Long Term Treatment with Eculizumab In Paroxysmal Nocturnal Hemoglobinuria (PNH): Sustained Efficacy and Improved Survival

Abstract Abstract 639 PNH is an acquired clonal hemolytic anemia associated with severe symptoms, life-threatening thrombosis, pulmonary hypertension (PH), chronic renal impairment (CRI) and bone marrow failure resulting in reduced quality of life (QoL) and survival (median: 10 – 15 years). Eculizumab is a monoclonal humanized antibody that inhibits terminal complement activity and thereby prevents intravascular hemolysis, reduces transfusions, improves QoL and protects against PH, CRI and thromboses. Eculizumab was approved for PNH in 2007 as a result of studies with short follow-up and with no information on it's impact on survival. We present data on 79 patients treated with eculizumab from the Leeds PNH Center between May 2002 – July 2010 including 34 patients from the clinical trials and a further 45 treated since, funded in England by the National Commissioning Group (NCG) or locally in Scotland and Wales. The NCG indications for treatment include transfusion-dependent hemolysis (4 or more transfusions in 12 months) or significant PNH-related complications (i.e. thrombosis or renal failure) regardless of transfusion history. Three patients did not fulfil these criteria but were treated for profound symptoms as agreed with the NCG. Forty men and 39 women were treated for a mean of 39 months (1-98). Median age at diagnosis was 37yo (12-79) and at initiation of eculizumab was 46yo (14-84). Median granulocyte clone size at the start of eculizumab was 96.38% (41.78-99.98). Patient survival on eculizumab was compared with age and sex matched controls obtained using data from the UK Office of National Statistics. We previously published that there was a significantly worse survival for PNH patients compared to matched controls with ~ 50% of patients dying as a result of PNH (Hillmen et al., NEJM 1995). In the current series there was no difference in mortality between patients on eculizumab and the normal population (P=0.46; Fig 1). Patients over 70yo had worse survival (P=0.0042) with none of the 45 patients under the age of 50yo dying. Three patients died: a 55yo man from metastatic caecal carcinoma diagnosed prior to eculizumab, a 76yo woman who died from pneumionia following a long history of recurrent bronchopneumonia prior to eculizumab and a 79yo man with a preceding history of ischaemic heart disease who died from cardiac failure. Three patients have had a clonal evolution of their PNH, 1 to acute myeloid leukemia and 2 to myelodysplasia. Two patients have stopped eculizumab: - 1 due to pre-existing aplastic anemia and 1 with spontaneous remission of his PNH. Seventy four patients remain on eculizumab to date.Figure 1Kaplan-Meier survival plots depicting PNH patients on eculizumab compared to age and sex matched controlsFigure 1. Kaplan-Meier survival plots depicting PNH patients on eculizumab compared to age and sex matched controls There were 34 thrombotic episodes in 21/79 patients (27%) prior to eculizumab and only 2 thromboses since. Importantly primary prophylaxis with warfarin has now been stopped in 21 patients (mean duration of 8.4 months (range: 1–25) and total of > 14 years) with no thromboses occurring. Seven patients had thrombosis within 12 months prior to starting eculizumab and they had no further thromboses on therapy. Therefore eculizumab is effective in preventing new, or evolution of pre-existing thrombosis, and appears to remove the need for primary prophylactic anticoagulation. We have not systematically stopped the anticoagulation of patients with a previous history of thrombosis. Patients had a mean of 19.9 units transfused (0-156) in the 12 months before eculizumab. Of the 64 patients on eculizumab for at least a year, 43 (67%) have been transfusion independent for >12 months. Twenty one patients still needing transfusions had a significant (P=0.028) reduction in their mean requirement of 24.6 (4-52) units in the 12 months before eculizumab compared to a mean of 14.6 (2-50) units in the last 12 months. Eculizumab is well tolerated long-term (> 8 years of therapy) with continued improvement in PNH associated symptoms, reduction in transfusion requirements and a higher proportion of transfusion independent patients than previously seen. There is a significant reduction in the development of thromboembolism on eculizumab therapy and importantly we have been able to stop primary prophylaxis with warfarin in 21 patients without any thrombotic complications. We demonstrate for the first time that eculizumab has a major impact on survival in PNH so that survival is comparable to an age- and sex-matched control population. Disclosures: Kelly: Alexion Pharmaceuticals: Honoraria. Hill:Alexion Pharmaceuticals: Honoraria, Speakers Bureau. Richards:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Arnold:Alexion Pharmaceuticals: Honoraria. Hillmen:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Efficacy and Safety of Deferasirox (Exjade®) in Patients with β-Thalassemia Major Treated for up to 5 Years.

Blood ◽

10.1182/blood.v114.22.4063.4063 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4063-4063 ◽

Cited By ~ 4

Author(s):

M. Domenica Cappellini ◽

Silverio Perrotta ◽

Leyla Agaoglu ◽

Yesim Aydinok ◽

Marcello Capra ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Iron Concentration ◽

Term Treatment ◽

Efficacy And Safety ◽

Advisory Committees ◽

Absolute Change ◽

Transfusion Requirements ◽

Long Term Treatment

Abstract Abstract 4063 Poster Board III-998 Background In a large, 1-yr Phase 3 clinical trial, patients (pts) with β-thalassemia (aged ≥2 yrs) were randomized to receive deferasirox (Exjade®) or deferoxamine (DFO), with doses assigned according to baseline liver iron concentration (LIC). Pts completing the 1-yr core were permitted to enter a 4-yr extension; those receiving deferasirox continued on this therapy (deferasirox cohort), while those receiving DFO crossed over to deferasirox (crossover cohort). This analysis evaluates the efficacy and safety of deferasirox over 5 yrs. Methods Based on analyses showing that iron burden and transfusional iron intake need to be considered for appropriate dosing of deferasirox, dose adjustments were permitted in the extension to ensure optimal dosing. Deferasirox dose in the extension was initially based on dose response in the core (deferasirox cohort only) and end-of-core LIC (biopsy or SQUID); subsequent adjustments in steps of 5–10 mg/kg/day were based on serum ferritin (SF) levels and safety markers. Efficacy was assessed by monthly SF levels and LIC at baseline, end of 1-year core and end of study (EOS) (or upon discontinuation). Safety was assessed by incidence and type of adverse events (AEs) and changes in laboratory parameters. Results 296 pts (deferasirox cohort) and 259 pts (crossover cohort) received ≥1 dose of deferasirox; 181 (61%) & 190 (73%) pts from each cohort respectively completed the extension. Most common reasons for discontinuation: consent withdrawal (n=62) and AEs (n=43). Most common AEs leading to discontinuation: increased ALT [n=5], increased transaminases [n=4], glycosuria [n=4]. 2 deaths occurred during the extension in the deferasirox cohort (cardiac failure, cardiomyopathy); 2 in the crossover cohort (cardio-respiratory arrest, road traffic accident); none considered to be related to study drug. Median duration of deferasirox treatment was 61.2 & 48.1 mths in deferasirox & crossover cohorts, respectively. At start of deferasirox, mean LIC was 14.0 ± 9.8 & 10.4 ± 7.6 mg Fe/g dry weight (dw) and median SF was 2211 & 1758 ng/mL in deferasirox and crossover cohorts, respectively. Transfusion requirements at start of deferasirox were comparable; most pts (81% & 83%, respectively) receiving 7–14 mL/kg/mth. Mean deferasirox dose during study: 21.6 ± 6.4 & 23.2 ± 5.9 mg/kg/d (final actual dose: 24.4 ± 8.7 & 27.0 ± 8.0 mg/kg/d) in deferasirox and crossover groups, respectively. Most pts were receiving 15–<35 mg/kg/day at EOS (75% & 78%, respectively); 11% & 17% were receiving ≥35 mg/kg/day. In pts who received at least 5 yrs of deferasirox and at least 4 yrs in the crossover group, mean absolute change in LIC were –5.3 ± 10.1 mg Fe/g dw (n=173; P<0.001) & –2.4 ± 7.6 mg Fe/g dw (n=99; P<0.001) and median absolute change in SF were –775 ng/mL (range: –10164–2572; n=182; P<0.001) & –371 ng/mL (range: –4498–2636; n=151; P<0.001), respectively (Figure). Percentage of pts with LIC<7 mg Fe/g dw increased from 35% to 45% & SF≤1000 ng/mL increased from 12% to 33% from the start of deferasirox to EOS (LIC: EOS, last available value; SF: EOS, average of at most 3 available values after start of deferasirox). Most common drug-related AEs (≥5% overall) after start of deferasirox in deferasirox & crossover cohort, respectively: increased blood creatinine (n=42, 14%; n=20, 8%), nausea (n=28, 10%; n=13, 5%), vomiting (n=18, 6%; n=17, 7%), diarrhea (n=13, 4%; n=15, 6%) & rash (n=17, 6%; n=19, 7%). Frequency of drug-related AEs decreased from year to year. In deferasirox & crossover cohorts, 26 (9%) & 11 (4%) pts had 2 consecutive serum creatinine increases >33% above baseline & upper limit of normal (ULN) & 3 (1%) & 2 (1%) pts had ALT >10 x ULN on 2 consecutive visits, respectively, after start of deferasirox. Conclusions Long-term treatment with deferasirox (for up to 5 yrs) significantly decreased iron burden in β-thalassemia pts aged ≥2 yrs with an increasing percentage of pts achieving therapeutic goals of LIC<7 mg Fe/g dw and SF≤1000 ng/mL. Significant improvements in LIC and SF were also observed after switching from DFO. Deferasirox was well tolerated over this long-term treatment, and the frequency of AEs decreased over time. Disclosures: Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Perrotta:Novartis: Consultancy, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Piga:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Griffel:Novartis Pharmaceuticals: Employment, Equity Ownership. Lagrone:Novartis Pharmaceuticals: Employment. Clark:Novartis Pharma AG: Employment. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau.

Download Full-text

Long Term Safety and Efficacy of Sustained Eculizumab Treatment In Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽

10.1182/blood.v116.21.4237.4237 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4237-4237 ◽

Cited By ~ 4

Author(s):

Robert A Brodsky ◽

Carlos de Castro ◽

Hubert Schrezenmeier ◽

Antonio M. Risitano ◽

Joerg Schubert ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Term Treatment ◽

Advisory Committees ◽

Serious Infections ◽

Long Term Treatment ◽

History Of ◽

Terminal Complement

Abstract Abstract 4237 PNH is a chronic, life-threatening, acquired disease associated with deficiency of GPI-anchored complement inhibitory proteins on blood cells. The resulting defective regulation of terminal complement activation is responsible for hemolysis and can lead to thromboembolism (TE), chronic kidney disease (CKD) and pulmonary hypertension. The risk of TE is high, with an observed 6.24 venous TE events per 100 patient years, or approximately 62-fold higher compared to the general population: in fact, TE accounts for 40–67% of PNH related deaths. The effectiveness of anticoagulation (AC) in PNH patients (pts) is uncertain, as AC treated PNH may still experience TE. The terminal complement inhibitor eculizumab reduces intravascular hemolysis rapidly and significantly; it also leads to a reduction in TE events, pulmonary hypertension and improvements in CKD and quality of life. Here, we report on prolonged treatment of PNH patients with eculizumab for safety and sustained patient outcomes. Methods: All pts (N=195) in the PNH eculizumab clinical trials (Pilot (N=11), TRIUMPH (N=87) and SHEPHERD (N=97)) and subsequent Extension studies were assessed for long term safety and efficacy. Median age was 40 yrs, 54% female, 29% had a history of aplastic anemia and 1.5% with history of myelodysplasia. TE was reported in 32% (63/195) of pts prior to eculizumab treatment. There was high adherence to long term treatment; 90% (175/195) of pts completed the parent and extension trials. Results: The median eculizumab treatment duration was 29 mo (1 -66; IQR:23-32m); with a total eculizumab exposure of 474.1 patient-years. Intravascular hemolysis was rapidly reduced in 100% of pts after eculizumab treatment. LDH was reduced from a median of 2,133 U/L (∼10x ULN) at baseline to 310 U/L at 1 month of treatment (P<0.0001) and was sustained at 272U/L at 36 months (P<0.0001). There was an 81% (P<0.0005) reduction in TE events from 52 pre treatment events to 10 trial events using a match time analysis (P<0.0005). Of the 7 (7/195) pts who experienced a TE on drug, 5 had a history of TE and 2 were concomitantly treated with AC. Of pts treated with AC, 59% (58/98) experienced at least 1 TE prior to treatment. In 11 pts who discontinued AC, there were no TE reported with eculizumab treatment during or following AC discontinuation. Prevalence of CKD was reduced from 69% of pts at baseline to 31% (n=29) after 36 months of treatment, consistent with previous results. A fraction of pts still require blood transfusions and a fraction of pts, even without need for blood transfusions, had no significant increase (>1gm/dL) in steady state hemoglobin level over baseline. Eculizumab was well tolerated. Twenty pts (∼10%) did not complete the trial including 9 pts following a reported adverse event (AE). In 16 week follow-up to the 20 pts who discontinued eculizumab treatment, TE was reported in 3 pts, including 1 death. Most AEs (95%) were mild or moderate in severity and 90.8% of adverse events were deemed unrelated to study drug. Frequent AEs were: nasopharyngitis, (40%); headache (37%) and upper respiratory tract infection, (31%). There were 2 cases of meningococcal sepsis and both were successfully treated without sequelae. Serious infections were reported in 21% of pts and 2 pts discontinued therapy due to infections (meningococcal, staphylococcal sepsis: both resolved). Most commonly reported serious infections included pyrexia (4.6%) and viral (3.1%), lower respiratory tract (1.5%) and urinary tract (1.5%) infections. There were 4 patient deaths during treatment. Three deaths were considered not related to study drug and 1 possibly related to study drug by the investigator. Causes of death were progression from myelodysplasia to chronic myelomonocytic leukemia, adenoma progressing to adenocarcinoma, brain herniation following trauma injury, and TE of the small bowel. Conclusion: Long term treatment of PNH pts with eculizumab is associated with a favorable benefit/risk ratio and the clinical benefits demonstrated at earlier timepoints are sustained over 36 months. Improvement in TE and CKD was maintained over 36 months when compared to baseline and previous published data. Considering that thrombosis and CKD have been demonstrated to be significant causes of death in PNH, it is reasonable to expect that eculizumab treatment, by decreasing the risk of thrombosis and improving renal function, may increase the life expectancy of PNH pts. Disclosures: Brodsky: Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion Pharmaceuticals, Inc: Speakers Bureau. Schrezenmeier:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schubert:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria. Maciejewski:Alexion Pharmaceuticals, Inc: Consultancy. Duehrsen:Alexion Pharmaceuticals, Inc: Honoraria, Research Funding. Luzzatto:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Muus:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding. Szer:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socié:Alexion Pharmaceuticals, Inc: Consultancy. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Long-Term Survival Benefit of Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from the International PNH Registry

Blood ◽

10.1182/blood-2021-153560 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2188-2188

Author(s):

Louis Terriou ◽

Christopher J. Patriquin ◽

Morag Griffin ◽

Jong Wook Lee ◽

Philippe Gustovic ◽

...

Keyword(s):

Rare Disease ◽

Board Of Directors ◽

Survival Probability ◽

Advisory Committees ◽

Term Survival ◽

Treatment Status ◽

History Of ◽

Baseline Characteristics

Abstract Background Eculizumab, the first C5 inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH), transformed PNH treatment by improving survival to that of an age- and sex- matched general population. Previous analyses demonstrating the survival benefit of eculizumab in patients with PNH leveraged historical data and were limited by small patient numbers and short follow-up durations; few evaluated survival of patients receiving eculizumab compared with untreated patients. The objective of the current analysis was to describe the baseline characteristics and overall survival of a large international cohort of eculizumab-treated patients compared with a contemporaneous untreated cohort using data from the prospective, observational International PNH Registry (NCT01374360). Methods Data from patients enrolled in the Registry after March 16, 2007 with complete information for birth date, sex, enrollment date, and treatment status were included (database cut-off, April 12, 2021). Ever-treated patients were those who received eculizumab for a minimum treatment period of 35 days while enrolled in the Registry; never-treated patients did not receive eculizumab at any time before or during Registry participation. Univariate and multivariate analyses were performed using a Cox proportional hazards that incorporated the following parameters at baseline as covariates: treatment status, presence of high disease activity (HDA), age, sex, history of bone marrow failure (BMF), history of thrombotic events (TE), transfusion dependence, and estimated glomerular filtration rate ≤60 mL/min/1.73 m 2. HDA was defined as lactate dehydrogenase (LDH) ratio ≥1.5 × upper limit of normal (ULN) and ≥1 of the following: history of major adverse vascular events (including TE); anemia (hemoglobin <10 g/dL), or physician-documented abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction at any time before and including baseline. Baseline was defined as the date of eculizumab treatment initiation (ever-treated patients) or date of Registry enrollment (never-treated patients). Survival time was analyzed using a left-truncation approach that mapped time in patients' survival based on disease start date, defined as the earliest date of first-reported PNH diagnosis, PNH symptom, or first consistent flow cytometry result. Results Baseline characteristics of the 4627 patients included in the analysis (mean [SD] age at disease start, 40.2 [18.71] years; 53% female; 75% white) were comparable between the ever-treated and never-treated groups (n=1892 and n=2735, respectively). Compared with never-treated patients, more ever-treated patients had LDH ≥1.5 × ULN (90% vs 35%), and fewer had <10% PNH granulocytes (3% vs 57%) or history of BMF (45% vs 76%). The univariate Cox proportional hazard ratio (HR) for mortality in ever-treated vs never-treated patients was 0.48 (95% CI, 0.39-0.60; P<0.0001), indicating a 52% increase in survival in the treated group (Table). Among ever-treated patients, those with HDA at baseline experienced the largest reduction in mortality risk (HR [95% CI], 0.46 [0.33-0.64]; n=174); however, decreased mortality was also evident in ever-treated patients without HDA (HR, 0.65 [0.39-1.10]; n=212) or with unknown HDA status (HR, 0.50 [0.32-0.76; n=120) at baseline. Overall survival probability by treatment status was consistently greater in ever-treated vs never-treated patients through 20 years of follow-up; survival probability at 20 years was 82% (ever-treated) vs 69% (never-treated). Although long-term survival probability was greatest throughout follow-up in ever-treated patients with HDA at baseline, increased survival among ever-treated patients was evident in all 3 HDA status groups (Figure). Conclusion In this analysis of Registry data, treatment with the C5 inhibitor eculizumab improved patient survival compared with a never-treated cohort at a comparable time point in their disease course. Covariates were assessed at baseline only and competing risks and time on treatment were not controlled for, which are potential limitations. Survival benefits conferred by eculizumab treatment were observed regardless of HDA status at baseline, were more pronounced in treated patients with HDA vs those without HDA, and were maintained through 2 decades of real-world follow-up. Figure 1 Figure 1. Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin: Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Biocryst: Honoraria; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Griffin: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Educational grant support. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gustovic: Alexion, AstraZeneca Rare Disease: Current Employment. Patel: Alexion, AstraZeneca Rare Disease: Current Employment. Szer: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text

Long Term Treatment and Prevention Of Recurrent VTE In Cancer Patients: Results Of The Canadian Proact Survey

Blood ◽

10.1182/blood.v122.21.5581.5581 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5581-5581

Author(s):

Normand Blais ◽

Charles A. Butts ◽

Mark A. Crowther ◽

Nanette Cox-Kennett ◽

Josée Martineau

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Research Funding ◽

Term Treatment ◽

Advisory Committees ◽

Extended Treatment ◽

Treatment And Prevention ◽

Long Term Treatment ◽

Recurrent Vte

Abstract Introduction Cancer associated thrombosis (CAT) is the second leading cause of death in cancer patients after death from cancer. Despite multiple available guidelines for CAT management, there remains variability in treatment practices. In order to gain insight on this variability in Canada, a survey was conducted to identify the perceived importance of managing CAT, identify differences in the pharmacological management of CAT, highlight the main barriers to optimal extended treatment and prevention of recurrent venous thromboembolism (VTE), outline challenges associated with long term treatment adherence, and identify predictors of patient non-adherence. Methods A survey was designed targeting physicians involved in the management of CAT. The questionnaire included queries on physician practice, 37 items related to beliefs and attitudes about extended treatment for prevention of recurrence of VTE, and a 30-item patient-specific profile. Results Responses were obtained from 21 professionals from four Canadian provinces (Nova Scotia, Quebec, Ontario, and Alberta); 76% were hematologists and/or oncologists, 14% were internists and 10% were pharmacists. Community and academic centers were well represented. Specific management profiles were obtained for 131 patients. Most care givers felt that VTE recurrence was an important issue deserving extended therapy for most patients. Although more than 90% believed bleeding and recurrent VTE risk should influence the length of treatment, only 62% believe that VTE recurrence risk should modify the type of treatment and 52% were concerned of the risk of bleeding with long term therapy (≥6 months). 71% of respondents believed patients’ lack of awareness of the risk of recurrent VTE reduces adherence to anticoagulant therapy for extended treatment of VTE. Although 100% of respondents detailed giving verbal patient counseling, only 19% provided written information to patients. 95% stated they assessed compliance verbally; less than 20% used more objective measures (pharmacy records, laboratory monitoring). Participants admitted to using results of clinical trials (95%) more than clinical guidelines (48%) as most felt that the published guidelines contained conflicting recommendations. The main drivers of treatment choice were clinical evidence, efficacy, and personal experience. No respondents indicated they preferred to use oral anticoagulants for extended therapy of CAT and 43% believed that LMWHs should not be used interchangeably. Most (95%) stated they follow-up with patients directly to reassess therapy after 3-6 months of treatment. The patient profile information showed the median age of patients was 62 years and 60% were female. Lung cancer, colon cancer, breast cancer, and lymphoma were the most common tumor sites and accounted for 50% of described cases. Cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) were evenly represented and 82% were symptomatic. Most events were temporally related to cancer therapy (69%), presence of a central venous catheter (18%), and recent surgery (17%). Less than 5% of these cases presented with a contraindication to anticoagulation therapy (severe thrombocytopenia, active bleeding) at CAT diagnosis. Most patients were treated in the outpatient setting. Nonetheless, hospitalization was required in 33% of cases with an average patient stay of 10.8 days. Hospitalized patients were preferentially treated with LMWH (84%) and usually stayed on the same regimen upon discharge (8.3 ± 6.4 months). Long term treatment was largely managed with LMWHs (most frequently dalteparin – 80% of all treated patients) while few were managed with vitamin K antagonists (6%) or novel direct antithrombotics (2%). Anticoagulant therapy for outpatients was prescribed for 9.0 ± 7.7 months after the most recent VTE episode. Conclusion In Canada, CAT is believed to be an important complication of cancer. Extended therapy is indicated for most patients with CAT. Although bleeding risk is perceived as an important reason to modify therapy, contraindications to LMWHs were rare in the reported cases. Uptake of outpatient therapy of CAT is widespread in this country, yet hospitalization is still frequently required at diagnosis and is associated with prolonged inpatient stays. Even if non-adherence to antithrombotic therapy was believed to be rare among patients with CAT, this was rarely rigorously monitored. Disclosures: Blais: Pfizer: Consultancy; Sanofi: Consultancy; Leo: Consultancy. Butts:Pfizer: Consultancy, Honoraria, Speakers Bureau. Crowther:Pfizer: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Merck: Consultancy; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, 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; Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; 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. Cox-Kennett:Pfizer: honorarium as a speaker Other. Martineau:Pfizer: honorarium as a speaker Other; Boehringer: honorarium as a speaker, honorarium as a speaker Other; Bayer: honorarium as a speaker, honorarium as a speaker Other; Sanofi: honorarium as a speaker and participated in clinical trial, honorarium as a speaker and participated in clinical trial Other; BMS: honorarium as a speaker Other.

Download Full-text

Curing Multiple Myeloma (MM) with Total Therapy (TT)

Blood ◽

10.1182/blood.v124.21.195.195 ◽

2014 ◽

Vol 124 (21) ◽

pp. 195-195 ◽

Cited By ~ 2

Author(s):

Bart Barlogie ◽

Alan Mitchell ◽

Frits van Rhee ◽

Joshua Epstein ◽

Shmuel Yaccoby ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Board Of Directors ◽

Phase 2 ◽

Advisory Committees ◽

Cure Fraction ◽

Metronomic Therapy ◽

Age And Sex

Abstract Intra-tumoral heterogeneity is a hindrance to curing malignant disease. By employing all MM-active drugs upfront, TT was designed to overcome such obstacle by targeting all potential MM sub-clones broadly. We are reporting on long-term results of phase-2 TT1, phase-3 TT2 and phase-2 TT3a trials, with median follow-up times of 21yr, 12yr and 9yr, respectively. Five year estimates of OS, PFS and CR duration (CRD) increased from 58%, 28% and 40% with TT1 to 65%, 42% and 50% with TT2’s control arm (TT2-), to 68%, 56% and 58% with TT2’s thalidomide arm (TT2+), and to 74%, 65% and 74% with TT3a (all p<0.0001). The 5-yr estimates of time to progression (TTP)/time to relapse (TTR) from CR decreased from 59%/58% in TT1 to 43%/42% in TT2-, to 28%/34% in TT2+, and to 22%/18% in TT3a (all p<0.0001). When examined in the era of gene expression profiling (GEP) of purified plasma cells, 5-yr estimates of TTP/TTR in GEP70 low-risk MM were 47%/46% with TT2-, 26%%/36% with TT2+, and 18%/16% with TT3a (all p<0.0001); the corresponding data for the 15% with high-risk MM were 60%/50% with TT2-, 62%/64% in TT2+, and 48%/35% in TT3a (NS). Relative survival (RS) was computed per year in relationship to age- and sex-matched controls. RS ratios approached 1 at 10–15 years for TT1 and TT2-, but earlier, at 5-10 years, for TT2+ and TT3a. A parametric mixture cure model was used to estimate PFS and CR duration for each protocol, from baseline and from a 5-year landmark. The cure model fits the data well and provides cure-fraction estimates that increase with later protocols (Figure 1). Importantly, when comparing data from GEP-defined low-risk and high-risk MM, plateaus for both PFS- and CRD-based cure fractions emerged at 10 years in the former and earlier, at 5 years, in the latter (data not shown). PFS-based cure-fraction estimates increasedsignificantly with successive TT trials: 9% in TT1, 16% in TT2-, 25% in TT2+, and 33% in TT3a (p=0.04). CRD-based cure-fraction estimates were 18%, 28%, 36%, and 49%, respectively (p=0.17) (Table 1). When a 5-year landmark was applied to exclude early myeloma-related events, PFS-based cure fraction estimates were 28% in TT1, 39% in TT2-, 51% in TT2+, and 70% in TT3a (p<0.001); in this setting, CRD-based cure fraction estimates were 32%, 47%, 56%, and 75%, respectively (p=0.007). MRD flow cytometry was available in 83 of 175 TT2 PFS patients, of whom 78% were MRD-. Our TT results are consistent with curability of MM. Solely novel agent-based trials without transplant lack the long-term follow-up to determine their cure potential. As MM usurps the bone marrow micro-environment (ME) for its growth and survival, we reasoned that ME alterations reflecting an angiogenic switch may persist beyond the state of clinical CR and even MRD. We therefore performed GEP analyses of bone marrow biopsies in CR and compared findings with age- and sex-matched controls. Indeed, biopsy “normalization” was linked to superior CR duration and is being developed as an early “cure surrogate” marker to help define the length of maintenance therapy in future trials. Although about 50% of CR patients treated with TT3a can be considered cured, the median PFS in high-risk MM of 2yr has not improved with successive TT trials. Reasoning that cytokine storms emanating after myelosuppressive therapies to restore normal hematopoiesis may be growth-stimulatory to MM cells, we applied non-myelotoxic metronomic therapy (Papanikolaou, Haematologica, 2014). Six newly diagnosed transplant-ineligible high-risk patients were offered an extended 28-day course of low-dose metronomic therapy with bortezomib, thalidomide, dexamethasone and continuous infusions of doxorubicin and cisplatin, to which were added arsenic trioxide and vincristine infusions. Remarkably, 5 of 6 achieved CR status after a single course and remain disease-free without further therapy 6-8 months later. Our results attest to the curability of MM with TT and, given the short PFS of 2yr in high-risk MM, such patients should be the focus of future novel interventions that yield information in a timely manner. Table 1 Cure fraction estimates Protocol PFS CR duration N Cure Fraction N Cure Fraction From start of therapy TT1 231 8.8% 79 17.9% TT2 -Thal 345 15.5% 146 28.2% TT2 +Thal 323 25.1% 200 35.6% TT3a 303 32.9% 189 48.8% From 5-yr landmark TT1 65 28.4% 33 32.3% TT2 -Thal 145 39.2% 84 47.4% TT2 +Thal 150 51.1% 134 55.9% TT3a 197 69.8% 148 74.7% PFS CR duration Figure 1 Cure fraction estimates from baseline Figure 1. Cure fraction estimates from baseline Disclosures van Rhee: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Heuck:Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Real-World Use of Therapeutic Anticoagulation in Patients with Paroxysmal Nocturnal Hemoglobinuria. Results of a Survey of Physicians in Australia

Blood ◽

10.1182/blood.v126.23.4537.4537 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4537-4537

Author(s):

Jeffrey Szer ◽

Cecily J Forsyth ◽

Anja Giese

Keyword(s):

Board Of Directors ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Primary Prophylaxis ◽

Secondary Prophylaxis ◽

Prior History ◽

Advisory Committees ◽

Vein Thrombosis ◽

Therapeutic Anticoagulation ◽

Increased Risk ◽

History Of

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematopoietic stem cell disorder characterized by uncontrolled complement-mediated hemolysis. Patients with PNH are at increased risk of thromboembolism and premature death. This risk is predominantly due to the effects of chronic hemolysis and platelet activation. Eculizumab, a monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis and dramatically reduce the rate of thromboembolism. A previous publication (Kelly et al, 2011) suggested that cessation of therapeutic anticoagulation (TAC) in PNH patients on eculizumab with no prior history of thrombosis is safe. There are very few reports on the outcomes of cessation of TAC in PNH patients on eculizumab who have a prior history of thrombosis or on the use of non-vitamin K antagonist oral anticoagulant (NOAC) agents in PNH patients with a history of thrombosis. In Australia, patients with PNH are predominantly managed by individual hematologists rather than at a single centre and hence anticoagulation practices following the introduction of eculizumab therapy are variable. We surveyed Australian hematologists managing eculizumab-treated patients with PNH to obtain the details of anticoagulation management and incidence of thrombotic events in their patients. We received responses from 30 hematologists caring for a total of 58 patients with PNH on eculizumab (1-17 patients per hematologist) and the table summarises the results. TAC as primary prophylaxis had been ceased in 10 patients with no recurrent thrombotic events. One (1) patient remains on primary prophylaxis due to persistently high D-dimer and factor VIII levels. TAC for secondary prophylaxis had been ceased in 2 patients due to bleeding (1 patient with subdural hematoma, 1 patient with gastrointestinal bleeding) and neither of these patients had a further thrombotic event. One patient, with a prior history of thrombosis, requested cessation of TAC and subsequently developed a provoked thrombosis. Three patients not receiving TAC when eculizumab was commenced developed thrombosis; two (2) patients had provoked deep venous thromboses and one patient developed a splanchnic vein thrombosis following a cholecystectomy in association with severe sepsis. One patient had a portal vein thrombosis immediately prior to commencing eculizumab therapy but has never received TAC due to severe coexistent thrombocytopenia from myelodysplasia. This patient has not had a recurrent thrombosis. Three (3) patients with thrombotic events prior to eculizumab therapy (1 patient with pulmonary emboli, 1 patient with cerebral venous sinus thrombosis and 1 patient with inferior vena cava thrombosis) had anticoagulant therapy changed from warfarin to rivaroxaban. At a follow-up of at least twelve months for all 3 patients there have been no recurrent thrombotic events and no bleeding complications. In conclusion, these Australian data are consistent with those reported by Kelly suggesting that cessation of primary prophylaxis in PNH patients on eculizumab is safe. Cessation of TAC in PNH patients on eculizumab with a prior thrombosis can be considered if there are clear contraindications to anticoagulation. Thromboprophylaxis in situations of increased risk of venous thromboembolism remains essential for all PNH patients not on TAC, even when they are on eculizumab therapy. The three patients on rivaroxaban as secondary prophylaxis are, to our knowledge, the first reported patients with PNH treated on a NOAC. Table. Number of patients New thrombotic events Eculizumab treated 58 Ceased TAC: Total1. As 1o prophylaxis2. As 2o prophylaxis(i) Due to bleeding(ii) At patient request 1410431 -None-None1 (provoked) TE in patients not on TAC at commencement of eculizumab 3 3 (provoked) NOAC as 2o prophylaxis 3 None Disclosures Szer: Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: 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, Speakers Bureau; Alexion Australia: Consultancy, Honoraria, 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, Speakers Bureau; Celgene: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Forsyth:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giese:Alexion: Employment.

Download Full-text

Prevalence and Risk Predictive Factors of Comorbid Malignancies in Patients with Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.1900.1900 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1900-1900

Author(s):

Tong-Yoon Kim ◽

Sung-Eun Lee ◽

Soo-Hyun Kim ◽

Soo-Young Choi ◽

Eun-Jung Jang ◽

...

Keyword(s):

Board Of Directors ◽

Medical Records ◽

Myeloid Leukemia ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Advisory Committees ◽

History Of

Abstract Introduction: As chronic myeloid leukemia (CML) patents are generally diagnosed at old age and live longer by active use of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the occurrence of other malignancy (OM) is becoming a critical issue as a long-term comorbidity. An increased rate of OM has been reported in myeloproliferative disorders and long-term TKI treatment may induce OM in CML. To explore exact prevalence and characteristics of OM, we reviewed medical records of CML patients and compared with those of age-matched Korean population. Methods: The medical records of 1,469 CML patients who diagnosed between January 2000 and December 2014 were reviewed using Korean data-set of Asia CML Registry (ACR). With a cut-off date of July 2016, age-standardized prevalence rates (A-SPR) of OM (except benign tumors and other leukemias) were analyzed and compared with that of general population in Korea Central Cancer Registry (KCCR). In addition, we analyzed cumulative incidence rate of OM and various risk factors. Results: The median duration of follow-up was 84 (1-197) months, and 96 CML patients had at least one OM. Forty three patients had a history of OM before a median 69 (1-161) months of CML diagnosis and 53 patients developed OM after a median 53 (range; 0.2-172) months of CML diagnosis. The OM included 32 thyroid cancers, 19 colorectal cancers, 16 stomach cancers, 9 breast cancers, 4 gynecological cancers (3 cervical cancers and 1 uterine endometrial cancers), 3 lymphoma (2 non-Hodgkin's lymphoma and 1 Hodgkin's lymphoma), 3 biliary cancer, 3 skin cancers, 3 prostate cancers, 2 lung cancer, 2 tongue cancer, 2 liver cancer, 2 esophageal cancer, 1 pancreatic cancer, and 1 bladder cancer.A-SPR of OM was 1.7 times higher in CML patients. Hodgkin's lymphoma (8.7 times), thyroid cancer (2.6 times), biliary cancer (2.6 times), colorectal cancer (2 times), non-Hodgkin's lymphoma (1.8 times), cervical cancer (1.8 times), and breast cancer (1.6 times) had a higher A-SPR. On the other hands, skin cancer (3.3 times), lung cancer (2 times), and liver cancer (2 times) were lower than that of general population. With 53 patients who had OM after CML diagnosis, we analyzed the cumulative incidence. The risk of OM was increased over the follow-up period (2.7% at 7 years) Univariate analysis revealed that patients who were more than 37 years old at CML diagnosis (4.3% vs. 0.4%, p<0.001) and who had family history of cancer (8.2% vs. 2.3%, p=0.002) were associated with a higher OM. After adjusting for factors, multivariate analysis showed that older age (HR of 4.19, P<0.001) and family history (HR of 3.17, P=0.001) were independently associated with increased risk. There was no difference in 7-year overall survival (OS) between patients with OM (n=96) and without OM (n=1,373) (84.9% vs. 86.9%, p=0.573). However advanced cancer stages (stage 3 and 4) of OM significantly affected poor OS ( 88.3% vs. 65.6% P=0.0406). Conclusion: Although comorbid malignancies did not significantly affect CML survival, poor survival in advanced stages and the high risk of other cancers warn the need of systematic screening in long-term CML survivors. In addition, the specific cancer types with a significantly higher A-SPR should be considered for further studies including genetic mechanisms. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Download Full-text

Unmet Needs for Symptom Control in Essential Thrombocythemia with Front Line Therapy

Blood ◽

10.1182/blood.v126.23.5175.5175 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5175-5175

Author(s):

Holly Geyer ◽

Robyn M. Scherber ◽

Heidi Kosiorek ◽

Amylou C. Dueck ◽

Jean-Jacques Kiladjian ◽

...

Keyword(s):

High Risk ◽

Blood Cell ◽

Board Of Directors ◽

Research Funding ◽

Symptom Burden ◽

Red Blood Cell Transfusion ◽

Risk Scores ◽

Advisory Committees ◽

Transfusion Requirements ◽

History Of

Abstract Background: Thrombotic and hemorrhagic complications are commonly encountered in uncontrolled essential thrombocythemia (ET). Both anagrelide and hydroxyurea (HU) have proven efficacious in cytoreduction as well as reducing these events and remain first line therapy for most high-risk ET patients. Independent of their role in risk-reduction, little is known about how these therapies impact patient symptomatology or quality of life. In this study, we compared the clinical and symptomatic profiles of ET patients receiving HU or anagrelide against patients with no previous experience with these agents. Methods: Data was assessed from a prospectively collected international database of ET patients in which demographics, disease features, and ET symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. ET risk scores were calculated using the IPSET scoring algorithm (Passamonti 2012). Thrombocytopenia was defined as a platelet count <100 x 10(9)/L, anemia was defined as hemoglobin<10 g/dL and leukopenia was defined as a white blood cell count <4.0 x 10(9)/L. Associations between the MPN-SAF individual symptoms were investigated using chi-square test for categorical data and ANOVA F-test for continuous variables. Results Hydroxyurea vs. HU Naive A total of 402 ET patients with active HU use were compared to 392 ET patients with no history of HU use. Patients using HU were older (63.5 years vs. 52.3 years, p<0.001) and had a greater concentration of both high risk (24.9% vs. 11.4%, p=0.001) and intermediate risk (53.9% vs 38.4%, p<0.001) patients. They also had a higher rate of prior thrombosis (29.8% vs 11.3%, p<0.001) and leukopenia (10.1% vs. 3.0%, p<0.001). No differences were noted between gender, a history of prior hemorrhage, red blood cell transfusion requirements, or the presence of anemia/thrombocytopenia. In comparing symptom profiles, no significant differences were noted between TSS or individual symptoms with the exception of slightly more severe cough in HU patients (1.5 vs. 1.1, p=0.02, Figure 1). Anagrelide vs. Anagrelide Naive A total of 49 ET patients with active anagrelide use were compared to 794 ET patients with no history of anagrelide use. Patients using anagrelide had a longer mean disease duration (8.1 years vs. 5.8 years) and were more anemic (9.1% vs. 1.2%, p<0.001). No differences were noted between age, gender, risk scores, the presence of leukopenia/thrombocytopenia, a history of prior thrombosis or hemorrhage complications or red blood cell transfusion requirements. Additionally, there were no significant differences between TSS or individual symptom items (Figure 1). HU vs. Anagrelide A total of 402 patients currently using HU were compared to 39 patients currently using anagrelide. Overall, HU users were slightly older (63.5 years vs. 55.1 years, p<0.001) with a greater population of patients meeting high risk criteria (24.9% vs. 2.8%, p=0.002) and having a history of prior thrombosis (29.8% vs. 12.8%, p=0.02). Patients receiving anagrelide had a slightly longer disease duration (8.2 years vs. 6.0 years, p=0.0446). In comparing symptom profiles, no differences were noted in TSS or individual symptom items between cohorts. Discussion In this retrospective analysis, it does not appear cytoreduction with either HU and/or anagrelide has a significant impact on ET symptom burden despite reducing vascular events. Importantly, the higher risk scores in HU patients did not translate directly into greater patient symptomatology supporting previous studies demonstrating a poor association between these two items. Prospective trials measuring ET symptom change, in the setting of randomized trials will better quantify impact of cytoreduction on symptom burden as well as quantify impact of newer agents such as interferon or jak inhibition. Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Disclosures Kiladjian: Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. te Boekhorst:Novartis: Consultancy; CTI Biopharma: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Download Full-text

Implementation of Escort-HU Extension: European Sickle Cell Disease Cohort - Hydroxyurea - Extension Study : Interests and Methodology

Blood ◽

10.1182/blood-2021-152525 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3098-3098

Author(s):

Mariane de Montalembert ◽

Ersi Voskaridou ◽

Lena Oevermann ◽

Giovanna Cannas ◽

Anoosha Habibi ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Steering Committee ◽

Leg Ulcers ◽

Cell Disease ◽

Advisory Committees ◽

History Of

Abstract The efficacy and long-term effectiveness of hydroxycarbamide/hydroxyurea (HU) in the prevention of painful crises and in the decrease of mortality and morbidity in sickle cell disease (SCD) patients have been established (Charache et al. 1992; Steinberg et al 2010, Voskaridou et al 2010). From January 2009 to March 2019, the non-interventional prospective cohort study ESCORT-HU was conducted to evaluate the use of HU in real-life conditions and to collect information on the long-term safety of HU when used in current practice for the prevention or treatment of symptomatic complications in patients with sickle cell disease (SCD) (Montalembert et al 2021). A total of 1906 patients, 55% of adults, were enrolled in this study in 62 centres (Germany, Greece, Italy and France). The mean exposure to HU in this cohort was 30 months, for a cumulative exposure of 7310 patient-per year. The main objectives of ESCORT-HU have been fulfilled as regards the collection of data on the most common concerns associated with the use of HU in SCD patients: myelosuppression, child growth, concomitant administration of live vaccines, safety in population with renal and hepatic impairment and frequency of SCD events (painful crises, acute chest syndrome, stroke, acute splenic sequestration, infections, blood transfusions and hospitalizations) (Montalembert et al 2021). In order to better identify potential long-term risks and specific concerns of HU therapy, ESCORT-HU extension is being implemented in Europe with the goal of 2500 patients enrolled. Main risks targeted by the study are leg ulcers, one of the most limiting factors to continue a treatment with HU. Patients will be recruited over a 5-year period. In addition to patients already involved in the first ESCORT-HU study, new at-risk patients might be added such as patients with a history of HU exposure of at least 5 years, to allow a follow-up of patients treated with long-term HU to fully estimate the incidence of potential risk of malignancies prepubescent children aged more than 10 years for girls and more than 13 years for boys in order to document impact or not of HU on puberty and realisation of cryopreservation,patients with a history of leg ulcers, to search for discriminating criteria between leg ulcer caused by the disease and HU-induced leg ulcer,pregnant women without interruption of HU 3 months before the beginning of the pregnancy and males treated with HU whose partner is pregnant and without discontinuation of HU 3 months before the beginning of the pregnancy. To date, there is a limited number of pregnancies exposed to HU with documented outcome. Despite no adverse effects on pregnancy or on the health of the foetus/new-born have been registered, an increase of the number of pregnancies with documented outcomes will allow for meaningful assessment of foetal outcome following exposure to HU during pregnancy, 10 months after the beginning of ESCORT-HU extension, 818 patients have been enrolled in 70 investigational sites in 4 countries (Greece, Italy, Germany and France) (see Graph below). A first steering committee was hold in June 2021. Its conclusions were that distribution of patients (genotype, sex, age) was consistent with the first study and the number of events reported until now was coherent with what was expected per year, with no occurrence of major concern. This extension study involves most of competence centres which manage SCD patients. SC patients have become increasingly well cared for in recent decades and have seen their life expectancy increase. HU treatment is now a chronic treatment possibly for life in many patients with SCD, better its knowledge of its efficiency and tolerance, better patient adherence to treatment will be. Figure 1 Figure 1. Disclosures de Montalembert: Addmedica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Voskaridou: ADDMEDICA: Consultancy, Research Funding; BMS: Consultancy, Research Funding; GENESIS: Consultancy, Research Funding; NOVARTIS: Research Funding; PROTAGONIST: Research Funding; IMARA: Research Funding. Oevermann: NOVARTIS: Consultancy; GBT: Consultancy. Joseph: bluebird bio: Consultancy. Colombatti: BlueBirdBio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Bartolucci: INNOVHEM: Other: Co-founder; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Fabre Foundation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy; Emmaus: Consultancy; Hemanext: Consultancy. Brousse: BLUEBIRDBIO: Consultancy; ADDMEDICA: Consultancy. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Tapering Eltrombopag in Patients with Chronic ITP: How Successful Is This and in Whom Does It Work?

Blood ◽

10.1182/blood.v126.23.1054.1054 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1054-1054 ◽

Cited By ~ 5

Author(s):

James B. Bussel ◽

Shah N. Mahmud ◽

Sophie L Brigstocke ◽

Sarah M Torneten

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Term Treatment ◽

Bleeding Events ◽

Advisory Committees ◽

Platelet Counts ◽

Need For Treatment ◽

Chronic Itp ◽

Long Term Treatment

Abstract Background: Thrombopoietin receptor agonists (TPO-RA) eg eltrombopag (Epag), are highly effective treatments of ITP as demonstrated in multiple randomized studies. Studies have shown effective and safe long-term use; toxicity appears tolerable with thromboembolism the most common serious adverse event. An important question is if there will be an indefinite long-term need for treatment with these agents once initiated. The aim of this study is to taper eltrombopag in a single arm study to determine how many and which patients will be able to discontinue treatment over time. It specifically targets patients with adequate counts ie 50-100,000/uL, not waiting for patients whose counts spontaneously increase to high levels and thus indicate that they are being over-dosed. Methods: All patients on eltrombopag at doses of 75 mg daily or less for at least 4 months were offered study entry; only one refused. Initially the study tapered Epag rapidly but then changed to slow tapering over up to 2 years. Patients whose platelet counts were >50,000/uL were tapered at 4 week intervals in 10-20% dose increments. Tapering could be postponed for clinical reasons ie impending procedure or trip, infection skewing count, sports or other physical activity, etc. Analysis was descriptive and t test comparisons used to assess variables associated with successful tapering. Results: Patients were divided into 3 groups: 10 responders (those able to discontinue eltrombopag completely within 2 years, fig 1A), 10 tapering (those still tapering who have reduced their medication but not discontinued it, fig 1B), and 12 non-responders (those who tried and failed to discontinue within 2 years). To complete being a responder required >12 weeks without any ITP treatment, platelet count > 30,000/uL and 20,000/uL more than baseline after the last dose of eltrombopag. Eight of the 10 responders have remained off therapy for more than 1 year with platelet counts consistently > 50,000/uL. No medication was provided in the study. No serious AEs occurred and no serious bleeding events were seen. Fig 1a illustrates the discontinuation of eltrombopag treatment in responders: 4 discontinued within 8 weeks while the longest discontinuation required a full 2 years. Fig 1b shows patients who are tapering eltrombopag but have not reached 2 years by indicating how many are on <70% and <40% of their starting doses; it shows that tapering is typically a slow process but that at least dose reduction can be achieved in many patients even if they do not discontinue their eltrombopag. Table 1 compares means and medians of the 3 groups for a number of clinical variables. While the numbers are small and the results preliminary, it surprisingly shows that patients who have been on eltrombopag longer prior to tapering and those who have received more treatments are more likely to successfully discontinue eltrombopag. In contrast, non-responders failed splenectomy and rituximab more often than did those tapering and responders. Finally AIPF at initiation of study did not predict a successful taper. Summary: A substantial fraction of patients with chronic ITP will be able to successfully taper off eltrombopag; the exact number (somewhere between 10 and 20 of the 32 patients) depends upon the group still tapering. The tapering schedule selected is slow and requires regular monitoring and individualization/flexibility. Even if patients do not fully taper off eltrombopag, they may be able to substantially reduce their dose. We speculate that tapering eltrombopag as outlined here may reduce the toxicity and costs of long-term treatment without diminishing hemostatic efficacy. Table 1. Comparison Table (Responders, Tapering, Non-Responders) Responders (n=10) Tapering (n=10) Non-Responders (n=12) Age (years) (median/average) 29/37.4 11/25.70 21/30.58 Gender (m/f) 3/7 6/4 5/7 Duration ITP (years) (median/average) 8.75/11.95 5.5/17.45 7/8.25 Duration of TPO-RA Therapy (years) (median/average) 5/4.2 5.5/7.45 2.5/3.38 # of prior ITP treatments (median/average) 4.5/5.5 2/2.14 3.5/3.83 # of patients with previous splenectomy 4 0 6 patients with previous Rituximab treatments 5 4 9 Baseline AIPF (tapering counts) (*10E2/uL) (median/average) 81.75/75.5 63/57.43 75/69 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Bussel: Immunomedics: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; BiologicTx: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Momenta: Membership on an entity's Board of Directors or advisory committees; Symphogen: Membership on an entity's Board of Directors or advisory committees; Protalex: Membership on an entity's Board of Directors or advisory committees.

Download Full-text