Exploring Emerging Therapies and Their Potential for Curative Intent in SCD

Biree Andemariam, MD: Nirmish, we’ve got hydroxyurea, l-glutamine, crizanlizumab, and voxelotor. They’re not curative therapies, but do these have the potential to be curative, disease-modifying therapies over time?

Nirmish Shah, MD: You keep giving us questions that have 60-minute answers that we could go into, but we have to put it into a couple of minutes. This is a great topic because we’re continuing to get more therapies. We have 4. They’re not curative, but how do we interplay these medications to help our patients? Because we don’t have that holy grail that Elna brought up—a biomarker or even genetic cell phenotyping—we have to make our best estimates. What’s our opinion on trying to do our best?

Take the model of hydroxyurea, which is the gold standard. We have increasing data to show that hydroxyurea is prophylactic. It’s preventing complications, preventing end-organ damage, preserving spleen function, preventing cognitive issues and TCDs [transcranial Doppler ultrasound velocities]—the list continues to grow. That took time. Even though they’re not curative, disease-modifying therapies are great. What hydroxyurea has done for pediatrics is it has kicked the can down the road. It prevents complications down the road. But it hasn’t stopped it, and it’s not for all. Adding another therapy will hopefully kick the can further, and hopefully I can delay issues down the road.

While we’re waiting for new drugs, that’s important. We’re trying to address if a patient is having 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 issues? I have medicines to add to hydroxyurea. This is all added to hydroxyurea, not saying substituting. Two-thirds of the patients in the trial for crizanlizumab and two-thirds of the patients of the trial for voxelotor were on hydroxyurea and still had that benefit. I’m glad they did the trial that way.

As Matt Heeney said, we need to combine therapies that have different mechanisms of action. If I have something that’s antihemolytic and something that’s antiadhesive, why not consider doing those together? The efforts and the thought process are already underway. I’m glad to see that. That’s how I think about these newer therapies. Can I prevent complications even further?

The last point is that there are some phenotypes and specific complications that some of these new drugs may be beneficial for. We’re evaluating patients with priapism, renal disease, and leg ulcers with some of these newer drugs. Those are difficult-to-treat complications, and maybe these newer medications have a role in helping that.

Biree Andemariam, MD: Elna, although disease-modifying therapies are not intended to be curative, what about bone marrow transplant and hematopoietic stem cell transplantation? What are the benefits and downfalls? Whom do you have this discussion with? Whom do you target when it comes to curative stem cell transplantation?

Elna Saah, MD: When you talk about curative interventions, even the bone marrow transplant depends on the donor and the type of bone marrow transplant you’re going to use. An approach that’s gaining a little more popularity is to match related sibling transplant. If a patient has a genotype, either SS or S beta thalassemia, and they have a sibling who is HLA matched, we’re recommending in some centers…to transplant them earlier. In the past 10 years, the data have shown that the transplant-related morbidity, the graft-vs-host disease, the mortality and CMV [cytomegalovirus] and all those complications tend to be a little higher when you transplant them over age 13.

Back to the discussion of whom would you recommend for that. It’s a little more region, provider, and environment driven. Fortunately for me, in the environments I’ve been in—in the Midwest and Atlanta—we’re a little more forthcoming and we recommend earlier transplants before any severe complications. As Nirmish and Matt said, you’re just kicking the can down the road until something comes along. If you transplant the patient after they’ve already had a complication, like renal function stroke, the sequelae of that complication do not change by your curative intervention. It’s best to figure out getting your curative intervention prior to the onset of irreversible secondary complications.

The other thing…we can come to it in the second part of the question is infertility. The complications of such interventions are limiting. Then there’s the availability of donors. First, it’s also a 1 of 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 shrinks the availability of donors for you to even have the discussion.

My approach, in practices I’ve been in, is for any patient who has a full sibling donor—whether the parents or not are ready to have the discussion—let’s find out if that’s an option. We take some hyperbole out of the discussion—“What if, what if, what if.” Take a look at that probability. Know that’s a discussion, and we keep it on the back burner until we’re ready to have deeper conversations.

Then we have alternative donors. Are 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 full sibling donor, because there are limitations from that. There’s appearance from half of your HLA. Let’s say you’re using the mother of someone who’s a haploidentical match.

Also gaining popularity—we’re using it more in adults and older adolescents who’ve already displayed severe sickle cell complications—are matching unrelated donor transplants. That’s also being limited by donor availability. With some minority patients, we don’t have as much in the donor pool as you would have for patients who aren’t in an ethnic minority.

With stem cell transplant, when you look at that on the questionnaires, are you going to prefer stem cell transplant and gene therapy over hematopoietic stem cell transplant? That’s another intense conversation depending where you’re coming from and what age you’re going to do that. From the patient standpoint, a lot of them hear about gene therapy and a cure, and they come in very excited. When you tell them, “We still have to give you chemotherapy to prepare you, to create space for that altered gene product,” some of them pause. The secondary malignant neoplasms from both gene therapy and transplant by giving chemotherapy is a very important conversation to be had.

Let’s look at those 2, going back to biomarkers and end points. Except for the related full HLA-matched sibling donor, you can say all those transplant-related mortalities are much easier to swallow. If we do not have good end points or biomarkers of disease for us to incorporate in these studies, then it comes to risk vs benefit and patient comfort level. At what age are you going to do that? Or you wait for the patient to declare that you have severe disease. There is transplant-related mortality and complications of stem cell transplant, but the benefits far outweigh the risk of living with sickle cell because the mortality of sickle cell is also clear, present, and imminent.

Transcript Edited for Clarity