Biree Andemariam, MD: Nirmish, we have hydroxyurea, l-glutamine, crizanlizumab, and voxelotor. They are not curative therapies, but do they have the potential to be curative therapies that modify the disease over time?
Dr Nirmish Shah: You keep asking us questions that have 60-minute answers that we could dig into, but we have to put them in a couple of minutes. This is a big topic because we continue to receive more therapies. We have 4. They are not curative, but how do we interact with these drugs to help our patients? Because we don’t have that holy grail that Elna mentioned, a biomarker or even a genetic cell phenotype, we have to make our best guesses. What’s our take on trying to do your best?
Take the hydroxyurea model, which is the gold standard. We have more and more data showing that hydroxyurea is prophylactic. It is preventing complications, preventing target organ damage, preserving spleen function, preventing cognitive problems and TCD. [transcranial Doppler ultrasound velocities]-The list continues to grow. That took time. Although not curative, disease-modifying therapies are excellent. What hydroxyurea has done for pediatrics is that it has left the can behind. Prevent complications on the road. But it hasn’t stopped him, and it’s not for everyone. Hopefully adding another therapy will push the can even higher, and hopefully I’ll be able to stave off problems in the future.
While we wait for new drugs, that’s important. We’re trying to address if a patient has a significant amount of anemia and hemolysis. I have a drug for that. Does the patient have a significant amount of pain or acute chest problems? I have medication to add to the hydroxyurea. All this is added to hydroxyurea, without saying substitution. Two-thirds of patients in the crizanlizumab trial and two-thirds of patients in the voxelotor trial were taking hydroxyurea and still had that benefit. I’m glad they did the essay that way.
As Matt Heeney said, we need to combine therapies that have different mechanisms of action. If I have something that is antihemolytic and something that is antiadhesive, why not consider doing it together? The efforts and thought process are already underway. I’m glad to see that. That’s how I think about these new therapies. Can I prevent further complications?
The last point is that there are some specific phenotypes and complications for which some of these new drugs may be beneficial. We are testing patients with priapism, kidney disease, and leg ulcers on some of these newer drugs. Those are difficult complications to treat, and maybe these newer drugs have a role in helping with that.
Biree Andemariam, MD: Elna, although disease-modifying therapies are not intended to be curative, what about bone marrow transplantation and hematopoietic stem cell transplantation? What are the benefits and disadvantages? Who are you having this discussion with? Who do you turn to when it comes to curative stem cell transplantation?
Dr. Elna Saah: When you talk about curative interventions, even bone marrow transplant depends on the donor and the type of bone marrow transplant you are going to use. One approach that is gaining a bit more popularity is matching related sibling transplantation. If a patient has a genotype, either SS or S beta thalassemia, and they have an HLA-matched sibling, we recommend in some centers… to transplant them sooner. Over the past 10 years, data have shown that transplant-related morbidity, graft-versus-host disease, mortality, and CMV [cytomegalovirus] And all those complications tend to be a little bit higher when you transplant them after the age of 13.
Back to the discussion of who would you recommend for that. It’s a bit more driven by region, carrier, and environment. Fortunately for me, in the settings I’ve been in, in the Midwest and Atlanta, we’re a little more forthcoming and recommend earlier transplants before any serious complications. As Nirmish and Matt said, you’re just kicking the can down the road until something comes up. If you transplant the patient after they have already had a complication, such as a stroke of kidney function, the sequelae of that complication are not changed by your curative intervention. It is best to find out how to obtain your curative intervention before the appearance of irreversible secondary complications.
The other thing… we can get to it in the second part of the question is infertility. Complications of such interventions are limiting. Then there is the availability of donors. First, there is also a 1 in 4 chance that the full sibling will be a full match and not have sickle cell disease. You’re looking at 3 of 16. That reduces the availability of donors so you don’t even have the discussion.
My approach, in practices that I’ve been in, is that any patient who has a full sibling donor, whether or not the parents are ready to talk, let’s find out if that’s an option. We removed some of the hyperbole from the discussion: “what if, what if, what if.” Take a look at that probability. Know that it is a discussion, and we keep it on the back burner until we are ready to have deeper conversations.
So we have alternate donors. Are you going to have a haploidentical bone marrow transplant? There are more studies, by NIH [National Institutes of Health] and others, showing that there are other regimens to prepare you to reduce the complications of not using a whole sibling donor, because that has its limitations. There is appearance of half of your HLA. Let’s say you’re using someone’s mother who is a haploidentical match.
Also gaining popularity (we use it more in adults and older adolescents who have already had severe sickle cell complications) are matched transplants from unrelated donors. That too is limited by the availability of donors. With some minority patients, we don’t have as much in the donor pool as you would for non-ethnic minority patients.
With stem cell transplant, when you look at that on the questionnaires, will you prefer stem cell transplant and gene therapy to hematopoietic stem cell transplant? That’s another intense conversation depending on where you’re from and what age you’re going to do that. From the patient’s point of view, many of them hear about gene therapy and a cure, and they come very excited. When you tell them, “We still have to give you chemotherapy to prepare you, to make room for that altered gene product,” some pause. Secondary malignancies from both gene therapy and transplantation when administering chemotherapy is a very important conversation to have.
Let’s look at those 2, going back to biomarkers and endpoints. Except for the related full HLA matched donor sibling, all those transplant-related mortalities are arguably much easier to digest. If we don’t have good endpoints or biomarkers of disease for us to incorporate into these studies, then it’s all about risk versus benefit and patient comfort level. At what age are you going to do that? Or wait for the patient to declare that she has a serious illness. There is transplant-related mortality and complications of stem cell transplantation, but the benefits far outweigh the risk of living with sickle cell because sickle cell mortality is also clear, present, and imminent.
Transcript edited for clarity