Opening Doors to a Sickle Cell Cure -- In-Depth Doctor's Interview

What's new about this sickle cell disease trial?

Dr. Shenoy: It's a multi-center trial that is being run through the bone marrow transplant clinical trials network, which is a consortium that was borne from the NHLBI to focus on transplant-related questions, both adult and pediatric. Each of the studies that are run through the network is asking an important question on transplants. The one that we're talking about is called the SCURT trial -- S-C-U-R-T stands for Sickle Cell Unrelated Trial. It is looking at the benefits of transplanting children with severe sickle cell disease using a reduced intensity conditioning, so a patient coming to transplant has to have preparation to accept donor cells. The conditioning is not the high dose chemotherapy or radiation therapy that we use for cancer. It's a reduced intensity preparation, looking to make them tolerate the process better, perhaps have less effects and toxicities from the transplant, and yet have a successful transplant, attempting to cure their disease. The donors that would be suitable for this trial would be donors of either bone marrow or if we have tissue matches in the cord blood registry, those would be suitable, too. There are specifics on how well matched they need to be to be able to proceed with this transplant process. It is for children only, because adults with sickle cell disease have a lot more morbidity associated with the disorder. We are starting with those patients that have manifested early, have proved that they have a bad disease who would have a very poor quality of life, and probably early morbidity and mortality because of their disease. This would provide them a curative option of replacing their sickle hemoglobin completely with normal hemoglobin, and hopefully allow them to heal their tissues that are affected by sickle cell disease, and move on without those complications. The trial was based on a trial of non-malignant or non-cancer disorders that we did over here. We started a trial in 2001 where we wanted to make transplant a little safer for patients without cancer, and then offer them the chance for cure. The conditioning that we used is the exact same that we are using now for this unrelated donor, or this SCURT trial for sickle cell disease. Because we've had success with the parent trial and the children seem to tolerate it quite well, we're able to get donor cells in, we're able to have a successful transplant. The SCURT trial is specific for sickle cell disease, and we'll look at about 45 patients and their outcomes after they've gone through about two years of follow up post-transplant.

Are blood transfusions and bone marrow transplants the standard for severe sickle cell?

Dr. Shenoy: Bone marrow transplantation for sickle cell disease probably dates back to the late 1990's when patients were transplanted using matched sibling donors, for the most part. There were trials that were run both in the United States and in several European countries that showed that if you take a sickle cell disease patient successfully through transplant, they could potentially be cured of their disease and have a good lifestyle. The studies that were done in the past used matched sibling donors and also used a pretty intense chemotherapy which we call mylo-oblative transplants. They showed that it improves the disease, but there are some long-term toxicities that you deal with -- sterility, ovarian failure, and so on -- but you could actually get rid of their disease. The problem with that was that only about 10 to 14 percent of patients had a matched sibling donor. If there was no sibling, trying an unrelated donor transplant with that same very intense conditioning resulted in a lot of morbidity and mortality. Patients that have tried the mylo-oblative unrelated donor transplants have seen a lot of toxicities because of that approach and there were several things that resulted in a higher risk transplant. One was the intensity of the conditioning; two was the disease status of the patient; and three was the age of the patient. If these patients were older, they were unable to take that conditioning and go through a transplant successfully, so the number of unrelated donor transplants that have been done have been very sparse, very few, and with mixed results and with a lot of toxicity. That's why this trial is specifically looking at unrelated donor transplants in children using this different conditioning approach -- that's the difference.

Where are you getting the unrelated donor transplants?

Dr. Shenoy: They would come from the national marrow donor program, which actually has provided a lot of support for this study and to the clinical trials network to get the study going. The idea is to try to make the transplant available to different groups of patients and to make it available to patients that need it, and to try to find the right donor for those patients. That always has been an issue with a minority population. The number of tissue match donors directly depends on what the donor pool looks like when it comes to an unrelated donor transplant. They have made an effort to increase their minority population donors to try to find tissue match donors, especially for studies like these that are going to have a minority recipient population. It will draw from both the national marrow donor's pool of donors and from cord blood registries that store cord blood for these purposes.

What is different about the new kind of conditioning you will use in this trial?

Dr. Shenoy:  I refer to it as reduced intensity conditioning -- RIT for short. The difference is when you use the traditional old high-dose chemotherapy radiation, you oblate the patient's bone marrow completely and then allow the new donor cells to come in. If the donor cells don't come in, the patient stays ablated for a very long period of time, which means they don't have any blood producing cells in them at all, and they need to be supported which has a high mortality in itself. With the reduced intensity conditioning, you are reducing the toxicities of each of these agents that you use as conditioning because you're using it either in lower intensity or they're not on chemotherapy or radiation medications at all. Also, if they don't take the donor cells, if they reject the graft, then their own bone marrow comes back and gets going and doesn't leave them ablated for a prolonged period of time. They would at best return back to baseline and not be down and out for several months, depending on how intense the conditioning was. The conditioning itself uses three different medications. They are called alentuzumab, fludarabine and melphelan. The alentuzumab is not even a chemotherapy agent -- it's a protein that's an antibody that's trying to decrease the immune cells in the recipient. Fludarabine is also a very immunosuppressive agent. Melphalan is the therapeutic agent that's given at a low dose so that it's not ablative, it just helps get the graft in. The conditioning, actually, is very unlike the conditioning regimen from other transplant studies that all are given in the span of say about a week before transplant. This one starts conditioning about three weeks in advance. The idea is that the donor's immune system should be completely down and out by the time the recipient's immune system needs to be all gone before the donor cells come in so that rejection doesn't happen. It's prolonged conditioning, not all in the hospital. They're in and out of there --it's not three weeks of an inpatient hospital stay to get the conditioning done.

Is it still dangerous to have this kind of conditioning because the immune system gets wiped out?

Dr. Shenoy: Yes. The dangers would include infection for sure. Infection is going to be a part of any transplant process, because unless you get an immune system down and out, you aren't going to be able to graft donor cells. For a period of time, until the donor's immune system is up and running in the patient, there is going to be a risk for infections, and that is a thing to monitor for during that risk period. The late effects, though, would be minimal, because the therapy gets out of the system very quickly. It's not being given in very high doses and it's not a very intense treatment, so we hope to preserve fertility. We want to minimize the effect of late toxicities they would have. We want to keep the early toxicities such as the breakdown of your skin, which chemotherapy can do, to a minimum as well with this.

Is there a higher risk of rejection because these are unrelated donors?

Dr. Shenoy: The level of matching is very important to try to get a successful transplant without the transplant-related complication such as graft versus hostesses, so we're very careful about the kind of donors we choose. Even though they're unrelated, we want them very well tissue matched with the patient to try to reduce that. Having said that, the unrelated donor is still a higher risk transplant. A related brother or sister donating to the patient is much better than having any matched unrelated donor. The risk of transplant related complications are going to be higher with an unrelated donor and would only be done in the absence of a related donor. Graft rejection rates can be higher for two reasons: First, the intensity of the conditioning is not that high -- the more intense the conditioning, the better the graft takes. The other reason is the disease itself. Patients who come to transplant having had several blood transfusions are very immune competent because they've seen a lot of other transfusion products, they can reject much more than they would if they hadn't had any of that. They also haven't seen any chemotherapy or radiation before, unlike cancers. They're naive, very normal immune system patients that are coming to transplant, so the risk of graft rejection with reduced intensity is going to be higher, or it's likely to be higher. The plus side is that unlike a cancer, they don't need to completely replace the cells with donor cells, because their own cells can live side by side with donor cells. As long as the donor cells are making the normal hemoglobin, they are okay. If they are what we call mixed chimera, they're half donor and half recipient, as long as that's stable and as long as that continues for a lifetime, they're okay. There are some pluses and minuses to having a non-malignant disorder, but if it can reduce toxicity and still get a successful transplant -- not necessarily a complete engraftment -- but stable engraftment that will allow them to be disease free. I think the benefits outweigh the rejection risks.

What are the main benefits of this over the traditional sibling transplant?

Dr. Shenoy: The tolerability of the conditioning regimen is likely to be better. Because it's reduced intensity, the toxicities are likely to be less with the reduced intensity. The late toxicities -- organ dysfunction, perhaps liver dysfunction, ovarian failure, sterility -- those are likely to be less with the reduced intensity. Those would be the pluses. The minuses would be the increased risk for graft rejection, which has to be monitored carefully. There are also risks that are common for all transplants -- it doesn't matter what the conditioning is -- there is going to be the infectious risk until the new immune system comes in. It's going to be the risk of graft versus host disease because we are using unrelated donors. However well matched they are, there is still a risk for graft versus host disease. That breaks our hearts as pediatricians, because really what we want is for a child to leave here healthy, and maintain their lifestyle. They may be gone for five days and then they're back again with pain all over again and we're starting from scratch one more time to help them out of their pain. It's a daunting task treating these patients and it's not as if we're getting rid of their disease and curing them when they leave. We know that we have helped them for a short while and then they're going to be back again and we're going to start this process all over again.

END OF INTERVIEW

This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.

If you would like more information, please contact:

Jackie Ferman-Grothe

St. Louis Children's Hospital

(314) 286-0304

To read the full report Opening Doors to a Sickle Cell Cure, click here.