Immune Tolerance Utilizing Intermediate Purity Factor VIII Concentrate in Hemophilia A Patients with High Factor VIII Titers.
Authors: Heisel Kurth Margaret A. , Christie Beverly , Hanneman Vicky , Osip Joni , Appert Kristen , Moertel Christopher L. , Watterson Jan , Hag-Alshiekh Maha 
Published: April 2020

Immune tolerance therapy (ITT) is a treatment that is used to eliminate factor VIII inhibitors associated with hemophilia A. However, standard ITT is not successful in approximately 20% of patients. In those who do not attain tolerance, the length of treatment with resultant cost of factor concentrate and family stress are major concerns. Utilization of intermediate purity products (IPP) has been suggested as a means to increase the success rate of ITT, shorten the duration of ITT, and decrease the quantity of factor concentrate used. We retrospectively analyzed outcomes for 8 patients who received IPP as part of an ITT regimen from 1993–2004. Four patients were switched from recombinant/monoclonal factor VIII to IPP during ITT because of poor response to initial therapy (Table 1). Four others were started on IPP at the initiation of ITT because they had already failed ITT or past history indicated a likelihood of failing standard ITT (Table 2). Tolerance was defined as having a Bethesda titer of &lt;1 BU/ml, &gt; 66% recovery of factor VIII, and/or a half-life of 6 hours or greater. In the first group, all four patients attained tolerance. In these patients the switch to IPP resulted in a faster drop in inhibitor titer than had been previously achieved. In the second group, one patient attained tolerance rapidly; one achieved partial tolerance and uses prophylactic IPP. A third patient is currently undergoing ITT and is responding well. The fourth patient has failed to achieve tolerance. These four patients had adverse risk factors that made them poor candidates for conventional ITT. Of the 6 patients who have achieved partial or complete tolerance, 4 have been switched back to recombinant factor VIII and have maintained tolerance. However, two patients have been maintained on IPP because attempts to switch to recombinant factor VIII resulted in a rise in their inhibitor titers. If tolerance can be achieved with IPP it can result in major cost savings for these patients. At our institution the cost of IPP is about 50–66% of the cost of recombinant factor VIII. These data are presented as further evidence that choice of factor may influence ITT success and that a subset of patients may benefit from an IPP regimen for ITT.

Table 1: Recombinant/Monoclonal Use; Patients Switched to IPP

ID Age at Inhibitor Dx (yrs) Peak Inhibitor (BU) Age at Start of ITT (yrs) Inhibitor at ITT Start (BU) Age at Switch to IPP (yrs) Reason for Switch Time to Tolerization 001 6.8 34 9.8 2 10.0 Poor response to ITT 12 months 002 8.2 100 11.8 1 12.1 Poor response to ITT by brother (001) 6 months 005 5.2 124 6.3 9 6.5–7.0 /8.2-present Poor response to initial therapy / inability to sustain tolerization 36 months 007 3.9 270 3.9 13 4.1 Poor response to ITT and bleeding complications 16 months

Table 2: Patients Started on IPP Initially

ID Age at Inhibitor Dx (yrs) Peak Inhibitor (BU) Age at Start of ITT (yrs) Inhibitor at ITT Start (BU) Time to Partial Tolerization Time to Tolerization 003 4.0 4833 21.4 6 Did not achieve NA 004 1.2 1000 12.4 10–20 29 months NA 006 1.3 600 12.4 0–1 6 months 8 months 008 0.8 277 5.8 1.1 6 months NA