Low-Dose Combined Immunosuppression Results In Rapid Remission In Patients With Acquired Hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3589-3589 ◽  
Author(s):  
Andrea Várkonyi ◽  
Attila Szederjesi ◽  
János Dolgos ◽  
Péter Farkas ◽  
Júlia Galgóczi ◽  
...  
Keyword(s):  
Low Dose ◽  
Hemophilia A ◽  
Bleeding Control ◽  
Off Label Use ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Off Label ◽  
Bypassing Agents ◽  
Inhibitor Titer

Abstract Introduction Acquired hemophilia A (AHA) is a rare severe disorder caused by autoantibodies against FVIII resulting in significant morbidity and mortality up to 20 % in some studies. The two pillars of treatment include acute bleeding control, and immunosuppressive therapy which aims to stop the underlying autoimmune phenomenon. Although critical for long-term disease-free survival, there is currently no consensus for the best immunosuppressive regimen. Most authors use steroids first line, followed by cyclophosphamide and/or rituximab in steroid failures. However, upfront low-dose combined regimens offer the theoretical advantage of reduced steroid-exposure and toxicity as well as increased effectiveness. In the current retrospective analysis, we aim to review our institutional experience with such a regimen. Patients and Methods We identified 16 (7 males and 9 females) AHA patients newly diagnosed between October 2009 and June 2013; all treated with an identical regimen on an institutional protocol. Patient age varied between 53-86 (median 76,4) years. Mean initial inhibitor titer was 30.5 Bethesda units (BU; range 2 - >500). In 4 out of 16 patients (26,7 %) an underlying disease was identified, the remaining 12 cases were considered idiopathic. Low-dose combined immunosuppression consisted of the following regimen: 1000 mg cyclophosphamide on day 1 and 22, 40 mg dexamethasone on day 1, 8, 15 and 22, and 100 mg rituximab on day 1, 8, 15 and 22 (the regimen was termed CyDRi). Simultaneous use of bypassing agents was left to the discretion of the treating physician (8/16 patients, 50 %). All patients received at least 1 cycle of CyDRi. If complete remission (CR, defined as cessation of bleeding and an undetectable FVIII inhibitor in the Bethesda assay) was not achieved, the CyDRi therapy was repeated every 6 weeks until remission. Laboratory follow-up included CBC, routine chemistry and APTT (with a mixing study when prolonged), as well as FVIII levels and the Bethesda assay. Clinical monitoring varied according to the localization of bleeding. Results 50 % of patients presented with severe active bleeding symptoms, and they all received bypassing agents simultaneously with the CyDRi regimen. The remaining 8 patients had a recent history of bleeding but were not actively bleeding at the time of admission, and were given CyDRi without concurrent bypassing agents – none of them had a subsequent episode of bleeding (time to bleeding control = 0; Figure) Bleeding control was also rapidly achieved in the other patients with >90 % of patients free of bleeding within 3 weeks (Figure). CR was achieved in 15/16 patients (93,75 %). The time to CR was short with more than 75% of patients in CR by week 7 (Figure). Toxicity and side effects were infinitesimal compared to commonly used prolonged steroid therapies: One patient acquired pneumonia three weeks after discharge from the hospital, and two patients developed Clostridium difficile colitis during hospitalization. All three patients responded to antibiotic treatment. 8 of 16 patients (50 %) required more than one cycle of CyDRi to achieve a durable CR, either due to slow response or a laboratory relapse (6 and 2 patients, respectively). Two of the 8 patients required a third cycle of CyDRi (one for a very slow response, the other for a second relapse). CyDRi was equally effective in treating relapses. One patient died from a cause deemed unrelated to AHA (elderly patient with a femoral neck fracture). Her inhibitor titer was falling rapidly, but she died before achieving CR. Follow-up of our cohort is median 21 (range 2-45) months. Conclusion The CyDRi low-dose combined immunosuppression produced higher complete remission rates with a remarkably rapid cessation of bleeding and a significantly improved side-effect profile and mortality rate in this retrospective AHA cohort, compared to regimens previously described in the literature. A prospective randomized comparison seems warranted to confirm these results. Disclosures: Off Label Use: Cyclophosphamide, dexamethasone and rituximab are all off label use for the treatment of acquired hemophilia A.

scholarly journals Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry

Blood ◽  
2012 ◽  
Vol 120 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Francesco Baudo ◽  
Peter Collins ◽  
Angela Huth-Kühne ◽  
Hervé Lévesque ◽  
Pascual Marco ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Hemostatic Agent ◽  
Symptomatic Therapy ◽  
Bleeding Control ◽  
First Line ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Acquired Haemophilia ◽  
Bleeding Episodes ◽  
Bypassing Agents

AbstractAcquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

Acquired Hemophilia A. Experience Of a Single Center

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4781-4781 ◽  
Author(s):  
Mauricio A Alzate ◽  
Susana S Meschengieser ◽  
Alicia Blanco ◽  
Silvia Grosso ◽  
María A Lazzari ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Initial Symptoms ◽  
Bleeding Episodes ◽  
The Mean ◽  
Inhibitor Titer

Introduction Acquired hemophilia A is a rare and serious autoimmune disease. Morbidity and mortality are associated with advanced age, comorbidities, toxicity of treatment and bleeding severity. Treatment goals are control of the bleeding and eradication of the inhibitor, while treating the underlying condition if it is present. Objective To describe the baseline characteristics of acquired hemophilia A patients and to assess the response to treatment. Patients and Methods Between November 1991 and April 2013, 27 patients were diagnosed with acquired hemophilia A (mean age 59, range 21-86; 18 women - 66%) in the Departamento de Hemostasia y Trombosis. Five patients were lost from follow-up. APTT mixing studies with normal plasma (1:1) and time-temperature dependent effect on the APTT were performed for a-FVIII diagnosis. Whenever possible, inhibitor activity was titrated by Bethesda method at diagnosis (BU/mL). Medical records were reviewed to evaluate the initial symptoms, underlying diseases, treatments and outcome. Results The mean follow-up was 86 weeks (range 1-640). Underlying etiologies included: idiopathic 70.4%, postpartum 14.8%, malignancy 11.1%, autoimmune disease 3.7%. All patients had bleeding at diagnosis. The most frequent sites of bleeding were: muscular 32%, soft tissue 18%, urinary tract 9%, gastrointestinal tract 6%; being from multiple sites in 9%. At diagnosis, the mean value for FVIII was 6% (range 1-40), and inhibitor titer 220 BU/mL (range 2.2-1173). Initial therapeutic scheme included glucocorticoids in 97% of the patients, 13 in monotherapy (mean age 53 years ± 19), 13 with cyclophosphamide (63 years ± 18) (p= ns), and human immunoglobulin in 1 patient. This last patient died after 1 week of diagnosis due to uncontrolled gastrointestinal bleeding (previous to the era of rVIIa). As a second-line therapy, rituximab was used in 3 patients. Sixty-three (63%) patients achieved complete response (CR) (inhibitor titer < 0.6 BU/mL without bleeding episodes), and 23% achieved partial response (PR) (reduction in inhibitor titer > 50% without bleeding episodes), without differences between monotherapy or combined. Overall, women responded more frequently than men (93.3% vs. 71.4%, p= ns). All patients that received rituximab achieved CR. Conclusions In this study, the overall response rate was higher than 80%. In most cases, the disease has a prolonged course like other autoimmune diseases, with remissions and relapses. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Diagnosis and Treatment of Acquired Hemophilia: One Single-Center Experience from PR. China

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4250-4250
Author(s):  
Rong-Fu Zhou ◽  
Yueyi Xu ◽  
Wenjin Gao
Keyword(s):  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Clinical Manifestations ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Coagulation Factor Vii ◽  
Prolonged Aptt ◽  
Inhibitor Titer

Abstract Objective: To deepen the understanding of the clinical manifestations of acquired hemophilia A for timely and correctly treatment. Methods: The clinical data of the acquired hemophilia A patients diagnosed in the hospital from Jan 2006 to Mar 2021 were retrospectively analyzed, and the relevant literature was reviewed. Results: 17 patients with acquired hemophilia A, male: female =10: 7, median age 61 years (19 to 78 years), were diagnosed and treated in the hospital with the median time from the onset to diagnosis 21 days (2 days to 6 months). Six patients had comorbidity, including hepatitis B carrying, chronic myelomonocytic leukemia, diabetes, hypertension and positive autoantibodies, pemphigoid and gastric cancer, respectively. Other 11 patients were healthy before the onset. All patients had large large ecchymosis of skin, and one case was combined with hematuria, and one case with retroperitoneal hematoma. All patients had APTT extension (45s-144.7s) and the prolonged APTT could not be corrected with normal mixed plasma with and without incubation at 37℃ for 2 hours. FVIII activity was 1% - 8.9% and inhibitor titer 2 - 128 Bu/ml. All patients with bleeding were with prothrombin complex/recombinant activated coagulation factor VII, some of them with pd-coagulation factor FVIII preparations. Inhibitors were removed with prednisone acetate (1 case) + chemotherapy (1 case), prednisone acetate / + CTX (11 cases) + chemotherapy (1 case), prednisone acetate/prednisolone + mabthera (2 cases) + CTX (1 case), respectively. The removal time of inhibitor was from 8 days to 4 years. During the treatment process, two patients developed lower extremity venous thrombosis, and one patient was complicated with lung infection. Conclusion: Patients with unexplained bleeding and prolonged APTT should be conducted normal mixed plasma correction test, coagulation factor activity and inhibitor titer examination. After correctly diagnosis, bypass agents /coagulation factor VIII preparations should be given timely for hemostasis, protocol based on glucocorticoid + CTX/mabthera to remove the inhibitor and symptomatic treatment for patients with primary comorbidity disease at the same time. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acquired Hemophilia A (FVIII Deficiency) Associated with Papillary Thyroid Cancer: Treatment with Recombinant Porcine FVIII

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
S. Nguyen ◽  
P. Teh ◽  
J. Zhou ◽  
E. Y. Chang ◽  
A. von Drygalski
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Hemophilia A ◽  
Autoimmune Disorder ◽  
Bleeding Complications ◽  
Papillary Thyroid ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Rescue Treatment ◽  
Bypassing Agents

Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by autoantibodies against Factor VIII (FVIII). It has a high mortality due to bleeding complications. FVIIa-based bypassing agents are the first line of treatment but not always effective. Recombinant porcine (rp) FVIII (Obizur®) was recently approved for rescue treatment but with little evidence-based information regarding efficacy. We report a case of papillary thyroid cancer associated with AHA malignancy that responded to a single dose of rpFVIII after failure to achieve hemostasis with FVIIa-based bypassing products.

Emicizumab for the treatment of acquired hemophilia A

Blood ◽  
2020 ◽  
Author(s):  
Paul Knoebl ◽  
Johannes Thaler ◽  
Petra Jilma ◽  
Peter Quehenberger ◽  
Karoline Veronika Gleixner ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Coagulation Factor ◽  
Standard Of Care ◽  
Early Discharge ◽  
Severe Bleeding ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Breakthrough Bleeding ◽  
Hemostatic Efficacy ◽  
Bypassing Agents

Acquired hemophilia A (AHA) is a severe bleeding disorder caused by inhibiting autoantibodies to coagulation factor VIII (FVIII). For hemostatic treatment, bypassing agents, human or porcine FVIII are currently standard of care. Emicizumab is a bispecific, FVIII-mimetic therapeutic antibody, that reduced the annualized bleeding rates in congenital hemophiliacs. Here we report on 12 patients with AHA, 6 male, 6 female, age 74 yrs (64/80) (all data medians and IQR), treated with emicizumab. Initial FVIII was &lt;1%, inhibitor 22.3BU/mL (range 3-2000). Eight patients had severe bleeding. Emicizumab was started with 3mg/kg sc. weekly for 2-3 doses, followed by 1.5mg/kg every 3 weeks to keep the lowest effective FVIII levels. For FVIII monitoring, chromogenic assays with human and bovine reagents were used. All patients received immunosuppression with steroids and/or rituximab. After the first dose of emicizumab, APTT normalized in 1-3 days, FVIII (human reagents) exceeded 10% after 11 (7.5/12) days. Hemostatic efficacy was obtained and bypassing therapy stopped after 1.5 (1/4) days. FVIII (bovine reagents) exceeded 50%, indicating complete remission, after 115 (67/185), and emicizumab was stopped after 31 days (15/79), in median 5 injections (range 3-9) were given. No patient died from bleeding or thromboembolism, and no breakthrough bleeding was observed after the first dose of emicizumab. In conclusion, emicizumab seems to be an effective hemostatic therapy for AHA, with the advantages of sc. therapy (every 1-3 weeks), good hemostatic efficacy, early discharge, reduction of immunosuppression and adverse events.

scholarly journals Treatment of Acquired Hemophilia a with Rituximab and Emicizumab

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Evan C. Chen ◽  
William J. Gibson ◽  
Paula Temoczko ◽  
Nathan T. Connell ◽  
Robert Handin ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Case Series ◽  
High Dose ◽  
Recurrent Bleeding ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Private Company ◽  
Fviii Inhibitor ◽  
Fviii Activity

Background Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies that inhibit coagulation factor VIII (FVIII). The disorder is understudied given its rarity and there are no randomized prospective trials to guide therapy. In practice, treatment involves attaining hemostasis and eliminating the FVIII inhibitor, typically with high-dose steroids (1 mg/kg daily) and either cyclophosphamide or rituximab. However, current approaches carry risk of significant adverse events and delayed or inadequate responses. Emicizumab is a bispecific antibody that targets coagulation factors IXa and X to recapitulate the function of endogenous FVIII. We present a case series of patients with acquired hemophilia A who were successfully treated with a regimen consisting of rituximab and emicizumab. Methods We identified patients &gt;18 years who were diagnosed with acquired hemophilia A and received treatment with rituximab and emicizumab at Brigham and Women's Hospital between 2019 and 2020. We performed a retrospective chart review. Data collected included the patients' clinical presentation, laboratory studies (including coagulation testing, FVIII activity, and FVIII inhibitor titer), and treatments received (including systemic therapies, recombinant factor VIIa [rFVIIa], red blood cell [RBC] transfusions, and vascular embolization). We recorded the time to normalization of the activated partial thromboplastin time (aPTT) and chromogenic FVIII activity following emicizumab and rituximab initiation, respectively. Activated prothrombin complex concentrate was avoided given the use of emicizumab. Results We identified 8 patients with acquired hemophilia A who received treatment with emicizumab and rituximab. The median patient age was 81 (range 47-93). All patients sought medical attention for extensive ecchymoses or bleeding and were found to have prolonged aPTT leading to FVIII inhibitor identification (Table 1). The median inhibitor titer was 18 Bethesda units (range 9.2-107.5). Patients concurrently received 4 weekly doses of rituximab 375mg/m2 and 4 weekly loading doses of emicizumab 3mg/kg. Patient (Pt) #1 continued emicizumab 3mg/kg every two weeks to complete three months of treatment. Pts #2, #3, and #8 received high-dose prednisone (1mg/kg) at the start of treatment for a range of 10-14 days. Pt #8 received 7 additional days of prednisone for an initial aPTT of 60.7 seconds before starting emicizumab and rituximab; she had no clinical response when treated with prednisone alone. Pts #2, #5, and #7 required vascular embolization. 7 patients (Pts #2 through #8) had aPTT retested within 1 week of starting emicizumab, and the aPTT for these patients normalized within 10 days of starting emicizumab (i.e. after only 1-2 doses; Figure 1). Except for Pt #5 who had recurrent hematuria from a persistent anatomic bladder defect that eventually required prostatic artery embolization, patients did not require rFVIIa or RBC transfusions for more than 7 days after starting emicizumab. Except for Pt #5 who required 28 doses of rFVIIa and 3 units of RBC transfusions after starting emicizumab, the median number of rFVIIa doses and RBC units given to the remaining 7 patients was zero (range 0-6 doses) and zero (range 0-4 units), respectively. Pts #2 and #3 had chromogenic FVIII levels obtained &gt;30 days after starting rituximab with improvement in FVIII activity to 29% (day 71) and 86% (day 91), respectively. During a median follow-up of 102 days, no patients experienced recurrent bleeding. However, Pt #3 exhibited a slowly increasing aPTT that reached 46.3 seconds on day 233 of follow-up without symptoms; further diagnostic testing is pending. Conclusion Our case series demonstrates that the combination of rituximab and emicizumab can be an effective and safe regimen for the treatment of acquired hemophilia A. No thrombotic events or thrombotic microangiopathy occurred. Treatment with weekly emicizumab led to aPTT normalization after 1-2 doses and facilitated hemostasis, as reflected by a median usage of zero rFVIIA doses and zero RBC transfusions after starting emicizumab when excluding one patient with hematuria from an anatomic defect. This compares favorably to historical reports. While no patient has had recurrent bleeding, additional chromogenic FVIII activity testing for patients is needed to confirm long-term normalization of FVIII activity. Disclosures Gibson: Ampressa therapeutics: Current equity holder in private company; nference: Consultancy, Current equity holder in private company; ImmPACT-Bio: Consultancy; Boston Clinical Research Institute: Consultancy. Parnes:Bayer: Consultancy; I-Mab: Consultancy; Sunovion: Consultancy; UniQure: Consultancy; Sigilon: Consultancy; Shire/Takeda: Consultancy, Research Funding; Genentech: Research Funding; Geron: Current equity holder in publicly-traded company. OffLabel Disclosure: Emicizumab is used off-label in our case series for the treatment of acquired hemophilia A.

scholarly journals Low-Dose Immune Tolerance Induction for Hemophilia a Children with Poor-Risk High-Titer Inhibitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1122-1122
Author(s):  
Zekun Li ◽  
Zhenping Chen ◽  
Xiaoling Cheng ◽  
Xinyi Wu ◽  
Li Gang ◽  
...  
Keyword(s):  
Success Rate ◽  
Board Of Directors ◽  
Immune Tolerance ◽  
Low Dose ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Advisory Committees ◽  
Immune Tolerance Induction ◽  
Inhibitor Titer

Background: Low-dose immune tolerance induction (ITI) +/- immunosuppression as a practical ITI strategy in China showed a relatively satisfactory success rate and economic advantages in pilot study. However, the outcome still needs to be verified by larger cohort. Aim: To report the efficacy of this low-dose ITI +/- immunosuppression strategy in hemophilia A children ≥ 10 BU. Methods: This was a single center, prospective study in 53 hemophilia A subjects from Sep 2016 to Apr 2019. All subjects having ≥ 10 BU receiving ~50IU/kg FVIII every other day using domestic intermediate purity pdFVIII/VWF products, either alone or in combination with rituximab and prednisone judging by inhibitors and ITI response. Results: Finally, 46 subjects received this strategy at a median of 3.2 (IQR, 2.3-6.5) years old, their pre-ITI inhibitor titer was median 30.0 (range, 10.1-416) BU. Analysis at median 15.1 (range 3.0-34.4) months follow-up, success (inhibitor <0.6BU) was achieved in 32 (69.6%) subjects, partial success (inhibitor <5BU but >0.6BU) in 11 (23.9%) subjects, and failure in 5 (10.9%) subjects. Between subjects administered ITI-alone and ITI- immunosuppression, no significant difference was observed in time to success (median 8.5; IQR 6.7-11.7 vs 10.2; IQR 5.1-25.1, P=0.164). The mean monthly bleeding rate on ITI was 0.49 which declined 59.3% compared with pre-ITI period. Subjects administered ITI-immunosuppression (0.54 ± 0.46) was higher than ITI-alone (0.42 ± 0.69) although with no significantly difference (P=0.089). Seven (21.9%) subjects experienced inhibitor recurrence, 4 subjects treated with ITI-alone, 3 with ITI-immunosuppression. Recurrence occurred at a median of 4.8 (range, 2.8-10.8) months after successful ITI with inhibitor titer transiently rising to median 0.7 (range, 0.7-1.5) BU. Conclusion: This low-dose ITI +/- immunosuppression therapy in subjects with pre-ITI inhibitor ≥ 10 BU showed a success rate similar to other high/intermediate-dose regimen for the whole inhibitor patients. The subjects treated with ITI-immunosuppression did not showed higher recurrence at present, while a longer time follow-up is still needed. Disclosures Poon: Roche: 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; Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; World Federation of Hemophilia: Other: Not-for-profit organization affiliation: volunteer ; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation in sponsored research; CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Takeda/Shire: 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.

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.

Recombinant human activated FVII as prophylaxis in surgical treatment of cancer patient with acquired hemophilia A.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17006-e17006
Author(s):  
Giacinto La Verde ◽  
Antonella Ferrari ◽  
Vincenzo Ziparo ◽  
Virginia Naso ◽  
Maria Paola Bianchi ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Activity Level ◽  
Cytotoxic Agents ◽  
Bleeding Complications ◽  
Normal Range ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Inhibitor ◽  
Post Surgery ◽  
Inhibitor Titer

e17006 Background: Acquired hemophilia A is caused by the development of factor (F)VIII autoantibodies and results in more serious haemorrhagic symptoms than in congenital severe HA. About 50% of cases, not identified as idiopathic, are related to autoimmune diseases, viral infections, pregnancy and also neoplasms. To treat bleeds recombinant factor VIIa and activated prothrombin complex concentrate are equally efficacious while immunosuppression with steroids alone or combined with cytotoxic agents should be started as soon as the diagnosis is made. Methods: In February 2010 a woman of 58 years with acquired hemophilia A, previously treated in 1978 with cyclophosphamide and steroids without clinical benefits, was admitted to the Hematology Department of Sant’Andrea Hospital in Rome for a recent episode of spontaneous massive enterorrhagia. The diagnostic exams revealed a colorectal carcinoma (moderately differentiated G3) associated with papillary urothelial neoplasia with low malignant potential. A coagulation panel showed an aPTT ratio of 3.75 (normal range 0.8-1.2), INR 1.03 (normal range 0.9-1.2), fibrinogen 327 mg/dL (normal range 238-500), FVIII activity level of 3% (normal reference 50-150%) and FVIII inhibitor titer > 100 Bethesda Units. Results: The patient was treated with left hemicolectomy and removal of the bladder lesion associated with chemotherapy XELOX (oxaliplatin 130 mg/sm day 1 q21, capecitabine 1000 mg/sm orally day 1-14 q21). From day -1 to day +15 post surgery, the patient was treated with intravenous recombinant human activated FVII at standard dose (NovoSeven®, 90 mcg/kg every 4 hours). Our treatment avoided both intra and post-operative surgical bleeding complications, while not changing the titer of the inhibitor nor by normalizing the aPTT ratio. Actually the patient is in good clinical conditions with no further hemorrhagic episodes, although the FVIII inhibitor titer still remains high. Conclusions: We have described this case to emphasize that the presence of acquired hemophilia A in cancer patients, thanks to its specific prophylactic treatment, cannot be a limit in performing routine diagnostic and therapeutic procedures, especially surgical ones.

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