Acquired Hemophilia A in an African-American Male After Stem Cell Transplant for Sickle Cell Disease: Successful Treatment with Recombinant Porcine Factor VIII (OBI-1) and Tolerance Induction with Rituximab and Prednisone

Abstract 4631

A 44 year old African-American asplenic male with sickle cell disease (HbSS) underwent allogeneic HSCT in September 2009. Upon engraftment, the patient had 97% donor myeloid, and 30% donor lymphoid chimerism, and he was free of his sickle cell disease with HbA 97%, HbA₂ 2.9%,and HbF <1%. Post-transplant he was maintained on sirolimus for GVHD prevention, Bactrim for PCP prophylaxis, and PCN-VK due to his asplenic state.

Twenty eight months later, he experienced onset of minor soft tissue hemorrhage associated with a long aPTT, and low FVIII activity (14% of normal), two weeks after an upper respiratory infection. vWF levels were elevated (antigen 263% & activity 246%), and the FIX level (113%), PT (13.2 seconds), and fibrinogen (395 mg/dL) were normal. He had stable FVIII levels of 10–14% for two months, but then had acute onset of pain, swelling and decreased grip strength in the right hand, consistent with a compartment syndrome. He was treated with Humate-P at a dose of 3000 U every 12 hours, which initially normalized the aPTT and corrected the FVIII to 121%, permitting fasciotomy of the palmar and volar surfaces of the forearm to treat his acute compartment syndrome. After 4 days' treatment on the same 3000 U Q 12 hour dose of Humate P, the recovered FVIII levels declined to only 18%. He was switched to Kogenate with no change in FVIII recovery, then rhFVIIa at doses of 90 μg/kg Q 4 hrs was started eleven days after surgery. Despite inhibitor bypassing therapy, the patient had recurrent pain, swelling, decreased grip strength, decreased range of motion, and numbness in the right hand, consistent with recurrent bleeding. His human FVIII inhibitor titer was 12 BIAU, but < 1 BIAU for porcine FVIII. Recombinant porcine FVIII (OBI-1) was obtained for use under an expanded access provision of IND 16395, and 200 units per kg were given 16 days after surgery, and a second dose of 100 units per kg was given 19 days after surgery. A FVIII level of 540 U/dL was obtained 20 minutes after the first treatment, and the volume of distribution was 2652 mL and the half life was 16.3 hrs. Within 8 hours the pain was diminished (4/10 vs. 7/10), and grip strength measured by dynamometer went from 8 lbs to 55 lbs (compared to unaffected left hand grip strength of 110 lbs). After the 2nd dose of OBI-1 a FVIII level of 621 U/dL was obtained 20 minutes later, and the volume of distribution was 2287 ml, and the half life was 14.7 hrs. Within two weeks the patient had improved range of motion, pain free status, and right hand grip strength of 82 lbs. The patient's grip strength was restored to 101 lbs, 76 days later with physiatry and occupational therapy hand program.

Immunosuppression with rituximab and high dose corticosteroids was begun at the onset of OBI-1 porcine factor VIII treatment; cyclophosphamide was not used to minimize risk for loss of the stem cell graft that cured his sickle cell disease. The inhibitor titer to human FVIII declined from 12 BIAU to less than 0.5 BIAU within three weeks, and there was no loss of donor erythropoiesis (HbA remained >96%). Concomitantly, the patient's endogenous FVIII rose to >100% of normal by day 22, and remained normal after completion of three doses of rituximab and a complete taper of prednisone over the next two months.

The patient had an H2 FVIII haplotype sequence, whereas his donor was heterozygous for the FVIII H1 and H2 haplotypes. A study of stored samples showed that at the onset of mild soft tissue hemorrhage the Bethesda inhibitor titer against a recombinant FVIII with H2 haplotype sequence (Recombinate) was higher (4.2 BIAU) than that against H1 (Kogenate) or “mixed” haplotypes derived from pooled plasma (1.9 BIAU). However, by the time of his compartment syndrome hemorrhage the differential reactivity of neutralizing titers to the H2 haplotype FVIII was not as pronounced (5.2 BIAU for H2 haplotype vs. 4–4.5 BIAU for all other haplotypes/products), suggesting that any initial specificity for the H2 FVIII haplotype had been diminished. No inhibition of OBI-1 porcine factor VIII was seen prior to treatment, or in the 90 day period after treatment. Interestingly, FVIII binding antibodies could be detected prior to the viral infection preceding the overt clinical inhibitor and soft tissue hemorrhage.

In summary we demonstrate use of recombinant porcine FVIII in a patient with a compartment syndrome due to acquired hemophilia, and elimination of the inhibitor, while preserving the transplant that corrected his sickle cell disease.