scholarly journals Efficacy of Caplacizumab in Patients with aTTP in the HERCULES Study According to Initial Immunosuppression Regimen

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2365-2365
Author(s):  
Katerina Pavenski ◽  
Paul Knoebl ◽  
Marie Scully ◽  
Johanna A. Kremer Hovinga ◽  
Paul Coppo ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Immunosuppressive Therapy ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Advisory Committees ◽  
Double Blind ◽  
Improved Outcomes ◽  
Count Response ◽  
Immunosuppression Regimen

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is an acute, life-threatening thrombotic microangiopathy that requires urgent and specialized treatment. Prior to the introduction of caplacizumab, the treatment for aTTP was based on daily therapeutic plasma exchange (TPE; to replenish functional ADAMTS13 enzyme) plus immunosuppression (mainly corticosteroids and rituximab; to suppress anti-ADAMTS13 autoantibody production). TPE combined with immunosuppressive therapy improved outcomes in patients; however, episodes of aTTP are still associated with an acute mortality of up to 20% as these therapies do not have an immediate effect on the pathologic microvascular thrombosis. The primary results of the randomized, double-blind, placebo-controlled phase 3 HERCULES study showed that, in combination with TPE and corticosteroids, caplacizumab shortened the time to platelet count response and reduced the incidence of a composite outcome of TTP-related death, exacerbation, or major thromboembolic events, by inhibiting vWF-platelet interaction and, thereby, stopping the formation of microthrombi. As additional immunosuppression per local practice was permitted in HERCULES, the present analysis aimed to determine whether there was any difference in the efficacy of caplacizumab according to the initial immunosuppression regimen. Methods: Data of patients participating in HERCULES were stratified based on the type of first-line immunosuppression regimen (i.e. therapy started up to Day 3 of the treatment period) and analyzed descriptively. The main 2 groups analyzed were those receiving corticosteroids only and those receiving a combined regimen of corticosteroids and rituximab. Differences in dose or dosing frequency were not taken into consideration in this descriptive analysis. Results: Of the 145 randomized patients in the HERCULES study, 112 (77.2%) patients received only corticosteroids as first-line immunosuppressive therapy, while 24 (16.6%) patients received corticosteroids and rituximab (initiated within the first 3 days of the study). Three patients (2.1%) received another type of initial immunosuppression (cyclophosphamide + corticosteroids [n=1], hydroxychloroquine [n=1], and mycophenolate mofetil + corticosteroids [n=1]), 1 patient (0.7%) started immunosuppression later in the study (cyclophosphamide + corticosteroids), while 5 patients (3.4%) did not receive any immunosuppressive treatment during the study. Baseline characteristics between the main 2 subgroups were well balanced (Table 1). Immunosuppressive therapy intensification occurred in 38 patients (33.9%) initiated on corticosteroids alone (most often addition of rituximab [n=37], others included splenectomy [n=2], bortezomib [n=1], mycophenolate mofetil [n=1]), and in 3 patients (12.5%) initiated on corticosteroids with rituximab (bortezomib [n=1] and mycophenolate mofetil [n=3]). Caplacizumab treatment improved outcomes in patients with aTTP irrespective of the type of initial immunosuppression. Data on time to platelet count response and clinical outcomes are summarized in Table 2. Caplacizumab reduced the rate of the composite endpoint of TTP-related death, exacerbation, and major thromboembolic events during the double-blind treatment period irrespective of baseline immunosuppression regimen. Notably, in the placebo arm, exacerbations occurred in both subgroups to a similar extent, indicating that corticosteroids, with or without rituximab, are not immediately effective. Overall, recurrences (exacerbations or relapses) during the study were also reduced by caplacizumab in both subgroups (Table 2). Two placebo patients died during the treatment period in the corticosteroid only subgroup versus none in the corticosteroid plus rituximab subgroup (one other placebo patient died during the study drug treatment period while receiving another type of immunosuppression). Conclusion: Immunosuppressive therapy in aTTP aims to control the underlying autoimmune disease, but requires time to take effect; this exposes patients to thrombotic complications and death. Caplacizumab treatment prevents disease exacerbations and death, irrespective of the type of initial immunosuppression used, allowing time for immunosuppressive therapy to take effect. Disclosures Pavenski: Ablynx: Honoraria, Research Funding; Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Bioverativ: Research Funding. Knoebl:Novo-Nordisk: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy; CSL-Behring: Consultancy; Shire/Takeda: Consultancy; Roche: Consultancy. Scully:Shire: Research Funding; Alexion: Consultancy; Ablynx/Sanofi: Consultancy; Shire/Takeda: Consultancy; Novartis: Consultancy. Kremer Hovinga:Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Coppo:Shire: Consultancy; Ablynx/Sanofi: Consultancy; Alexion: Consultancy. Peyvandi:Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Metjian:Genentech: Consultancy, Research Funding; AblynxNV/Sanofi: Consultancy, Research Funding. De La Rubia:Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; AMGEN: Consultancy; Janssen: Consultancy. De Winter:Ablynx, a Sanofi company: Employment. de Passos Sousa:Sanofi: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

scholarly journals Concomitant Hydroxyurea and Voxelotor: Results from the HOPE Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1003-1003
Author(s):  
Russell E. Ware ◽  
Clark Brown ◽  
Mariane de Montalembert ◽  
Margaret Tonda ◽  
Barbara Tong ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Double Blind ◽  
Distribution Width ◽  
Hydroxyurea Treatment ◽  
Equity Ownership ◽  
Research Drug

Background: Sickle cell disease (SCD) is a chronic, debilitating disorder caused by a mutation in beta globin, which leads to the production of sickle hemoglobin (HbS). Deoxygenated HbS polymerization results in red blood cell (RBC) sickling, which leads to anemia, hemolysis, vaso-occlusion, and organ damage. Voxelotor a first-in-class therapy in development for the treatment of SCD, stabilizes HbS in the oxygenated state and has been shown to reduce anemia and hemolysis. Hydroxyurea induces fetal hemoglobin (HbF) and is an FDA- and EMA-approved treatment for SCD. Because both voxelotor and hydroxyurea can affect anemia and hemolysis, and potentially have additive mechanisms of protection against HbS polymerization, the effects of concomitant hydroxyurea in the setting of voxelotor treatment were investigated. The objective of this analysis was to evaluate RBC parameters, such as hemoglobin (Hb), mean corpuscular volume (MCV), %HbF, absolute reticulocyte count (ARC), and red cell distribution width (RDW), as well as the absolute neutrophil count (ANC) to examine the potential impact of concomitant hydroxyurea use on the effects of voxelotor and on medication adherence during the treatment period. Serum erythropoietin (EPO) levels were also monitored to investigate the effects of increased Hb concentrations on oxygen delivery. Methods: The HOPE study is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo in participants aged 12 to 65 years with SCD. A per-protocol analysis was performed using available data for all participants at the interim data cutoff on October 31,2018. Concomitant hydroxyurea treatment was permitted per protocol if the dose was stable at enrollment and maintained, unless dose adjustments were required due to toxicities. Laboratory parameters were compared in participants with or without concomitant hydroxyurea use. Results: From the HOPE study, 274 participants with lab values for the specified parameters (Hb, MCV, %HbF, ARC, RDW, ANC, EPO) available through week 24 were analyzed. A total of 179 of 274 (65%) participants were receiving hydroxyurea at study enrollment, and they were evenly distributed across the 3 treatment arms. Baseline lab values documented the effects of current hydroxyurea treatment, with higher average Hb, MCV, and %HbF but slightly lower average ARC and ANC compared with those not receiving hydroxyurea. Voxelotor treatment led to significant dose-dependent Hb increases, regardless of concomitant hydroxyurea therapy (Table 1), but the average MCV, %HbF, ANC, and RDW were unchanged. A lower average ARC was noted, which was attributed to the increased Hb level, whereas EPO levels showed wide variability but no significant changes from baseline. Conclusions: The HOPE study demonstrated that voxelotor treatment increased Hb levels in study participants with SCD, irrespective of hydroxyurea use. Significant voxelotor-associated Hb increases were observed for participants on stable-dose hydroxyurea and were equivalent to those observed in participants not taking hydroxyurea. The lack of observed changes in MCV and ANC was consistent with stable hydroxyurea exposure throughout the treatment period, thus addressing questions about potential changes in hydroxyurea compliance during the study. The additive treatment effects on anemia and hemolysis by voxelotor suggest that combination therapy with hydroxyurea may be safe and effective for optimal disease modification. Disclosures Ware: Addmedica: Other: Research Drug Donation; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Research Drug Donation. Brown:Novartis, Inc: Research Funding; Imara, Inc: Consultancy, Research Funding; Global Blood Therapeutics, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. de Montalembert:bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Hoppe:Novartis: Consultancy; Bioverativ: Consultancy; Global Blood Therapeutics: Employment, Equity Ownership; Imara: Consultancy. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Abboud:Novartis: Consultancy, Honoraria, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Modus: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Research Funding; Amgen: Other: Travel support; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase 3 Study of Danicopan, an Oral Complement Factor D Inhibitor, As Add-on Therapy to a C5 Inhibitor in Patients with Paroxysmal Nocturnal Hemoglobinuria with Clinically Evident Extravascular Hemolysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Austin Kulasekararaj ◽  
Antonio Risitano ◽  
Jong Wook Lee ◽  
Mingjun Huang ◽  
Jun-Ichi Nishimura ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Reticulocyte Count ◽  
Complement Factor ◽  
Publicly Traded ◽  
Phase 3 ◽  
Advisory Committees ◽  
Double Blind ◽  
Secondary Endpoints

Background: PNH is a rare, life-threatening disease caused by uncontrolled terminal pathway activation leading to intravascular hemolysis (IVH). The C5 inhibitors eculizumab (ECU) and ravulizumab (RAV) prevent IVH by inhibiting terminal complement; however, some C5 inhibitor-treated patients may experience persistent anemia due to extravascular hemolysis (EVH) caused by C3 fragment deposition and opsonization driven by constitutive activation of the alternative pathway (AP). Inhibition of factor D (FD), the rate limiting enzyme of the AP, acts on the complement cascade upstream of C3. Danicopan (ALXN2040, ACH-4471) is a first-in-class oral small molecule FD inhibitor. In vitro studies with RBCs collected from PNH patients have shown that danicopan not only inhibited hemolysis but also prevented deposition of C3 fragments on PNH RBCs. In a 24-week Phase 2 study of ECU-treated PNH patients with transfusion-dependent anemia (hemoglobin [Hgb] <10 g/dL), danicopan add-on resulted in clinically significant improvements in Hgb, near transfusion-independence, improvements in FACIT-Fatigue scores, and was generally well-tolerated; 96% of treatment-emergent adverse events were mild-to-moderate in severity and did not result in discontinuation. The purpose of this randomized, double-blind, pivotal Phase 3 trial (NCT04469465; EudraCT 2019-003829-18) is to evaluate the efficacy of oral danicopan add-on therapy in PNH patients with clinically evident EVH (CE-EVH) on an approved C5 inhibitor. Study Design and Methods: This study consists of a 12-week double-blind placebo-controlled treatment period 1 followed by a 12-week danicopan+C5 inhibitor treatment period 2 and a long-term extension up to 1-year. Patients (target enrollment, N=84) will be randomized to danicopan or matched placebo TID in a 2:1 ratio for the 12-week treatment period 1. Patients randomized to placebo for treatment period 1 will switch to danicopan at week 12 (Figure). Eligible adult patients must be receiving a stable regimen of ECU or RAV (no change in drug/dose/interval for ≥24 weeks), and have CE-EVH, defined by anemia (Hgb ≤9.5 g/dL), absolute reticulocyte count ≥120 x 109/L, and ≥1 transfusion within 6 months before study entry. The starting dose of danicopan is 150 mg TID. Patients with alanine aminotransferase (ALT) or direct bilirubin values >1.5 × upper limit of normal (ULN) will start at 100 mg TID. Doses may be escalated in 50-mg increments, with ≥4 weeks between escalations, to a maximum of 200 mg TID based on safety and clinical effect at protocol-specified time points. Exclusion criteria include major organ transplant or hematopoietic stem cell transplantation (HSCT), aplastic anemia requiring HSCT, complement deficiency, or ALT >2 × ULN. The primary efficacy endpoint is change in Hgb at week 12. Secondary endpoints are proportion of patients not requiring a transfusion through week 12, change from baseline in FACIT-Fatigue scores, and change from baseline in absolute reticulocyte count at week 12. Other secondary endpoints (at weeks 12 and 24) include RBC units transfused, Hgb stabilization, laboratory markers (including bilirubin, LDH, and PNH clone size), and patient-reported outcomes (EQ-5D-3L, EORTC-QLQ-C30, WPAI, and health resource utilization). Primary and secondary efficacy analyses will be performed on the intent-to-treat population; safety analyses will include all patients who received ≥1 dose of study drug. Danicopan has the potential to be the first oral PNH therapy, and offers an opportunity to enhance the well-characterized efficacy of C5 inhibitors without compromising safety. This Phase 3, pivotal trial will be the largest clinical evaluation of danicopan to date. More importantly, the trial has the potential to generate robust data to demonstrate the efficacy and safety of add-on, oral danicopan to C5 inhibitor therapy in PNH patients with clinically evident hemolysis. Figure Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; 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; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huang:Alexion: Current Employment, Current equity holder in publicly-traded company. Nishimura:Alexion: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; Chugai: Consultancy. Ramirez-Santiago:Alexion: Current Employment, Current equity holder in publicly-traded company.

The Characteristics, Treatment Patterns, and Outcomes of Older Adults with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4463-4463
Author(s):  
Mark A. Fiala ◽  
Tanya M. Wildes ◽  
Mark A. Schroeder ◽  
Armin Ghobadi ◽  
Keith E. Stockerl-Goldstein ◽  
...  
Keyword(s):  
Older Adults ◽  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Patient Characteristics ◽  
Treatment Patterns ◽  
Advisory Committees ◽  
Improved Outcomes ◽  
Immunomodulatory Drug

Abstract Background: Advances in the treatment for multiple myeloma (MM) have dramatically improved outcomes for younger patients. Older adults, particularly those 80 years of age or older at diagnosis, have seen more modest gains. MM incidence increases with age, and as more of the population is living later into life, the segment of the MM population over 80 will continue to grow. In this study, we sought to better understand the characteristics, treatment, and outcomes of older patients with MM. Methods: We identified all patients diagnosed with MM at age 80 or older in the Surveillance, Epidemiology, and End Results Program (SEER) database from 2007-2013 to determine incidence and outcomes. Subset analysis was then performed on patients included in the SEER-Medicare linked database who were enrolled in Medicare Parts A, B, and D to further explore patient characteristics and treatment patterns. Results: The incidence of MM increases over age, peaking after age 80. The annual incidence for those aged 65-69, 70-74, 75-79, 80-84 and 85+ was 24.4, 32.7, 39.5, 42.8 and 36.4 per 100,000, respectively. Based on 2010 US population estimates, approximately 4,500 new cases of MM were diagnosed annually 2007-2013 in patients age 80 or older. In that period, 8,093 cases, approximately 1,150 per year, were reported to SEER. The estimated median overall survival (OS) of these patients was 14 months (95% CI 13.2-14.8). The estimated relative 12 month survival was 58.9% (95% CI 57.4-60.4) compared to their peers without cancer. Of the 8,093 cases of MM reported to SEER during the study period, 2,385 were present in the SEER-Medicare linked dataset. Of these, 225 were identified as smoldering MM using a previously established algorithm (Fiala, et al, JCOCCI, 2018) and excluded leaving 2,160 for the analyses. The median age was 84 (range 80-100) and 55% were female. 81% were white, 13% black or African-American, and 6% another race. At disease presentation, 22% had claims indicating hypercalcemia, 61% renal failure or chronic kidney disease, 59% anemia, and 34% MM bone involvement. The estimated median OS was 13.4 months (95% CI 12.2-15.1). Only 52% of patients had claims indicating they received systemic MM treatment within 6 months post-diagnosis. Nearly all that did received novel agents; 38% received bortezomib-based treatment, 41% immunomodulatory drug (IMID)-based, and 14% both. The others received antineoplastic chemotherapies such as melphalan or cyclophosphamide. Interestingly, bortezomib utilization increased incrementally from 25% of patients treated in 2007 to 62% in 2013 while IMID utilization declined from 67% to 49%. The median OS of those receiving treatment was 21 months (95% CI 18.5-23.1) compared to 6.3 months (95% CI 5.3-7.3) for those who did not (p <0.0001). MM treatment was associated with a 26% decrease in hazard for death (aHR 0.74; 95% CI 0.67-0.82; p < 0.0001) independent of age, race, gender, poverty, comorbidities, and proxy measures of performance status. Outcomes improved for patients in more recent years; the hazard for death decreased by 3% (HR 0.97; 95% CI 0.94-0.99; p = 0.0096) each year 2007-2013. This can be attributed to increasing treatment rates. In 2007, only 41% of patients received treatment compared to 61% in 2013. After controlling for MM treatment, the year of diagnosis was no longer a significant predictor of survival. Conclusions: The outcomes of patients with MM over 80 years old are still relatively poor; nearly half of the patients do not receive systemic treatment and for those who do the median OS is just 21 months. The population over 80, when MM incidence peaks, is projected to triple over the next few decades. It is imperative that we improve our understanding of the needs of this vulnerable subgroup of patients of MM. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Improved Survival in Patients with First Relapsed or Refractory Acute Myeloid Leukemia (AML) Treated with Vosaroxin Plus Cytarabine Versus Placebo Plus Cytarabine: Results of a Phase 3 Double-Blind Randomized Controlled Multinational Study (VALOR)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. LBA-6-LBA-6 ◽  
Author(s):  
Farhad Ravandi ◽  
Ellen Ritchie ◽  
Hamid Sayar ◽  
Jeffrey Lancet ◽  
Michael D. Craig ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Adaptive Design ◽  
Late Relapse ◽  
Advisory Committees ◽  
Double Blind ◽  
Early Relapse ◽  
Equity Ownership ◽  
To Receive

Abstract Introduction: Despite 40 years of intense clinical research, there remain no new approved treatments or standard of care for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). New safe and effective salvage treatments are urgently needed. Vosaroxin is a first-in-class anticancer quinolone derivative that is active in AML. Vosaroxin is minimally metabolized, evades P glycoprotein receptor–mediated efflux and has activity independent of p53 status. VALOR is a rigorously designed and conducted phase 3, adaptive design, randomized, double-blind, placebo-controlled trial evaluating vosaroxin plus cytarabine (vos/cyt) vs placebo plus cytarabine (pla/cyt) in patients with R/R AML (NCT01191801). Methods: Patients were randomized 1:1 to receive cytarabine (1 g/m2 IV over 2 hr, d 1-5) plus either vosaroxin (90 mg/m2 IV over 10 min d 1 and 4; 70 mg/m2 in subsequent cycles) or placebo. Up to 2 induction and 2 consolidation cycles were administered. Eligible patients had refractory disease (persistent disease after induction, or first complete remission [CR1] < 90 d) or were in first relapse (early relapse: CR1 of 90 d to 12 mo; late relapse: CR1 of 12 mo to 24 mo). Patients had received 1-2 cycles of prior induction chemotherapy including at least 1 cycle of anthracycline (or anthracenedione) and cytarabine. Randomization was stratified by disease status (refractory, early relapse, late relapse), age (< 60, ≥ 60 years), and geographic location (US, non-US). Primary efficacy and safety endpoints were overall survival (OS) and 30- and 60-day mortality; secondary endpoints were complete remission (CR) rate and incidence of adverse events (AEs). Results: Between Dec 2010 and Sept 2013, 711 patients were randomized to receive vos/cyt (n = 356) or pla/cyt (n = 355) at 124 sites; per the adaptive design, a prespecified 1-time sample size increase of 225 patients was implemented after the interim analysis. At the final analysis, median OS was 7.5 mo (95% CI: 6.4-8.5) with vos/cyt vs 6.1 mo (95% CI: 5.2-7.1) with pla/cyt (HR = 0.866 [95% CI: 0.73-1.02]; 2-sided unstratified log-rank P = 0.06) (Figure). The OS difference was statistically significant in a preplanned analysis accounting for the stratification factors at randomization (2-sided stratified log-rank P = 0.02). Overall, 29.5% of patients underwent allogeneic stem cell transplant (ASCT), including 45.8% of patients < 60 years and 20.2% of patients ≥ 60 years. Transplant rates were comparable between the 2 treatment arms (30.1% with vos/cyt and 29.0% with pla/cyt). In a predefined analysis censoring for subsequent ASCT, median OS was improved with vos/cyt (6.7 mo vs 5.3 mo with pla/cyt; HR = 0.81 [95% CI: 0.67-0.97]; P = 0.02; stratified P = 0.03) (Figure). In predefined subgroup analyses, OS benefit was greatest in patients aged ≥ 60 years (7.1 mo with vos/cyt vs 5.0 mo with pla/cyt; HR = 0.75; P = 0.003) (Figure) and those with early relapse (6.7 mo vs 5.2 mo; HR = 0.77; P = 0.04). OS with vos/cyt vs pla/cyt was 9.1 mo vs 7.9 mo in patients < 60 years (HR = 1.08; P = 0.60); 6.7 mo vs 5.0 mo in patients with refractory disease (HR = 0.87; P = 0.23); and 14.1 mo vs 12.3 mo in patients with late relapse (HR = 0.98; P = 0.96), respectively. A CR was achieved in 30.1% of patients treated with vos/cyt vs 16.3% treated with pla/cyt (P = 0.00001). Thirty-day and 60-day all-cause mortality was similar in the 2 arms (30-day: 7.9% vs 6.6%; 60-day: 19.7% vs 19.4% with vos/cyt vs pla/cyt, respectively). Most common serious AEs were febrile neutropenia (11.3% with vos/cyt vs 7.4% with pla/cyt), sepsis (8.7% vs 4.3%), pneumonia (7.6% vs 4.9%), bacteremia (8.5% vs 2.9%), and stomatitis (3.4% vs 1.4%). Serious and non-serious cardiac, renal, neurologic, and hepatic AEs were comparable between treatment groups. Conclusion: Vos/cyt demonstrated improved OS and higher CR rates in patients with R/R AML without increased early mortality. In the primary OS analysis, the overall clinical benefit associated with vosaroxin may be underestimated, particularly in younger patients, due to the confounding effect of high transplant rates, a methodological limitation of AML trials. Vosaroxin-containing therapy had acceptable tolerability. VALOR results represent one of the largest datasets available in this setting, and the OS benefit was confirmed by a robust sensitivity analysis. These data support the use of this combination as a new option for salvage therapy in patients with R/R AML. Figure 1 Figure 1. Disclosures Ravandi: Sunesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sayar:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Strickland:Sunesis: Membership on an entity's Board of Directors or advisory committees. Schiller:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Pigneux:Sunesis: Consultancy. Horst:Sunesis: Research Funding. Recher:Sunesis: Consultancy; Celgene: Consultancy, Research Funding; Chugai: Research Funding. Klimek:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Craig:Sunesis: Equity Ownership. Fox:Sunesis: Consultancy, Equity Ownership. Ward:Sunesis: Employment, Equity Ownership. Smith:Sunesis: Employment, Equity Ownership. Acton:Sunesis: Consultancy. Mehta:Sunesis: Consultancy. Stuart:Sunesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

First Analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL Treated with R-CHOP in First Line, the Remarc Study from Lysa

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 471-471 ◽  
Author(s):  
Catherine Thieblemont ◽  
Hervé Tilly ◽  
Maria Gomez da Silva ◽  
Rene-Olivier Casasnovas ◽  
Christophe Fruchart ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
First Line ◽  
Advisory Committees ◽  
Double Blind

Abstract Background. R-CHOP is the standard first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). However 30% of patients will relapse and 70% of relapsed patients will die within 2 years of diagnosis. The REMARC study (clinicalTrials.gov NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide (LEN) maintenance after response to R-CHOP in patients aged 60 to 80 years with untreated DLBCL, FL3b or transformed lymphoma. Patients achieving CR or PR at the end of 6 or 8 cycles of R-CHOP21 or R-CHOP14 were stratified by CR/PR status and country and randomized 1:1 to receive 2 years of LEN maintenance (25 mg/day for 21 of every 28 days) or placebo (PBO). The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were safety, PR to CR conversion rate, and overall survival (OS). Diagnosis was retrospectively centrally reviewed. In patients with adequate samples, GCB/nonGCB profile was assessed by the Hans algorithm and GCB/ABC/unclassified profile was assessed using NanoString gene expression profiling technology. Methods. From 05/2009 to 05/2014, 784 patients were enrolled either before R-CHOP (n= 437) or after completion of 6 or 8 cycles of R-CHOP (n= 347). At the end of R-CHOP therapy, 650 patients were randomized to maintenance, either in CR (n= 495) or in PR (n= 152). Central review found that 3 patients were randomized in SD or PD, all in LEN arm. At time of diagnosis, median age was 68 y (range 58-80), 43.5% were older than 70 y, and 56% were male. aaIPI was low in 38.5% and high in 57.5% of patients (missing data 4%). COO analyses are ongoing for both Hans algorithm and NanoString technology. Results. With a median follow-up of 40 months, median PFS (according to independent centralized radiology review) was not reached in the LEN group versus 68 months in the PBO group (hazard ratio favoring the LEN group, 0.708 (95% CI 0.537-0.932; p=0.0135))(See Figure). In the LEN group, 18 patients (21%) converted from PR to CR during maintenance compared to 13 patients (14%) in the PBO group. Immature overall survival data did not show any benefit for LEN arm, a lack of difference not attributable to an excess of lymphoma relapse, secondary cancer or safety problems in LEN arm. Deaths generally occurred off study drug (median time from last dose of study drug to death was 277 days (range 20, 1291) in LEN arm and 334 (41, 1594) in control arm. During maintenance, the most common observed grade 3 or 4 AEs were neutropenia (56% vs. 22%), rash (5% vs. 1%), infections (8% vs. 6%), and thrombocytopenia (2.5% vs. 0.6%) in LEN and PBO arms, respectively. Dose adjustments were necessary in 72% of the LEN patients and 42% of PBO patients. 59% of patients stopped LEN and 40% stopped PBO for toxicity (p<0.001). Median number of cycles was 15 in LEN and 25 in PBO (p<0.001). Secondary primary malignancies occurred in 33 patients receiving LEN and in 42 patients on PBO. Conclusion. This analysis of the REMARC study shows that 2 years of LEN maintenance in patients responding to R-CHOP significantly improved PFS (primary endpoint) without an early significant impact on OS. The COO analysis is currently ongoing. This is the first report finding that using an immunomodulatory agent as maintenance therapy prolongs PFS for patients with DLBCL after first line treatment with R-CHOP. Figure 1. Progression-free survival of elderly patients with diffuse large B-cell lymphoma in response to R-CHOP treated in maintenance with either lenalidomide or placebo Figure 1 Figure 1. Disclosures Thieblemont: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gomez da Silva:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; ROche: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Haioun:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cabecadas:celgene: Consultancy, Honoraria. Salles:Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Honoraria, 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; Celltrion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Efficacy and Safety of Three Bortezomib-Based Combinations in Elderly, Newly Diagnosed Multiple Myeloma Patients: Results From All Randomized Patients in the Community-Based, Phase 3b UPFRONT Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 478-478 ◽  
Author(s):  
Ruben Niesvizky ◽  
Ian W. Flinn ◽  
Robert Rifkin ◽  
Nashat Gabrail ◽  
Veena Charu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Community Based ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 478 Background: The US community-based, phase 3b randomized, open-label, multicenter UPFRONT trial compares the efficacy and safety of three bortezomib (VELCADE®, Vc)-based regimens, VcD (Vc-dexamethasone), VcTD (Vc-thalidomide-dexamethasone), and VcMP (Vc-melphalan-prednisone), followed by weekly Vc maintenance, in elderly, newly diagnosed, transplant-ineligible multiple myeloma (MM) patients. This is the first phase 3 study of VcD and VcTD in this patient population. Methods: Patients with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc as before; T 100 mg/day, days 1–21; D as before); VcMP: Vc as before; M 9 mg/m2 and P 60 mg/m2, days 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with weekly Vc 1.6 mg/m2, days 1, 8, 15, 22. Patients in the VcTD arm received concomitant prophylaxis with aspirin, full-dose warfarin, or low-molecular weight heparin unless medically contraindicated. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR)/near CR (nCR) and very good partial response (VGPR) rates, overall survival (OS), and safety. Best confirmed responses were assessed by investigators per modified International Myeloma Working Group (IMWG) criteria. Adverse events (AEs) were graded by NCI-CTCAE v3.0. PFS and OS were estimated by Kaplan–Meier methodology. For the first time, we report results from the entire cohort of 502 randomized patients (VcD, n=168; VcTD, n=167; VcMP, n=167), who completed up to a maximum of 13 cycles of treatment. Results: Patients in the VcD, VcTD, and VcMP arms had a median age of 74.5, 73.0, and 72.0 years, respectively, and 71%, 62%, and 72% had ISS stage II/III disease. Patients received a median of 8 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles; 50%, 38%, and 42% of patients, respectively, received Vc maintenance. Response and safety data are summarized in the table. All three Vc-based induction regimens exhibited substantial activity, with ORR of 73% (VcD), 80% (VcTD), and 69% (VcMP) during the treatment period. After a median follow-up of 21.8 months, no significant difference in PFS was observed between the treatment arms; median PFS was 13.8 months (VcD), 14.7 months (VcTD), and 17.3 months (VcMP), respectively (Figure). 1-year OS estimates were 87.4% (VcD), 86.1% (VcTD), and 88.9% (VcMP). Rates of grade ≥3 AEs, serious AEs (SAEs), and discontinuations due to AEs during the treatment period were highest for the VcTD arm. The most common grade ≥3 AEs across all three arms during the treatment period were neuropathy peripheral (23%), fatigue (10%), and diarrhea (9%). Grade ≥3 pneumonia was reported in 10% (VcD), 6% (VcTD), and 6% (VcMP) of patients. AEs of deep vein thrombosis/pulmonary embolism were reported in 8% (VcD), 7% (VcTD), and 2% (VcMP) of patients. Compared with rates during induction, Vc maintenance produced little additional toxicity; across all three treatment arms, only 5% of patients experienced grade ≥3 peripheral neuropathy during cycles 9–13. One second primary malignancy (lung neoplasm) was reported in the VcMP arm. Conclusions: VcD, VcTD, and VcMP induction followed by weekly Vc maintenance produced similar activity in elderly, newly diagnosed, transplant-ineligible MM patients. Patients in the VcD doublet arm appear to have similar long-term outcomes to patients in the VcTD and VcMP triplet arms. Disclosures: Niesvizky: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Charu:GSK: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership; Pfizer: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment.

An Interim Analysis Of a Phase 2, Single-Arm Study Of Platelet Responses and Remission Rates In Patients With Immune Thrombocytopenia (ITP) Receiving Romiplostim

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1074-1074 ◽  
Author(s):  
Roberto Stasi ◽  
Adrian Newland ◽  
Bertrand Godeau ◽  
Victor Priego ◽  
Jean-Francois Viallard ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Alternative Therapy ◽  
Platelet Response ◽  
Advisory Committees ◽  
Serious Adverse Events ◽  
Platelet Counts

Abstract Background We describe here platelet response and remission observed with romiplostim treatment in patients with ITP. Methods Patients with an ITP diagnosis for less than 6 months who received first-line therapies only (ie, corticosteroids, IVIG, anti-D) received QW romiplostim for up to 12 months in the treatment period (Fig 1). The primary objective was to describe the number of months with a platelet response during the 12-month treatment period; secondary objectives included incidence of ITP remission and splenectomy. The romiplostim dose was increased QW by 1 μg/kg from 1 μg/kg up to 10 μg/kg to reach a platelet count of ≥50x109/L, adjusting to maintain a platelet count of 50-200x109/L. Patients who maintained platelet counts ≥50x109/L on romiplostim only entered a dose-tapering period in which the romiplostim dose was decreased by 1 μg/kg Q2W as long as platelet counts remained ≥50x109/L. Starting when the dose tapered to 0 during either the 12-month treatment period or at the end of the dose-tapering period, patients were followed to determine whether they had ITP remission (24 weeks platelet counts ≥50x109/L without any treatment for ITP, including romiplostim). At the end of 12 months, patients who 1) had platelet counts ≤20x109/L for <4 consecutive weeks, 2) had platelet counts of 20-50x109/L, and/or 3) were receiving treatment for ITP besides romiplostim had the option to enter a stabilization period (≤8 weeks) while the investigator determined suitable post-study therapy. Patients with platelet counts ≤20x109/L for ≥4 consecutive weeks on the highest romiplostim dose were discontinued from the study for non-response. Interim data up to March 2013 are reported here. Results Of the patient population (N = 71), 59.2% were women, median (Q1, Q3) age was 37 (28, 56) years, median (Q1, Q3) time since ITP diagnosis was 2.2 (0.9, 4.4) months, and median (Q1, Q3) platelet count at screening was 20 (12, 25) x109/L. Past treatments included steroids (96%), IVIG (42%), and anti-D (1%). Prior to the study, platelet transfusions were received by 9% of patients. 30 patients (42%) completed treatment, 31 (44%) are continuing treatment, and 10 (14%) discontinued romiplostim (due to consent withdrawn n = 2, adverse event n = 3, requirement for alternative therapy n = 3, lost to follow-up n = 1, death n = 1). Patients had a median (Q1, Q3) of 51 (34, 52) weeks of treatment with a median (Q1, Q3) average QW dose of 2.1 (1, 3.8) μg/kg. 66 (93%) patients had a peak platelet count ≥50x109/L. The median (Q1, Q3) time with a platelet response was 9 (6, 12) months; the median (95% CI) time to platelet response was 2.1 (1.1, 3.1) weeks; platelet counts are in Fig 2. Of 38 evaluable patients (ie, known remission status), 11 (29%, 95% CI 15% to 46%) had ITP remission. One patient had a splenectomy and 6 had treatment failure (defined as platelet count ≤20x109/L for 4 consecutive weeks at 10 μg/kg QW, requirement of alternative therapy, or death). Of the 71 patients receiving romiplostim, 9 patients had serious adverse events (2 treatment-related: 1 case each of gastritis and increased transaminases). There were also 3 adverse events leading to discontinuation of romiplostim (non-Hodgkin's lymphoma, leukocytosis, and the aforementioned increased transaminases, these last 2 treatment-related). Other serious adverse events, also occurring in 1 patient each, included atrial fibrillation, dapsone syndrome, fecaloma, the aforementioned non-Hodgkin's lymphoma, pleuritic pain, and tendon rupture. There were no fatalities reported as adverse events; the death leading to discontinuation was due to cerebral hemorrhage which began before the patient received romiplostim. The most common adverse events were headache (17%), arthralgia (13%), and nasopharyngitis (10%). The most common hemorrhage adverse events were hematoma (7%), petechiae (7%), and epistaxis (7%). No bone marrow findings were reported. Conclusions In this trial, patients with an ITP diagnosis for less than 6 months treated with romiplostim had a high response rate (over 90%), with platelet responses occurring quickly (median time to response of 2 weeks) and median number of months with a platelet response of 9 months. To date, 29% of evaluable patients have shown remission (24 weeks of platelet counts ≥50x109/L without any ITP treatment). There were no new safety signals. Updated data from this ongoing study will be presented in the future. Disclosures: Stasi: Amgen: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Genzyme: Honoraria, Speakers Bureau; Suppremol: Consultancy. Newland:Geron: Consultancy; Amgen: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Research Funding. Godeau:Amgen: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Roche: Consultancy, Research Funding; GSK: Consultancy; LFB: Consultancy. Jia:Amgen: Employment, Equity Ownership. Lopez:Amgen: Employment, Equity Ownership.

Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS) without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3 Study (CC-5013-MDS-005)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 409-409 ◽  
Author(s):  
Valeria Santini ◽  
Antonio Almeida ◽  
Aristoteles Giagounidis ◽  
Stephanie Gröpper ◽  
Anna Jonasova ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Double Blind ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

scholarly journals A Multicenter, Case-Control Study Evaluating the Characteristics and Outcome of ITP Patients Refractory to, Rituximab, Splenectomy and Both TPO Receptor Agonists

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3460-3460 ◽  
Author(s):  
Matthieu Mahévas ◽  
Mathieu Gerfaud-Valentin ◽  
Guillaume Moulis ◽  
Louis Terriou ◽  
Sylvain Audia ◽  
...  
Keyword(s):  
Immunosuppressive Therapy ◽  
Board Of Directors ◽  
Steroid Therapy ◽  
Monoclonal Gammopathy ◽  
Research Funding ◽  
Morbidity And Mortality ◽  
Advisory Committees ◽  
Receptor Agonists

Abstract Introduction: Before the emergence of new treatments, refractory immune thrombocytopenia (ITP) was defined as the failure to achieve a minimum response to splenectomy and the requirement of long-term treatments to reduce risk of significant bleeding events. These patients experience a significant morbidity and mortality rate (1). The first aim of this study was to describe the characteristics of patients with multirefractory ITP (multi-ref ITP) according to an updated definition, i.e., patients who failed to respond to splenectomy, monoclonal anti-CD20 antibodies (rituximab, RTX) and both thrombopoietin-receptor agonists (TPO-RAs), as well as to identify associated factors with this phenotype. The second aim was to examine the long-term outcome of these patients. Patients and Methods: We carried out a multicenter retrospective study in France. Inclusion criteria of patients with multi-ref ITP were failure to splenectomy, rituximab and the two marketed TPO-RAs, or presentation of an absolute contraindication to these treatments. Failure to treatment was defined according to standardized international criteria and bleeding score as described by Khellaf et al. Physicians were interviewed and patients' medical charts collected using the standardized form of the Referral Center for Adult ITP. In order to assess the variables associated with multirefractory occurrences, patients with multi-ref ITP were compared with non-multirefractory patients: for each case, 5 controls were randomly selected from the ITP clinical research database at Henri-Mondor Hospital, matched on the year of diagnosis. This database includes all ITP patients followed in the French national center for autoimmune cytopenias. Univariate and multivariate conditional logistic regression models were performed (backward procedure, α=5%). Results: Thirty-seven patients (12 men/25 women) with multi-ref ITP and 183 controls were included in the study. Patients with multi-ref ITP have presented more initial bleeding symptoms than controls (75.6% vs 52.75%, p=.012)), had more frequently secondary ITP (35% vs 8.74%, p<.001), presented more clinical/biological auto-immune abnormalities (59.46% vs 28.42%, p=0008) and had more frequently a monoclonal gammopathy of undetermined significance than controls (19% vs 2.89%, p<.001). Only 24 patients with multi-ref ITP (68.57%) achieved initial transient response to steroid therapy (CR: n=10, R: n=12), compared to 91.61% responders in controls (p<.0001). In multivariate analysis, 4 factors were found to be associated with multi-ref ITP occurrence: (1) secondary ITP (OR: 4.81, 95%CI [1.31-17.86], p=.018), (2) presence of monoclonal gammopathy (OR: 5.93, 95%CI [1.08-32.48], p<.04), (3) bleeding symptoms at diagnosis (OR: 3.54 95%CI [1.11-11.22], p=.032) and (4) no response to steroid therapy (OR: 0.38 95%CI [0.20-0.72], p= .003). After a median follow-up of 84 months (range: 12-455), patients with multi-ref ITP have received a median of 10.5 lines of treatments (range: 6-15) including splenectomy, TPO-RAs and RTX, 5 patients (14%) died (intracranial hemorrhage, n=2; sepsis, n=1; breast cancer, n=1; unknown, n=1). Throughout the course of ITP, all patients required hospitalization; 22 (60%) received platelet transfusion, and 6 red-blood cells transfusion, 9 (24%) were admitted to intensive care units, 15 (40%) presented at least one bacterial infection, and 9 experienced at least one thrombosis (arterial, n=3; venous, n=6). At the end of follow-up, 20 patients (54%) were still non responders. Nine patients achieved a complete response: one after autologous hematopoietic stem cell transplantation, 2 after chemotherapy for hematological malignancy, and 5 after a combination of immunosuppressive therapy and TPO-RA. Conclusion: Our study demonstrated that multirefractory ITP is an extremely serious condition, associated with a high morbidity and mortality. Factors significantly associated with this phenotype were secondary ITP, association with autoimmune disorders, monoclonal gammopathy and no response to steroids. Most of these patients remained non-responsive to alternative lines of rescue treatment, but some successes has been obtained with the combination of immunosuppressive therapy and TPO-RA. (1) McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004;104(4):956-60 Disclosures Salles: Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau. Cheze:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Michel:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Godeau:Roche: Research Funding; Amgen: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. LBA-1-LBA-1 ◽  
Author(s):  
Marie Scully ◽  
Spero R Cataland ◽  
Flora Peyvandi ◽  
Paul Coppo ◽  
Paul Knöbl ◽  
...  
Keyword(s):  
Platelet Count ◽  
Drug Treatment ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Thromboembolic Event ◽  
Study Drug ◽  
Adamts13 Activity ◽  
Advisory Committees

Abstract Introduction: Acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) is a life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. Inhibitory autoantibodies cause a severe deficiency of the von Willebrand factor (vWF) cleaving enzyme ADAMTS13, leading to intravascular vWF-platelet aggregation and microvascular thrombosis. The mainstays of treatment are plasma exchange (PE) and immunosuppression. Caplacizumab, a bivalent Nanobody, targets the A1 domain of vWF, inhibiting the interaction between ultra-large vWF and platelets. Methods: Patients with an acute episode of aTTP who had received one PE treatment were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and a SC dose was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug (Figure 1). Primary endpoint was time to platelet count response, defined as platelet count ≥ 150×109/L with stop of daily PE within 5 days. There were 4 key secondary endpoints, hierarchically ranked. The 1st was a composite of aTTP-related death, aTTP recurrence, or major thromboembolic event during the study drug treatment period. A blinded, independent committee adjudicated aTTP-related deaths and major thromboembolic events. The 2nd looked at recurrences during the entire study period, including the follow up period. The 3d evaluated refractoriness to therapy, defined as absence of platelet count doubling after 4 days of treatment and LDH still above normal. The 4th was the time to normalization of 3 organ damage markers: LDH, cardiac troponin I and serum creatinine. Results: 145 patients were randomized, 73 to placebo and 72 to caplacizumab. Demographics and baseline disease characteristics were balanced between groups, except for a higher proportion of initial episodes in the caplacizumab arm. Compared to patients treated with placebo, those on caplacizumab were &gt;50% more likely to achieve a platelet response at any given time point (platelet count normalization rate 1.55, 95% CI 1.10 - 2.20, p &lt;0.01). During the study drug treatment period, treatment with caplacizumab resulted in a 74% reduction in TTP-related death, recurrence of TTP, or a major thromboembolic event (p &lt;0.0001, Table 1). During the overall study period, 28 patients in the placebo group experienced a recurrence versus 9 patients in the caplacizumab group, a 67% reduction (p &lt;0.001, Table 2). In all 6 caplacizumab-treated patients with a relapse during the follow up period, ADAMTS13 activity was still &lt;10% at stop of study drug, reflecting ongoing disease. No caplacizumab-treated patients were refractory to therapy, while 3 patients on placebo were (p =0.057). Treatment with caplacizumab was associated with a trend toward faster normalization of the 3 organ damage markers. Safety is summarized in Table 3. In the caplacizumab group, the most common study drug-related TEAEs were epistaxis, gingival bleeding, and bruising. During the study drug treatment period, 3 patients on placebo died. One death occurred during the follow up period in a caplacizumab-treated patient and was assessed by the investigator as not related to study drug. Conclusions: Results of the Phase 3 HERCULES study confirm that treatment with caplacizumab reduces the time to platelet count response, resulting in faster resolution of aTTP. Treatment with caplacizumab also resulted in a highly clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment. The relapses after stop of study drug in patients with ADAMTS13 activity &lt;10% suggest that treatment should be continued until complete resolution of the underlying disease. Caplacizumab has a favorable safety profile, with mucocutaneous bleeding the most frequently reported AE. Caplacizumab, through rapid blocking of vWF-mediated platelet aggregation, represents a novel treatment option for patients with aTTP. (clinicaltrials.gov: NCT02553317) Disclosures Scully: Ablynx: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Novartis: Honoraria; Alexion: Honoraria. Cataland:Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Peyvandi:Ablynx, Roche: Membership on an entity's Board of Directors or advisory committees; Ablynx, Bayer, Grifols, Novo Nordisk, Sobi: Speakers Bureau;Freeline, Kedrion, LFB, Octapharma: Consultancy. Coppo:Ablynx: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Knöbl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Kremer Hovinga:Baxalta/Shire: Other: unrestricted grant hereditary TTP registry; Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Metjian:Ablynx NV, Shire, Omeros: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Other: Honoraria; Celgene: Other: Honoraria; Janssen: Other: Honoraria. Pavenski:Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Ablynx: Other: participation in industry sponsored RCT; CSL Behring: Research Funding. Callewaert:Ablynx NV: Employment. Biswas:Ablynx NV: Employment. De Winter:Ablynx NV: Employment. Zeldin:Ablynx NV: Employment.

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