Baseline Characteristics of Patients in Peak: A Global, Longitudinal Registry of Patients with Pyruvate Kinase Deficiency

Background: Pyruvate kinase (PK) deficiency is a rare, inherited hemolytic anemia caused by autosomal recessive mutations in the PKLR gene, whereby a glycolytic defect causes a reduction in adenosine triphosphate generation. Current treatment options are supportive and include splenectomy, blood transfusions, and iron chelation therapy. To better understand the natural history, treatment patterns, and burden of disease, the observational PK Deficiency Natural History Study (NHS) (NCT02053480) enrolled 254 adult and pediatric patients with PK deficiency at 30 sites in 6 countries between 2014 and 2017 and followed patients for 2 years. The Peak Registry (NCT03481738) was developed to continue and expand on this research. This retrospective and prospective observational registry aims to enroll 500 adult and pediatric patients at ~ 60 sites in up to 20 countries over 7 years, with 2-9 years of follow-up. Objective: This analysis aimed to characterize the baseline demographics and clinical characteristics of patients with PK deficiency enrolled in the Peak Registry as of 24March2020. Methods: Demographic, diagnostic, medical history, laboratory, treatment, and other relevant data were collected from participating clinicians via electronic case report forms. To be eligible for inclusion in this analysis, patients were required to have genetically confirmed PK deficiency and available demographic information. All analyses reported here are descriptive and based on data as of the date of enrollment in the registry. Continuous variables are summarized by the number of non-missing observations, mean, standard deviation (SD), median, and range. Categorical variables are summarized as counts and percentages. Results: A total of 141 patients met the inclusion criteria, across 11 countries in North America and Europe. A summary of baseline demographics and clinical characteristics is shown in the Table. Fifty patients (35.5%) had completed 2 years of follow-up in the NHS and then moved to the Peak Registry; the remainder were newly recruited to the Peak Registry. The mean age of study participants at enrollment was 25.5 years (SD 19.1); 78 patients (55.3%) were female. Mean reported age at first symptoms was 5.8 years (SD 13.2) and mean age at diagnosis was 11.7 years (SD 16.0). Fifty-seven percent of patients were classified as having missense/missense mutations, 34.4% as having missense/non-missense mutations, and 8.6% as having non-missense/non-missense mutations. The mean hemoglobin at enrollment was 8.8 g/dL (range: 5.8-12.9 g/dL). Mean reticulocyte count was 19.8% (range: 2.2-42.4%), mean lactate dehydrogenase was 382 IU/L (range: 135-849 IU/L), and mean indirect bilirubin was 4.3 mg/dL (range: 0.8-23.1 mg/dL). Among the 45.2% of patients who had been splenectomized, the mean age at splenectomy was 7.2 years. Chelation therapy had been previously prescribed to 40.3% of patients. Among the 27 patients for whom ferritin data were available, the mean was 867.9 ng/L (range: 78.1-2499.0 ng/L), and 18 patients (66.7%) had a level > 500 ng/L. Ninety-nine patients (70.2%) had received at least one transfusion in their lifetime. Among the 45 patients who were known to have received at ≥ 1 transfusion in the 12 months prior to enrollment, the mean number of transfusions during that period was 5 (SD 4.3), with 18 of those patients (40.0%) having received ≥ 6 transfusions. Conclusions: New data emerging from the Peak Registry will provide valuable insights into the patient characteristics, treatment patterns, and burden associated with PK deficiency. The population is demographically heterogenous and represents a broad geography. Patients have a wide range of hemoglobin levels, and iron overload is common. The substantial rates of splenectomy, cholecystectomy, transfusions, and chelation use are indicative of a high disease and treatment burden in patients with PK deficiency. This abstract is presented on behalf of the Peak Registry Steering Committee and Peak Registry Investigators. Disclosures Grace: Novartis: Research Funding; Pfizer: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees. Boscoe:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Glader:Agios Pharmaceuticals, Inc.: Consultancy. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yan:Agios Pharmaceuticals: Consultancy. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor.

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Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽

10.1182/blood.v128.22.3778.3778 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3778-3778

Author(s):

Amy L. Dunn ◽

Alexis A. Thompson ◽

Werner Engl ◽

Marlies Sharkhawy ◽

Brigitt E. Abbuehl

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Pediatric Patients ◽

Hemophilia A ◽

Point Estimate ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

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A Decade Follow-up of a Thalassemia Major (TM) Cohort Monitored by Cardiac Magnetic Resonance Imaging (CMR): Significant Reduction In Patients with Cardiac Iron and In Total Mortality

Blood ◽

10.1182/blood.v116.21.1011.1011 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1011-1011 ◽

Cited By ~ 7

Author(s):

Alison S Thomas ◽

Maciej Garbowski ◽

Ai Leen Ang ◽

Farrukh T Shah ◽

J. Malcolm Walker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Thalassemia Major ◽

Iron Loading ◽

Myocardial Iron ◽

Advisory Committees ◽

Cardiac Iron

Abstract Abstract 1011 Background. CMR was introduced in London to assess myocardial iron loading in 1999 and some of these patients now have 10 years of follow-up, most with contemporary CMR determinations. The impact of long-term monitoring of myocardial iron loading in thalassemia major (TM) on the proportion of patients with increased myocardial iron (cT2* <20ms) and on patterns of mortality has not been previously described in a longitudinal cohort over this duration. Patients and Methods. All patients regularly attending two London thalassemia centres, who received their first CMR Jan 1999 - Dec 2000 were analyzed as a cohort. Patients underwent initial CMR at the Royal Brompton Hospital and received CMR follow up (FU) either there or at the Heart Hospital (UCLH). 132 patients were identified as having received a CMR in 1999–2000. A minimum 7 years CMR FU was required for inclusion in the long-term CMR analysis. 109 patients had at least 7 years of CMR follow up (range 7.0–10.6 years, median 9.2). The median age at 1st CMR was 27.9 years (range 7.7 – 49.5 years). At baseline, patients were receiving chelation with deferoxamine (DFO) monotherapy (70%), deferiprone (DFP) monotherapy (21%), or a combination of these agents (9%). At latest FU, patients were receiving DFO (32%), deferasirox (DFX) (28%), DFP (22%), or combined DFP and DFO therapy (18%). Results: Improvement in cardiac iron: In 1999–2000, 60% of TM patients had cT2* values ≤20ms and 17% had cT2* values <10ms. By contrast, at long term FU, only 23% now have cT2* ≤20ms, 7% have cT2* values <10ms (p<0.001). Changes to chelation therapy: 31% of patients stayed on the same chelator; 33% had 1 chelator switch, 26% 2 switches and 11% 3 or more switches. 18 switches in chelation therapy were due to side-effects (12 DFP, 5 DFX, 1 DFO). There were 9 breaks in chelation therapy during pregnancy in 8 different women. The proportions of patients with T2* < 20ms fell significantly for those who remained on DFO or DFP monotherapies throughout, or who changed chelation modalities on only one (p=0.002) or two (p=0.02) occasions. Patients who received had 3 or more switches did not show a improvement in this respect. The latter group was also the only subset that showed significant deterioration in myocardial iron (p<0.001). Mortality rates: the overall mortality rate for the initial cohort was 1.65 per 1000 patient years (95% CI 0.71 – 3.24); median age at death 35.6 years (range 27.3–48.4). This is a substantial improvement in the mortality index compared with the UK thalassemia registry data, of 4.3 per 1000 patient years during the period 2000–2003 (Modell et al, JCMR, 2008). The incidence rate ratio is 0.387 (95% CI 0.11–0.961), p<0.05, with patients in our cohort 61% less likely to die than those in the 2000–2003 cohort. Causes of death: there were 8 deaths during the FU period: 3 with complications of hepatitis C (all with cT2* > 20ms), 3 with sepsis (2 with cT2* <10ms and impaired ejection fraction, 1 with cT2* of 18ms), 1 with breast cancer, 1 with sudden unexplained death (cT2* > 20ms). Thus in only 2 patients could excessive cardiac iron loading be considered a causal/contributory factor. There was no significant difference in the baseline cT2* between those who died and those currently still alive (p= 0.2), meaning that death as a drop-out cause does not explain iron loading trends over FU. Chelators at death: DFO (4), DFP (2), DFX (1), combination (1). Conclusions: Over a decade we have seen an almost 3 fold fall in the proportion of patients with myocardial iron overload. Mortality has become substantially lower and cardiac iron overload is no longer the leading cause of mortality. In addition to CMR, this decade has seen the advent of two new oral iron chelators and many patients switched chelation regimen, sometimes several times, during the follow up period. Whilst the contribution of the individual components of this practice to the improved outcome cannot be concluded without randomized studies, it is clear that this modern management of TM is associated with reduced TM mortality. Disclosures: Off Label Use: Deferiprone is off label in the USA but licensed in Europe. Shah:Novartis: Honoraria, Speakers Bureau; Apotex/ Swedish Orphan: Honoraria. Pennell:Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardiovascular Imaging Solutions: Director of CVIS, Equity Ownership. Porter:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Analysis Of Warfarin Drug-Drug Interactions With Antibiotics In The Ambulatory Care Setting

Blood ◽

10.1182/blood.v122.21.1143.1143 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1143-1143

Author(s):

Nathan P Clark ◽

Thomas Delate ◽

Catherine S Riggs ◽

Daniel M Witt ◽

Elaine M Hylek ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Warfarin Dose ◽

Acute Illness ◽

Control Groups ◽

Advisory Committees ◽

Antibiotic Group ◽

The Mean ◽

Excessive Anticoagulation

Abstract Background The typical effect of antibiotic initiation on the international normalized ratio (INR) in a real-world, stable warfarin population has not been adequately described. In addition, the influence of acute illness on the risk of excessive anticoagulation is not known. Methods This retrospective, longitudinal cohort study evaluated patients who received stable warfarin therapy between January 1, 2005 and March 31, 2011. The protocol for patients receiving warfarin and initiating antibiotic therapy during the study time-frame was to continue the warfarin dose unchanged and measure an INR within 3 to 7 days. Patients who purchased an antibiotic (antibiotic group) were compared to those purchasing a warfarin refill (stable controls) and patients with upper respiratory infection who did not purchase an antibiotic (sick controls). Primary outcomes included the mean INR change between the last INR prior to study inclusion (pre-index INR) and the first follow-up INR as well as the percentage of patients with a follow-up INR ≥ 5.0. The influence of interaction mechanism on the risk of a follow-up INR ≥ 5.0 was evaluated and predictors of a follow-up INR ≥ 5.0 were identified. Results A total of 5905 (49.0%), 5579 (46.2%), and 570 (4.8%) patients were included in the antibiotic, stable control, and sick control groups, respectively. The mean age was 68.3 years and the median pre-index INR was 2.5 (IQR 2.2-2.9). The mean change in INR was greater in the antibiotic group compared to the stable and sick control groups (both p< 0.05) but the increase was not clinically relevant (i.e., mean increase was less than 0.1 INR units). There were 3.2%, 2.6%, and 1.2% of patients with a follow-up INR ≥ 5.0 in the antibiotic, sick, and stable groups respectively (antibiotics v. stable and sick v. stable p<0.001; antibiotics v. sick p=0.434). Antibiotics interfering with warfarin metabolism were more likely to result in a follow-up INR ≥ 5.0 (9.6%) than those disrupting Vitamin K synthesis (3.1%) and those without a known interaction with warfarin (2.1%) (p<0.01) (Table). Antibiotic use, acute illness, cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR ≥ 5.0. Conclusion In the absence of antibiotics, acute illness alone increases the risk of excessive anticoagulation in previously stable warfarin patients. The risk of an INR ≥ 5.0 was greatest among antibiotics interfering with warfarin metabolism. In addition to antibiotics and acute illness, patients with cancer, elevated baseline INR, and females were most susceptible to excessive anticoagulation. Disclosures: Hylek: Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy. Garcia:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Roche Diagnostics: Consultancy; CSL Behring: Consultancy. Crowther:Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Consultancy; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees.

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Characterization of the Severe Phenotype of Pyruvate Kinase Deficiency

Blood ◽

10.1182/blood-2019-125352 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 949-949

Author(s):

Hanny Al-Samkari ◽

Eduard J. van Beers ◽

D Holmes Morton ◽

Wilma Barcellini ◽

Stefan W. Eber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Extramedullary Hematopoiesis ◽

Advisory Board ◽

Missense Mutations ◽

Severe Phenotype ◽

Advisory Committees ◽

Transfusion Requirements ◽

Over Time

Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p<0.0001), have received chelation therapy (90% vs. 42%, p<0.0001), and had more lifetime transfusions (median: 77 versus 15, p<0.0001). Rates of other PKD complications including pulmonary hypertension, extramedullary hematopoiesis, liver cirrhosis, endocrinopathy, and bone fracture appear similar between the two groups. Laboratory values, including hemoglobin, total bilirubin, normalized PK enzyme activity, and median absolute reticulocyte count appear similar between the two groups. The underlying genetic mutation patterns (missense mutations versus non-missense mutations) were also similar between the groups. Phenotype stability over time was highly variable: of the patients with a severe phenotype at enrollment, 62% had a severe phenotype during the first follow-up year and 39% had a severe phenotype at the second follow-up year. Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers:RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini:Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic:Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek:Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Prophylactic Antibiotic Use and Risk of Meningococcal Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Eculizumab Who Received Meningococcal Vaccination: Results from the International PNH Registry

Blood ◽

10.1182/blood-2019-127005 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4802-4802 ◽

Cited By ~ 2

Author(s):

Christopher J. Patriquin ◽

Austin Kulasekararaj ◽

Régis Peffault de Latour ◽

Jun-Ho Jang ◽

Saskia Langemeijer ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Infection Risk ◽

Meningococcal Infection ◽

Meningococcal Infections ◽

Advisory Committees ◽

Start Date ◽

The Mean

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) patients treated with eculizumab have an increased susceptibility to serious meningococcal infections. In the largest safety data set to date, representing >10 years of postmarketing pharmacovigilance surveillance of eculizumab for the treatment of PNH, the reported meningococcal infection rate was 0.24 per 100 patient-years (PY); cumulative exposure to eculizumab in PNH was 21,016 PY (Socié G, et al. Br J Haematol. 2019). To reduce infection risk, it is recommended that PNH patients receive meningococcal vaccination ≥2 weeks prior to the first dose of eculizumab; patients vaccinated <2 weeks prior to eculizumab initiation are treated with appropriate prophylactic antibiotics (P-Abx) until 2 weeks after vaccination. However, some patients may still experience meningococcal infections, as vaccination reduces but does not eliminate the risk of meningococcal infection; thus, some physicians use long-term P-Abx in addition to meningococcal vaccination to lower infection risk. The real-world use of P-Abx is not well characterized, and their effect on the incidence of meningococcal infection is unknown. The objective of this study was to assess meningococcal infection rates in PNH patients who received eculizumab with or without P-Abx. METHODS This was a cohort study consisting of eculizumab-treated PNH patients from the International PNH Registry (NCT01374360). Eligible patients received meningococcal vaccination within 6 months prior to or up to 1-month post-eculizumab initiation; had a known birth date, sex, enrollment date, and status of P-Abx use; and were evaluable for infection during the study period. To prospectively assess the rates of meningococcal infections, the start of the follow-up period was defined as the later of the registry enrollment date or eculizumab treatment start date and the end of the follow-up period was defined as the earlier of the last eculizumab treatment follow-up date or date of the first meningococcal infection (i.e., patients were censored when they developed the first meningococcal infection after registry enrollment). To compare the demographic and disease characteristics between patients who started P-Abx and those who did not (No P-Abx), data were summarized at the later of the eculizumab start date, P-Abx start date, or enrollment date for patients with P-Abx use or at the last eculizumab treatment follow-up for No P-Abx patients. Event rates and corresponding 95% CIs were calculated for meningococcal infections for patients with and those without P-Abx using Poisson regression with an offset for the log of the treatment duration. RESULTS As of January 8, 2019, 1,815 eculizumab-treated patients were enrolled in the International PNH Registry, of whom 1,231 met all inclusion criteria for this study. Of the eligible patients, 501 received P-Abx and 730 did not. For the P-Abx and No P-Abx groups, the mean age of PNH onset (37.3 vs 36.8 y, respectively) and mean age at eculizumab initiation (44.4 vs 43.1 y, respectively) were similar. P-Abx use was higher in Europe (76.6%) than in other regions (Table 1). Both P-Abx and No P-Abx groups had similar medical event histories; the mean duration of the study period was 4.3 years (SD, 2.28 years) for the P-Abx group and 3.8 years (SD, 2.48 years) for the No P-Abx group. The mean duration of P-Abx use during the study period was 0.4 years (SD, 1.01 years). The most commonly used P-Abx was penicillin (314 of 500 patients). In total, 7 patients (3 from the P-Abx group and 4 from the No P-Abx group) experienced a meningococcal infection during the study period. In these 7 patients, the mean time from meningococcal vaccination to eculizumab initiation was 0.7 months (SD, 0.23 months) for the P-Abx group and 2.4 months (SD, 1.20 months) for the No P-Abx group. The estimated rates of meningococcal infection per 100 PY were 0.1 (95% CI, 0.0-0.4) for the P-Abx group and 0.1 (95% CI, 0.1-0.4) for the No P-Abx group (Table 2). CONCLUSIONS Rates of meningococcal infection were consistent with previously reported rates and were similar in PNH patients who received eculizumab therapy with or without P-Abx. It is important to note the small number of meningococcal infections and the limited details of P-Abx use reported in the registry. Further work will assess if patients were on P-Abx at the time of infection, and what meningococcal serotypes were identified. Disclosures Patriquin: Apellis: Consultancy, Honoraria, Research Funding; Ra Pharma: Consultancy, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding. Kulasekararaj:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Wilson:Alexion Pharmaceuticals Inc.: Employment. Jain:Alexion Pharmaceuticals Inc.: Employment. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

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Long-Term Durable Responses after Autologous Stem Cell Transplantation in POEMS Syndrome

Blood ◽

10.1182/blood-2018-99-115710 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4606-4606

Author(s):

Neeraj Y Saini ◽

Romil Patel ◽

Ankur Varma ◽

Qaiser Bashir ◽

Omar Hasan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Median Number ◽

Castleman Disease ◽

Poems Syndrome ◽

Bone Lesions ◽

Advisory Committees ◽

Entire Cohort ◽

The Mean

Abstract Abstract: Background: POEMS syndrome is a constellation of symptoms of polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Other features often present in this syndrome include papilledema, extravascular volume overload, sclerotic bone lesions, Castleman disease, high vascular endothelial growth factor (VEGF) levels and thrombocytosis/polycythemia. The standard of care has not been established in the management of the disease. We had previously reported on the role of auto-HCT in a smaller cohort of POEMS patients at our institution1. Here, we present an updated analysis in a larger cohort of POEMS patients who underwent auto-HCT. Methods: We retrospectively reviewed the outcomes of POEMS patients who underwent auto-HCT at our institution from the period of January, 1999, through June, 2018. The Kaplan-Meier method was used to caculate progression-free survival (PFS) and overall survival (OS). Hematologic response was defined as per the International Myeloma Working Group (IMWG) criteria. OS was defined as the duration from the date of transplant to death or last date of follow-up in alive patients. PFS was defined as the duration from the date of transplant to either progressive disease or death, whichever occurred first. Results: 16 patients (13 males, 3 females) with POEMS syndrome received a total of 17 auto-HCTs. One patient underwent auto-HCT two times for multiple relapses. The median age at auto-HCT was 48 years (range: 18-75). The median time from diagnosis to auto-HCT was 15 months (2-141 months). All 16 (100%) patients had peripheral neuropathy and monoclonal gammopathy: IgG lambda in 7, IgA lambda in 6, IgG kappa in 2 and light chain in 1 patient. Other features were: osteosclerotic bone lesions in 13 (81%), endocrinopathy in 10 (69%), skin involvement in 8 (50%) and extravascular fluid overload in 7 (44%). Three (18%) patients had biopsy-proven co-existent Castleman disease. Among patients with available data (n=7), the mean serum VEGF level pre-transplant was 389 pg/ml (268-1622). The median HCT-CI (comorbidity index) score available for 15 patients was 2 (range 0-7). The median number of chemotherapies received before the transplant was 1 (range 1-3). Table 1 summarizes the prior systemic chemotherapies received before auto-HCT. Two patients also received plasmapheresis, and eight patients received radiation therapy for bone disease. The mobilization regimens used for collecting peripheral blood stem cells were granulocyte colony-stimulating factor (G-CSF) alone, cyclophosphamide+G-CSF and G-CSf+plerixafor in 16, 2 and one patient, respectively. The median number of CD34+ stem cells collected was 3.43 X 106 cells/kg (range 1.73 - 6.5). The overall response rate, as per the IMWG criteria, for the entire cohort was 94% (16/17): 5 (29.4%) CR, 4 (23.5%) nCR, 1 (5.8%) VGPR, and 6 (35.2%) PR. The mean serum VEGF levels improved from 389 pg/ml before transplant to a level of 35 pg/ml (31-86) post-transplant. Engraftment syndrome was seen only in 1 patient who required corticosteroid use. One-year transplant-related mortality was 0%. Median follow-up among surviving patients is 52 months (5-120 months). The median PFS and OS have not been reached yet. All 16 patients had a complete or partial resolution of their clinical symptoms after auto-HCT. 4-year PFS and OS rate for the entire cohort is 80.2% and 100% respectively. At ten years, PFS and OS rate is 59.4% and 80% respectively. Fourteen out of 16 patients were alive at the time of the last follow-up. One patient died six years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease, and the second patient died after 11 years post auto-HCT of unknown cause. Conclusions: Upfront Auto-HCT provides durable chemotherapy free remission and significant clinical improvement in patients with POEMS syndrome. References: Patel, K. et al. Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome. Bone marrow transplantation49, 465-6 (2014). Figure. Figure. Disclosures Thomas: Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Array Pharma: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Poseida: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Patel:Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

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Outcomes of Adult and Pediatric Patients with Hematologic Malignancies and COVID-19: A Systematic Review and Meta-Analysis of 1847 Patients

Blood ◽

10.1182/blood-2020-141235 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-41

Author(s):

Abi Vijenthira ◽

Inna Gong ◽

Thomas A Fox ◽

Stephen Booth ◽

Gordon Cook ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Hematologic Malignancy ◽

Meta Analysis ◽

Advisory Board ◽

Hospitalized Patients ◽

Private Company ◽

Advisory Committees ◽

Risk Of Death

Introduction: Clinical outcomes for patients with hematologic malignancy and COVID-19 have not been aggregated. We completed a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. Methods: We searched Pubmed and EMBASE up to July 25, 2020, to identify reports of patients with hematologic malignancy and COVID-19 (including papers where the patients with hematologic malignancy were a subset of the total study population). The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included pooled estimates for the risk of ICU admission, mechanical ventilation, and non-invasive ventilation in hospitalized patients. Mortality data were stratified by age, treatment status, and malignancy subtype. For treatment status, "systemic anti-cancer therapy (SACT)" was defined as patients on any anti-cancer therapy. "Cytotoxic SACT" was defined as patients on cytotoxic therapy only. "Not on treatment" was defined as patients on observation or those who were at least 28 days beyond their last active treatment. Sensitivity analyses were conducted on the primary outcomes limiting to studies with low risk of bias, and to studies including both outpatients and hospitalized patients. Due to data limitations, only the primary outcome was assessed for pediatric studies. Pooled prevalence and risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model using MetaXL and Revman 5.4 software. Results: A total of 25 adult studies and 4 pediatric studies comprising 1847 patients from China, Europe, the United Kingdom, and North America were included (Figure 1 and Table 1). The majority of patients were hospitalized (83%). The overall risk of death amongst all patients was 36% (95% CI 31-41, N=1763), and amongst hospitalized patients was 40% (95% CI 36-45, 24 studies with 1295 patients) (Figure 2). Patients aged >60 years had a significantly higher risk of death than patients <60 years (46% vs. 26%, RR 1.56, 95%CI 1.15-2.13, N=597) (Figure 3). The pooled risk of death in pediatric patients was 4% (95% CI 1-9, N=102) (Figure 2). The risk of ICU admission among hospitalized adult patients was 23% (95% CI 17-29, N=1165); mechanical ventilation 16% (95% CI 12-21, N= 826); and non-invasive ventilation 16% (95% CI 9-26%, N=373). The estimated RR of death among patients on SACT compared to no treatment was 1.22 (95% CI 0.84-1.78; N=457, Figure 3a). The RR of death among patients on cytotoxic SACT versus no treatment was similar at 1.29 (95% CI 0.78-2.15; N=176, Figure 3b). All subgroups of hematologic malignancy had high risks of overall mortality: acquired bone marrow dysfunction syndromes 57% (95% CI 42-72, 11 studies, 42 patients); leukemias 44% (95% CI 31-58, 15 studies, 159 patients), plasma cell dyscrasias 38% (95% CI 29-47, 18 studies, 387 patients); lymphomas (including CLL) 32% (95% CI 26-38, 16 studies, 696 patients); lymphomas (excluding CLL) 32% (95% CI 18-48, 11 studies, 156 patients); CLL 31% (95% CI 24-39, 13 studies, 457 patients); myeloproliferative neoplasms 37% (95% CI 25-49, 9 studies, 62 patients). Sensitivity analysis including only studies with a low risk of bias showed a similar estimate for risk of death among all patients (37% (95% CI 31-42, 20 studies with 1412 patients)) compared to all studies. Sensitivity analysis including only studies reporting on a combination of outpatients and hospitalized patients also showed a similar estimate for risk of death among all patients (38% (95% CI 32-44), 11 studies with 1214 patients) compared to all studies. Conclusion: Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, appear to experience a high risk of dying (pooled risk estimate 36%). Older patients experience higher mortality, and pediatric patients appear to be relatively spared. Importantly, based on the observational data available to date, recent cancer treatment does not appear to significantly increase the risk of dying. These data highlight the need for robust strategies to prevent patients with hematologic malignancy from contracting COVID-19, and may help inform discussions about prevention strategies, treatment, and goals of care. Disclosures Cook: Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; IQVIA: Research Funding; Sanofi: Consultancy; Amgen: Consultancy; Roche: Consultancy; Karyopharm: Consultancy. Zwicker:Dova: Honoraria, Other: Advisory board; Portola: Honoraria, Other: Advisory board; Incyte: Research Funding; Quercegen: Research Funding; Parexel: Consultancy; Sanofi: Consultancy; CSL: Consultancy; Pfizer/BMS: Honoraria, Other: Advisory board. Scarfo:Gilead: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wood:Pfizer: Research Funding; Best Doctors/Teladoc: Consultancy; Koneksa Health: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Elektra Labs: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ASH Research Collaborative: Honoraria; Genentech: Research Funding. Hicks:Gilead Sciences: Research Funding.

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

Blood ◽

10.1182/blood-2019-122535 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2059-2059 ◽

Cited By ~ 5

Author(s):

Wolfgang Miesbach ◽

Karina Meijer ◽

Michiel Coppens ◽

Peter Kampmann ◽

Dr. Klamroth ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

First Year ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean ◽

Second Year

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

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Treatment Patterns and Outcomes in Patients with Relapsed/Refractory Follicular Lymphoma Who Received Third Line Therapy at the Christie NHS Foundation Trust in the UK

Blood ◽

10.1182/blood-2021-148490 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 5011-5011

Author(s):

Kim Linton ◽

Cristina Julian ◽

Adam Gibb ◽

Ellie White ◽

Emma-Frances Armstrong ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Index Date ◽

Treatment Patterns ◽

Advisory Committees ◽

Time Period ◽

Third Line ◽

Privately Held

Abstract Background: There are limited data on real-world treatment patterns and outcomes for follicular lymphoma (FL) in the relapsed/refractory (r/r) setting, with shorter response durations reported after each relapse (Link et al, 2019; Rivas-Delgado et al, 2019 and Batlevi et al, 2020). We examined treatment patterns for patients with FL initiating third line (3L) therapy at a single institution by time period in the post-rituximab era (2004-2010 and 2011-2020), and clinical outcomes for the overall cohort receiving therapy between 2004 and 2020. Methods: This is a retrospective, observational study of patients with FL who initiated 3L therapy between 2004 and 2020 in routine clinical practice at The Christie NHS Foundation Trust, UK. We selected patients aged ≥18 years at 3L initiation, with histologically documented FL Grade 1−3a treated with two prior lines of systemic therapy including an anti-CD20 monoclonal antibody and an alkylating agent, and at least one year of follow-up after initiating 3L therapy; follow-up ended June 2021. We excluded patients with grade 3b FL or transformation to high grade lymphoma any time before 3L treatment. Overall response rate (ORR) and complete response (CR) to 3L therapy was calculated, and overall survival (OS), progression free survival (PFS) and time to next treatment (TTNT) were estimated using the Kaplan-Meier (KM) method with 3L therapy initiation date as the index date. Results: Overall, 41 patients met all eligibility criteria; 11 and 30 patients received 3L therapy between 2004-2010 and 2011-2020, respectively. Median age at index date was 59 years and 53.7% were male; 73.2% had grade 1 or 2 FL; 78.1% had advanced stage (III/IV) FL at diagnosis. Median follow-up was 33.9 (IQR: 14.5, 63.0) months, and median time from diagnosis to 3L treatment was 60.2 (IQR: 29.4, 89.1) months. The most common regimen in 3L was rituximab plus bendamustine (R-benda) followed by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab used as a single agent (R-mono). Treatment patterns differed by time period (Table 1). R-benda was more commonly used between 2011 and 2020. The most common sequence was rituximab plus cyclophosphamide, vincristine and prednisone (R-CVP) followed by R-CHOP and R-benda (Figure 1). ORR to 3L treatment was 61.0%, CR 29.3%. Median OS, PFS and TTNT with 95% confidence interval (CI) were 70.0 (30.2-NR), 19.2 (9.5-34.7) and 11.8 (9.0-27.6) months after 3L initiation, respectively. Two- and five-year OS rates were 79% and 50%, and two-year PFS rate was 37%. Conclusions: Patients with r/r FL treated in the routine 3L setting have highly variable treatment patterns and unfavorable outcomes, representing a continued unmet medical need. This study is limited by its small size and evolving treatments, warranting a larger study of more recently treated 3L patients to evaluate the impact of modern treatment pathways and novel therapies on clinical outcomes for r/r FL. Figure 1 Figure 1. Disclosures Linton: University of Manchester: Current Employment; BeiGene: Research Funding; Hartley Taylor: Honoraria; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Julian: Genentech, Inc.: Current Employment, Current holder of stock options in a privately-held company. Gibb: The Christie NHS Foundation Trust: Current Employment; Takeda: Honoraria, Research Funding, Speakers Bureau. Li: Genesis Research: Current Employment. Liu: Genesis Research: Current Employment. Shewade: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Radford: BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company.

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High-Dose Melphalan Significantly Increases Mutational Burden in Multiple Myeloma Cells at Relapse: Results from a Randomized Study in Multiple Myeloma

Blood ◽

10.1182/blood-2020-139014 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-5

Author(s):

Mehmet K. Samur ◽

Marco Roncador ◽

Anil Aktas-Samur ◽

Mariateresa Fulciniti ◽

Abdul Hamid Bazarbachi ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Publicly Traded ◽

Private Company ◽

Advisory Committees ◽

High Dose Melphalan ◽

New Mutations

We recently shown that high-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) as first line therapy in young (<66 yrs) multiple myeloma (MM) patients significantly improves progression-free survival (IFM/DFCI 2009 study). However, the impact of alkylating agent melphalan inducing N-alkylpurine-monoadducts forming interstrand crosslinks (ICLs) in surviving myeloma cells remains an important biological question. We here profiled samples from the IFM/DFCI 2009 study, where patients were randomized to RVD+HDM vs RVD alone, to identify genomic changes induced by HDM and observed at relapse. We analyzed paired purified MM cells collected at diagnosis and at relapse from 68 patients using deep (75X) whole genome sequencing. Forty-five patients were treated with RVD only, while 23 patients received RVD followed by HDM. There was no significant difference between the 2 groups in regard to disease characteristics including sex, age, cytogenetic risk, and best response. Median follow-up was similar (29 vs 31 months, respectively), removing longer follow up as a confounding variable. The number of mutations at diagnosis was similar on both arms (7137 [IQR=3742] vs. 7230 [IQR=3702], p value = 0.67). Although mutational load increased in both arms; there was a significantly higher increase in number of mutations and indels in the HDM arm compared to RVD alone (mutations 5686 vs 1745, p=1.4e-5; and indels 467 vs 360, p= 0.02, respectively). Using a model incorporating number of new mutations, depth, and purity, we found that HDM causes a 4.1 fold higher mutation accumulation rate per month than RVD only (158.3 vs 38.3 mutations/ month; p=0.003). Importantly, newly acquired mutations were localized to regions which overlap with transcribed regions, and accumulated at significantly higher rate in the HDM group (p=0.009). In contrast, we did not observe any significant changes in copy number alterations (CNAs) and structural variants, including translocations, between both arms. A significant change in frequency of driver mutations including RAS/RAF, FAM46C, TP53, and DIS3 was not observed at the time of relapse. Clonality level was increased only for KRAS (p=0.054), while all other specific driver genes had similar clonality level at diagnosis and relapse. Interestingly, a significant increase in mutations involving MYO16 and SLC7A8 genes was observed at relapse in both arms, implicating components of the induction regimen (RVD). Investigating the mutational signature utilization in only newly acquired mutations identified 4 signatures: APOBEC, HR Double Strand Repair, clock-like signature, and unknown. k-means clustering analysis of samples based on signature utilization showed four distinct clusters. All patients clustering with high DNA repair signature utilization were in the HDM arm (65% HDM patients), the majority of whom achieved CR or sCR (74%); these patients acquired 8308 (range 3302-19107) new mutations between diagnosis and relapse. None of the RVD only treated patients were in this cluster. The remaining 35% HDM group patients were clustered with RVD samples and showed unknown signature utilization. Furthermore, motif enrichment analysis identified CYWR and ATGAGATV (p < 1e-130) as enriched motifs around the new mutations in HDM compared to RVD cohort. Importantly and as expected, DNA damage repair pathway genes were frequently targeted in the HDM group: 72% HDM samples accumulated DDR gene mutations vs. only 17% in the RVD alone arm (p < 0.001). At the time of relapse, 100% HDM arm patients had at least one DDR gene mutation and 80% had two or more, while only 37% RVD only group had one or more such mutation. Finally, we have reconstructed phylogenetic and evolutionary trajectories based on mutation and copy-number data from samples at diagnosis and relapse. The clonal composition in both arms was similar at diagnosis; however, HDM caused a significant shift to more subclonal mutations at relapse. chromothripsis and chromoplexy events were detected in 30% patients at diagnosis, which remained constant at relapse regardless of treatment. In summary, we describe significant accumulation of mutations following high dose melphalan. This fundamental molecular change in the disease at relapse, suggests the need for reappraisal of the optimal use and sequencing of high dose melphalan in the era of novel agents. Disclosures Fulciniti: NIH: Research Funding. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Moreau:Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Anderson:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Parmigiani:Phaeno Biotehnologies: Current equity holder in publicly-traded company; CRA Health: Current equity holder in publicly-traded company; Foundation Medicine Institute: Consultancy; Delphi Diagnostics: Consultancy; BayesMendel Laboratory: Other: Co-lead. Munshi:Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; C4: Current equity holder in private company; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Legend: Consultancy.

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