Intensive Treatment With Recombinant Factor VIIa (NovoSeven®) To Prevent Joint Bleeding In 4 Patients With Haemophilia A With Inhibitors Undergoing a Regular Program Of Physical Therapy

Abstract Introduction The development of anti-factor VIII inhibitors is the main complication of modern therapy of hemophilia A (HA) occurring in 25%-30% of severe forms. Inhibitors affect the possibility of a primary prophylaxis and regular physiotherapy, which is an important therapeutic tool to preserve joint function. In patients with severe HA with inhibitors, a prospective randomized study (Konkle et al J Thromb Haemost 5:1904, 2007) and the PRO-PACT retrospective multicenter observational study of a large case series (Young et al Thromb Res 130:864, 2012) have demonstrated the feasibility and effectiveness of secondary prophylaxis with recombinant activated factor VII (rFVIIa, NovoSeven®) in reducing hemarthrosis. Aim of the study: This study describes the unique experience of Hemophilia Pediatric Center of Turin (Italy) in a case series of 4 children with severe hemophilia A, history of high-titer inhibitor and mild or severe artropathy, who underwent to regular rehabilitation programme despite presence of inhibitors. Methods Postural evaluation and gait analysis have been performed for each patient to assess posture and gait performance and plan a tailored therapeutic-rehabilitative treatment. Each physiotherapy session lasted about 45 minutes. rFVIIa at a dose of 90-180 mcg/kg in a preparation for rehabilitative treatment was administered immediately prior to each session. During physiotherapy sessions, children carried out both active and passive rehabilitation exercises to maintain adequate muscle strength and preserve joint range of movement (ROM). Basal and final joints angles (in degree) were measured with a goniometer. Manual Muscle Testing (MMT) was applied for grading muscle strength. Results Clinical characteristics and individual physiotherapy program are listed below: Patient 1 A 10-years-old African child with 2 target joints (knees) and 1 bleeding episode/month, has performed 102 sessions of active and passive rehabilitation treatment (November 2010 to November 2012) while on immune tolerance therapy (ITI). Patient 2 A 12-years-old Caucasian child with 3 target joints (left elbow, knees) has performed a total of 16 sessions (February 2011 to April 2011). Patient 3 A 2-years-old Caucasian child with a target joint (knee) has performed a total of 20 sessions (February 2011 to August 2012) while on ITI. Patient 4 A 8-years-old Caucasian child with 4 target joint (elbow, 2 ankles) has performed a total of 149 sessions (November 2009 to November 2012) after failed ITI. Within 72 hours after each session, no joint nor muscle bleeding have been observed as evidence of the potential role of rFVIIa in preventing bleeding. The 4 children had a total of 287 physiotherapy sessions, each of them preceded by a single administration of rFVIIa. Treatment provided adequate hemostasis in all patients; no bleeding was observed during the sessions and in the following 3 days. The rehabilitative program obtained a gain of ROM in most of the 9 joints assessed and an improvement in muscle strength was also observed, as described in table. Postural evaluation and gait analysis confirmed these results. We did not observe thrombotic events nor infectious episodes. Conclusion Combination of rFVIIa and physiotherapy improved joint ROM and muscle strength in hemophilic children with inhibitors. The rehabilitation program has not given rise to safety issues in these young patients. Disclosures: Messina: Pfizer: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Baxter: Honoraria; Bayer: Honoraria. Forneris:Novo Nordisk: Honoraria, the autor has received reimbursement for attending a symposium and fees for speaking by Novo Nordisk Other. Off Label Use: rFVIIa is not licensed for nonsurgical prophylaxis in Italy. The use of rFVIIa in prophylaxis as a preparation for physiotherapy treatment currently is considered off label in Italy.

Download Full-text

Immune Tolerance Induction (ITI) with a Plasma-Derived Factor VIII for Patients with Hemophilia a and Inhibitors: A Retrospective Study

Blood ◽

10.1182/blood-2019-122949 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4923-4923

Author(s):

Miguel A. Escobar ◽

Linda Shaffer ◽

Mark Holguin ◽

Timothy McCavit ◽

Sandeep K. Rajan ◽

...

Keyword(s):

Board Of Directors ◽

Immune Tolerance ◽

Hemophilia A ◽

Tolerance Induction ◽

Advisory Committees ◽

Immune Tolerance Induction ◽

Off Label ◽

Inhibitor Titer ◽

Antihemophilic Factor ◽

Partial Success

Introduction: A serious complication in hemophilia A is the formation of inhibitors to clotting factors. The primary means for eradicating inhibitors is immune tolerance induction (ITI) therapy. Antihemophilic factor (human) (Koate®-DVI) is a purified dried concentrate indicated for the treatment of hemophilia A with insufficient activity of Factor VIII (FVIII). Although other plasma-derived concentrates containing von Willebrand factor have been utilized successfully for ITI, studies evaluating this product for ITI therapy have not been published. An evaluation of patient- and treatment-related factors associated with outcomes following primary or rescue ITI with antihemophilic factor (human) in patients with hemophilia A and inhibitors was conducted in this retrospective multicenter chart review project. Methods: An evaluation of medical records of 13 inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012, and July 31, 2017, was conducted in five US hemophilia treatment centers. To be eligible for inclusion, patients were required to have a diagnosis of hemophilia A of any severity level, inhibitor to FVIII at the time of treatment initiation with antihemophilic factor (human), and ongoing treatment with antihemophilic factor (human) for primary or rescue ITI. Data were de-identified and analyzed descriptively. Outcome measures were defined, per the International Immune Tolerance consensus recommendations, as "complete success" (inhibitor titer <0.6 Bethesda Units [BU] at 33 months of ITI, FVIII recovery ≥66% and half-life ≥6 hours), "partial success" (a reduction in inhibitor titer to <5 BU mL with FVIII recovery <66% and/or FVIII half-life <6 hours associated with clinical response to FVIII therapy not followed by a treatment-limiting anamnestic rise in inhibitors to >5 BU mL), or "failure" (neither complete nor partial success). Results: All (N=13) patients who met the inclusion criteria were males with severe hemophilia, with the exception of one with moderate hemophilia. Six patients were African American, four were Hispanic, two Caucasian, and one was Asian. They were diagnosed with inhibitors between the ages of 8 months and 39 years and were 5 to 53 years old upon ITI with antihemophilic factor (human). Ten of 13 patients (76.9%) had successful ITI; seven with complete success and three with partial success (Table). Three patients failed ITI. As primary therapy, complete success was obtained with all but one of the six patients treated with antihemophilic factor (human). These six patients were all older than 7 at the initiation of ITI, a risk factor for poor ITI. Seven of the 13 total patients had a combined previous 12 attempts at ITI with other products (plasma derived and/or recombinant). Of these seven rescue patients, ITI with antihemophilic factor (human) was completely successful in two and partially successful in three. Adverse events reported once in separate patients during treatment with antihemophilic factor (human) included catheter infection, portal infection, bacteremia, peritonitis due to a ruptured appendix, and complications in treatment. One patient had several adverse events, including cellulitis at the port site, abdominal wall hematoma, right thumb fracture and hematoma, and left shoulder hemarthrosis. Conclusions: While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and inhibitors. The data suggest that antihemophilic factor (human) may be most appropriate for patients when used as primary ITI, as even patients older than 7 years achieved complete success. Additional patients need to be evaluated to make a definitive conclusion regarding the impact of age on success of ITI therapy in addition to other risk factors. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rajan:Bayer, Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Amega:Kedrion Biopharma: Employment. OffLabel Disclosure: Koate is not approved to treat vWD, nor, cTTP however, based on some published reports using kotae for these indications, we are anticipating those type of off label inquiries. I will clearly disclose to the participants that these are off label indications.

Download Full-text

Off-Label Utilization Trend for Recombinant Factor VIIa in Children's Hospitals in the United States

Blood ◽

10.1182/blood-2019-126294 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2177-2177

Author(s):

Shveta Gupta ◽

Joseph R. Stanek ◽

Sarah H. O'Brien

Keyword(s):

Mortality Rate ◽

Board Of Directors ◽

The United States ◽

Factor Vii ◽

Off Label Use ◽

Advisory Committees ◽

Diverse Range ◽

Off Label ◽

Factor Vii Deficiency ◽

Label Use

Background: Recombinant FVIIa (rFVIIa) was approved by the Food and Drug Administration (FDA) as a hemostatic agent in 1999 for the treatment of patients with hemophilia and inhibitory antibodies against either factor VIII or IX and subsequently approved for use in patients with congenital factor VII deficiency and Glanzmann Thrombasthenia refractory to platelet transfusions in 2005 and 2014 respectively. These are rare disorders and the use of rFVIIa in these conditions has been found to be effective and safe. Despite this very narrow indication for usage, rFVIIa is being used for a diverse range of off-label indications. Along with uncertainty regarding clinical efficacy, available data suggests that the risk of thromboembolic events is increased when rFVIIa is used in off-label settings. Studies on the off-label use of rFVIIa in children are limited to a few large case series. In a retrospective multicenter cohort study utilizing the Pediatric Health Information System (PHIS) administrative database, Witmer et al demonstrated a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007. The mortality rate in the off-label group was 34% and thrombotic events occurred in 11% of the off-label admissions. We conducted a follow up study to characterize the evolution of the off-label use of rFVIIa in children. Objective: To describe current trends of off-label utilization and adverse effects of rFVIIa in children. Study design: A retrospective multicenter cohort study utilizing the PHIS administrative database was conducted. The PHIS dataset includes 51 children's hospitals in the United States and is representative of tertiary care centers in the nation. In patients, 18 years of age or younger who received rFVIIa between 2012-2018 were included. A label admission was defined as an admission with an International Classification of Diseases (ICD-9 and ICD-10) diagnostic code for hemophilia, Factor VII deficiency or Glanzmann thrombaesthenia; admissions without these codes were classified as off-label. Data were analyzed descriptively. Results: There were 7,738 number of admissions, representing 6,493 unique individual subjects. A total of 78.3 % of the admissions were off-label. The rate of off-label use was stable at approximately 80% of the admissions from 2012-18. The most frequent admitting services for the off-label admissions included cardiology (29.8%), cardiovascular/thoracic surgery (15.7%), critical care (15.0%), neonatal-perinatal medicine (8.7%), and hematology/oncology (6.1%). Over half (54.6%) of off-label administration occurred in children younger than 1 year old. Among the off-label admissions 57 % were male and the median days of use of rFVIIa was 1 day. The mortality rate in the off-label group was 22.3 %. Thrombotic events occurred in 11.4% of the off-label admissions. Among the off-label admissions with thrombotic events, the most common admitting services were cardiology (35.0%) and critical care (21.2%). Conclusion: We have demonstrated that on a per admission basis the predominant use of rFVIIa is off-label. Thrombotic events are common. Although the mortality rate in the pediatric patients who received off-label rFVIIa is high; its lower when compared with the previous review. This may likely reflect, in part, the severity of illness in this patient group. In the absence of clearly supportive data demonstrating safety and efficacy, restraint should be exercised with careful consideration of risk versus benefit for use of rFVIIa in off-label settings. Disclosures Gupta: Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. O'Brien:Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Recombinant FVIIa (rFVIIa) was approved by the Food and Drug Administration (FDA) as a hemostatic agent in 1999 for the treatment of patients with hemophilia and inhibitory antibodies against either factor VIII or IX and subsequently approved for use in patients with congenital factor VII deficiency and Glanzmann Thrombasthenia refractory to platelet transfusions in 2005 and 2014 respectively. These are rare disorders and the use of rFVIIa in these conditions has been found to be effective and safe. Despite this very narrow indication for usage, rFVIIa is being used for a diverse range of off-label indications.

Download Full-text

Effect of Moderate and Severe Hemophilia a on Daily Life in Children and Their Caregivers: A CHESS Paediatrics Study Analysis

Blood ◽

10.1182/blood-2020-134658 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-45

Author(s):

Kate Khair ◽

Francis Nissen ◽

Mariabeth Silkey ◽

Tom Burke ◽

Aijing Shang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Disease Burden ◽

Hemophilia A ◽

Daily Life ◽

Social Activity ◽

Publicly Traded ◽

Advisory Committees ◽

Lost Work ◽

Hours Of Work

Introduction: Hemophilia A (HA) is a congenital bleeding disorder, caused by a deficiency in clotting factor VIII (FVIII) and characterized by uncontrolled bleeding and progressive joint damage. This analysis assesses the impact of disease burden on the daily life of children with hemophilia A (CwHA) and their caregivers, addressing a deficit of current research on this topic. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey in a Paediatric Population (CHESS Paediatrics) is a retrospective, burden-of-illness study in children with moderate and severe HA (defined by endogenous FVIII [IU/dL] relative to normal; moderate, 1-5%; severe, <1%) across France, Germany, Italy, Spain and the UK. CwHA were recruited and stratified by both age group (0-5 years:6-11 years:12-17 years=1:1:1) and disease severity (severe:moderate=approximately 2:1, prioritizing children with severe HA [CwSHA]). Data for this analysis were captured from physicians, children, and their caregivers. Physicians completed online case report forms for treated children, and the child and/or their caregivers completed a paper-based questionnaire utilizing 5-point Likert scales. For CwHA aged 0-7, the questionnaire was completed by the caregiver, while for CwHA aged 8-17, children and caregivers completed different sections. Hours of care provided by the caregiver and work lost by the caregiver were reported as median values due to non-normal data distribution. Informed consent was obtained for all participants. Upon review, the study was approved by the University of Chester ethical committee. Results: Data from child/caregiver questionnaires were available for 196 CwHA (moderate, 25.5%; severe, 74.5%); the majority of these children, as expected, were receiving prophylaxis (72.4%), and did not have FVIII inhibitors (89.8%; Table 1). There was a direct impact of disease burden on CwHA, particularly with regard to physical and social activities (Figure 1). Overall, it was agreed or strongly agreed by the child or caregiver that 48.0% and 57.5% of children with moderate HA (CwMHA) and CwSHA respectively, have reduced physical activity due to HA, and 46.0% and 57.5%, respectively, have reduced social activity due to HA. A total of 36.0% and 61.0% of CwMHA and CwSHA, respectively, had adapted their treatment in anticipation of physical or social activity (Table 1). Furthermore, 34.0% of CwMHA and 55.4% of CwSHA were frustrated due to their disease, and many (CwMHA, 36.0%; CwSHA, 50.7%) felt that they had missed opportunities (Figure 1). For 66.0% of CwMHA and 76.0% of CwSHA, it was reported that their daily life was compromised due to their HA. Caregivers provided a median (interquartile range [IQR]) of 19.0 (10.0-59.5) and 12.0 (5.0-20.0) hours a week of care for the hemophilia-related needs of their CwMHA (n=30) or CwSHA (n=105), respectively. Of those who responded, 17.4% (n=4/23) and 25.0% (n=20/80) of caregivers to CwMHA or CwSHA, respectively, stated they have lost work due to their caregiving duty. This was more than twice as common for caregivers in families with multiple CwHA (42.9%, n=9/21 responses) compared with those in families with one CwHA (18.5%, n=15/81 responses). Median (IQR) hours of work per week estimated to be lost were 20.0 (17.0-22.0) for caregivers of CwMHA (n=4) and 12.5 (4.50-20.0) for caregivers of CwSHA (n=20). Conclusions: In conclusion, both children and caregivers make sacrifices in their daily lives due to HA; many CwHA reported reduced physical and social activities, fewer opportunities and feelings of frustration due to their HA. Caregivers reported spending a significant number of hours caring for their child and some reported losing work due to their caring responsibilities. However, some outcomes may be limited by the small number of respondents and narrow response options, particularly those regarding the caregiver burden. Responses on the hours of work lost may be subject to selection bias, as caregivers who have lost work may be more likely to respond to this question. Additionally, as this question is targeted at caregivers in employment, it is unknown if some caregivers have left employment due to their caregiving responsibilities. According to this analysis, children/caregivers are frequently required to adapt the child's treatment before the child engages in activities. Overall, the burden of disease was similar in children with moderate and severe HA. Disclosures Khair: Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Haemnet: Membership on an entity's Board of Directors or advisory committees. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Silkey:Aerotek AG: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Shang:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Noone:Research Investigator PROBE: Research Funding; Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Disease Burden in Patients with Glanzmann Thrombasthenia: Perspectives from the Glanzmann Thrombasthenia Patient/Caregiver Questionnaire

Blood ◽

10.1182/blood-2019-128408 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3456-3456

Author(s):

Alexander Duncan ◽

Angela Kellum ◽

Shilpa Jain ◽

Skye Peltier ◽

Helen Smith ◽

...

Keyword(s):

Board Of Directors ◽

Adult Patients ◽

Factor Vii ◽

Hormonal Contraceptives ◽

Platelet Glycoprotein ◽

Care Providers ◽

Advisory Committees ◽

Glanzmann Thrombasthenia ◽

Female Patients ◽

Initial Symptoms

Introduction: Glanzmann thrombasthenia (GT) is a rare bleeding disorder (~1:1,000,000) caused by impaired function of platelet glycoprotein IIb/IIIa responsible for aggregation. This novel survey was designed to identify the burden of GT through better understanding of the management of the disorder and its psychosocial impact on patients and caregivers. Methods: Participants were recruited via a rare disease specialty recruiter from Comprehensive Health Education Services. Data were collected from January 31 through March 12, 2019, via a moderator-assisted online survey. On average, the survey was completed within 45 minutes. Information regarding demographics, diagnosis, treatment history, and quality of life was collected. Results: In total, 45 respondents (24 patients and 21 caregivers; 58% female) completed the survey. Many patients were born with significant bruising (76%) or bled extensively during circumcision (47%). As a result of their early symptoms, more than 50% of those surveyed were diagnosed prior to their first birthday. For others, the average time between experiencing initial symptoms and visiting a specialist was just over 1 year and to diagnosis was just over 2 years (average age, 2.6 years, range <1-38 years). Misdiagnosis with von Willebrand disease was common. Approximately 50% of patients experienced 1 bleed every day, and 13% reported over 500 bleeds per year; Most bleeds were skin bruises and mouth bleeds, but patients also reported joint/muscle and gastrointestinal bleeds. Only 24% of respondents reported being treated at a hemophilia treatment center; 71% reported visiting their hematologist regularly. The most common treatment for bleeds was antifibrinolytics (82%), followed by recombinant activated factor VII (rFVIIa; 42%). In addition, 73% reported receiving platelets and blood transfusions in the past year. Approximately 25% reported receiving more than 20 transfusions in their lifetime. Overall, 38% of patients reported having experienced refractoriness to platelets and 32% antibodies to platelets; notably, only these patients reported receiving treatment with rFVIIa. Many feared uncontrolled bleeding due to refractoriness or antibodies to platelets and stated that their health care providers (HCPs) were too quick to treat bleeds with platelets. Many female patients struggled to find a gynecologist with some knowledge of the management of menstruation, pregnancy, and childbirth in patients with GT; 11% of respondents reported menstrual bleeding that required hospitalization and/or emergency treatment. The majority (74%) of female patients reported taking hormonal contraceptives to prevent regular menstruation; some patients not taking hormones required monthly platelet transfusions. Fifty-eight percent of patients reported issues with excessive bleeding at school as children; 38% reported missing school days and 33% were bullied during childhood. In addition, 38% of adult patients and 24% of caregivers had missed work as a result of GT, and 21% of adult patients reported that their employer did not take their condition seriously. Many respondents (65%) were satisfied with the level of support they receive from their significant other, and 76% were satisfied with the level of support they receive from their friends. Conclusions: Many patients with GT are identified early in life owing to a severe phenotype, but diagnosis remains somewhat difficult. Patients with GT experience frequent bleeding episodes, commonly as bruises and nosebleeds, with 31% experiencing more than 100 bleeds per year. Additional support from outside the GT patient community is needed. Patients desire additional education for themselves and their HCPs, especially around menstruation, childbearing, and treatment options. Disclosures Duncan: Novo Nordisk Inc: Consultancy. Kellum:Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jain:Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; BPL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Peltier:Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees. Cooper:Novo Nordisk Inc.: Employment. Saad:Novo Nordisk Inc: Employment.

Download Full-text

Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽

10.1182/blood-2019-127270 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2409-2409

Author(s):

Tiffany Lin Lucas ◽

Shveta Gupta ◽

Joanna A. Davis ◽

Fernando F. Corrales-Medina

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

The United States ◽

Haemophilia A ◽

Advisory Committees ◽

Inhibitor Development ◽

Increased Risk ◽

Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽

10.1182/blood-2019-126659 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1126-1126

Author(s):

Karen L. Zimowski ◽

Glaivy M. Batsuli ◽

Paulette Bryant ◽

Jenny McDaniel ◽

Kelly Tickle ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Bleeding ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Acute Bleeding ◽

Fviii Activity ◽

Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

Download Full-text

Therapy for Chronic ITP in Germany - A Patient Survey.

Blood ◽

10.1182/blood.v114.22.4471.4471 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4471-4471

Author(s):

Axel C. Matzdorff ◽

Gabriele Arnold ◽

Abdulgabar Salama ◽

Helmut Ostermann ◽

Simone Hummler

Keyword(s):

Board Of Directors ◽

Patient Survey ◽

Advisory Committees ◽

Complementary Medicines ◽

Off Label ◽

Chronic Itp ◽

Frequent Use ◽

On Line ◽

And Gender ◽

Complementary And Alternative

Abstract Abstract 4471 Background Guidelines recommend glucocorticoids and splenectomy as standard 1st and 2nd line treatments for chronic ITP. We sought to find out how German ITP-patients are treated in respect of these guidelines. Methods Members of a patient support association >18 y with self-reported history of chronic ITP (>6 mo) were surveyed. A questionnaire was developed from literature review with clinician and patient input, and administered on-line. Results 123 questionnaires were evaluated. Age (median 51 years) and gender distribution (38% m, 62% f) are comparable to surveys from other countries. 70% of patients had chronic ITP for more than 5 years and 50% a “usual” platelet count of < 50.000/μl (20% < 30.000/μl). 69% had hematomas or petechiae within the last 12 months, 45% had oropharyngeal bleeds, and 11% had been admitted to a hospital within this year. 88% had received or receive glucocorticoids, 28% were splenectomized. IVIg was given to 55%, rituximab to 22%, anti-D to 11%, cyclosporine to 7%. Complementary and alternative medical treatments had been used by 36%. 38 women were under the age of 50 and 14 (36%) reported that they had been advised not to become pregnant. 23 became pregnant and 10 (44%) required ITP-treatment during their pregnancy. Conclusion Glucocorticoids are the most common therapy for chronic ITP but complementary and alternative treatments already come second and less than 1/3 of the patients are splenectomized. This and the frequent use of complementary medicines suggests dissatisfaction with conventional therapeutic approaches. Many patients receive off-label therapies (rituximab, anti-D, cyclosporine are not licensed for ITP in Germany). There is a major need for adequate counseling and care for pregnant ITP-patients. Disclosures: Matzdorff: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter: Consultancy, Honoraria. Off Label Use: Rituximab for chronic ITP Complementary medicines for ITP. Hummler:GlaxoSmithKline: Employment.

Download Full-text

Improvement in Right Ventricular Function Following 1 Year of Deferasirox Therapy in Patients with β-Thalassemia.

Blood ◽

10.1182/blood.v114.22.5106.5106 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5106-5106

Author(s):

Gillian Smith ◽

Dudley J. Pennell ◽

John B. Porter ◽

M. Domenica Cappellini ◽

Lee Lee Chan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Left Ventricular ◽

Myocardial Iron ◽

Advisory Committees ◽

Off Label ◽

Cardiac Siderosis ◽

Rv Function

Abstract Abstract 5106 Background Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients with β-thalassemia. Once-daily oral iron chelation therapy with deferasirox (Exjade®) has been shown to reduce body iron burden in patients with transfusion-dependent anemias, and the removal of myocardial iron has been demonstrated in several clinical studies including the prospective, multicenter EPIC study. Here we report for the first time an evaluation of right ventricular (RV) function assessed using magnetic resonance (MR) techniques in β-thalassemia patients with myocardial siderosis treated with deferasirox in the EPIC study. Methods The cardiac sub-study of EPIC enrolled patients with β-thalassemia aged ≥10 yrs who had MR myocardial T2* >5–<20 ms (indicating cardiac siderosis), left ventricular ejection fraction ≥56%, serum ferritin (SF) levels of >2500 ng/mL, MR (R2) liver iron concentration (LIC) of >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/day and subsequent dose adjustments of 5–10 mg/kg/day were based on changes in SF, month-6 cardiac T2* and safety parameters. The following RV parameters were assessed using MR; ejection fraction (RVEF), volumes (end-systolic [RVESV] and end-diastolic [RVEDV]) and mass (RVM). All parameters were assessed at the CMR core laboratory in London, UK after 6 and 12 months of deferasirox treatment. Results 114 patients were enrolled in the cardiac sub-study (54 male, 60 female; mean age 20.9 ± 7.3 years). Baseline myocardial T2* was <10 ms in 47 (41%), and 10–20 ms in 67 (59%) patients. Mean baseline LIC was 28.2 ± 10.0 mg Fe/g dw, median serum ferritin was 5235 ng/mL, and the mean amount of transfused blood in the previous year was 185 mL/kg. 68% of patients had received prior deferoxamine (DFO) and 32% DFO/deferiprone combination chelation therapy. Mean actual deferasirox dose over 12 months was 32.6 mg/kg/day. RVEF increased significantly from a mean ± SD baseline of 65.8 ± 6.2% to 67.6 ± 6.4% at 6 months (P=0.013) and 68.7 ± 5.7% at 12 months (P<0.0001; Figure). RVESV significantly decreased from 35.0 ± 14.5 mL at baseline, to 33.4 ± 12.8 mL (P=0.034; Figure) by 12 months and RVEDV significantly increased from 101.0 ± 31.8 mL at baseline to 105.7 ± 33.4 mL (P=0.04; Figure) by 12 months. There were no significant correlations between any of the RV function parameters assessed and T2*. There was a borderline significant reduction in RVM from 46.8 ± 14.6 g at baseline to 44.9 ± 12.4 g at 12 months (P=0.088). Reference RVEF, RVESV, RVEDV and RVM have been defined in healthy subjects as 66 ± 6 %, 50 ± 14 mL, 144 ± 23 mL and 48 ± 12 g, respectively (A M Maceira et al. Eur Heart J 2006;27:2879–88), although values were shown to vary significantly by gender, body surface area and age. Conclusions To our knowledge, this is the first study to show a change in RV volumes and improvement in RV function associated with iron chelation. The RVEF improved with increased RVEDV and decreased RVESV, which is suggestive of improved RV and left ventricular compliance respectively resulting from removal of myocardial iron. However, improvements in pulmonary vascular resistance may also play a role. Disclosures Smith: Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. 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. 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. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Lee:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Research Funding; GPO-L-ONE clinical study sponsor by Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Hmissi:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

Download Full-text

Phase II Trial of Rituximab in the Treatment of Inhibitors in Congenital Hemophilia A: Results of the RICH Study

Blood ◽

10.1182/blood.v118.21.27.27 ◽

2011 ◽

Vol 118 (21) ◽

pp. 27-27 ◽

Cited By ~ 1

Author(s):

Cindy A. Leissinger ◽

Rebecca Kruse-Jarres ◽

Suzanne Granger ◽

Barbara A Konkle ◽

Margaret V. Ragni ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Null Hypothesis ◽

Research Funding ◽

Hemophilia A ◽

High Titer ◽

Severe Hemophilia ◽

Advisory Committees ◽

Minor Response ◽

Inhibitor Titer

Abstract Abstract 27 Antibodies (inhibitors) to exogenously administered factor VIII (FVIII) develop in as many as 30 – 40% of patients with severe hemophilia A. Patients with persistent inhibitors are at increased risk of serious, poorly controlled bleeding which results in significant morbidity and in some cases early death. Rituximab, a chimeric murine/human monoclonal antibody directed against CD20, suppresses circulating and tissue B cells and pre-B cells and has been used in the treatment of a variety of autoimmune and alloimmune disorders. The primary objective of this NHLBI Transfusion Medicine Hemostasis network-sponsored study was to evaluate the role of rituximab as an approach to inhibit the production of FVIII antibodies in patients with severe congenital hemophilia A and high titer inhibitors. Methods: This was a prospective, multi-institution, single-arm, open-label Phase II trial. Eligible subjects were males over 18 months of age with severe hemophilia A and a history of an inhibitor ≥5 Bethesda units (BU). Individuals who were HIV positive, undergoing immune tolerance, or receiving immune modulating therapies were excluded. Following a challenge dose of recombinant FVIII (rAHF-PFM) at 50 IU/kg, and evidence of an inhibitor titer ≥ 5 BU at 5 – 14 days after the challenge dose, subjects received rituximab 375 mg/m2 weekly for 4 weeks. Starting two weeks after the fourth rituximab treatment, inhibitor titers were drawn every 4 weeks. A major response was defined as a fall in the inhibitor titer to < 5 BU at any time up to and including week 22, with the titer remaining < 5 BU following re-challenge with FVIII. A minor response was defined as inhibitor falling to < 5 BU at any time up to and including week 22, with the anamnestic peak following re-challenge with FVIII between 5–10 BU and less than 50% of the original anamnestic peak. The null hypothesis was that no more than 5% of subjects treated with rituximab would be major responders. Results: A total of 23 subjects were enrolled; 21 received the initial FVIII challenge. Of these, 4 subjects did not meet the criteria to receive rituximab treatment, and 1 subject withdrew consent. A total of 16 subjects received at least one dose of rituximab and are included in this analysis. The median age was 14 y (range 4 – 38 y). Three subjects (18.8%) had a major response. If the null hypothesis were true, the probability of 3 or more major responses in 16 subjects would be 0.043, so the null hypothesis was rejected. One subject (6.2%) had a minor response to treatment. All 4 responders and 8 non-responders had a baseline inhibitor titer < 20 BU, resulting in a response rate of 33% in that group vs. 0% in the 4 subjects with a baseline inhibitor titer ≥ 20 BU. Discussion: Infusion of rituximab 375 mg/m2 once per week for four weeks was effective in reducing the anamnestic inhibitor response in 25% of severe hemophilia A subjects with inhibitors who were not receiving concurrent immune tolerance therapy. Those who responded tended to have lower baseline inhibitor levels compared to the group that did not meet the criteria for response. This Phase II study, designed as a proof of concept, demonstrated that rituximab may be useful in lowering inhibitor levels and anamnesis in some patients with inhibitors, but that the effect as a solo treatment strategy is modest, and possibly restricted to patients with inhibitor titers under 20 BU. Further studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerization strategies. Acknowledgments: The authors acknowledge the support of Genentech for the provision of rituximab and partial financial support for the study. The authors also acknowledge Baxter Healthcare Corporation for donating the recombinant FVIII used in the trial. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab, a drug approved for use in treating lymphoma, was studied for its efficacy in suppressing inhibitors against factor VIII in patients with hemophilia and high titer inhibitors. Kruse-Jarres:Baxter: Consultancy, Honoraria; Bayer:; Griforls: Consultancy, Honoraria; Inspiration: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria. Konkle:Baxter Corporation: Consultancy, Research Funding; Bayer Corp: Consultancy; Inspiration Biopharmaceuticals: Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees. Neufeld:Genentech: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Bennett:Biogen IDEC: Honoraria. Valentino:Baxter Bioscience, Bayer Healthcare, GTC Biotherapeutics, NovoNordisk, Pfizer, CSL Behring, Inspiration Bioscience, and Biogen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Rituximab-CHOP21 Plus Lenalidomide (LR-CHOP21) Is Effective and Feasible in Elderly Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results of Phase II REAL07 Study of the Fondazione Italiana Linfomi (FIL)

Blood ◽

10.1182/blood.v120.21.903.903 ◽

2012 ◽

Vol 120 (21) ◽

pp. 903-903

Author(s):

Annalisa Chiappella ◽

Silvia Franceschetti ◽

Alessia Castellino ◽

Angelo Michele Carella ◽

Ileana Baldi ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Board Of Directors ◽

Phase Ii ◽

Phase Ii Study ◽

Dose Finding ◽

Phase Iii ◽

Advisory Committees ◽

Off Label ◽

Grade Iii

Abstract Abstract 903 Introduction. R-CHOP21 is the standard treatment for untreated elderly DLBCL, however up to 40% of patients fail. There is a need to improve the efficacy of R-CHOP21; an option may be the addition of novel drugs in first line induction therapy. Lenalidomide has a complex mechanism of action as immunemodulation, antiangiogenesis, restoration of immunesynapses and direct antitumor effects. Lenalidomide monotherapy exhibits significant activity in patients with relapsed aggressive B-cell NHL and has in vitro synergy with rituximab and cytotoxic therapy. This rationale prompted FIL to conduct a prospective multicenter dose finding phase I-II trial aimed at evaluating toxicity and activity of lenalidomide plus R-CHOP21 (LR-CHOP21) in elderly untreated DLBCL (NCT00907348). In the dose-finding phase I study, 21 patients were enrolled, and 15 mg lenalidomide from day 1 to day 14 was identified as the maximum tolerated dose (MTD) in combination with R-CHOP21 (Vitolo, Ann Oncol 2011;22(4):331a). Patients and Methods. Based on the phase I results, 15 mg of lenalidomide in combination to R-CHOP21 was tested in a phase II study. Phase II was designed according to Simon's two stage design; primary endpoint was an improvement of overall response rate (ORR) of 15% in LR-CHOP21 compared to 70% of standard R-CHOP21 and the study would be considered of interest if at least 16/23 in step 1 and 39/49 in step 2 responses occurred. Response was evaluated according to 2007 Cheson criteria. PET scan was mandatory at the end of the treatment; patients in partial remission (PR) who underwent radiotherapy were considered as failure in progression free survival (PFS) analysis. Inclusion criteria were: age 60–80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; IPI at LI/IH/H risk. Treatment plan was: R-CHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. Mandatory supportive care included: GCSF or PegGCSF, cotrimoxazole as Pneumocystis Jiroveci prophylaxis and low molecular weight heparin or low dose aspirin as deep venous thrombosis prophylaxis. Results. From April 2010 to May 2011, 49 patients were enrolled in the phase II study including 9 patients treated at the MTD during phase I. Clinical characteristics were: median age 69 years (range 61–80); stage III/IV 43 (88%), performance status >1 31 (63%), IPI IH/H 30 (61%). The step-1 of the trial showed an ORR of 22/23. At the end of 6 LR-CHOP21, ORR was 45/49 (92%). Complete remissions (CR) were 42 (86%) and PR 3 (6%); 3 patients (6%) did not respond and one (2%) died for violent death. At a median follow-up of 18 months, overall survival (OS) was 94% (95% CI: 82–98) and PFS was 75% (95% CI: 57–86). (Figure 1). Of the 294 planned courses of LR-CHOP21, 277 (94%) were administered, of which 221 (75%) with lenalidomide as planned, 40 (14%) with dose and/or day reduction and 16 (5%) without lenalidomide. Median dose of lenalidomide delivered in 49 patients was 1185 mg (IQR 900–1260), i.e. 94% of the planned dose (1260 mg). The most frequent cause of lenalidomide reduction or withdrawal was neutropenia. At least 90% of the planned dose of doxorubicine, cyclophosphamide and vincristine were administered, in: 91%, 95% and 83% of the R-CHOP21 courses, respectively. Median interval time between R-CHOP21 courses was 21 days (range 19–48). Hematological toxicity was mild: grade III/IV thrombocytopenia occurred in 13% of courses, anemia in 5% and neutropenia in 33%, with only 4% of febrile neutropenia. No grade IV extra-hematological toxicities were observed. Grade III non-hematological toxicities were reported in 7 patients: cardiologic, gastroenteric and renal in one patient respectively, grade III neurological toxicities, sensory and motorial neuropathy in two, thromboembolic event in one not receiving anti-thrombotic prophylaxis, and skin rash in one. No toxic deaths occurred during treatment. One patient died three months off therapy while in CR, due to aeromonas hydrophila sepsis and multi-organ failure. Conclusions. The addition of 15 mg lenalidomide on days 1–14 to R-CHOP21 is safe, feasible and effective in elderly untreated DLBCL. The primary objective of the phase II study was met, with 92% of ORR of which 86% CR and promising PFS rates. The addition of lenalidomide did not impair the administration of R-CHOP21. Based on these data, the efficacy of LR-CHOP21 needs to be investigated in a large phase III randomized trial in elderly DLBCL. Disclosures: Off Label Use: Trial partially supported by a research grant by Celgene. Lenalidomide was provided free by Celgene. The use of Lenalidomide is off-label in untreated DLBCL. Dreyling:Roche: Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

Download Full-text