Is There a Right Decision?

Today, I awoke with a strange feeling deep within the pit of my stomach. I didn't sleep well last night and the only reason I know I did is because I have the dreams to remind me.


Yesterday, we had our meeting with the immunology team to discuss treatment for Parker. Now, recall Parker is clinically healthy at the moment so the focus of the meeting was to provide my wife and myself with information about the three forms of treatment available. Those being a bone marrow transplant, enzyme replacement (PEG-ADA), and gene therapy (as a clinical study).

After three hours of information and questions, to be honest I felt as if I left the meeting knowing no more than I did before it began. The reason they said I felt that way that was because I was very knowledgeable before entering the meeting. Yes, I had done my research, I read medical papers, learned how different procedures are performed, but I would definitely not call myself an expert. I went into the meeting expecting some direction in regards to which treatment to choose, and I did not get that.

Looking back, I understand the reason for not giving us a definitive answer on which treatment would best suit Parker, but I do feel that I should have gotten something from the meeting that I did not already know. At least some information about gene therapy that that would have been gathered since the last published paper from 2004.

As I will explain shortly, the decision on which treatment to choose for Parker falls in the hands of my wife and I, and time is of the essence. We have approximately one week to gather any more information we need and then make a decision. I will now explain the three different kinds of treatment and the benefits and cons of all three.

ENZYME REPLACEMENT THERAPY (PEG-ADA)
The problem with Parker is that he has a gene that does not work correctly. The gene is responsible for regulating the amount of an enzyme called ADA into his body. Parker does not produce any ADA and as a result toxins that would normally be removed by the ADA have taken over his body. These toxins have killed off his immune system, and in some children have caused damage to their other organs, as the ADA is missing from all of his cells in his body.

The idea behind enzyme replacement therapy was that if you could give ADA to a patient that did not have any, if would solve the problem. In 1990, PEG-ADA was approved by the FDA for this use.

The studies have shown that PEG-ADA has helped the metabolic problem that I have spoken of in previous articles; however, its solution to immune reconstitution is not an ideal one. The number of T-cells do increase for some time but to levels lower than a healthy child. After approximately three years the number of T-cells decreases quite dramatically. There have been some individuals that have been on PEG-ADA since its introduction, but their immune system is still very compromised.

Lastly, PEG-ADA is considered an orphan drug, meaning that it is meant for a very small portion of the population. It is not produced in Canada and must be brought in from the United States. The cost of this drug is $125, 000/year. As an outpatient, the cost of this drug falls in the hands of the patient. Although there is a drug programme called Trillium that has been implemented by the Ontario Government to help with the costs, there is a process that must be followed to receive funding, and the funding does not cover the complete cost of the drug.

Bone Marrow Transplant
Bone marrow transplants are the specialty of the Hospital for Sick Children in Toronto. It has been relatively successful for children with Severe Combined Immune Deficiencies; that said, the success does not translate to children diagnosed with SCID caused by an ADA deficiency.

As previously mentioned, my wife and I are haploidentical matches with Parker in regards to our HLA. There are three problems with doing such a transplant. The first is that Parker may not engraft. This means the bone marrow that is transplanted into Parker does not take and we are no better off than we were before. Secondly, there is some chemotherapy (using Bulsufan) that will need to be done to remove the little immune system that he has so that he does not reject the bone marrow. Busulfen, has many side effects, especially for a child diagnosed with ADA as the chemotherapy may cause similar damage that the toxins have already caused. Thirdly, with a haploidentical bone marrow transplant the risk of having Graph Versus Host Disease (GVHD), a potentially deadly outcome is increased. If Parker does have the BMT and it does not engraft, the chances of a subsequent BMT being successful is even less then the original. I had mentioned previously that time was of the essence. The reason being is that once Parker is three months, the chances of engraftment decreases, while GVHD increases.

In addition, he would be excluded from the clinical trial involving gene therapy, as he would have not only his own cells but his donors as well. This would cause a variable to be added to the study that they are not willing to include. If the BMT is successful, it will alleviate the problem of not having any T-cells; however, it will not yield him B-cells. Parker would have to be on immunoglobulins to supply him with working B-cells. This is not a major concern.

Gene Therapy
I previously wrote quite a bit of information on gene therapy in a previous article so I will not go into how gene therapy actually works. I will just talk about the benefits and cons of this form of treatment. Clinical trials on gene therapy are being conducted in Los Angelos and Milan, Italy. The idea behind gene therapy is to take Parker's bone marrow using a needle in his hipbone, and then insert a good ADA gene into these cells using a virus and then infuse these modified cells back into Parker.

To date, I am unaware of how many patients have gone through the LA trial and what percentage of them were successful. Dr. Kohn, in LA, has not published his data using the newest protocol and for that reason I do not have enough information to make an intelligent decision. The protocol that is being used in this trial is based on the protocol developed from the trial taking place in Italy by Dr. Aiuiti.

The trial in Italy does have some published data from 2004 to discuss five patients that have undergone the gene therapy. This paper does describe relative success with these patients. It is my understanding that there have been four more patients since then but I am unaware of their outcome. I will need to speak with Dr. Aiuiti to discuss his most recent results with his study.

The major downfall in regards to gene therapy involves the fact that very few patients have gone through the study. Yes, it seems to be safer, as there is no chance of GVHD; however, if the new DNA does not interact with his current DNA correctly then there is a chance of Parker developing cancer. Although this is a possibility, there has not been a single ADA patient to date that has undergone the therapy and then developed cancer.

The other major difficulty with choosing gene therapy is that if gene therapy does not work then the ideal time to do a BMT has passed, and the only viable solution, in my opinion, would be to place Parker on PEG-ADA until a better protocol for gene therapy has been approved and written. Prior to taking part in either study in gene therapy, Parker would be placed on PEG-ADA for six months as an outpatient.

So I remain with that strange feeling, in the pit of my stomach, pondering the question, is there a right decision.