Restarting Weekly Infusions. Wait. What???

Sarah and I just agreed to have a new central line placed for Ethan and to restart him on weekly enzyme replacement therapy.

I can't believe I just said that.  Moreover, I can't believe that Sarah and I have volunteered to do this to Ethan.  But we have.
Ethan and me at one of his first Aldurazyme infusions.  This was even before his central line was placed, so would have been August 2009. (Picture by Sarah.)

Sarah and I just sent in the consent forms to enrol Ethan in a study at the University of Minnesota, examining the effects of weekly enzyme replacement therapy in Hurler's kids after transplant. It means travelling to Minneapolis in the near future for base line evaluations, followed by surgery to place a central line to deliver infusions, then 4-6 hour infusions weekly for the next two years.

Why we decided to do this is a difficult question to answer, but let me see if I can explain.

I've talked before on this blog about some of the surgeries that Ethan may face in the future.  He had bilateral carpal tunnel surgery last, and he's due to have surgery on both knees as well as bi-lateral hip replacement sometime in the next 2 years or so.

Further down the road, into his tens and teens, we don't know how things will progress.  I know that we see a number of Hurler kids who get cornea replacements to correct the corneal clouding that come the disease brings.  Some kids get spinal surgery on their lower or upper spine to correct instability or curvatures.  And some kids get heart valve replacement surgery.

Why are these surgeries necessary even after the bone marrow transplant enables Hurler kids to start producing their own enzyme? That's a complicated question.  part of the answer is that the surgeries help correct or alleviate damage that was done pre-transplant.   More importantly, perhaps, damage from the disease continues after transplant.  The doctors think there may be a couple of reasons for this.  It may be that our kids need more enzyme in their bodies to more fully clear out the GAG storage material that built up before transplant.  Or, it may be that the fact that the enzyme in post transplant kids is not produced in and carried by all of the cells of the body, it's only produced in the bone marrow produced red cells.  The Hurler defect still means that no enzyme naturally occurs in cells produced within the various organs, only in the cells produced by the bone marrow.

Studies in Hurler research dogs have shown that higher doses of synthetic enzyme can lead to better outcomes in their orthopaedic conditions.  That research outcome, together with the types of ongoing deterioration noted above, has led the doctors to wonder whether additional intravenous synthetic enzyme could improve long-term outcomes for Hurler kids.  Now, we've just got to test that theory.

What's involved.
As a part of the study, Ethan and I (or more likely Ethan, Caleb and I) will travel to Minnesota in May or June for baseline evaluations.  They'll run him through most of the same evaluations that are standard for any kid with Hurler's.  They'll also run through x-rays and some bone density scans.

Then, in Minnesota, or after we get home, Ethan will have surgery to place a new central line.  This will not be the same type of line he had during transplant.  That was a hickman line.  That had a part that was permanently outside of the skin and had two lines for infusions, medication and blood draws.  Because it came out of the skin, it required nightly maintenance to keep the line clear and carried a greater risk of infection.  The new line will almost certainly be a port-a-cath.  It resides under the skin of the chest, where there is a self-sealing hard rubber disk at the end of the line.  To access the line, patients usually get some numbing cream over the site, then the needle is inserted through the skin and punctures the disk and into the line. Since the entire line is beneath the skin, there's less risk of an infection and the line only needs maintenance weekly if it's not used.

Once the line is in, Ethan will start weekly enzyme replacement treatments here in Portland.  This will be almost exactly like the 18 months he received ERT before.  Ethan will get pre-medications, including benadryl and tylenol and about 45 minutes later, they'll access his port and start the Aldurazyme infusion.  The infusion will last about 4 hours or so, after which they'll be about a half-hour of monitoring.

As with any Aldurazyme infusion, there is a risk of a severe allergic reaction called anaphylactic shock.  That's far less of a risk in Ethan's case because he's had synthetic enzyme before and his body produces enzyme naturally now.  There are also risk of more localized reactions,, more of a light shocky reaction.  Ethan's only had those reactions twice and both times were when he also had something else going on, either an illness or recovering from a surgery.  In both cases, we were able to lower the infusion rate, cover him with blankets and snuggle with him until it passed.

Whenever Aldurzayme is administered, patients develop anti-bodies, which are an immune response to this foreign substance in the body.  The worst case scenario is that his body will develop a strong immune response to the synthetic enzyme that could, conceivably, also target the enzyme that his body is producing from the transplant.   This is a very unlikely response since his body is now producing enzyme and the synthetic enzyme is almost identical to that naturally produced enzyme.

The doctors think that this is a low enough risk that the study is generally safe.  They'll be testing his blood for anti-bodies ever three months.  If he starts to develop an unusual response we will pull him from the study.

Outside of the medical risks, there are some developmental risks.  It's just in the last six months that Ethan's started to desensitize from all of the invasive medical procedures he's endured.  Last week he bravely battled the evil x-ray machine and allowed us to get two standing x-rays.   In the past, we've had to give him a light sedation, as an anti-anxiety medication, so that he would cooperate enough to remain standing for those x-rays.

Most of the tests that he'll get for the study are the same ones that he would get annually anyway.  But there are a few additional ones, and he'll have to reacclimate to sitting through infusions  every week.

One of my biggest real fears about this study is that those few extra things will delay or reverse some of the developmental gains that he's made recently.   Cognitively, Ethan's making progress, but this isn't something that we can explain to him in the abstract.  We're just going to need to work with the child life specialists on a case by case basis and try to support him through things as we're able.

So, there are risks.  We think that the probability of Ethan having a significant negative response are outweighed by the chances that he'll receive some benefit.  But, as you can tell, it's impossible to know if he'll actually see a benefit or whether that benefit will be significant.

Why in the hell are we doing this, then?

No one knows how long Ethan will live.  This science is too young. The first transplants were done in the mid 80s.  The oldest living transplant recipients I know if are in their low to mid-twenties and are in generally good health.   In 2003 - 2004, enzyme replacement therapy before transplant was developed, and that will improve outcomes for kids who were transplanted after that point.

In some areas, Ethan is in pretty good shape, his cardiac function is good.  His eyes are not too bad.  It might be that he's in good enough shape that, ten years down the road, he won't need any of these surgeries. If we enrol Ethan in this study and it keeps his heart healthier, helps him avoid valve replacement or adds 5 or more years to his heart health, that seems a small price to pay.

But we already know about two orthopaedic surgeries that he will need.  We know that there's a solid possibility that his kyphosis will degrade to the point that he needs spinal fusion.  I fully expect that he'll need carpal tunnel surgery again.

Committing Ethan to participate in this study without his knowledge, understanding or consent just stinks.  There's no way around that.  But, if signing him up for this study and subjecting him to weekly infusions again means that we can lower the risk in future surgeries, make the recovery period easier and increase his quality of life and his function 10 or more years from now, then Sarah and I feel that's worth the risk.

It also needs to be said that, in addition to all of the other challenges and hardships they carry, our kids are guinea pigs.  Each of our Hurler kids helps improve understanding of the disease, of the effectiveness or ineffectiveness of various therapies.  Sarah, Caleb, Ethan and I all owe a huge debt to the kids and families who came before us, the ones who tried bone marrow transplant.  The kids and families trialed enzyme replacement.  Their successes--and not to be morbid-- their tragic failures, were instrumental in helping us get to where we are today. It's not fair that Ethan should have to carry that additional weight going forward.  While our main focus is on the potential benefit to Ethan, it is also true that all of the MPS families fight this disease together.

(Something that I think about from time to time is the fact that enzyme replacement therapy wasn't available until well after Sarah and I got married, in fact about the time Caleb was born.  If we had kids when we were first married, and one or more of those kids had Hurler's, how would their treatment and our life have been different without ERT?)

In other news, Caleb just brought home his second trimester report card.  He's doing great!  He got off to a slow start in first grade, but since then he's really come along.  I don't think there were any skills on his report card that weren't  on pace.  And his best marks were in his courtesy, effort, cooperation, and all around earnestness. Exactly the best areas to enable him to succeed in everything else.

Caleb's new room.
We also just finished painting Caleb's room.  We updated
it from a  farmish kind of preschool scene to a capable and fun 8-year-old's room.   Caleb said that he wanted the room to be American flag colors.  So the ceiling is white.  With two blue walls and two red walls.  It came out great and Caleb looks quite comfy in there in the queen sized bed that he inherited from the guest room.


Erica J. Thiel said…
Ports need access to be flushed just once a month not weekly.

Please keep in mind that ERT does not help the heart valves, the carpal tunnel or the bones (knees, spine, hips, though it has been thought to slow the corneal clouding progression for some of us, not all). This all said and not that my opinion matters but I dont think it ever hurts to try something new-ish with Ethan. There are new treatments on the horizon that may offer even better options though to, things that UofMn may not even be aware of as they are not the ones studying the drugs so those are things to think of to down the road potentially for Ethan. :)

Caleb's room seems very fitting in light of this
week's events, he has good taste, even if his design/style was chosen pre-monday!
Sandi said…
Hard decisions, huh! I had a feeling you would end up going for the infusions since you are quite proactive. Hope it all goes well. ERT is tiresome, but it does become routine after a while. Good luck with the 4 hour infusions though- Shannae is still on 4.5 hours, and that is after they increased her rates recently!
Teresa Jeffery said…
As always you explain things so well. I do think if it was on offer to us we would have done the same. Ethan is a tough cookie as are you all. Caleb's room looks fab and so wonderful that he's doing great at school. Love to you all xx
Brian Hulett said…
1st. THANK YOU! That was a lot to take in. Well explained and got me thinking maybe we should look into this also. Agree with Sandi, you are proactive as we have been reactive. But I don't know if we should put an almost 10y/o through this. Biggest question when I hear research, is there a placebo group? You guy's are above and beyond wonderful!