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2494 Outcome of Immune Tolerance Induction Using an Extended Half-Life Clotting Factor Concentrate - Recombinant Factor VIII Fc (Eloctate™) – a Report from India

Program: Oral and Poster Abstracts
Session: 322. Disorders of Coagulation or Fibrinolysis: Poster II
Hematology Disease Topics & Pathways:
Hemophilia, Biological, Adult, Diseases, Therapies, Bleeding and clotting, Pediatric, Study Population, immunotherapy, Clinically relevant, Quality Improvement
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Aby Abraham, MD, DM1*, Shashikant Apte, MD, FRCPA2, Chandrakala Shamukhaiah, MD; DM3*, Fouzia N., DNB, DM1*, Kannan Subramaniam, DNB, DM2*, Akshata Rahate, MD; DM3*, Abraham Sunder Singh, BSc1*, Aditi Joshi, BAMS2*, Kavitha M Lakshmi, MSc1*, Rajesh Phatale, MD2*, Shrimati Shetty, PhD4*, Sukesh Chandran Nair, MD5*, Biju George, DM1, Vikram Mathews, MD 6 and Alok Srivastava, MD., FRACP, FRCPA1

1Department of Haematology, Christian Medical College, Vellore, India
2Department of Haematology, Sahyadri Specialty Hospitals, Pune, India
3Department of Haematology, KEM Hospital, Mumbai, India
4ICMR, Institute of Immunohematology, Mumbai, India
5Department of Transfusion Medicine & Immunohematology, Christian Medical College, Vellore, India
6Department of Haematology, Christian Medical College, Vellore, Tamil Nadu, India

The development of inhibitors is the most serious adverse effect of replacement theray with clotting factor concentrates (CFC) in hemophilia. Its eradication is also difficult, usually requiring months of frequent exposure to high doses of the CFC – immune tolerance induction (ITI). There is limited data on use of extended half-life (EHL) CFC for ITI. A limited program of ITI was made possible in India with some of the rFVIIIFc (Eloctate™) provided through the humanitarian aid program of the World Federation of Hemophilia. This report summarizes the interim outcome of ITI in these patients treated at three centers participating in this program.

ITI with rFVIIIFc was offered to patients with hemophilia A and significant inhibitors. The CFC dose used ranged from 50 IU/kg, 3x/week, to 200 IU/kg per day, depending on the weight, convenience and early response as well as availability of rFVIIIFc. All patients completing at least 10 weeks of ITI are included in this analysis. Bethesda assay was done every 2-4 weeks. Successful ITI was defined as a negative Bethesda assay with a FVIII recovery of >60%. Patients received either FEIBA or rVIIa for breakthrough bleeds.

Thirty eight patients were included in this analysis. The median age at initiation of ITI was 15 years (range:2 -39). Nine (24%) patients had a family history of inhibitors. The median age at which inhibitors developed was 11 years (range:0.6 -38). Nine (24%) patients had history of surgery prior to onset of inhibitor. Ten patients (26%) had exposure to only plasma derived factors. All patients were on episodic CFC replacement therapy except two (5%) who were receiving low-dose prophylaxis prior to inhibitor development. The median exposures to FVIII was 20 (range:2-80) and duration of inhibitors prior to ITI was 2 years (range:0.1 - 20). The median highest inhibitor titre recorded prior to ITI was 19 BU (range:4-1177). Only 3 patients had their maximum inhibitor titer below 5BU. The median inhibitor titre at the time of starting ITI was 10.4 BU (range: 0.6–1177). The median peak inhibitor titer after starting ITI was 40.4 BU (range:3.5–13933). Out of the 38, 17 (45%) patients achieved a negative inhibitor status after ITI for a median duration of 23 weeks (range: 10-64). Among the 17 patients who had successful ITI, the median duration of ITI required to achieve negative inhibitor status was 20 weeks (range:10-60). Among the other 21 patients who had persistence of inhibitors, 4 were included in other clinical trials, 3 discontinued due to personal reasons while the other 14 are continuing ITI based on availability of appropriate EHL CFC. Among these patients with persistence of inhibitors, the last inhibitor titer was 6.4 BU (range:0.9-9240) after a median of 26 weeks of ITI (range:11-64). The median number of breakthrough bleeds during ITI was 1 (range:0-12), being 1 (range:0-6) among responders and 1 (range:0-12) among those with persistence of inhibitors. A comparison of the group which responded within this duration of ITI and those who did not respond is shown in the table. Older age and the peak inhibitor titer prior to ITI were the two significant variables which affected early outcome of ITI.

These data show that EHL rFVIIIFc can be effective in ITI with nearly 45% of patients achieving a negative inhibitor titer within 1 year and with responses starting as early as 1 month and nearly half of them within 4 months. There was also a relatively low median annualized bleed rate during ITI. More patients need to be treated with different doses of rFVIIIFc to assess its potential in ITI and to determine the optimal protocols but the initial data is promising.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH