Prospective hemophilia inhibitor PUP study reveals distinct antibody signatures during FVIII inhibitor eradication.

FVIII inhibitor formation is a major clinical concern during replacement therapy in hemophilia A patients. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. HIPS (Hemophilia Inhibitor Previously Untreated Patients [PUPs] Study [HIPS]; www.clinicaltrials.gov #NCT01652027) was a prospective clinical trial to investigate changes in the immune system of severe hemophilia A PUPs. Five patients, who developed persistent FVIII inhibitors during HIPS, entered an ITI-extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure or for a maximum of two years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in two patients and failed in three. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the IgG1 and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, one patient with partial ITI success and one patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies.