Long-Term Follow-up of Hemophilia a Patients Who Previously Showed Complete or Partial Success in Immune Tolerance Induction Therapy with a Single Plasma-Derived FVIII/VWF Product: Long-Term ITI Study
Authors: Jiménez-Yuste Víctor , Oldenburg Johannes , Rangarajan Savita , Peiró Roser , Santagostino Elena 
Published: October 2019

Abstract
Introduction
Inhibitor development against infused FVIII is a serious complication in hemophilia A that greatly increases the risk of developing major bleeding episodes. Immune tolerance induction (ITI) is the standard therapy for the management and eradication of inhibitors and return to effective FVIII therapy. Little evidence exists on the long-term status of patients who eradicated the inhibitor totally or partially by ITI. Therefore, the aim of this study is to investigate the clinical status and sustainability of tolerance in patients who succeeded on ITI therapy.
Methods
The Long-term ITI study was an international, multicenter, observational, retrospective study performed on hemophilia A patients who received primary or rescue ITI therapy using a single pdFVIII/VWF concentrate (Fanhdi®, Grifols, Spain) and who showed partial or total success in the Grifols-ITI study (Oldenburg J et al. Haemophilia 2014;20:83, Rangarajan S et al. J Thromb Haemost 2013;11 suppl 2;1081). In the G-ITI study, 60 patients from Germany, Italy and Spain showed a success rate of 85% and nine other G-ITI patients from UK obtained a 78% of ITI success. Demographics and clinical data relevant for the Long-term ITI study were extracted from the medical records of eligible patients. Primary endpoints were to describe the long-term status and post-ITI outcomes (including comorbidities, joint status, bleeding episodes, inhibitor relapses, venous access complications, hospitalizations and surgeries). Secondary endpoints included regular hemophilia therapy as well adjuvant and concomitant therapy used. Statistical analysis performed was descriptive.
Results
Forty-four out of the 57 eligible patients signed the informed consent and were included in the study. The mean follow up period after ITI success was 9.3 ±3.3 years (range: 2.1-17.7). At least one co-morbidity was reported in 17 (38.6%) patients, which included liver and lung cancer, hypertension, liver disease, hepatitis C and HIV infection. Twenty-one (47.7%) patients had a total of 37 affected -joints of which 5 patients had 2 affected joints, 1 patient had 3 affected joints and 3 patients had 4 affected joints. In 38 (86.4%) patients at least 1 bleeding episode was reported (mean annual bleeding rate: 1.0±1.2; range 0.1-3.9). A total of 330 bleeding episodes were described, of which 271 were treated with Fanhdi. Four (9.0%) patients had inhibitor relapse. Of those, 2 patients did not attempt rescue ITI because in one case the inhibitor (0.5 BU) disappeared after the next infusion with Fanhdi, and the other was considered of low titer (3.5 BU). The 2 patients who attempted rescue ITI (one under prophylaxis with Kogenate and the other treated on demand with Emoclot at the time of inhibitor relapse) were both successfully tolerized, one completely after 3.9 months of ITI with Fanhdi and the other partially after 9.1 months of ITI with Haemate P. Twenty venous access complications were reported in 10 (22.7%) patients. Thirty-nine surgical/invasive procedures were reported in 22 (50.0%) patients, 37 procedures requiring extra treatment with FVIII (Fanhdi), 25 of them for more than 3 days and 14 for more than 5 days. Hospitalizations reported were 79, 17 of them due to bleeding, 18 due to venous access complications, 33 due to surgical/invasive procedures, and 11 due to other reasons. Treatment product for hemophilia after ITI success was always Fanhdi in 29 (65.9%) patients, while 13 (29.5%) other patients were first treated with Fanhdi and then switched to other FVIII products, and 2 patients were immediately switched post-ITI to other FVIII products. The most common regimen used was prophylaxis (42 patients, 95.4%), and the most common treatment frequency was every 48 hours (16 patients, 36.4%). The FVIII dose ranged from 20 to 85 IU/Kg. Use of NSAIDs was reported for 6 patients and immunesuppressors for 5 patients.
Conclusions
After an average of more than 9 years of post-ITI success follow up of patients participating in the G-ITI Study, all of them continue with regular FVIII treatment for hemophilia. The few inhibitor relapses were successfully overcome.

Disclosures
Jiménez-Yuste: Baxter, Bayer, CSL-Behring, Grifols, Novo Nordisk, Octapharma and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Oldenburg:Baxter, Bayer, Biogen Idec, Biotest, CSL-Behring, Grifols, Novo Nordisk, Octapharma, Swedish Orphan Biovitrum and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rangarajan:Baxter, Grifols, Biotest and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Peiró:Grifols: Employment. Santagostino:Bayer, Baxter, Pfizer, CSL Behring, Novo-Nordisk, Sobi/Biogen, Octapharma, Kedrion, Roche and Grifols: Consultancy, Honoraria, Research Funding, Speakers Bureau.