeated measures by subgroups based on baseline age group, sex, race, number of packed red blood cell transfusions (<4 vs ≥4) within the 12 months prior to day −28, and platelet count at screening (<100,000/mm3 vs ≥100,000/mm3). The key secondary endpoint of transfusion avoidance was analyzed by calculating the number and proportion of patients who were transfusion-free and also analyzed by subgroups. For patients transfused during the randomized control period or who withdrew from the study, the primary and secondary data endpoints up to the transfusion or time of withdrawal were included, but all subsequent values were censored. RESULTS Pegcetacoplan treatment was associated with significantly greater increases in Hb levels than ECU at week 16, regardless of baseline age group, sex, race, prior transfusions, or platelet count (Tables 1-2). At week 16, regardless of baseline platelet count strata, mean Hb significantly increased from baseline in the pegcetacoplan group and decreased in the ECU group. The proportion of transfusion-free patients was similar in the pegcetacoplan group, regardless of age (≤65 years, 87.1%; >65 years, 80%), sex (female, 81.5%; male, 92.9%), race (Asian, 100%; black, 100%; white, 75.0%), transfusion strata (<4 transfusions, 85.0%; ≥4 transfusions, 85.7%), or platelet strata (<100,000/mm3, 83.3%; ≥100,000/mm3, 86.2%). A smaller proportion of patients were transfusion-free with ECU, regardless of age (≤65 years, 18.8%; >65 years, 0%), sex (female, 18.2%; male, 11.8%), race (Asian, 28.6%; black, 0%; white, 16.0%), transfusion strata (<4 transfusions, 31.3%; ≥4 transfusions, 4.3%), or platelet strata (<100,000/mm3, 0%; ≥100,000/mm3, 20.0%). Similar trends for more favorable results with pegcetacoplan versus ECU were seen across the prespecified subgroups for ARC and LDH. CONCLUSIONS In this prespecified stratified analysis of the phase 3 PEGASUS study of patients with PNH and persistent anemia, mean Hb levels increased significantly more, the proportion of transfusion-free patients was significantly higher, ARC change from baseline at week 16 was significantly lower, and LDH decreases were larger with pegcetacoplan versus ECU, regardless of baseline age group, sex, race, prior transfusion numbers, and platelet count. Disclosures Peffault De Latour: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion: Honoraria, Research Funding; Apellis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Other: Steering committee; Biocryst: Honoraria, Other: Data monitoring committee. Szer:Apellis: Consultancy; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usuki:Alexion: Research Funding, Speakers Bureau; Apellis: Research Funding; Chugai: Research Funding; Novartis: Research Funding, Speakers Bureau. Hillmen:Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees. Hamdani:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

Download Full-text

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-134193 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Frederick Lansigan ◽

David Jacob Andorsky ◽

Morton Coleman ◽

Abdulraheem Yacoub ◽

Jason M. Melear ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Publicly Traded ◽

Advisory Committees ◽

The Past ◽

Genetics Research ◽

Non Hodgkin Lymphoma ◽

Phase Iiib ◽

Post Hoc

Background: Lenalidomide combined with rituximab (R2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with indolent non-Hodgkin lymphoma. Patients with advanced age at diagnosis are considered to be high risk, supporting post-hoc subgroup analyses by age, with a focus on patients aged ≥ 70 years from the MAGNIFY study. Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg on days 1-21 of a 28-day cycle + rituximab 375 mg/m2/week cycle 1 and then every 8 weeks starting with cycle 3 (R2) are administered for 12 cycles followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 vs rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable FL grade 1-3a and MZL patients (FL grade 3b, tFL, and MCL not included) receiving ≥ 1 treatment with baseline/postbaseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Post-hoc analyses were performed by analyzing data from patients aged ≥ 70 years at time of study entry. Results: As of November 30, 2019, 393 patients have enrolled and 152 (39%) were aged ≥ 70 years. Baseline characteristics including histology, disease status, and prior treatments of patients ≥ 70 and the overall population are shown in the table. Median PFS in the ≥ 70 subgroup was 36.0 months (95% CI, 28.3-NR). Overall response rate and CR/CRu were 75% and 38%, with a median duration of response that was not reached (95% CI, 27.1-NR). Efficacy results for the overall population are shown in the table. In patients ≥ 70 the most common (≥ 20%) any-grade treatment emergent adverse events (TEAEs) were fatigue (44%), neutropenia (41%), diarrhea (34%), constipation (34%), and nausea (27%). Neutropenia (35%) was the only grade 3/4 TEAE occurring in > 10% of patients (febrile neutropenia occurred in 3 patients [2%]). TEAEs led to lenalidomide dose reduction in 69 patients (46%) and discontinuation in 40 patients (26%). Seventy-eight patients ≥ 70 (51%) completed all 12 cycles of induction treatment, and 72 (47%) have entered the maintenance phase. Sixty-one patients ≥ 70 (40%), compared to 35% of patients in overall population, prematurely discontinued both lenalidomide and rituximab, due to TEAEs (n = 26; 17%), progressive disease (n = 15; 10%), patient withdrawal (n = 12; 8%), death (n = 5; 3%), and other reasons (n = 3; 2%). Neutropenia was the only TEAE leading to discontinuation of lenalidomide in more than 2 patients (n = 10; 7%). Conclusions: Similar to findings in the overall population, R2 treatment in advanced-age patients with R/R FL and MZL resulted in encouraging efficacy, and with close attention to dose reduction there is a tolerable safety profile. Table Disclosures Lansigan: BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy. Andorsky:AstraZeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding. Coleman:Novartis Pharmaceuticals: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Incyte Corporation: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Seattle Genetics: Research Funding. Yacoub:Novartis: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning:Prisma Health: Current Employment; Abbvie: Consultancy; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi Aventis: Speakers Bureau. Kolibaba:Compass Oncology: Ended employment in the past 24 months; Atara Biotech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; AbbVie: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria; Janssen: Research Funding; Novartix: Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding. Gharibo:Bayer: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Amgen GmbH: Honoraria; Roche: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding.

Download Full-text

BRUIN CLL-313: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Blood ◽

10.1182/blood-2021-145938 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3732-3732

Author(s):

Wojciech Jurczak ◽

Caroline Dartigeas ◽

Marta Coscia ◽

Peter S. Ganly ◽

Ghassan Al-Jazayrly ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Small Lymphocytic Lymphoma ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Advisory Committees ◽

Mutation Status

Abstract Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In a phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397, 10277:892-901). Study Design and Methods: BRUIN CLL-313 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus bendamustine plus rituximab (BR) in treatment naïve CLL/SLL patients with retained 17p. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by IGHV mutation status (mutated vs unmutated), and Rai stage (low/intermediate vs high). Patients in the BR arm are eligible to crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 and confirmed by an independent review committee (IRC). Eligible patients are adults with confirmed diagnosis of CLL/SLL and who require therapy per iwCLL 2018 criteria. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation to DLBCL, prolymphocytic leukemia or Hodgkin lymphoma any time pre-enrollment, presence of 17p deletion, prior systemic therapy for CLL/SLL, and significant cardiovascular disease. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an IRC. Secondary endpoints include investigator-assessed PFS, overall survival (OS), overall response rate (ORR), duration of response (DoR), safety and tolerability, and patient reported outcomes. The global study is currently enrolling patients. Disclosures Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Coscia: Gilead: Honoraria; AbbVie: Honoraria, Other; Janssen: Honoraria, Other, Research Funding; AstraZeneca: Honoraria. Wang: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Bao: Loxo Oncology at Lilly: Current Employment; Genentech: Ended employment in the past 24 months. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Zinzani: Eusapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Celtrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau.

Download Full-text