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β-Thalassemia FAQs
Management of β-Thalassemia: Expert Responses to Frequently Asked Questions

Released: February 21, 2020

Expiration: February 19, 2021

Janet L. Kwiatkowski
Janet L. Kwiatkowski, MD, MSCE
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In this commentary, I answer a selection of questions that were posed by the audience during an ASH 2019 satellite symposium focused on the optimal management of patients with β-thalassemia.

Gene Therapy and Stem Cell Transplantation
Is the gene therapy stem cell drug product lymphocyte depleted? At what point after successful gene therapy should the patient discontinue immunosuppression?
Gene therapy in β-thalassemia involves an autologous hematopoietic stem cell transplant (HSCT), which means that the stem cells used to generate the gene therapy drug product are collected from the patients themselves. This is in contrast to an allogeneic HSCT, which uses stem cells from a donor and thereby incurs a risk for graft-vs-host disease in the recipient due to the presence of donor lymphocytes and necessitates posttransplant immunosuppression. Because a patient’s own stem cells are used for gene therapy in β-thalassemia, lymphocyte depletion and posttransplant immunosuppression are not needed.

Development of the gene therapy drug product in β-thalassemia typically involves the following steps. The patient’s own stem cells are collected by apheresis following mobilization by G-CSF and plerixafor. The collected cells are then selected for CD34 (a known stem cell marker) that results in a lymphocyte-depleted drug product despite graft-vs-host disease not being a concern with autologous HSCT. The purified CD34-positive stem cells then undergo ex vivo gene addition via transduction with a lentiviral vector or gene editing and are reinfused back into the patient.

What factors guide your choice between using allogeneic HSCT or gene therapy in the treatment of a patient with β-thalassemia?
If a patient has an available HLA-identical sibling donor, a matched sibling donor HSCT would be the treatment of choice. In fact, in the current gene therapy trials, having an available matched sibling donor is an exclusion criterion.

When faced with the decision between HSCT with an unrelated donor and gene therapy, the choice is less clear. If the unrelated donor is a good match (ie, 10/10), allogeneic HSCT could be considered, especially for children where the benefit of transplantation with a 10/10 matched unrelated donor approaches that of HSCT with an HLA-identical sibling. However, gene therapy could also be considered, especially for older patients or families who would rather not pursue HSCT with an unrelated donor.

The β-thalassemia genotype also matters when considering gene therapy. In early phase I/II studies of LentiGlobin BB305 vector–based gene therapy, patients with non-β0/β0 genotypes were more likely to discontinue transfusions than patients with a β0/β0 genotype (the most severe form of the disease). This difference appears to be related to their respective baseline hemoglobin levels prior to gene therapy. Patients with non-β0/β0 genotypes produce some β-globin and, therefore, likely have higher baseline hemoglobin levels than patients with β0/β0 genotypes who do not produce any β-globin and, therefore, have low baseline hemoglobin levels that are limited to fetal hemoglobin production. In these studies, the median vector-derived hemoglobin production was approximately 6 g/dL, which was sufficient to raise the hemoglobin level of patients with non-β0/β0 genotypes to ≥ 9 g/dL and enable them to discontinue transfusion. By contrast, adding 6 g/dL of hemoglobin to a patient with a β0/β0 genotype did not raise the hemoglobin level enough to be able to discontinue transfusions, although it generally helped to reduce the transfusion requirement. 

That said, the more recent phase III trials evaluating LentiGlobin BB305 vector–based gene therapy for the treatment of β-thalassemia are using a modified transduction approach that results in higher levels of vector-derived hemoglobin. Thus, it is possible that the distinction between non-β0/β0 and β0/β0 genotypes may not be as important of a consideration in this decision in the future.

There is also some indication that gene therapy might be more effective in younger patients. In a phase I/II study evaluating gene therapy with the lentiviral GLOBE vector, younger patients achieved better transfusion discontinuation rates than older patients. However, more and better long-term data will be needed to determine whether this difference is meaningful.

The chosen therapy should be based on a discussion with the patient and family, including the risks and benefits of each option and long-term considerations, especially regarding treatment of children. At this time, both HSCT and gene therapy approaches require administration of chemotherapy. Gene therapy, as mentioned above, has the benefit over HSCT of using the patient’s own stem cells, thereby avoiding the risk for graft-vs-host disease as well as eliminating concerns about donor availability. However, in the absence of long-term data, much about gene therapy remains unknown, including long-term stability and the associated risk for insertional mutagenesis with lentiviral-based gene therapy that could predispose a recipient to development of a myelodysplastic syndrome or a leukemia or off-target effects with gene editing. When making these decisions, it is helpful to employ a multidisciplinary approach where patients and families can be evaluated by and speak with the hematologist, the bone marrow transplant team, a psychologist, a social worker, and the fertility preservation team, the latter of which is particularly important for children and young adults.

Biologic Therapy
How do you decide which patients are good candidates for luspatercept?
I think information about luspatercept should be provided to all adult patients with transfusion-dependent β-thalassemia, the patient population for which it is approved for use by the FDA. However, as with most therapy decisions, a discussion with the patient or the patient’s family is necessary to determine whether luspatercept is a good fit for them.

Luspatercept may be of particular benefit for patients who have a high transfusion burden or difficulty controlling their iron burden, especially older patients who may not wish to undergo the risks of transplantation associated with curative options. In patients receiving regular red blood cell transfusions, luspatercept would ideally function to improve their quality of life by extending the time between transfusions (ie, if patients who are currently receiving transfusions every 2 weeks could shift to every 3 weeks) or reducing their overall transfusion requirement (ie, 1 unit instead of 2 units) even if frequency were unaffected. Although the exact effect of luspatercept on iron burden awaits further data, a reduction in transfusion burden by either route could, in effect, reduce patients’ iron loading and lead to better control of their iron burden.

It is also important to note that all-grade thromboembolism occurred in 3.6% of the luspatercept-treated patients in the BELIEVE trial, a risk that must be discussed with all patients considering luspatercept, in particular those with additional risk factors for thrombosis such as splenectomy, a history of a prior clot, or receiving oral contraceptives. The risk for thromboembolism needs to be weighed against the potential benefits that luspatercept can provide for the patient, with possible consideration of thromboprophylaxis for at-risk patients.

One important caveat is that luspatercept should not be given to pregnant women due to the risk of embryofetal toxicity observed in animal reproductive studies. Likewise, it should not be used in women who are breastfeeding as the drug was detected in the milk of lactating rats in animal studies.

What about using luspatercept in patients with nontransfusion-dependent β-thalassemia?
As mentioned above, luspatercept is currently approved in the United States only for patients with transfusion-dependent β-thalassemia. However, there are early-phase data suggesting a benefit for patients with nontransfusion-dependent disease as well as an ongoing randomized, placebo-controlled phase II study seeking to better determine the role of luspatercept in this setting.

In an open-label, nonrandomized, dose-finding phase II trial of luspatercept conducted in 64 patients with either transfusion dependent or nontransfusion-dependent β-thalassemia, luspatercept achieved a durable hemoglobin increase of ≥ 1.5 g/dL from baseline in 58% of 31 patients with nontransfusion-dependent β-thalassemia who were treated with higher dose levels of drug (0.60-1.25 mg/kg). Furthermore, quality-of-life scores (FACIT-F tool) significantly correlated with the mean 12-week change in hemoglobin in the nontransfusion-dependent patients (n = 21; r = 0.64; P = .002). Of note, 6 patients with multiple leg ulcers (including patients in the nontransfusion-dependent group) had complete healing of at least 1 ulcer, with 9 fully healed, 2 partially healed, and only 3 not improved.

A slight rise in hemoglobin levels in combination with improvements in ineffective erythropoiesis as achieved by luspatercept could prove to be very beneficial in patients with nontransfusion dependent β-thalassemia. Whether luspatercept will be approved in this setting awaits results from the ongoing randomized phase II BEYOND study comparing luspatercept with placebo in adults with nontransfusion-dependent β-thalassemia (planned N = 145). The primary endpoint is the mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval (Weeks 13-24) compared with baseline. Other endpoints include quality of life, safety, and effect on related symptoms such as hypertension and leg ulcers.

Iron Chelation Therapy and Hydroxyurea
What factors guide your choice of iron chelation therapy in the treatment of iron overload in patients with β-thalassemia?
Multiple factors are considered when choosing which iron chelation regimen to use for a patient, including the patient’s preference, degree of organ-specific iron burden, adverse events, and comorbidities. Patient preference and his/her ability to adhere with the prescribed treatment are of paramount importance. In other words, you want to choose a therapy that is going to be tolerated by patients and that they will take. This should involve a conversation with patients, and their families in the case of children, about the advantages and disadvantages of each option, including potential adverse events, and a joint decision on which is the best fit for the patients. This should then be followed by periodic reassessment as to whether the iron burden is being controlled by the drug they are receiving or if they are experiencing adverse events. If patients are experiencing adverse events or if their iron burden is not controlled, options include modifying the dose of their current agent, switching to another agent, or adding another chelator to use as combination therapy.

Most patients opt to start with deferasirox because it is administered orally (as either a film-coated tablet or granule form) once daily and, therefore, is easier to take. This is in contrast to deferoxamine, which is delivered parenterally as a subcutaneous or intravenous infusion, typically over 8-10 hours 5-7 days per week. This onerous mode of administration can limit adherence. Furthermore, deferasirox has a longer half-life than deferoxamine. If a patient is compliant with once-daily deferasirox, he/she will have continuous iron chelation exposure for 24 hours. By contrast, shortly after discontinuing deferoxamine infusion, no chelator is left in the patient’s system. When chelator is present, it binds to toxic nontransferrin-bound iron and can protect from iron-mediated tissue injury. Thus, continuous coverage to protect from the harmful effects of iron is preferable.

In some countries, deferoxamine is the preferred chelation for young children. Because it can be difficult to get a toddler to take oral medication, choosing a subcutaneous agent places adherence under the parents’ control. In addition, the many years of experience with deferoxamine that we have—it was approved by the FDA in 1968—makes it a good first option. The risk of adverse events with deferoxamine are increased when the iron burden is low. This includes ophthalmologic and audiologic adverse events but also adverse events on growing bones. Thus, it is important to avoid overchelation with this medication.

Finally, deferiprone, which is also an oral agent, is given 3 times daily due to its short half-life. In addition, it is only approved in the United States as a second-line agent after failure of deferoxamine or deferasirox. This agent is particularly good at removing iron from the heart and so should be considered for use in patients who have evidence of increased cardiac iron. In patients with severe iron overload, deferiprone can be combined with deferasirox or deferoxamine for more intensive iron chelation. This agent also may be a good choice for patients whose iron burden is low, as deferiprone seems to have fewer adverse events than deferoxamine in this setting. The most concerning adverse event of deferiprone is agranulocytosis, which occurs in 1% to 2% of patients and requires weekly blood count monitoring and immediate medical evaluation for all fevers.

In which patients would you choose to use an agent like hydroxyurea to induce fetal hemoglobin production?
Hydroxyurea may be useful in the treatment of patients with nontransfusion-dependent β-thalassemia to increase their hemoglobin levels via induction of fetal hemoglobin production. Currently, hydroxyurea is not labeled for use in β-thalassemia; certain formulations have received FDA approval for the treatment of sickle cell anemia in children as young as 2 years of age. In contrast to the dosing used in sickle cell disease, for β-thalassemia, we typically start with a lower dose of 10 mg/kg and monitor closely for neutropenia, which is the main adverse event of concern in this patient population. If well tolerated, dose escalation to approximately 20 mg/kg can be considered. The goal is to increase a patient’s hemoglobin level and reduce ineffective erythropoiesis, which may lead to an improvement in fatigue and quality of life. The use of hydroxyurea also has been linked to decreased risk of some complications associated with nontransfusion-dependent β-thalassemia such as pulmonary hypertension, extramedullary hematopoiesis, and leg ulcers.

Your Thoughts?
What are your most pressing clinical questions about the treatment of β-thalassemia? I encourage you to answer the polling question and join the conversation in the discussion box below.