Insights From the 62nd ASH Annual Meeting and Exposition

Insights From the 62nd ASH Annual Meeting and Exposition

Question

Which research findings presented at the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition had the most clinical potential for the treatment of thalassemias? Are treatments for some thalassemias more promising than others?

Answer

I thought that the presentation that generated the most “buzz” was from CRISPR Therapeutics and Vertex Pharmaceuticals Incorporated on the CLIMB THAL-111 (ClinicalTrials.gov Identifier: NCT03655678) and CLIMB SCD-121 (ClinicalTrials.gov Identifier: NCT03745287) studies.¹ CRISPR/Cas9 gene editing reagents were used to knock out an erythroid-specific enhancer region of the gene encoding BCL11A, a protein involved in the switch from fetal hemoglobin (γ-globin) to the adult form of hemoglobin (β-globin) and thereby induced fetal hemoglobin expression in patients’ hematopoietic stem cells. The investigators presented data from patients who had a transfusion-dependent thalassemia (n=5) and spectacularly showed that in patients with a very high level of fetal hemoglobin expression, infusion of the drug product (CTX001) was sufficient to stop the transfusions. This was the first indication that this approach of inducing re-expression of fetal hemoglobin might have broad utility for both disorders, not just in sickle cell disease, which was not as surprising.

Question

Study results presented at ASH 2020 suggest that betibeglogene autotemcel (beti-cel) gene therapy provides durable and stable responses in patients with transfusion-dependent β-thalassemia with up to 6 years of follow-up.² Are these outcomes surprising to you?

Answer

The outcomes were not surprising; they were very reassuring. One of the concerns about using a lentiviral vector is that the lentivirus has sequences that are known to be targeted by the genome for silencing, which would prevent expression of the edited gene, but that has not happened. There has been durable expression, and it could be that most of the time the vector lands in an active region of the genome so that transcription is already ongoing at some of the integration sites, resulting in durable expression of the vector DNA in the long term.

Question

In the same study, most patients with β-thalassemia who were able to achieve transfusion independence were able to stop iron chelation; however, the majority of patients restarted chelation at a median of 12.7 months following beti-cel infusion.² More than half of those patients later stopped iron chelation. What are some factors that might determine how long it would take, if at all, for a patient to achieve transfusion independence?

Answer

It depends on how high the hemoglobin is. To do phlebotomy safely, hemoglobin has to be above 11 g/dL, and not every patient achieved that. So the only way to remove the iron for those patients safely would be through iron chelation therapy. Most of us delay resuming iron chelation therapy because in the course of recovering, hematologically, iron chelation can have an immunosuppressive effect and lead to certain kinds of infections. So, we typically like to delay that for the 6 to 9 months that it takes for the immune system to fully recover before resuming the iron chelation therapy. Some of the delay in restarting iron chelation after the infusion has to do with that concern, but once the immune system has recovered fully, it should be possible to resume the therapy. How long it takes to be able to stop iron chelation therapy depends on what the iron level was before the treatment. So, the higher the iron was before they got the treatment, the longer it is going to take to remove it. Some of the patients were very well chelated, so their iron burden was not very great and thus, they did not need nearly as long a duration of chelation before it was safe to stop.

Question

For patients with β-thalassemia, allogeneic stem cell therapy is thought to be a potentially curative option, especially in younger patients, and this has prompted investigations of beti-cel therapy in children. In one such study, the safety and efficacy profiles of beti-cel in pediatric patients with β-thalassemia were comparable to those of adult patients.³ What does the future of treatment look like to you for both younger and older patients with transfusion-dependent or nontransfusion-dependent thalassemia?

Answer

That is the $64,000 dollar question, is it not? Yes, in parallel, allogeneic transplantation has evolved and has become safer, and it is also possible to use mismatched, even parental, donors to have a successful outcome. A large study conducted in Thailand suggested that is really quite feasible and safe to do.⁴ The question then becomes what are the advantages and disadvantages of all of these various curative therapies? Having to administer high-dose busulfan is a problem and is probably universal for both types of treatments. However, the emergence of reduced-intensity conditioning before an allogeneic transplant might make that approach more interesting, or safer, in children because it will not necessarily cause infertility the way that conditioning for the gene therapy will. Unfortunately, gene therapy absolutely relies on ablating the thalassemia-producing bone marrow so that the modified cells have a chance to grow and expand and fill the space. For example, if you only wipe out half of the thalassemia cells, the benefit from the gene therapy will be decreased too much. So, that is not really an option in the short term. Even though some of the vector copy numbers now are quite high, it seems that ablation is really necessary. That is one issue that might arise in the future. If we could perform transplantations with an alternate donor, and not have to give the full dose of chemotherapy, then that might be a favorable option. But allogeneic transplantation will always be riskier than gene therapy because gene therapy uses one’s own cells. They will not be rejected the way an allogeneic transplant might be, and they will not cause graft-vs-host disease, which is a leading problem after allogeneic transplantation. By eliminating those 2 principal problems, that immediately makes gene therapy more appealing to a lot of patients and their families. Those are the kinds of discussions we are having now as patients and families navigate these new curative therapies. It is great that they now have more than 1 choice. But now we have to parse out what is the safest, what is the most effective, what is better in children, and what is better for a particular genotype of thalassemia. For example, compared with patients who produce some but not enough endogenous hemoglobin (β+/β0 genotypes), those with β0/β0 genotypes who produce no endogenous hemoglobin will have a harder time achieving transfusion independence and that will also affect which strategy patients and their families pursue. It is an interesting time in medicine as we deal with these inquiries about these advances. With nontransfusion-dependent thalassemia, we do not really know. That has not been developed yet, in terms of gene therapy. The question is: are there other medical therapies that might be better? For example, currently in development is luspatercept, which might raise hemoglobin by 1 to 2 g, which might be sufficient for patients with nontransfusion-dependent thalassemia.⁵ If it does not allow for transfusion independence, it may at least significantly decrease the transfusion burden in those patients. Thus, a transplant approach would not be appropriate because it would be too intensive. So as the medical therapies, including hepcidin agonists, are developed, they may be better for patients with nontransfusion-dependent thalassemia, but again, we have to wait and see.⁶