Registry Of Patients Treated With Protein C Concentrate (Human) In The United States and Europe: Interim Results

Abstract Background Protein C (PC) is a naturally occurring, vitamin-K dependent anticoagulant produced by the liver. Deficiency of PC, which can be congenital or acquired, results in a hypercoagulable state. Patients with severe PC deficiency may manifest severe, often life-threatening, disseminated intravascular coagulation (DIC), purpura fulminans (PF), and/or thromboembolism. Highly purified protein C concentrate prepared from human donor plasma (Ceprotin; Baxter Healthcare Corporation, Westlake Village, CA) is an approved therapy for prevention and treatment of venous thrombosis and PF in patients with severe congenital PC deficiency (SCPCD) in the United States. It is indicated in patients with SCPCD for PF and coumarin-induced skin necrosis, and short-term prophylaxis in the European Union and other countries. Use of protein C concentrate (human) has been reported in patients with acquired PC deficiency. The Ceprotin Treatment Registry is a prospective, international, multi-center, open-label, non-interventional, observational study designed to examine the long-term safety and effectiveness of protein C concentrate (human) in the clinical setting. This is the first large, real-world assessment of the treatment of a rare disease with protein C concentrate (human). Here we report data from the first interim analysis in June 2013 covering a 3-year enrollment period. Methods Patients of any age who received, or were initiating/receiving protein C concentrate are included. The study duration is 5 years (3-year enrollment period plus 2 years of follow-up). All study visits/assessments are in accordance with standard of care, with protein C concentrate dose, dose frequency, duration and route of administration determined by the investigator. The study objectives are to determine the most common medical diagnoses associated with protein C concentrate treatment, protein C concentrate treatment regimens, and safety information based on all serious adverse events (SAEs) and rate of treatment-related AE. Other objectives include: an examination of the relationship between protein C concentrate treatment and outcomes in all registry participants, as well as various subgroups. Descriptive statistical analyses are used. Results At the time of data extraction, 34 patients were enrolled from 26 centers; 10 centers in the United States and 16 centers in Europe. Half of the patients were males. The primary diagnosis of PC deficiency was congenital in 25 patients (73.5%) and acquired in 9 patients (26.5%). The median age at diagnosis was 0.03 years (range 0–19.9). Mean plasma PC activity level was 9% (range 1–40.0). The most common (in ≥3 patients) thrombotic disease-associated conditions were PF (50.0%); blindness (44.1%); thromboembolic disease (41.2%), which included deep vein thrombosis, arterial thrombosis and DIC; stroke (32.4%), and renal dysfunction (8.8%). Of the 23 patients being treated with protein C concentrate, 15 were administered protein C concentrate intravenously, and 8 patients received protein C concentrate subcutaneously. The body weights of patients receiving subcutaneous treatment ranged from 10.0 kg to 57.9 kg. A total of 15 patients received an anticoagulant treatment in addition to protein C concentrate. Eight patients reported 23 SAEs, all of which were considered not related to treatment. Eighteen (52.9%) patients reported 72 AEs; only 1 of them, an episode of upper respiratory infection, was considered possibly treatment-related. In 18 patients in whom PC activity recovery was determined after protein C concentrate treatment, there were no patients documented with poor recovery. Protein C concentrate was used during 18 surgeries/invasive procedures and considered effective in all interventions for which data were available. Conclusions Data from the first interim analysis of the Ceprotin Treatment Registry demonstrate that patients with both congenital and acquired severe PC deficiency who are treated with protein C concentrate (human) have a low incidence of treatment related SAEs and AEs, and treatment with protein C concentrate appears to be effective when used during surgery/invasive procedures. Further patient follow up will shed light onto clinical treatment outcomes. Disclosures: Manco-Johnson: CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Research Funding. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria. Shapiro:Cangene: Research Funding; Biogen Idec: Research Funding; Baxter BioScience: Research Funding; Bayer HealthCare: Research Funding. Finnerty:Baxter: Employment, Equity Ownership. Yel:Baxter: Employment, Equity Ownership. Gelmont:Baxter: Employment, Equity Ownership.

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A Registry Study on Treatment of Patients with Acquired Protein C Deficiency with a Protein C Concentrate (Human)

Blood ◽

10.1182/blood.v128.22.3816.3816 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3816-3816

Author(s):

Paul Knoebl ◽

Michael Sasse ◽

Maria Pia De Carolis ◽

Jacqueline A Dyck-Jones ◽

Sandra Ehrle ◽

...

Keyword(s):

Protein C ◽

Purpura Fulminans ◽

Protein C Deficiency ◽

Employment Equity ◽

Advisory Committees ◽

Protein C Concentrate ◽

Concentrate Treatment ◽

Uremic Syndrome ◽

Equity Ownership ◽

The Eu

Abstract The objective of this non-interventional, international registry was to collect and assess data on the indications, safety, and the outcomes of treatment of patients with acquired protein C deficiency with a plasma-derived, human non-activated protein C concentrate (Ceprotin, Baxalta/Shire). Any patient who received treatment with protein C concentrate was eligible for the study; there were no exclusion criteria. This was an observational study with no required predefined visits, medical or laboratory tests, procedures or interventions either at enrollment or during the study. The study was conducted from June 2010 to June 2015. Management of patients was according to the discretion of the investigator. The primary endpoints were the medical diagnoses associated with protein C concentrate treatment, the protein C concentrate treatment regimens (dose, frequency), treatment outcomes and safety information. Here we report the results from 18 patients with severe acquired protein C deficiency (SAPCD - as judged by the treating physician) from 4 European (EU) investigative sites. Protein C concentrate is not currently approved for treatment of acquired protein C deficiency in the EU. The median age at study entry was 1.9 years (range: birth to 73.1 years); 5 [27.8%] patients were <1 month, 4 (22%) from 1 month to <2 years of age, 2 (11.1%) from 2 to <12 years, 2 (11.1%) from 12 to <18 and 5 (27.8%) ≥18 years of age. Eighteen patients were treated with protein C concentrate. At clinical presentation, 15/18 (83.3%) of these patients had sepsis, 2 had necrotizing enterocolitis and 1 had hemolytic uremic syndrome. Thromboembolic disease was present in 8/18 (25.8%) patients, all of whom had purpura fulminans. Of these 8 patients, 2 had disseminated intravascular coagulation (DIC) in addition to other conditions; 1 patient also had arterial thrombosis, and the other patient had macrovascular thrombosis and skin necrosis. The remaining 10 (74.2%) patients had no evidence of thromboembolic disease: of these, 7 patients had sepsis, 2 necrotizing enterocolitis and 1 hemolytic uremic syndrome. Dose level and frequency were variable: the most common dosage was 100 IU/kg and the most common interval between doses was 6 hours. There were no infusions administered for surgical interventions or for prophylaxis. At the time of final analysis 17/18 (94.4%) of patients had at least one follow-up visit. The median duration of study participation was 17.8 months (range 0.4-39.6 months). The mortality rate was 2/18 (11%) patients, including one case of fatal peritonitis, coinciding with protein C concentrate treatment in a 44 day-old, very low birthweight preterm infant and a case of multi-organ failure in a 19 year-old patient. Both deaths were considered not related to protein C concentrate. Ten patients received anticoagulation therapies in addition to protein C including: 4 treatments with antithrombin concentrates, 1 with clopidogrel, 6 with low molecular weight heparin and 7 with unfractionated heparin. Data from historical protein C concentrate treatments which occurred prior to enrollment in the study were collected from 3 patients upon their enrollment into the study (all 3 treatments resulted in halting/reversal of coagulopathy). During the entire study period, 13 adverse events (AEs) were reported in 5 patients with acquired deficiency; among these, 4 were serious adverse events (SAEs). During the period of treatment with protein C concentrate, there were 2 AEs including an SAE of gastroenteritis; neither were considered related AEs. The results of this registry demonstrate that in current clinical practice in the EU, treatment with protein C concentrate was safe with a mortality rate of 11% in patients with acute SAPCD and thrombotic episodes observed in association with sepsis and/or purpura fulminans in this study. Disclosures Knoebl: Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sasse:Baxter/Baxalta/Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding. De Carolis:Baxalta/Baxter: Other: Baxter Investigator for CEPROTIN Registry. Dyck-Jones:Baxter/Baxalta/Shire: Employment, Equity Ownership. Ehrle:Baxter/Baxalta/Shire: Employment, Equity Ownership. Finnerty:Baxalta/Baxter: Employment. Gelmont:Baxter/Baxalta/Shire: Employment, Equity Ownership. Yel:Baxter/Baxalta/Shire: Employment, Equity Ownership. Loghman-Adham:Baxter/Baxalta/Shire: Employment, Equity Ownership. Fischer:Baxter/Baxalta GmBH: Honoraria, Other: 'Weimarer Sepsis Update 2013'; Baxter/Baxalta GmBH: Consultancy, Other: Co-Authorship for E- Book-Preparing (Importance of the Protein C pathway in coagulation disorders and intensive care medicine / Treatment of congenital and acquired protein C deficiency.

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Patterns of Care of Aged Chronic Lymphocytic Leukemia Patients in the United States: Systematic Analysis of 457 Patients in the Connect CLL Registry

Blood ◽

10.1182/blood.v124.21.4672.4672 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4672-4672

Author(s):

Chadi Nabhan ◽

Natalie Galanina ◽

Neil E. Kay ◽

Anthony R. Mato ◽

David L. Grinblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

The United States ◽

Initial Therapy ◽

Patterns Of Care ◽

First Line ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Baseline Characteristics

Abstract Introduction: The median age at diagnosis for CLL pts in the US is 72 years. As clinical trials in CLL have largely enrolled younger pt populations, data on disease and pts' characteristics, patterns of care, prognosis, and molecular features in aged CLL pts are limited. With this in mind, we conducted a prospective study to update critical demographic data and patterns of care for aged CLL pt. Patients and Methods: Connect®-CLL is a US-based prospective, longitudinal, multi-center, observational registry that is aimed at understanding patterns of CLL management without a study-specific intervention. We enrolled pts treated at an academic (n=155) or community (n=1340) setting between 2010 and 2014. Eligible pts were adults with a clinical diagnosis of CLL who required therapy 2 or less months after enrollment. Data on demographics, baseline characteristics, and treatment selection are presented here using descriptive statistics. Continuous variables are reported using appropriate measures of dispersion and central tendency (means, medians, ranges and standard deviations) while categorical variables are summarized as number and percentage of the analysis population. Results: Of 1495 enrolled pts, 457 (30.5%) were ≥75 years (57.3% males, 94.2% white). Rai stage III/IV was noted in 33% and B symptoms (predominantly fatigue (58.4%)) were observed in 68.1%. These and other clinical baseline characteristics appeared similar to pts younger than 75 years except that older pts had more prior malignancies (33.5% vs. 19.8%) and co-morbidities (69.3% vs. 53.6%). Cardiac, neurologic, and renal disorders were the most common morbidities in pts ≥75 years (11.5%, 8.8%, and 4.6% respectively). Imaging studies were performed in 157 (60.2%) older pts and in 416 (65.7%) pts less than 75 years prior to initial therapy. Percentage of pts with bulky nodes (> 5 cm) by imaging was similar in the two groups, 19.3% overall. Prognostic biomarker data were available on 247 pts (178 (72%) <75 years; 69 (28%) ≥75 years). While a higher proportion of older pts had CD38+ CLL (55.1% vs. 40.5%, P=0.038), the proportions of patients with ZAP-70+ CLL were similar between the two groups. In total, 137 (9%) older and 378 (25%) younger pts had 17p and 11q analysis by FISH at enrollment prior to first-line therapy. Of these, 27.0% of pts ≥75 years and 20.6% of pts <75 years had a deletion of either 17p or 11q (P=0.125). Out of all pts enrolled in the registry, 894 (60%) received first-line treatment (261 (29%) pts ≥75 years and 633 (71%) <75 years) as their indication for study entry. Amongst these treated pts, interim analysis shows (data cutoff date: 25 June 2014) progressive marrow failure was more commonly used as the indication for therapy in older pts compared to younger pts (52.1% vs. 38.5%; P<0.001), while splenomegaly was a more common cause for therapy in younger pts (16% vs. 9%; P<0.01). Rai stage III/IV at time of first therapy was 46% and 49% for younger and older pts, respectively. Progressive lymphocytosis was used as the indication for therapy in one third of pts regardless of age. Seventy-four percent of older CLL pts received first-line therapies containing rituximab (R) vs. 85% in pts <75 years (P<0.0001). R-bendamustine was the most common first-line regimen for CLL pts ≥75 (23.4%) while FCR was more commonly given to pts <75 years (32.5%). R-monotherapy was used in 18.8% of older pts versus 9.5% in pts <75 years (P<0.0001). Of note, approximately 25% of CLL pts ≥75 years did not receive R-based regimens for initial therapy. Conclusions: Connect®-CLL is the largest prospective, multicenter CLL registry in the United States. CLL Pts ≥75 years more frequently overexpress CD38 and may more commonly demonstrate high risk cytogenetics by FISH, although the difference did not reach statistical significance. Pts ≥75 years also more commonly had co-morbid diseases, and surprisingly 25% did not receive first-line R-based therapy. CLL pts are rarely included in front-line clinical trials (<3%). Given that novel therapies are increasingly available for CLL patients a continued analysis is warranted to determine their use in elderly vs younger patients as well. A longer follow up is needed to evaluate the impact of these findings on outcomes. Disclosures Nabhan: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide in CLL. Kay:Celgene: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy. Flinn:Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Kristen:Celgene: Employment, Equity Ownership. Flowers:Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy; Gilead, Spectrum, Millennium, Janssen: Research Funding.

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Disease and Clinical Characteristics of Patients with Essential Thrombocythemia Enrolled in the MOST Study

Blood ◽

10.1182/blood-2018-99-112183 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4306-4306

Author(s):

Abdulraheem Yacoub ◽

Roger M. Lyons ◽

Srdan Verstovsek ◽

Ryan Shao ◽

David Tin Chu ◽

...

Keyword(s):

United States ◽

Observational Study ◽

Board Of Directors ◽

Essential Thrombocythemia ◽

Research Funding ◽

Clinical Characteristics ◽

The United States ◽

Advisory Committees ◽

History Of ◽

Equity Ownership

Abstract Introduction: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by clonal platelet production and an increased risk for thrombotic and hemorrhagic events. Limited real-world data exist regarding the clinical characteristics and treatment patterns of ET in the United States; most prior data have been generated outside the United States. The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) is an ongoing observational study being conducted to describe contemporary demographics, burden of disease, clinical management, and patient-reported outcomes in patients with specific risk categories of myelofibrosis (MF) or ET in the United States. This analysis describes the clinical characteristics of patients with ET currently enrolled in MOST. Methods: MOST is a multicenter, noninterventional, prospective, observational study in patients with a clinical diagnosis of specific risk categories of MF or ET (NCT02953704). Eligible patients with ET included high-risk patients (≥ 60 years of age and/or a history of thromboembolic events [TEs]), or low-risk patients currently receiving ET-directed therapy. Key exclusion criteria included participation in blinded investigational drug studies, life expectancy ≤ 6 months, or diagnosis of other malignancy. Data regarding disease and clinical characteristics are collected at usual-care visits over a planned 36-month observation period. Patient demographics and clinical characteristics at enrollment were described with descriptive statistics. Results: At data cutoff (May 18, 2018), 793 eligible patients were enrolled from 85 sites since November 29, 2016. The median age at enrollment was 70 (range, 24-95) years, 66.5% were female, and 89.8% were Caucasian. The median time from ET diagnosis to enrollment was 4.2 (range, 0.0-42.1) years with a proportion of patients diagnosed within 1 year (19.5%), 1 to < 5 years (35.0%), 5 to < 10 years (21.7%), or ≥ 10 years (23.8%) of enrollment. Approximately 40% of patients were retired and 42.7% were working full- or part-time at enrollment. A total of 212 patients (26.7%) had a history of TE at the time of enrollment. The type of TE was available for 148 patients, the most common was arterial events (53.4%); 33.1% had venous, and 13.5% of patients had both arterial and venous events. Six hundred and eighty-eight patients (86.8%) were classified as high-risk. Assessments at the time of ET diagnosis, among evaluable patients, included bone marrow biopsy (51.4%; 393/765) and mutational testing (77.2%; 590/764). Three hundred and forty-nine patients had mutation test results reported at the time of diagnosis; of patients with JAK2 V617F test results reported at the time of diagnosis (n = 313), 78.6% were positive for JAK2 V617F (Table 1). Laboratory values and peripheral blood counts were reported for patients with available data (Table 2). The majority of patients (87.9%) had received at least 1 ET-directed therapy prior to enrollment, which in some cases was the same medication the patient was receiving at the time of enrollment. At the time of enrollment, 740 patients (93.3%) were receiving at least 1 current ET-directed therapy, including HU (71.6%; 530/740), anagrelide (13.1%; 97/740), ruxolitinib (4.7%; 35/740), interferon (3.0%; 22/740), and busulfan (0.3%; 2/740). Of 793 patients, the most frequently occurring relevant comorbid conditions were hypertension (52.7%), history of smoking (44.7%), and hyperlipidemia (24.1%). Among 761 patients with ET-related symptoms assessed at diagnosis, the most common symptoms documented by healthcare providers included constitutional (22.9%), vasomotor (16.0%), and spleen-associated symptoms (3.9%), and pruritus (2.6%). Conclusions: Prior real-world data in ET has predominately been generated outside of the United States or has been reported from single institutional experiences. The MOST study will provide a more complete picture of the patient characteristics and outcomes of patients receiving ET-directed therapy in the United States. Ultimately, these data will be important for determining ET treatment gaps and areas of unmet need. Disclosures Yacoub: Cara Therapeutics: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ardelyx, INC.: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Shao:ASH: Membership on an entity's Board of Directors or advisory committees; ASCO: Membership on an entity's Board of Directors or advisory committees. Agrawal:Incyte: Speakers Bureau. Sivaraman:Incyte: Employment. Colucci:Incyte: Employment, Equity Ownership. Yao:Incyte: Employment. Mascarenhas:Celgene: Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Research Funding.

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Defibrotide for the Treatment of Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with/without Multi-Organ Dysfunction Following Chemotherapy: Results from an Ongoing Expanded Access Program

Blood ◽

10.1182/blood.v126.23.3121.3121 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3121-3121

Author(s):

Nancy A. Kernan ◽

Paul G. Richardson ◽

Angela R. Smith ◽

Brandon M. Triplett ◽

Stephan A. Grupp ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

The United States ◽

Occlusive Disease ◽

Sinusoidal Obstruction Syndrome ◽

Employment Equity ◽

Advisory Committees ◽

Kaplan Meier ◽

Equity Ownership ◽

Chemotherapy Patients

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Although VOD/SOS usually is thought of as a complication of HSCT, there is also a known risk in patients following chemotherapy in a non-HSCT setting. Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Endothelial cell (EC) damage is a critical factor in the pathophysiology of VOD/SOS. Preclinical data suggest that defibrotide stabilizes ECs with direct, as well as EC-mediated, restoration of the thrombo-fibrinolytic balance. Defibrotide is approved for treatment of severe hepatic VOD/SOS in adult and pediatric patients in the European Union. In the United States, defibrotide is available as an investigational drug through an ongoing expanded-access protocol for treatment of hepatic VOD/SOS. Methods In the original protocol, patients were eligible if they had hepatic VOD/SOS by Baltimore criteria post-HSCT and MOD, defined by renal (tripling of creatinine levels or reduced creatinine clearance with or without dialysis) and/or pulmonary (need for oxygen supplementation with or without assisted ventilation) dysfunction. Symptoms of VOD/SOS were not considered adverse events (AEs) unless the event was considered serious. The protocol was later amended to include (1) post-chemotherapy patients with hepatic VOD/SOS; (2) patients with hepatic VOD/SOS without MOD, and (3) VOD/SOS per modified Seattle criteria. Enrolled patients received defibrotide 25 mg/kg/d in 4 divided doses for a recommended ≥21 days. Here, we describe efficacy and safety results with defibrotide for the subset of patients that developed VOD/SOS post-chemotherapy. Results Out of 642 patients who developed VOD/SOS and received ≥1 dose of defibrotide, 69 patients received chemotherapy without HSCT; 52% (n=36) had MOD, and 48% (n=33) did not. Median age was 8 years (range, <1 month-58.0 years), and 55 patients (80%) were ≤16 years (39 patients were children aged 2-11); 54% of patients were male. The most common primary diseases were acute lymphocytic leukemia (44%) and acute myelogenous leukemia (10%). Chemotherapeutic agents received by more than 30% of patients were vincristine, cyclophosphamide, cytarabine, doxorubicin, methotrexate and PEG-L-asparaginase. Antibody-drug conjugates linked to ozogamicin that are associated with development of VOD/SOS (gemtuzumab and inotuzumab) were received by 3 and 1 patient, respectively. The Kaplan-Meier estimated day +100 survival rate was 77.4% (95% confidence interval, 65.4%-85.7%). For patients with MOD and without MOD, the Kaplan-Meier estimated day +100 survival rates were 74.3% (56.4%-85.7%) and 80.9% (62.3%-90.9%), respectively. Overall, ≥1 AE was reported in 44 chemotherapy patients (63.8%). Of these, 14 (20.3%) had AEs assessed by the investigator as possibly, probably, or definitely related to defibrotide. Treatment-related AEs occurring in ≥2 patients were hypotension (4.3%), nausea (2.9%), vomiting (2.9%), and epistaxis (2.9%). Hemorrhagic AEs of any severity occurring in ≥2 patients were pulmonary (7.2%), epistaxis (5.8%), and gastric (2.9%). Serious AEs were reported in 26 patients (37.7%), most commonly multi-organ failure (7.2%), hypoxia (5.8%), and pulmonary hemorrhage (5.8%). AEs led to discontinuation in 4 patients (gastric, gastrointestinal and mouth hemorrhages, epistaxis, and hypotension). No treatment-related deaths were reported. Conclusions Day+100 survival of 77.4% in patients developing VOD/SOS following a variety of chemotherapy regimens without HSCT (80% of which were pediatric, primarily children) is a clinically encouraging finding. Defibrotide treatment in this group of 69 patients developing VOD/SOS post-chemotherapy was generally well-tolerated, with only 5.8% of patients discontinuing due to an AE and no treatment-related fatalities. Enrollment to the study continues. Support: Jazz Pharmaceuticals. Disclosures Kernan: Gentium S.p.A.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis: Consultancy, Research Funding. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Treatment of Patients with Severe Congenital Protein C Deficiency in a Registry Study of Protein C Concentrate (Human)

Blood ◽

10.1182/blood.v128.22.2605.2605 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2605-2605

Author(s):

Marilyn Manco-Johnson ◽

Hans-Joerg Hertfelder ◽

Theodosia A. Kalfa ◽

Emmett H. Broxson ◽

Lisa Bomgaars ◽

...

Keyword(s):

Clinical Research ◽

Board Of Directors ◽

Protein C ◽

Protein C Deficiency ◽

Employment Equity ◽

Advisory Committees ◽

Research Protocols ◽

Protein C Concentrate ◽

Equity Ownership ◽

Congenital Protein C Deficiency

Abstract The objective of this non-interventional, international registry was to collect and assess safety and outcomes of all treatment with protein C concentrate for patients with protein C deficiency in Europe and the United States. Here we report the results from 25 patients with severe congenital protein C deficiency (SCPCD). Any patient who received treatment with protein C concentrate was eligible for the study; there were no exclusion criteria. There were no predefined visits, laboratory tests and/or procedures, or interventions at enrollment or during the study. Management of patients was at the discretion of the investigator. Clinical data collected during the treatment course of these patients are reported here. Twenty-five patients with congenital protein C deficiency from 10 US study sites and 10 study sites in the EU were enrolled into the study. The median age at study entry was 11.12 years (range: 1.3- 43.7 years). No patient was <1 month old, 2 (8.0%) patients were 1 month to <2 years old, 12 (48.0%) patients were 2 to <12 years old, 3 (12%) patients were 12 to <18 and 8 (32%) patients were ≥18 years old. The median duration of study participation was 39.7 months (range: 0.9 to 59.9 months). Thirteen (52%) patients were male and 12 (48%) were female. The initial clinical presentation that led to the diagnosis of SCPCD occurred prior to enrollment into the study (years in some cases). The initial presentations included primarily thromboembolic events (18 [52.9%]) or purpura fulminans (16 [47.1%]). During the study there were 259 treatment regimens with protein C concentrate, including 113 (43.6%) for acute episodes, 29 (11.2%) for short term replacement for surgical procedures, and 117 (45.2%) for long term prophylaxis. There were large variations in protein C treatments prescribed. The most common dose and frequency in patients treated for acute episodes was 60 IU/kg administered once a day. Protein C concentrate was administered at enrollment either intravenously or subcutaneously (SQ). During the study, 217/259 (83.8%) treatment regimens of protein C concentrate were administered intravenously and 42 (16.2%) were administered SQ. Nine patients received SQ infusions prophylactically and three of these 9 patients also used SQ infusions for treatment of an acute episode. Of 25 acute episodes in 7 patients treated with protein C concentrate, 22 (88.0%) resulted in recovery, 2 (8.0%) showed improvement and 1 (4.0%) was unchanged; there was no instance of worsening of an acute episode. Protein C concentrate was effective in prevention of coagulopathy and thrombosis in 23 (100%) short-term replacement treatments for surgery/invasive procedures performed in 13 patients with SCPCD. The median protein C activity level increased from 2.5% (range: 0.0 to 40.0%) at diagnosis (unaugmented) to 41.0% (range: 1.0% to 264.0%) following protein C concentrate infusion. One patient (4.0%) with congenital heart disease died of congestive heart failure, assessed as not related to protein C concentrate. Of 111 AEs in 22 patients, 83 AEs in 17 patients occurred during treatment with protein C concentrate. Of these 83 AEs, only 3 were considered related to protein C concentrate: a single patient had 2 SAEs (abdominal pain and pain in extremity) and 1 nonserious AE (purpura fulminans) that were considered by the investigator to be possibly related to administration of protein C concentrate. The results of this registry provide additional evidence for the use of protein C concentrate as an effective and safe short-term replacement therapy for surgery/invasive procedures and for acute episodes in patients with congenital protein C deficiency. No new safety concerns were identified. Disclosures Manco-Johnson: Bayer: Honoraria, Research Funding; Baxter/Baxalta/Shire: Honoraria; Biogen: Honoraria; NovoNordisk: Honoraria; CSL Behring: Honoraria. Hertfelder:Bayer Healthcare: Consultancy, Honoraria, Other: Support of Congress, Educational and Scientific Meeting Participations; Baxter/Baxalta/Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of Congress Participation; Pfizer: Consultancy, Honoraria, Other: Support of Congress, Educational and Scientific Meeting Participations; Daiichi-Sankyo Germany: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of Congress Participations; NovoNordisc: Other: Support of Congress Participations; Sanofi Aventis: Honoraria, Other: Educational meeting Participations, Speakers Bureau; Octapharma Germany: Other: Support of Congress Participations. Kalfa:Baxter/Baxalta/Shire: Research Funding. Bomgaars:Boeringer Ingleheim: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Membership on DSMB. Shapiro:National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; OPKO: Other: Clinical research protocols; Octopharma: Other: Clinical research protocols; PTC Therapeutics: Other: Clinical research protocols; Bayer healthcare Pharmaceuticals: Other: International network on pediatric hemophilia; Baxter/Baxalta/Shire: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Daiichi Sankyo: Other: Clinical research protocols; Biogen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Consultancy; ProMetic Life Sciences: Consultancy; American Thrombosis and Hemostasis Network: Other: Medical Director; Selexys: Other: Clinical research protocols; Novartis: Other: Clinical research protocols; CSL Behring: Other: Clinical research protocols. Jacqueline:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Ehrle:Baxter/Baxalta/Shire: Employment, Equity Ownership. Finnerty:Baxalta/Baxter: Employment. Gelmont:Baxter/Baxalta/Shire: Employment, Equity Ownership. Yel:Baxter/Baxalta/Shire: Employment, Equity Ownership. Loghman-Adham:Baxter/Baxalta/Shire: Employment, Equity Ownership.

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Weekly Carfilzomib with Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma: Updated Results from the Phase 1/2 Study Champion-1 (NCT01677858)

Blood ◽

10.1182/blood.v126.23.373.373 ◽

2015 ◽

Vol 126 (23) ◽

pp. 373-373 ◽

Cited By ~ 2

Author(s):

James Berenson ◽

Alan Cartmell ◽

Roger Lyons ◽

Wael Harb ◽

Dimitrios Tzachanis ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

The United States ◽

Primary Objective ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: Carfilzomib is an irreversible proteasome inhibitor that is approved as a single agent in the United States and other countries for the treatment of relapsed and refractory multiple myeloma (MM); carfilzomib in combination with lenalidomide (LEN) and dexamethasone is also approved in the United States for the treatment of relapsed MM. The approved dose and schedule of carfilzomib is a twice-weekly, 10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (starting dose: 20 mg/m2 [days 1 and 2 of cycle 1]; escalated to a target dose of 27 mg/m2 thereafter). Here we present updated results from the multicenter, phase 1/2 study CHAMPION-1 (NCT01677858), which evaluated the safety and efficacy of once-weekly carfilzomib with dexamethasone (Kd) in patients with relapsed or refractory MM. Methods: Patients with relapsed or refractory MM (1-3 prior lines of therapy) were eligible. Patients received carfilzomib as a 30-min IV infusion on days 1, 8, and 15 of 28-day cycles. The phase 1 portion of the study utilized a standard 3+3 dose-escalation scheme. All patients received carfilzomib at 20 mg/m2 on day 1 of cycle 1; patients received 45, 56, 70, or 88 mg/m2 beginning on day 8 of cycle 1 in successive dose-level cohorts until the maximum tolerated dose (MTD) was reached. All patients received dexamethasone 40 mg (IV or oral administration) on days 1, 8, 15, and 22 of cycles 1-8; dexamethasone was omitted on day 22 in cycles ≥ 9. In the phase 2 portion, patients received carfilzomib at the MTD (carfilzomib dose of 20 mg/m2 on cycle 1, day 1; escalating to the MTD for subsequent doses) and dexamethasone at the same dose and schedule. Kd was administered until unacceptable toxicity or disease progression. The primary objective of the phase 1 portion was to determine the MTD of carfilzomib in the Kd regimen; the primary objective of the phase 2 portion was to determine the overall response rate (ORR [≥partial response]). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Results: A total of 27 patients were enrolled in phase 1; the MTD of carfilzomib was determined to be 70 mg/m2. Results are presented for all patients treated with Kd at the carfilzomib MTD in both the phase 1b (n=15) and phase 2 (n=89) portions of the study. Among these 104 patients, median patient age was 68.5 years (range, 41-88). Patients received a median of 1 prior line of therapy (range, 1-3); 83% of patients had received prior bortezomib (BTZ), 49% of patients were BTZ-refractory, 27% were LEN-refractory, and 16% were refractory to both BTZ and LEN. Median carfilzomib treatment duration was 7.7 months (range, 0.03-24.2). The ORR was 77% (95% confidence interval [CI]: 68%-85%); the clinical benefit rate (≥minimal response) was 84% (95% CI: 75%-90%). Kaplan-Meier median progression-free survival was 12.6 months (95% CI: 9.0-not estimable). Twelve patients (12%) discontinued treatment due to an adverse event. The most common adverse events of any grade and of grade ≥3 are shown in the Table. Five patients died on study: 1 patient each had cause of death reported as disease progression, acute respiratory distress syndrome, acute respiratory failure, acute kidney injury, and cardiopulmonary arrest. The mean area under the curve and maximum concentration following a 70-mg/m2 carfilzomib dose was 1050 ng×h/mL and 2510 ng/mL, respectively. At 1 hour post dosing of carfilzomib 70 mg/m2, the activity of the predominant chymotrypsin-like proteasome catalytic subunit in peripheral blood mononuclear cells (ie, low molecular mass polypeptide 7) was strongly inhibited (97% inhibition as determined by an enzyme-linked immunosorbent assay [ProCISE]; 93% inhibition as determined by a fluorogenic substrate assay). Conclusions: CHAMPION-1 is the first clinical study to evaluate carfilzomib on a weekly dosing schedule. Once-weekly carfilzomib (70 mg/m2) with dexamethasone demonstrated acceptable safety and tolerability with promising efficacy for patients with relapsed or refractory MM. The dose and schedule of carfilzomib used in the CHAMPION-1 study (20/70 mg/m2) is currently being compared with the regulatory-approved carfilzomib dose and schedule (20/27 mg/m2 administered twice-weekly) in the ongoing, phase 3, superiority study ARROW (NCT02412878). Disclosures Lyons: Amgen: Consultancy, Honoraria; Insyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Harb:Onyx Pharmaceuticals: Consultancy. Boccia:Incyte Corporation: Honoraria. Moss:Onyx: Honoraria, Research Funding. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: 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. Schupp:Amgen: Employment, Equity Ownership. Dixon:Onyx/Amgen: Employment, Equity Ownership. Ou:Onyx/Amgen: Employment, Equity Ownership. Anderl:Onyx/Amgen: Employment, Equity Ownership. Berdeja:Abbvie: Research Funding; BMS: Research Funding; Acetylon: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Onyx: Research Funding; Janssen: Research Funding; Novartis: Research Funding; MEI: Research Funding; Array: Research Funding; Curis: Research Funding.

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Examining the Clinical Features and Underlying Cardiovascular Risk Among Patients with Polycythemia Vera in the REVEAL Study

Blood ◽

10.1182/blood.v128.22.1934.1934 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1934-1934 ◽

Cited By ~ 1

Author(s):

Brady L. Stein ◽

Ahmad Naim ◽

Michael R. Grunwald ◽

Alison R. Moliterno ◽

Stephen T. Oh ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

The United States ◽

Employment Equity ◽

Advisory Committees ◽

Reveal Study ◽

History Of ◽

Equity Ownership

Abstract Background:Patients with polycythemia vera (PV) often present with a broad range of clinical characteristics that may contribute to increased risks of cardiovascular (CV) morbidity and mortality, including thrombotic events (TE). Limited contemporary real-world data have been reported about the clinical burden of PV and treatment patterns in the United States. The ongoing REVEAL study collects data on disease burden, clinical management, patient-reported outcomes, and healthcare resource utilization for patients with PV in the United States. This analysis reports clinical characteristics, including underlying CV risk factors, for patients enrolled in the REVEAL study as of April 28, 2016. Methods: REVEAL is a multicenter, nonrandomized, prospective, observational study enrolling patients ≥18 years of age with a PV diagnosis who are actively managed in an academic or community setting. For this analysis, data regarding PV disease and diagnosis, clinical characteristics, and treatment patterns were collected at enrollment during usual-care visits and were based on physician assessment, electronic medical records, and local laboratory values. Ten-year CV risk factors selected for this analysis were adapted from the Framingham Heart Study for CV diseases. Results: At data cutoff, 2307 patients were available for this analysis. Mean (SD) age was 66.3 (12.2) years, 54.4% were male, 89.9% were white, 62.7% had at least some college education, and 51.1% were retired. Approximately 6% of patients had a family history of PV, primarily in parents (35.1%) and siblings (33.8%). A history of second malignancies was reported for 344 patients (14.9%). The majority of patients (84.6%) were diagnosed with PV based on an abnormal blood test alone or in combination with a bone marrow test. Among patients who were diagnosed with a mutational test (n=1078), 95.2% were diagnosed via an abnormal JAK2V617F test result. Abnormal hemoglobin (57.3%), hematocrit (55.4%), or both (47.5%) were among the most common blood values assessed for PV diagnosis. At diagnosis, 58.5% of patients were classified with high-risk PV (age ≥60 years or history of a TE); this percentage increased to 77.3% at REVEAL enrollment. The average (SD) disease duration from diagnosis to enrollment was 5.8 (6.1) years. At enrollment, 91.5% of patients were under active management for PV (phlebotomy ± aspirin, 34.0%; hydroxyurea ± aspirin, 27.0%; and phlebotomy + hydroxyurea ± aspirin, 23.2%). Underlying CV risk factors that were either diagnosed or treated in 86.0% of enrolled patients included hypertension (66.5%), history of smoking (46.2%), current smoking at enrollment (10.9%), obesity (34.2%), hyperlipidemia (27.4%), and diabetes (14.8%). At enrollment, 431 (18.7%) patients reported having ≥1 TE, including 181 patients who had a TE between PV diagnosis and enrollment. Venous and arterial TEs were reported in 11.1% and 8.6% of patients, respectively. Most commonly reported venous TEs were deep vein thrombosis (5.9%) and pulmonary embolism (2.5%); most common arterial TEs were cerebrovascular arterial thrombosis including transient ischemic attack (5.1%) and acute myocardial infarction (1.7%). Increased rates of TEs were observed among patients with hyperlipidemia (23.6%) and hypertension (21.0%; Table 1), compared with patients who did not have any risk factors (10.5%). Conclusion: A large proportion of patients in the REVEAL study had 1 or more underlying CV risks, including age, hypertension, smoking, obesity, hyperlipidemia, and diabetes, which may contribute to the risk of thrombosis. Longitudinal data from REVEAL will provide a better understanding of how these factors affect CV outcomes over time. Disclosures Stein: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Naim:Incyte Corporation: Employment, Equity Ownership. Grunwald:Janssen: Research Funding; Forma Therapeutics: Research Funding; Medtronic: Equity Ownership; Alexion: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Oh:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; CTI: Research Funding. Paranagama:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Boccia:Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Eisai: Consultancy, Honoraria, Speakers Bureau. Mesa:Ariad: Consultancy; CTI: Research Funding; Gilead: Research Funding; Galena: Consultancy; Novartis: Consultancy; Promedior: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽

10.1182/blood-2019-126205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3129-3129

Author(s):

Hans C. Lee ◽

Sikander Ailawadhi ◽

Cristina Gasparetto ◽

Sundar Jagannath ◽

Robert M. Rifkin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Age Groups ◽

Treatment Patterns ◽

Age Group ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽

10.1182/blood-2019-122775 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4739-4739

Author(s):

Pieter Sonneveld ◽

Maria-Victoria Mateos ◽

Adrián Alegre ◽

Thierry Facon ◽

Cyrille Hulin ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Board Of Directors ◽

Research Funding ◽

Indirect Comparison ◽

Employment Equity ◽

Advisory Committees ◽

Post Transplant ◽

Post Induction ◽

Adjusted Indirect Comparison ◽

Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: 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. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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