Management of Bleeding In Acquired Hemophilia: Results of the European Acquired Hemophilia Registry (EACH2)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 716-716 ◽  
Author(s):  
Paul Knoebl ◽  
Francesco Baudo ◽  
Peter W Collins ◽  
Angela Huth-Kuehne ◽  
Herve Levesque ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
First Line ◽  
Acquired Hemophilia ◽  
Advisory Committees ◽  
Baxter Healthcare ◽  
Fviii Activity ◽  
Hemostatic Therapy ◽  
Bypassing Agents ◽  
Inhibitor Titer

Abstract Abstract 716 Objective. Acquired hemophilia (AH) is a hemorrhagic syndrome, caused by autoantibodies inhibiting coagulation FVIII. The optimal hemostatic therapy is not clear. This analysis aimed to describe the first-line management of bleeding in AH within Europe. Methods. Data from the EACH2 registry, a multicentre, international, web-based registry, were used to analyze the use of recombinant activated factor VII (rFVIIa), activated prothrombin complex concentrates (APCC), FVIII concentrates, and DDAVP as first line hemostatic therapy. There was no predefined treatment protocol, each center was free to follow local clinical practice. Response rate is the number of bleeds resolved as judged by each investigator. Data on demographics, pregnancy and immunosuppression will be presented in other abstracts. Data are given as medians and interquartile ranges (IQR) or odds ratios (OR) and 95% confidence intervals (CI). Results. Data of 501 patients (pts) (235 male, 266 female, median age 74 years (range 14–104)) were prospectively collected between 2003 and 2009 in 90 centers of 11 European countries. In 474 pts at least one bleeding episode is reported; 159 pts had 2 episodes (the second bleeding episode a median 26 (13/67) days after the first), 51 pts had 3 episodes, 16 pts. more than 3 bleedings. Of the 474 initial bleeding episodes, 70.3% were reported as severe (criteria prospectively defined), 50.2% had deep musculoskeletal or retroperitoneal bleeding, 53.2% skin hematomas, 31.6% mucosal bleeding, and only 4.9% hemarthroses. In 77.4% the bleedings occurred spontaneous, 8.4% after trauma, 8.2% after surgery. Median FVIII activity at the time of bleeding was 0.02 U/mL (0.01/0.05 U/mL), the inhibitor titer 19 BU/mL (5.5/64 BU/mL). There was no significant association between FVIII activity or inhibitor titer and severity of bleeding. Hemostatic therapy was given in 70.5% of the bleedings. First line therapy is presented in the table: Desmopressin was given in 6%, antifibrinolytic drugs in 18%, and high dose immunoglobulin infusions in 11.1%; immunoadsorption was performed in 5.4%, plasmapheresis in 0.6%. Overall bleeding resolved in 76.4%, in median after 4 days (IQR 2–10 days). Second line therapy with an alternative substance was applied in 23.6% (in 17.4% because bleeding did not resolve). The use of bypassing agents (rFVIIa or APCC) resulted in a significant higher rate of bleeding control (91.2 %) than the use of FVIII or desmopressin (71.0 %) (p<0.001), there was no difference between rFVIIa (90.9 %) and APCC (94.3 %). To minimize bias, propensity score matched data analysis (1) based on age, gender, FVIII level, inhibitor titre, hemoglobin level, site, severity and cause of bleeding was carried out. It confirmed that first line treatment with a bypassing agent resulting in a better control of bleeding compared to FVIII or desmopressin (OR 0.25, 95% CI 0.12–0.53; p=0.004). There was no difference in efficacy between rFVIIa and APCC (OR 1.0, 95%CI 0.24–4.18). No other patient- or disease-related parameters affected response rate. Deaths due to bleeding occurred in 3% of the patients, only few serious adverse events were recorded: 1.4% myocardial infarction, 0.2% stroke, 1.0% venous thromboembolic events. There was no significant association of death or severe adverse events with a specific hemostatic therapy. Conclusion. Bypassing agents are the preferred first line hemostatic therapy in AH (70.1% of the episodes) and have a significantly better efficacy than FVIII or DDAVP; rFVIIa was the agent preferred by most clinicians (~50%), rFVIIa and APCC were equally efficacious. Treatment with bypassing agents was safe and highly effective in controlling bleeding in AH. 1. D'Agostino RB Jr: Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998; 17:2265–2281. Disclosures: Knoebl: Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Collins:NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levesque:NovoNordisk: NovoNordisk fund the EACH2 registry. Marco:Novo Nordisk: Novonordisk fund the EACH2 registry. Nemes:Novo Nordisk: Novonordisk fund the EACH2 registry. Pellegrini:Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk. Tengborn:Novo Nordisk: Novonordisk fund the EACH2 registry.

Natural History Of Inhibitor Recurrence Following Successful Immune Tolerance Induction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1106-1106 ◽  
Author(s):  
Ana G. Antun ◽  
Paul Monahan ◽  
Marilyn J. Manco-Johnson ◽  
Michael Callaghan ◽  
Guy Young ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Immune Tolerance ◽  
Half Life ◽  
Research Funding ◽  
Tolerance Induction ◽  
Advisory Committees ◽  
Immune Tolerance Induction ◽  
Baxter Healthcare ◽  
Inhibitor Titer

Abstract Introduction The formation of Factor VIII (FVIII) inhibitory antibodies is a major complication of hemophilia A. Currently immune tolerance induction (ITI) is successful in up to 70% of patients. Outside of the International Immune Tolerance Registry, where 6 of 128 patients had a recurrent inhibitor between 1 and 6 years, little is known about the probability of inhibitor recurrence following successful ITI. Objective To determine the probability of inhibitor recurrence and the influence of adherence to post-ITI prophylaxis on inhibitor recurrence following successful ITI. Methods All persons with hemophilia A (FVIII level < 50%) who completed ITI (defined as inhibitor titer <0.6 BU/ml) between 1/1/1998 and 8/15/2010 at 12 U.S. Hemophilia Treatment Centers were identified. Demographic and clinical characteristics were obtained through review of subject medical records and included age at start of ITI, race, ethnicity, hemophilia severity, peak inhibitor titer prior to the start of ITI and ITI regimen. For those subjects where tolerance was confirmed with measurement of FVIII half-life > 6 hours and/or FVIII recovery > 66% in addition to inhibitor titer < 0.6 BU/ml, information was also collected on post-ITI prophylaxis regimen, adherence to post-ITI prophylaxis, and the presence of a recurrent inhibitor titer (≥ 0.6 BU/ml) or last inhibitor titer prior to 8/15/2011. Adherence during the 6 months prior to inhibitor recurrence or last inhibitor titer was determined by review of pharmacy and infusion logs compared with prescribed treatment regimen. Follow-up time started when the subject was considered tolerized (normalized half-life or recovery if half-life not performed) and ended at the time of inhibitor recurrence or the last recorded inhibitor titer. Estimates of the probability of remaining inhibitor-free at 1, 3 and 5 years were calculated with the Kaplan-Meier method. The association between adherence (completing >80% of prescribed infusions vs. < 80% of prescribed infusions) and inhibitor recurrence was assessed using the chi-square test. Results Eighty-three male subjects were enrolled. The median age at start of ITI was 3.3 years (range: 0.08 - 39). The majority of the subjects were white (73%) and non-Hispanic (73.5%). Seventy-one (85.6%) had severe hemophilia. The median peak inhibitor titer was 8.5 BU/ml (range: 0.6 - 950). Four subjects (5%) had a prior unsuccessful course of ITI. FVIII alone was used in 85% of subjects. Sixty-seven (80.7%) met criteria for tolerance and 64 had follow-up data available, with a median follow up time of 3.4 years (range: 0.08-12.4). Forty-four subjects (68.7%) remained tolerant without a recurrent inhibitor titer after a median 4.7 years (range: 0.25-12.4) of follow-up. Twenty subjects (31.3%) had at least one inhibitor titer ≥ 0.6 BU/ml after a median of 1.6 years (range 0.08-5.7). The probability of recurrent inhibitor at 1 year is 0.15 (95% CI: [0.05, 0.20]); at 3 years is 0.30 (95% CI: [0.2, 0.4]) and 5 years is 0.35 (95% CI: [0.2, 0.5]) (Figure 1). Four subjects discontinued post-ITI prophylaxis anywhere from 6 months to greater than 6 years after tolerance was achieved, of whom 2 (50%) developed a recurrent inhibitor. Of those that remained on post-ITI prophylaxis, 41 subjects (64.1%) were adherent (took >80% of prescribed infusions) to their post-ITI prophylaxis regimen, of whom 13 (31.7%) developed a recurrent inhibitor. Twenty-three (35.9%) who were non-adherent (took <80% of the prescribed infusions) of which 7 (30.4%) subjects developed a recurrent inhibitor; no statistically significant association was found between adherence and inhibitor-free status (p=0.92). Conclusion ITI is currently the most effective treatment to eradicate FVIII inhibitors, however 5 years after completion, 30-35% of patients will have at least one inhibitor titer ≥ 0.6 BU/ml. A recurrent inhibitor is unlikely after 5 years. Adherence to post-ITI prophylaxis does not appear to be a major driver of inhibitor recurrence. It is imperative to elucidate the factors that influence the durability of successful ITI to improve quality of life and cost of treatment in these patients. Disclosures: Monahan: Baxter: Consultancy, Honoraria, Research Funding, travel support, travel support Other; Bayer: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Prolor Biotech: Research Funding; Asklepios: Consultancy, Research Funding, travel support Other. Manco-Johnson:Eisai: Research Funding; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carpenter:Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding. Kruse-Jarres:Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy; Baxter Healthcare: Consultancy. Ragni:Novo Nordisk: Research Funding; Merck: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Tacere Benitec: Consultancy; Smith Kline Glaxo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Kempton:Novo Nordisk: Research Funding; Baxter Healthcare: Membership on an entity’s Board of Directors or advisory committees.

Inhibitor Eradication In Acquired Haemophilia A: Final Results of European Acquired Haemophilia Registry (EACH2)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 715-715 ◽  
Author(s):  
Peter W Collins ◽  
Francesco Baudo ◽  
Paul Knoebl ◽  
Herve Levesque ◽  
Laszlo Nemes ◽  
...  
Keyword(s):  
Propensity Score ◽  
Board Of Directors ◽  
Research Funding ◽  
Oral Prednisone ◽  
Haemophilia A ◽  
First Line ◽  
Advisory Committees ◽  
Acquired Haemophilia ◽  
Baxter Healthcare ◽  
Inhibitor Titre

Abstract Abstract 715 The optimal first line immunosuppression (IS) for eradicating factor (F)VIII inhibitors in acquired haemophilia A (AHA) is controversial. Steroids and cyclophosphamide are commonly used and there has been recent interest in the role of rituximab. Prospective randomised controlled trials (RCTs) would be challenging and in their absence registries may provide useful data to guide clinical practice. EACH2 collected data on 281 analysable patients who received first line IS. Complete remission (CR) was defined as inhibitor undetectable, FVIII>70IU/dL and IS stopped. Stable CR was defined as CR without relapse. A higher proportion of patients achieved CR with steroids and a cytotoxic (predominantly cyclophosphamide) (77%) than those treated with steroids alone (58%) (P<0.005) or a rituximab based regimen (61%) (P<0.02). The 12 patients treated with rituximab alone had the lowest proportion achieving CR (42%). Median time to normal FVIII and undetectable inhibitor was similar in the steroid alone and steroid and cytotoxic groups (about 5 weeks) but slower in those treated with a rituximab based regimens (about 9 weeks), although this was in part due to the slow response of patients treated with rituximab alone. Relapse was most common after initial treatment with steroids alone (19%). In this group relapse was diagnosed a median (range) 134 (13-695) days after stopping IS. In contrast, only 1 patient (4%) who achieved a CR with a rituximab based regimen relapsed. Stable CR after first line treatment was highest after steroids plus a cytotoxic (67%) and rituximab plus another IS (64%). Stable CR was lower in the steroids alone (48%) and rituximab alone groups (42%). Patients who achieved CR after first line IS had higher FVIII and lower inhibitor titres compared with those who did not, median (IQR) for FVIII 2 (1-7) compared to 1 (1-4)IU/dL (P<0.005) and inhibitor titre 13 (4-45) compared to 31 (7-75)BU/mL P<0.03. To minimise bias, propensity score matched analysis based on age, weight, gender, FVIII level, inhibitor titre and underlying aetiology was performed to compare oral prednisone plus oral cyclophosphamide with oral prednisone alone (n=70 in each arm). This showed an odds ratio (95% CI) of achieving a stable CR of 3.25 (1.51-6.99) (P<0.003) in favour of combined treatment despite the prednisone alone group being treated with a higher mean dose of prednisone/kg (P<0.005). There were insufficient patients to perform a propensity score matched analysis with the rituximab group. There was no statistically significant difference in survival between the groups and similarly a proportion of patients were alive and in CR at final follow up (FU), median (IQR) FU was 246 (66-665) days. In conclusion, stable CR after first line IS was more likely following combination therapy with oral prednisone and cyclophosphamide than oral prednisone alone. Although a lower proportion of patients achieved CR with rituximab based regimens than steroids plus cytotoxics the lower relapse rate resulted in a comparable proportion achieving stable CR. Stable CR after rituximab alone was low, although there were only 12 patients. These are the best data available to date relating to the response to first line IS in AHA and will be useful for informing treatment guidelines and designing future RCTs. Table. Outcome of first line immunosuppression (IS) for AHA. Regimen Age Years FVIII at diagnosis (IU/dL) Inhibitor titre at diagnosis (BU/mL) CR after 1st line IS N (%) Days from start of IS Relapse (%) Stable CR after 1st line IS % Alive and in CR at final FU % Inhibitor -ve FVIII >70 IU/dL IS stopped Steroids alone n=142 75 (63–81) 3 (1–6) 13 (5–43) 83 (58) 34 (17–76) 32 (15–51) 108 (55–208) 19 48 60 13–104 0–28 0.1–1020 5–321 3–551 11–1169 Steroids and cytotoxics n=88 76 (63–80) 1 (1–4) 22 (8–67) 68 (77) 32 (12–77) 40 (18–81) 74 (52–151) 14 67 60 16–101 0–34 0.4–2800 0–386 2–386 1–386 All rituximab regimen n=51 74 (5–78) 2 (0–7) 16 (6–62) 31 (61) 65 (29–144) 64 (28–206) 43 (22–96) 4 59 67 14–104 0–20 0.1–2176 10–436 10–569 17–257 Rituximab plus another IS n=39 75 (57–78) 2 (0–7) 16 (9–62) 26 (67) 47 (28–96) 38 (28–141) 55 (26–96) 4 64 61 14–104 0–20 0.1–2176 10–436 10–569 17–257 Rituximab alone n=12 69 (65–77) 1 (0–8) 16 (3–71) 5 (42) 53, 145, 209, 334* 145, 209, 252, 334* 21, 21, 21, 21, 22* 0 42 70 50–85 0–15 1–460 Data are median, interquartile range (IQR) and range, * actual days due to low number of patients. Disclosures: Collins: NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: The use of Rituximab for the treatment of acquired haemophilia. Baudo:NovoNordisk: Consultancy, Honoraria, NovoNordisk fund the EACH2 registry, Speakers Bureau; Bayer Healthcare: Honoraria, Speakers Bureau. Knoebl:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry, Research Funding; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levesque:NovoNordisk: NovoNordisk fund the EACH2 registry. Nemes: NovoNordisk: Novonordisk fund the EACH2 registry. Pellegrini:Novonordisk: Consultancy, Honoraria, Speakers Bureau, The EACH2 registry is funded by Novonordisk. Tengborn:NovoNordisk: NovoNordisk fund the EACH2 registry. Huth-Kuehne:NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, NovoNordisk fund the EACH2 registry; Baxter Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Prognostic Parameters For Remission Of and Survival In Acquired Hemophilia A: Results Of The GTH-AH 01/2010 Multicenter Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 205-205 ◽  
Author(s):  
Andreas Tiede ◽  
Jan-Malte Blumtritt ◽  
Robert Klamroth ◽  
Saskia Gottstein ◽  
Katharina Holstein ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Performance Status ◽  
Immunosuppressive Treatment ◽  
Treatment Protocol ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Titer

Abstract Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII:C). Immunosuppressive treatment may result in remission of disease over a period of days to months. Until remission, patients are at high risk of bleeding and complications from immunosuppression. Prognostic parameters to predict remission and the time needed to achieve remission could be helpful to guide treatment intensity, but have not been established so far. GTH-AH01/2010 was a prospective multicenter cohort study using a standardized immunosuppressive treatment protocol. The primary study endpoint was time to achieve partial remission (PR, defined as FVIII:C activity >50 IU/dl after cessation of any hemotherapy for >24h, and no active bleeding). Secondary endpoints were time to achieve complete remission (CR, defined as PR plus negative FVIII:C inhibitor, steroid tapered to <15 mg/d prednisolone, and cessation of any other immunosuppressive treatment), and overall survival (OS). Enrolment was strictly prospective and only allowed within 7 days of starting immunosuppression. Outcome data were recorded in all patients enrolled. The treatment protocol consisted of prednisolone (100 mg/d from day 1 to the day of PR, then tapered down to <15 mg/d over 5 weeks), oral cyclophosphamide (150 mg/d, from day 21-42, unless PR was achieved), and rituximab (375 mg/m2 weekly for 4 weeks starting on day 43, unless PR was achieved). If AHA was first diagnosed in patients previously on prednisolone >15 mg/d, or equivalent, they received prednisolone (100 mg/d) and rituximab from day 1. If cyclophosphamide was contraindicated, patients received prednisolone (100 mg/d) and rituximab from day 21. One hundred twenty-four patients from 21 treatment centers in Germany and Austria were enrolled between April 2010 and April 2013 (36 months). The patients from two centers not compliant with the treatment protocol were excluded (N=18), as were patients in whom AHA was not confirmed (N=2) or follow-up was too short at the time of this analysis (N=7). The remaining 97 patients from 17 centers were followed for a median of 256 days (interquartile range [IQR] 84-561). Median age was 74 years (IQR 64-82). AHA was associated with other autoimmune disorders (19%), malignancy (12%), pregnancy or puerperium (5%), but was most often idiopathic (66%). The median FVIII:C activity at baseline was 1 IU/dl (IQR <1-3), and the median inhibitor titer was 20 BU/ml (IQR 7.7-78). PR and CR were achieved after a median time of 35 and 102 days, respectively. Patients achieving PR prior to day 21 (N=22) compared with patients not achieving PR within 21 days (N=75) had a higher baseline FVIII:C activity (median 3 vs. <1 IU/dl, p<0.01) and a lower FVIII:C inhibitor (median 12 vs. 29 BU/ml, p<0.05). Multivariate analysis with adjustment for age, sex, underlying disorder, and WHO performance status on admission demonstrated that baseline FVIII:C activity (<1 IU/dl vs. >=1 IU/dl) had a strong impact on the time to achieve PR (HR 2.76 [95% confidence interval 1.73-4.42], p<0.001) and CR (HR 2.36 [1.34-4.14], p<0.01). Baseline FVIII:C activity was also a predictor of PR and CR when other cutoffs were used (2 or 3 IU/dl instead of 1 IU/dl), or when it was analyzed as a continuous variable in Cox regression analysis. In contrast, FVIII:C inhibitor titer assessed by the local laboratory did not affect time to PR or CR significantly. OS after 300 days, estimated by the Kaplan Meier method, was 69%. Age, WHO performance status, and FVIII:C activity at baseline were independent predictors of OS. In summary, GTH-AH 01/2010 is the largest prospective study of patients with AHA treated according to a standardized protocol. The study demonstrated a robust effect of baseline FVIII:C activity on the time needed to achieve PR and CR. Baseline FVIII:C activity, together with age and performance status, also affected OS. Therefore, baseline FVIII:C activity may be considered to guide individually tailored immunosuppression in future studies. Disclosures: Tiede: Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding. Off Label Use: Prednisolone, cyclophosphamid, and rituximab for immunosuppression in acquired hemophilia. Klamroth:Bayer: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding. Gottstein:Novo Nordisk: Honoraria; Baxter: Honoraria. Holstein:Baxter: Honoraria, Speakers Bureau. Scharf:CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria, Research Funding. Huth-Kühne:SRH Kurpfalz Hospital and Hemophilia Center: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Greil:Roche: Consultancy, Honoraria, Research Funding. Miesbach:Novo Nordisk: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Trappe:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Other; AMGEN: Research Funding, Travel, Travel Other; CSL Behring: Honoraria, Research Funding, Speakers Bureau, Travel, Travel Other; Mundipharma: Research Funding, Travel, Travel Other; Takeda: Consultancy, Research Funding, Travel Other; Novartis: Consultancy, Research Funding, Travel, Travel Other; Novartis: Research Funding, Travel Other; Cellgen: Travel, Travel Other. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria.

Beyond the Bethesda Assay- Towards Individualized Interpretation of Inhibitor Patients' FVIII Brand Specific Profiles

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2841-2841
Author(s):  
Tami Livnat ◽  
Amy Dunn ◽  
Shirley Azar- Avivi ◽  
Courtney Cox ◽  
Einat Avishai ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
High Titer ◽  
Individual Therapy ◽  
Advisory Committees ◽  
Fviii Activity ◽  
Group A ◽  
Inhibitory Antibodies ◽  
Bypassing Agents ◽  
Von Willebrand

Abstract Background: Patients with hemophilia A (HA) and inhibitory antibodies are typically treated with bypassing agents if the inhibitor titer is >5 Bethesda units (BU). However, some patients with elevated inhibitor titers are treated with FVIII therapy in conjunction with immune tolerance regimens or in combination with bypassing agents. The Bethesda assay detects the inhibitory capacity for FVIII neutralization after 2 hours' incubation of patient's plasma mixed with pooled normal plasma (PNP). Nonetheless the inhibitory titer does not express the kinetic behavior of the inhibitor throughout the 2 hours of incubation. Furthermore, standard plasma derived FVIII is used for the Bethesda assay, whereas many patients are currently treated with recombinant FVIII products. Patients with severe HA who develop inhibitors typically have a polyclonal response. In vitro responses to monoclonal specific anti- epitope antibodies showed that group A anti-A2 antibodies ( high titer, type I antibodies) rapidly and completely inhibit FVIII and are not affected by the presence of Von Willebrand factor (VWF). In contrast, many anti- C1 and C2 antibodies compete with VWF for binding to FVIII. As patients' response to various FVIII sources (eg: with/ without VWF) may be affected by their unique B cell epitope profile, personalized individually tailored FVIII brand specific therapy may be considered. Aims : We aimed to define our inhibitor patients' individual response to various FVIII sources by assessing the kinetics of FVIII inhibition and by patients' FVIII epitope specificity. Methods: Plasma was obtained from HA patients with inhibitors. FVIII neutralization profile was determined against PNP, recombinant full length FVIII (rFVIII= Kogenate- FS, Bayer), plasma derived Von Willebrand containing FVIII (pdFVIII = Optivate, BPL) and correlated to the inhibitory (BU) titer. To test FVIII neutralization profile, patients' platelet poor plasma was either incubated with PNP or spiked with 2U/ml rFVIII/pdFVIII and sequential measurements of residual FVIII activity was recorded over 120 minutes. FVIII activity was measured by one stage aPTT assay. All inhibitor assays were performed on the same sample simultaneously. Results were compared to the standard Bethesda assay. Domain-specific anti-FVIII antibody mapping was carried out by direct ELISA using purified single human domain hybrid FVIII protein. Patient plasma was serially diluted down the ELISA plate. Domain predominance was determined by comparison of resultant ELISA curves. In addition the presence of anti-A2 group A antibodies in the polyclonal patient plasma was assessed by competition ELISA. Results: Our patient cohort was heterogeneous, consisting of patients aged 3-70 years with inhibitor titers of 0.5-131 BU. No obvious correlation was found between kinetic profiles and the inhibitory BU titer. For each patient, variability of inhibitor activity against different FVIII sources was noted. In individual patients, discrepant inhibitory kinetics were identified when commercial FVIII (rFVIII or pd-FVIII) was added, compared to PNP, utilized for standard determination of inhibitory titer in BU/ml. Among patients with similar BU titer, different FVIII neutralization profile was noted. Furthermore, the source of FVIII yielded individual neutralization curves that did not correlate with the common gold standard of inhibitory (BU) titer (Figure). Correlation between patients' epitopes and their neutralization profile was difficult to assess as in most patients no single predominant inhibitory epitope could be defined. However, in patients with C2 predominance antibodies improved neutralization was detected with pd -FVIII as compared to rFVIII source. High titer patient plasmas that contained anti-A2 group A antibodies inhibited FVIII completely at the first time point regardless of the VWF content of the FVIII source. Conclusion: The Bethesda assay neither predicts inhibitory kinetics nor defines patients' response to various FVIII sources. Our combination of assays may identify the best potential FVIII source for treatment of patients with inhibitory antibodies. We suggest that FVIII source dependent neutralization kinetics and epitope mapping may be applied as additional tools for future individual therapy tailoring. Larger sample sizes and repeated samples over time will be required to validate these results. Figure 1 Figure 1. Disclosures Dunn: CSL Behring,: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfiser: Membership on an entity's Board of Directors or advisory committees. Meeks:Grifols: Membership on an entity's Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Baxter: Membership on an entity's Board of Directors or advisory committees. Kenet:BPL: Research Funding; Opko Biologics (Prolor Biotech): Consultancy, Research Funding; Novonordisk: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Baxter: Research Funding.

scholarly journals Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4112-4112
Author(s):  
Charline Moulin ◽  
Romain Morizot ◽  
Thomas Remen ◽  
Hélène Augé ◽  
Florian Bouclet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Intermediate Risk ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Long Term Survivors ◽  
First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 179-179
Author(s):  
Jessica K. Altman ◽  
Tsila Zuckerman ◽  
Olga Frankfurt ◽  
Selina M. Luger ◽  
Dale L. Bixby ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Standard Therapy ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Prior Exposure ◽  
Efficacy And Safety ◽  
First Line ◽  
Advisory Committees ◽  
Ongoing Phase

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

scholarly journals Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5263-5263
Author(s):  
Karin Hohloch ◽  
Christine Windemuth-Kieselbach ◽  
Pier Luigi Zinzani ◽  
Roberto E. Cacchione ◽  
Wojciech Jurczak ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Primary Therapy ◽  
First Line ◽  
Advisory Committees ◽  
Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: 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; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
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.

Major Improvement of Invasive Aspergillosis Outcome Is Not Enough to Improve Overall Survival In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Results From a Single-Center Retrospective Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1244-1244
Author(s):  
Géraldine Salmeron ◽  
Raphaël Porcher ◽  
Anne Bergeron ◽  
Marie Robin ◽  
Regis Peffault de Latour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
First Line Treatment

Abstract Abstract 1244 Background. Voriconazole (V) treatment has been shown to improve the 12 week (W) survival rate of hematological patients (pts) with invasive aspergillosis (IA), including recipients of allogeneic hematopoietic stem cell transplants (HSCT). We investigated whether this early survival advantage could translate into a significant increase in overall survival. Methods. We retrospectively reviewed all consecutive pts who received a transplant between Sept. 1997 and Dec. 2008 at Saint-Louis Hospital and were diagnosed as having IA. The temporal origin of the study was the date of IA diagnosis for each patient. Factors associated with survival were analyzed using Cox proportional hazard models. Separate models were estimated for survival up to 12 W and for survival between 12 W and 24 months (M) in pts surviving longer than 12 W. The deaths of pts with and without IA were analyzed with a competing risk framework. Cumulative incidence curves were compared using Gray's tests. Results. Our study examined 89 IA pts. The median follow-up was 70 M (range, 11–130 M). Two pts did not receive any antifungal treatment and were excluded from subsequent analyses. Of the 87 pts, 42 received first-line V and 45 primarily received a lipid formulation of amphotericin B (n=25), amphotericin B deoxycholate (n=10), caspofungin (n=8) or itraconazole (n=2). The primary characteristics of pts with IA and their causes of death, separated by V as first-line treatment, are shown in the table below. The median survival was 2.6 M, and the overall survival at 24 M was 19% (95% CI 12–30 M) (see figure). Overall, the survival rates of the two groups were significantly different (P= 0.010). However, the differences in survival were quite dramatic prior to 10 M, whereas both survival curves became very close after one year. At 18 M, the numbers of surviving pts were almost identical in the two groups [19% (95% CI: 11–34%) in pts who did not receive V as first-line treatment vs. 21% (95% CI 11–38%) in pts who did]. Pts who did not receive V as a first-line treatment displayed a higher probability of dying from IA than those who did (P=0.004), whereas opposite results were found for mortality in pts without IA (P=0.006). The 24-M cumulative incidence of death from IA was 47% (95% CI 31–61%) in the no V group and 19% (95% CI 9–33%) in the group treated with V. The 24-M cumulative incidence of death in pts without IA was 4% (95% CI 7–14%) in the no V group and 27% (95% CI 14–42%) in pts treated with V. The probability of death from another cause, with IA, was similar in both groups (29% vs. 36% at 24 M; P=0.46). After adjusting for donor type, conditioning regimen, progressive GVHD at diagnosis of IA and cumulated steroid dose (mg/kg) in the W preceding IA diagnosis, administration of V as first-line treatment was found to decrease the risk of death during the first 12 W by approximately 70% [HR=0.31 (95% CI 0.16–0.60); P=0.0005]. Conversely, analysis of mortality between 12 W and 24 M failed to identify any significant predictor of risk of death; however, only 24 pts died during this period. Conclusions. The finding that first-line treatment with V, which is associated with a tremendous improvement in IA outcome, does not translate into an increase in overall survival (even in the context of early diagnosis) is striking. Diagnosis of IA following HSCT, whatever the outcome, appears to be a strong marker for poor long-term prognosis. Disclosures: Bergeron: Pfizer: Speakers Bureau, none; Merck: Speakers Bureau, none; Schering: Speakers Bureau, none. Sulahian:Pfizer: Research Funding, non; Merck: Research Funding, none. Ribaud:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, none; Schering: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, none; Gilead: Speakers Bureau, none.

Clinicopathological Features of Nodular Sclerosis-Type Classical Hodgkin Lymphoma In the Elderly: Multicenter Study of Hodgkin Lymphoma In Japan

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2677-2677
Author(s):  
Naoko Asano ◽  
Tomohiro Kinoshita ◽  
Koichi Ohshima ◽  
Tadashi Yoshino ◽  
Nozomi Niitsu ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
The Elderly ◽  
Clinicopathological Features ◽  
Line Treatment ◽  
Classical Hodgkin Lymphoma ◽  
First Line ◽  
Advisory Committees ◽  
First Line Treatment

Abstract Abstract 2677 Background: Classical Hodgkin lymphoma (CHL), which is characterized by the presence of Hodgkin and Reed Sternberg (H-RS) cells in a background of non-neoplastic inflammatory cells, is divided into four histological subgroups, nodular sclerosis (NSCHL), mixed cellularity (MCCHL), lymphocyte-rich, and lymphocyte depletion. While NSCHL in young adults is characterized by a mediastinal mass and good prognosis, the clinicopathological characteristics of NSCHL in the elderly (NSCHL-e) remain uncertain. Patients and methods: Enrolled patients were diagnosed with CHL between 1986 and 2006 as part of the Hodgkin Lymphoma's Multicenter Study Group. To better characterize NSCHL-e, we compared the clinicopathological profiles of 84 NSCHL-e patients aged 50 or over with 237 NSCHL-y patients aged 49 or younger and 302 with MCCHL. Results: The total of 743 CHL patients consisted of 496 men and 247 women with a median age of 48 years (range, 15– 89 years). The pathological diagnoses were NSCHL in 324 patients (43%) and MCCHL in 303 (41%). NSCHL patients showed a bimodal age distribution, with an initial peak in their 20s and a second small peak in their 60s. We categorized the former as NSCHL-y (49 or younger) and the latter as NSCHL-e (50 and over). NSCHL-e patients were characterized by male predominance and a more advanced clinical stage (53%) than NSCHL-y. Immunophenotypically, H-RS cells had the prototypic immunophenotype of CD15+ CD30+ and Pax5+. NSCHL-e cases showed a significantly higher rate of CD20 (24%) than NSCHL-y (8%, P = 0.001). Furthermore, H-RS cells in 29 of 75 (39%) patients with NSCHL-e were positive for EBV RNA transcripts by in situ hybridization, whereas only 7% of NSCHL-y cases were EBER-positive (P < 0.0001) (Table). Regarding NSCHL-e and MCCHL, no significant difference between these patients was seen in clinical characteristics. Immunophenotypically, NSCHL-e patients showed significantly higher rates for CD3 and TIA-1, while MCCHL patients showed higher EBV positivity (75%). Fifty-five of 63 patients received systemic multi-agent chemotherapy as first-line treatment, consisting of doxorubicin, bleomycin, vinblastine, and dacarbacin (ABVD) in 38 patients; CHOP in 8; C-MOPP in 8; and BEACOPP in 1. Overall, 51 patients responded to first-line treatment, 39 with complete response and 12 with partial response. Disease-specific survival of NSCHL-e was poorer than that of NSCHL-y (P < 0.001) but similar to that of MCCHL (P = 0.43) (Figure). Conclusion: NSCHL-e is characterized by an unfavorable prognosis and different clinicopathological features to NSCHL-y, which is considered as typical NSCHL. A number of cases of NSCHL-e might have been associated with MCCHL, with most being EBV-positive. These results suggest the limitations of current histological subgroupings for CHL. Disclosures: Matsushita: Pfizer CO.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Co.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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