A mother’s intuition can lead to the diagnosis of an inhibitor, an antibody to infused factor product concentrate. For Amanda Heisey, 34, that hunch came in 2010, when her son, Peyton, was 10 months old. “Starting around September that year, he would continually get butt bleeds” in his gluteus muscles, says Amanda, a registered nurse from Elizabethtown, Pennsylvania. About every two weeks, Peyton, who has severe hemophilia A, was treated on demand for the bleeds, which were taking longer to resolve. “Instead of treating three days, we were treating him for four days, then five days. I was asking, ‘Should we increase the frequency?’” In November, Peyton was diagnosed with an inhibitor, an antibody to infused factor product.
While attending the National Hemophilia Foundation’s Inhibitor Summit in Miami in July 2011 (See sidebar below, “Inhibitor Education Summits”), Amanda became convinced that immune tolerance induction (ITI) was a necessity for Peyton. ITI is similar to allergy desensitization, familiarizing the body to infused factor so that the immune system recognizes it as “self,” not a foreign invader and stops producing antibodies. Her older brother, JR, who had severe hemophilia A with an inhibitor that was never treated, was relieved. “He had pushed for us to start ITI for months,” Amanda says. A date was then set for Peyton’s port placement for the ITI therapy. “It’s about time,” JR said.
Deciding if it’s time for you or your child to begin ITI depends on many variables, including the type of inhibitor, its initial and peak levels, if the regimen will be interrupted and the protocol of your hemophilia treatment center (HTC).
Who Develops Inhibitors
Genetics play a role in predicting who develops an inhibitor. Studies show that inhibitors are more common in African Americans, Asians and Hispanics. They tend to run in families and in those with specific genetic mutations.
Inhibitors occur in about 20% to 30% of people with severe hemophilia A versus about 3% to 13% of those with mild hemophilia A. That’s because people with severe hemophilia have less than 1% of factor VIII (FVIII) in their bloodstream. Their immune system identifies infused FVIII as a foreign invader and mounts an attack, producing inhibitors. Inhibitors then bind to the factor concentrate, neutralizing its ability to promote clotting.
Intensive, frequent exposure to factor concentrates at a young age can increase the risk of inhibitor development. A paper published in Hematology, the 2011 education program book for the annual meeting of the American Society of Hematology, by Rebecca Kruse-Jarres, reviewed previous studies of inhibitor patients. She found that children whose first exposure to factor product was intense and lasted at least five days in a row had a 3.3-fold risk of developing inhibitors, compared with those treated for only one to two days. When the treatment continued for 10 or more days, the children were 5.5 times more likely to develop inhibitors. Estimates vary, but inhibitors typically develop during the first 10 to 20 exposure days.
Inside Scoop on Inhibitors
An inhibitor is measured in Bethesda units. If the inhibitor level, or titer, in the blood is below 5 Bethesda units, it is considered low; if it’s above 5, it is considered high.
The immune response to factor product can also be low or high, depending on the individual’s immune system. For instance, a low-titer, low-responder patient might have a titer of 2 that doesn’t spike after a dose of infused FVIII. “That patient can be treated long term with FVIII, but he’ll need a high dose to overcome the inhibitor,” says Guy Young, MD, director of the Hemostasis and Thrombosis Center at Children’s Hospital Los Angeles.
Those with a high titer, on the other hand, tend to be high responders. If taken off factor, the inhibitor titer usually drops because there’s nothing for it to make antibodies against. “But as soon as you give them a dose of factor, their titer will shoot back up again,” Young says.
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There are two schools of thought regarding the best time to begin ITI. “The traditional approach is to wait until the titer is less than 10 before we start immune tolerance,” says Young. The newer approach is to start immediately. But Young stands by the data accumulated from studies. “The evidence that’s out there suggests that if your titer is low at the start of ITI, you’ll have a better response.”
During the pre-ITI period, factor product use is discontinued. “By not providing the immune system with exposure to factor, it will ratchet down and stop making antibody. The titer will slowly, slowly go down,” Young says.
But parents need not panic without factor product at the ready. “During that interval, we use FVIIa to treat bleeding when it occurs,” Young says. NovoSeven®, a FVIIa product manufactured by Novo Nordisk, is a bypass agent that circumvents the step in the clotting cascade where FVIII normally comes into play.
Although inhibitor titers drop at different rates, they should do so within three to six months, says Young. “It’s important to do monthly testing in the pre-ITI phase so that you can get to that less-than-10 level as soon as possible.”
Sometimes the inhibitor is stubborn, hitting a plateau and not budging for months. After five months, the titers for Carri Nease’s fraternal twins with severe hemophilia A and an inhibitor, Connor and Tyin, now 6, did the opposite—they rose. “They ended up getting fast-tracked for ports for ITI at 11 months old,” says Carri, a receptionist from Essex, Maryland. The ports were needed for the frequent factor infusions that ITI requires, which can be difficult in young children with difficult-to-find veins. “You shouldn’t be waiting a year to start ITI,” says Young.
Rationale and Regimen
The rationale behind ITI is similar to allergy desensitization. “You’re infusing very high concentrations of the antigen protein in the hope that the immune system becomes tolerant, or accepting, of that FVIII,” says Leonard A. Valentino, MD, medical director of the Hemophilia and Thrombophilia Center at Rush University Medical Center in Chicago. “It’s re-educating the immune system.”
Not just any FVIII product will do. “The standard of care has been to begin ITI with the factor product in which the inhibitor developed,” says Valentino. For most patients, that’s a recombinant product.
The best way to infuse the FVIII product for ITI is through a central venous access device, typically a port. The reasons for using a port in toddlers are legion. “They are chubby and have baby fat still, so it’s hard to find a vein,” says Young. “And they’re strong enough to fight you.”
Most parents find ports to be lifesavers. “When your child has a port, you have the freedom to treat him when you need to,” Amanda says. Good hygiene is a must. “We’ve only had one port infection, and that was in Connor this past year,” Carri says. “Just pay strict adherence to the protocol.” Families should be reminded that for any dental work, antibiotics must be prescribed to prevent infection of the port from bacteria in the mouth entering the bloodstream.
No universal standards of care exist yet for ITI, but registries of inhibitor patients in the US and Europe show that frequent, high-dose treatments are most effective in eradicating inhibitors. “Peyton was started on a daily high dose of 200 units per kilogram (U/kg),” says Amanda.
You can expect to make regular visits for lab work while on ITI. “Once you start ITI, the titer will shoot up when you give a dose of FVIII again, but then will start trending down,” Young says. “The only way to see that trend is with monthly testing.” Routine testing for Peyton revealed that his inhibitor dropped to 0.8 during the first month on ITI, so the factor dose was halved to 100 U/kg.
But there’s not always a consistent drop; inhibitor levels can fluctuate. During their ITI, the twins received high-dose daily infusion of recombinant FVIII. “They both hit zero a couple of times, but then Connor would rebound,” Carri says. Tyin’s peak level was 7 ½; Connor’s was nearly 20 times that—139.
Because each patient responds differently to ITI, the length of treatment is individualized. “A minimum time is 33 months, which has been shown through registry studies,” Valentino says. Tyin fits that time frame. “He was 3 ½ when his inhibitor just kind of faded away,” Carri says. Tyin was pronounced tolerized and is on prophylaxis four times weekly.
ITI is not just for kids, though. “It’s worthwhile to at least try it in an older patient who’s never experienced immune tolerance therapy,” says Valentino. However, there’s a concern about entrenched inhibitors. “That’s where the immune system has been cohabitating with the inhibitor for such a long time that it may not be possible to get rid of it.”
Resuming ITI after an interruption, such as for surgery, may also be feasible. “If you’ve never had a fair trial at ITI—the full dosing and length of therapy—it’s always worth trying,” Young says. But the longer the gap, the less successful it is.
Approximately 5% of patients with severe hemophilia B (factor IX deficiency) develop inhibitors. However, they can be tougher to tolerize. “ITI is probably no more than 40% to 50% successful, and possibly even less than that,” says Young.
Further, some FIX patients develop anaphylaxis, a severe allergic reaction that can be life-threatening. It can be accompanied by nephrotic syndrome, a cluster of symptoms indicating kidney damage. Because further exposure to FIX through ITI or on-demand treatment for bleeds could be dangerous, even the typical bypass agent—Baxter’s FEIBA—cannot be used because it contains FIX. “At that point, the only option they have for managing bleeding is NovoSeven, which is not always perfectly effective for them,” Young says.
“Success is defined as a Bethesda titer below 0.6, and a normal recovery and half-life,” Young says. A normal recovery means how much FVIII is available after an infusion. The half-life measures the time it takes for half the factor to remain in the bloodstream. Both values can be obtained using a survival, or pharmacokinetic, study. “You perform a series of six to eight blood tests over 24 to 48 hours, after a dose of FVIII is given,” Young says. “That’s the testing that’s required in order to pass any judgment on the success of ITI.”
Further Options for Failed Attempts
Despite comparable regimens, about one-third of ITI patients fail to tolerize the inhibitor, says Young. Those tend to be the high-risk patients who either have a high initial inhibitor titer of 200 or more, or one that never dips below 10, he says.
For such patients, there are several options. One involves switching to a plasma-derived von Willebrand factor (VWF)-containing FVIII product. VWF binds to FVIII in the bloodstream, helping transport and hide it. “The VWF, because it’s the carrier protein and because it’s so large, cloaks FVIII against the immune system,” says Valentino.
Another alternative is to switch FVIII products. “If someone doesn’t achieve success with one product, the standard would be to change,” Valentino says. Connor started with a recombinant FVIII (rFVIII) product, was put on a plasma-derived one after failing to respond to ITI, then returned to the rFVIII because his inhibitor was thought to be suppressed. “That’s when it came back with a vengeance,” Carri says. Now Connor’s on NovoSeven to treat bleeds until the inhibitor inches its way down. Then he’ll be placed back on the plasma-derived product and stay on it ad infinitum, says Carri.
A third option is to add an immune-modulating (IM) drug, such as rituximab. IM drugs block B cells that help orchestrate antibody production. Studies show that in patients with unresponsive inhibitors, about half had success when an IM drug was added.
However, IM drugs to treat inhibitors are an off-label use because they have not been approved for this use by the Food and Drug Administration. “They should be used only in the context of an experimental study, because we don’t really understand the risks versus the benefits of these,” says Valentino.
Even though Connor and Peyton are not yet tolerized, their families favor ITI. “It was the best thing for Peyton to try, to give him a better life without having any disability later,” says Amanda. ITI has resulted in fewer severe bleeds for Peyton, who no longer has chronic joint bleeds or spontaneous bleeds.
“While ITI was working, the twins only had normal little boy bruises,” says Carri. After five years of trying to tolerize Connor, her advice for other parents is this: “Keep going—it at least has some benefit.”