Disclosures: Szabolcs reports no relevant financial disclosures.
September 08, 2020
4 min read

Cord blood may be effective for treatment of 20 pediatric disorders

Disclosures: Szabolcs reports no relevant financial disclosures.
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Hematopoietic stem cell transplantation has proved effective for the treatment of many inherited nonmalignant disorders among children.

Although reduced-intensity conditioning prior to HSCT has demonstrated the potential to decrease treatment-related morbidity and mortality, such regimens have been associated with graft failure and infections among chemotherapy-naive children.

Paul Szabolcs, MD, division director of bone marrow transplantation and cellular therapies at UPMC Children’s Hospital.

In a study published in Blood Advances, researchers at UPMC Children’s Hospital of Pittsburgh found a novel reduced-intensity conditioning regimen paired with umbilical cord blood appeared safe and effective in treating several genetic noncancerous disorders.

“I first encountered many of these diseases when I was at Duke University, and in 2008 I designed the predecessor of this trial, which already showed that engraftment [with a reduced-intensity conditioning regimen] was not inferior compared with myeloablative [conditioning],” study senior author Paul Szabolcs, MD, division director of bone marrow transplantation and cellular therapies at UPMC Children’s Hospital, said in an interview with Healio. “That was a big thing, because reduced-intensity conditioning, with its obvious benefits, has led to more graft failure. The predecessor trial had already had engraftment success, but the [OS] was not yet superior.”

The reduced-intensity regimen evaluated by Szabolcs and colleagues consisted of alemtuzumab, hydroxyurea, fludarabine, melphalan and thiotepa, followed by a single-unit umbilical cord blood graft. The researchers assessed the regimen among 44 consecutive children born with conditions such as sickle cell disease, thalassemia, Hunter syndrome, Krabbe disease, metachromatic leukodystrophy and various immune deficiencies.

Szabolcs spoke with Healio about the study, its promising outcomes, and the advantages of treating several hematologic conditions with a universal approach.

Question: What motivated you to study this treatment approach for these children?

Answer: I was motivated by the fate of some other children who had to endure the more aggressive effects of myeloablative therapies initially designed for children with leukemia. Some of them succumb to regimen-related toxicity, which is the case regardless of the indication. However, when we perform these transplants for the quality-of-life indication, as opposed to saving someone from immediately dying of a leukemia relapse, it’s even more heartbreaking. It’s not only losing children, it’s watching them suffer through the various complications of these therapies.

Q: How did you conduct the trial?

A: Based on what we’ve learned about the immunology of cord blood over the years, this trial tried to stick with a chemotherapy backbone that remained unchanged for any disease, but also used alemtuzumab, which is like an antithymocyte globulin (ATG) serotherapy agent. We stratified patients into groups including standard risk, which applies to those who don’t have immune deficiency and don’t have transfusion-dependent anemia like thalassemia; higher rejection risk, for those with thalassemia sickle cell; and lower rejection risk. We then introduced a second variable that was based on lymphocyte count. In a sense, that reflects whether a patient has immunodeficiency and whether they had prior viral infections. Viral infection is an important factor. In the predecessor trial and other trials that use alemtuzumab or even ATG, there might be a better chance to engraft, but there is also a higher chance of losing the patients due to viral infections.

Q: What did you find?

A: Across 20 diseases, from osteopetrosis sickle cell thalassemia to inborn errors of metabolism, we were equally successful in bringing a cord blood graft into persistent engraftment, with very, very low transplant-related mortality. This is the highest number of diseases that has ever been studied, and it encompassed all three major categories of inheritable disorders: inheritable diseases of the immune system, of the bone marrow and of lysosomal storage.

We also found that we can do this treatment without adjusting and readjusting the chemotherapy. This is quite common and manageable for busulfan but far less straightforward or proven for fludarabine, ATG or alemtuzumab. Several investigators have been advocating for “harmonization” and fine-tuning of these agents based upon pharmacogenetics. Although that may have some influence in their regimens, it is extremely laborious, complicated, expensive and not easily transportable to many centers. Here, we don’t have to perform any measurement of drug concentrations.

Q: Could this type of treatment for multiple disorders become widespread?

A: I believe it could. To an extent, it has started already. We opened the current trial in 2012. Since then, there has been a small case series of nine or 10 patients in which this was successfully utilized. Some European investigators reached out after publication of this paper. It is widely applicable because it isn’t dependent on fine-tuning and measuring of drug concentrations.

Q: The title of your study references an “optional immune boost.” What is this?

A: This refers to donor leukocyte infusion, or DLI. DLI is a well-known concept in bone marrow transplantation, but it has never been explored in single-unit cord blood transplant. Basically, you go back to the original graft and infuse a small portion of it later. This is done for multiple reasons, but here we clearly do it for immune boosting purposes. We can hold back 5% and refreeze it, and give 95% to the patients on the day of transplant. A month or two after transplant, we could take it out of the freezer and infuse it as an immune boost. We did this in our trial for a subset of 20 patients. Among these patients, we can demonstrate early signals of improved immune reconstitution. This might be important because agents like alemtuzumab and ATG linger for weeks. So, on day zero when we infuse the graft, there is still some alemtuzumab in the patient’s blood, and this alemtuzumab is beneficial because it depletes many of the T cells of the graft. The resultant lack of extensive graft-versus-host disease is great and extremely important but, at the same time, that’s at the expense of immune reconstitution. If we wait a month or 2 after transplant, the alemtuzumab eventually fades away, and this 5% can be infused and jump-start the immune reconstitution.

I would love to see a multicenter trial of this DLI concept in centers that might use a different regimen. No matter how we might have blown away someone’s immune system, we could test how effective DLI is in boosting it. I think independently, this is a very important finding.

For more information:

Paul Szabolcs, MD, can be reached at 4401 Penn Ave., Pittsburgh, PA 15224; email: haree@upmc.edu.