Are New Treatment Options for Beta Thalassemia Ready for Widespread Use?

Alexis A. Thompson, MD, MPH
Dr. Thompson is head of the hematology section of the Division of Hematology Oncology Transplantation at the Ann and Robert H. Lurie Children’s Hospital of Chicago and associate director of Equity and Minority Health at Northwestern University.
Thomas Coates, MD
Dr. Coates is professor of pediatrics at Keck School of Medicine at the University of Southern California in Los Angeles.

Patients with transfusion-dependent beta thalassemia, the most severe form of the disease, require lifelong management with red blood cell (RBC) transfusions, presenting a substantial cost and burden to patients. The only curative treatment for patients with transfusion-dependent beta thalassemia is allogeneic hematopoietic cell transplantation (alloHCT), which also is associated with a variety of adverse events. Also, many patients lack a suitable donor for the procedure.

Finding new treatment options for these patients is a high priority for the hematology community. One of the most promising advances for patients with severe beta thalassemia in recent years is the use of gene therapy with autologous CD34-positive cells transduced with the beta globin–containing lentiviral vector. Last year, 2018 American Society of Hematology (ASH) president Alexis A. Thompson, MD, MPH, and colleagues published results of two companion phase I/II trials (HGB-204 and HGB-205) in which gene therapy reduced or eliminated the need for long-term RBC transfusions in certain patients with transfusion-dependent beta thalassemia.1

Similar results from the phase III Northstar-2 and Northstar-3 studies shared at the 2018 ASH Annual Meeting added to the excitement around using this type of gene therapy in patients with severe beta thalassemia.2

Also at the 2018 ASH Annual Meeting, researchers presented findings from the phase III BELIEVE study that evaluated luspatercept, a first-in-class recombinant fusion protein, in patients with transfusion-dependent beta thalassemia. Treatment with luspatercept alleviated patients’ transfusion burden, with approximately 70% of participants achieving a clinically significant reduction in RBC transfusion requirements during any consecutive 12 weeks of treatment, the authors reported.3

As the treatment options for transfusion-dependent beta thalassemia continue to expand, ASH Clinical News invited Dr. Thompson and Thomas Coates, MD, to discuss the status of these options and answer the question, “In patients with transfusion-dependent thalassemia, should gene therapy be the first approach or the last resort?”

Alexis Thompson, MD, MPH: In the very near future, patients with beta thalessemia may have a variety of treatment options that are either disease-modifying or potentially curative, so we need to think about which patients are the best candidates for these therapies and what the intent of therapy is.

Today, we have well-established conventional therapies, including transfusion and iron chelation (plus comprehensive care to manage complications), that are sufficient for most patients. We are thrilled to see adult patients with beta thalassemia living longer lives, but these methods, while life-sustaining, are not curative. Gene therapy represents a promising option for older children and young adults with beta thalassemia, and we are awaiting more information about its safety in people older than 40 years.

Thomas Coates, MD: Gene therapy absolutely is an exciting new option. Ultimately, it probably will be the direction that treatment will take, but right now, it is just barely ready for prime time.

One of the most pressing issues is that, in the U.S., few centers have expertise in managing thalassemia. We both know that if patients’ disease is managed well with transfusion and their iron level is controlled perfectly, they can expect to live into their 60s. The caveat is that they have to have a physician who understands all the nuances of how to manage the disease.

The ability to cure disease – especially in a younger patient – and eliminate decades of transfusions is a great opportunity. The good and the bad news for gene therapy, though, is that alloHCT methods are also rapidly improving. So, there are several competing options for patients with severe beta thalassemia.

“In patients with transfusion-dependent thalassemia, should gene therapy be the first approach or the last resort?”

Dr. Thompson: I agree; not every patient is looking for curative therapy. Some patients feel that their condition is being managed effectively and that they have made whatever lifestyle adjustments they needed to achieve an acceptable quality of life.

Given our improved ability to provide safe blood and chelate iron to control side effects, I can’t argue with patients who want to make only minor changes to therapy to maintain a certain quality of life. Others, like people with young children, have great enthusiasm about gene therapy. Research studies of gene therapy have been conducted in adolescents and young adults with beta thalassemia, and there are many reasons why this may be the population where we see the greatest long-term benefit.

For example, alloHCT with a sibling donor is considered a standard of care for transplant-eligible patients with beta thalassemia; many patients, however, lack this type of suitable donor. Gene therapy is quite appealing as an alternative, curative treatment.

Dr. Coates: Yes, if a patient has a matched sibling donor, we strongly recommend that approach. However, even if there is a perfectly matched sibling, there remains a 3% to 5% risk of transplant-related mortality. For most parents of young children with beta thalassemia, the only acceptable number is zero percent. Adequate management with transfusion and iron control gives the patient and his family the time and opportunity to discuss options.

Dr. Thompson: Any of these cures has a cost. In addition to the risk of transplant-related mortality, all curative approaches carry the risk of infertility.

No matter what kind of transplant – gene therapy, alloHCT, or autologous hematopoietic cell transplantation – infertility is still a burden we are not able to alleviate. I am encouraged by some of the progress in fertility cryopreservation in young children, but this is still experimental. In our experience, if fertility is a high priority, parents of children with sibling matches have deferred transplant to ensure that they allow the child time to participate in that decision.

Dr. Coates: Another concern about gene therapy are the less-exciting outcomes seen in patients with the ß0 genotype, compared with those in patients with the ß+ genotype. We also have seen that some patients who receive gene therapy are developing thalassemia intermedia instead, when only sporadic or no transfusions are required. These represent some of the most complicated patients to follow, even for physicians with extensive experience in managing thalassemias.

If patients undergo gene therapy and their hemoglobin levels are at 11 or 12 g/dL, I anticipate gene therapy will continue to provide long-term clinical benefit; however, if patients undergo gene therapy and their hemoglobin levels linger at 8 or 9 g/dL, they might develop the same long-term complications seen with thalassemia intermedia. In contrast, after a sibling or unrelated donor alloHCT, patients essentially no longer have thalassemia.

Dr. Thompson: We have managed a fair number of patients who have thalassemia intermedia, and I am struck by how severely their quality of life worsens over time compared with some of our patients with transfusion-dependent thalassemia – irrespective of transplantation. As we look to improve gene therapy, it must be with the intent to normalize hemoglobin and iron homeostasis. Without achieving those goals, we may see improvements in terms of scientific measures, but we will fall short in terms of clinical improvement.

Dr. Coates: Thalassemia intermedia brings me to another topic: the current enthusiasm for luspatercept.3 This drug is thought to work by inhibiting ineffective erythropoiesis. The BELIEVE trial showed that it was efficacious in transfusion-dependent patients, meeting all major transfusion burden–related endpoints. Data from the preliminary studies in non–transfusion-dependent patients also are quite exciting, showing that, while the approach did not cure the disease, it markedly improved disease burden – particularly in those with hemoglobin levels of 8 to 9 g/dL.4

Again, this is a huge problem in the U.S. because patients with non–transfusion-dependent beta thalassemia are often not recognized as having thalassemia by many hematologists or general practitioners. Luspatercept will probably be an exciting option for them, but I wonder what effect luspatercept would have on patients with hemoglobin levels of 8 or 9 g/dL who have received gene therapy.

Dr. Thompson: That is an intriguing idea. It could very well be that a treatment like luspatercept could be added post–gene-therapy infusion to increase hemoglobin levels and perhaps eliminate the need for transfusion.

It’s hard not to be thrilled with the early outcomes of gene therapy, yet the approach clearly is not for every patient with transfusion-dependent thalassemia. Certain patients feel that there are still too many questions about gene therapy, and they are concerned about the lifestyle changes necessary to undergo this procedure. I can imagine that a patient who is finishing college, has a first job, or is raising a young family might not want to put his or her life on hold for even two or three months to undergo a potential curative therapy for which we don’t have long-term data.

Luspatercept, understandably, would be more appealing for these types of patients: We could give them an injection when they come in for a transfusion and minimize or eliminate their need for future transfusions, and they can continue with their lives as usual.

Dr. Coates: When we talk about potentially curing thalassemia, we also must consider the other option: long-term maintenance. Again, I come back to the issue of the availability of physicians who understand how to manage thalassemia because it is such a rare disease.

At our center, we are aggressive with transfusions, so many patients receiving transfusions actually have beta thalassemia intermedia and would be considered by other centers to have non–transfusion-dependent disease. We see few complications when patients’ iron levels are controlled.

We also have to consider that, as patients with beta thalassemia intermedia age, they do not tolerate their anemia as well and later become transfusion dependent. Luspatercept will probably help a substantial portion of these “borderline transfusion-dependent” patients, without the need for transfusion. Therefore, luspatercept is going to make the prospect of a non-transplant option even more attractive to certain patients.

In clinical trials, the drug was shown to decrease RBC transfusion requirements by approximately 30%, including among patients with thalassemia intermedia and the β0 genotype. My hope is that luspatercept will allow us to achieve the same degree of hemoglobin increase with less transfusion, which would make the non-transplant approach even more palatable for patients with thalassemia intermedia.

Dr. Thompson: This is a remarkable time in the treatment of thalassemias. We have made it over the big hurdles of providing safe transfusions, monitoring iron noninvasively, and developing more convenient chelators, but I can’t help but think there is room for other advances for patients with thalassemia. For example, the newer oral chelators have represented such an improvement over the onerous medications like deferoxamine, which required nightly subcutaneous infusion. Given the dosing schedules and side-effect profiles of the oral options, though, compliance and adherence are still issues. Unfortunately, we do not have an ideal chelator for some patients. Similarly, we don’t yet know whether there is a role for drugs like hepcidin to help with balancing iron load in patients. The trials of gene-editing in thalassemia also are just preparing to launch.

Dr. Coates: The major challenge to overcome with chelation therapy is finding a chelator that can be administered in a less-frequent schedule. Of course, all these medications have the same fatal flaw: They don’t work if you don’t take them. The beauty of transplant is that, once a patient gets through the process, the daily drug therapy falls away.

Dr. Thompson: With gene therapy, at least in the current research setting, patients must adhere to a certain regimen postinfusion, but for a fairly fixed period. Many patients will need to resume iron chelation to fully unload residual tissue iron after gene therapy, but most will not need long-term medications. They will require close follow-up at a specialized center postinfusion, then less frequent monitoring after a few years. Compared with the burdens of transfusion, chelation, and management of other thalassemia complications, gene therapy should give most patients remarkable freedom.

Dr. Coates: That freedom is also one of the advantages of luspatercept; it is an injection administered approximately once every three weeks, so adherence should be a bit higher.

Iron is the factor I am always at the pulpit about. Pediatric patients who undergo transplant are now expected to survive for decades, so my biggest concern is the long-term consequences of malignant transformation. Research has shown that patients receiving transfusions have an elevated risk of developing leukemia and lymphoma later in life, compared with those who were not transfused.

Dr. Thompson: We can both agree that we need long-term follow-up to evaluate late effects of gene therapy, as well as the consequences of pre-existing organ injury from thalassemia. It is easy to talk about the intent of curative therapies, but the question we need to answer is, “Does this person still have thalassemia?” Patients want to consider themselves disease-free, and it is incumbent upon us to remind them that, even after one of these curative approaches, they will need surveillance for a long time.


  1. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018;378:1479-93.
  2. Locatelli F, Walters MC, Kwiatkowski JL, et al. Lentiglobin gene therapy for patients with transfusion-dependent β-thalassemia (TDT): results from the phase 3 Northstar-2 and Northstar-3 studies. Abstract #1025. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.
  3. Cappellini MD, Viprakasit V, Taher A, et al. The BELIEVE trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta thalassemia patients who require regular red blood cell (RBC) transfusions. Abstract #163. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.
  4. Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. 2019;133:1279-89.