Recent Advances in the Treatment of Sickle Cell Disease
Established interventions for sickle cell disease (SCD), such as hydroxyurea and chronic transfusion therapy, have greatly improved outcomes. As novel therapies that target differing facets and manifestations of SCD are introduced, an increasingly multimodal approach to treatment is anticipated.
What are some of the more recent (ie, in the last 5 years) treatment advances in SCD?
Associate Professor, Division of Hematology and Oncology
“Voxelotor and crizanlizumab are the 2 recently introduced therapies that are available for adolescents and adults with SCD. We have also seen an increase in allogeneic transplant and an interest in gene therapies, and I think that this reflects a greater awareness of these options.”
I treat mainly adults, but I also work closely with my pediatric colleagues who run our pediatric program. Voxelotor and crizanlizumab are the 2 recently introduced therapies that are available for adolescents and adults with SCD. We have also seen an increase in allogeneic transplant and an interest in gene therapies, and I think that this reflects a greater awareness of these options at our program, as well as nationally.
At our center, voxelotor is used more for patients with very low hemoglobin levels or for those who are very heavily alloimmunized and/or cannot be transfused for other reasons (eg, religious reasons). Gastrointestinal reports can be associated with all doses, but they are more common with the 1500-mg dose, so dose modifications may be considered. Responses to voxelotor have been more heterogeneous than expected based on the clinical studies (ie, some patients have demonstrated robust responses, but there are also some whose hemoglobin increases are only approximately 0.3 g/dL or 0.4 g/dL and some without any response). As reported in a recent article from The Lancet Haematology, a significant improvement in pain has not been observed with voxelotor use. I have only had 1 patient out of approximately 20 individuals on voxelotor who felt that their pain had improved.
With respect to crizanlizumab, we use it quite a lot. We have 55 patients, which is just over 10% of our patient population, currently receiving crizanlizumab. In addition, in our group of patients, we have seen that more than 50% respond with a greater than 50% decrease in acute pain crises. Some patients have not had any hospitalizations since they started receiving crizanlizumab. We have also had a few patients who did not experience benefits; we suggest a trial of at least 6 months with any new medication before concluding that it is not effective. Painful infusion reactions have been reported within the United States, but we, thankfully, have not seen that at our center. In our conversations with colleagues in the community, we note that there are no data to support concomitant corticosteroid administration with crizanlizumab, and we highly recommend not using any premedications.
Professor of Pediatrics and Medicine
“As has been the case for kidney disease and heart disease in the general population, individuals with SCD have multiple FDA-approved drugs available to them. Further, families are increasingly asking our team for the best evidence regarding their optimal combination of FDA-approved SCD treatments.”
I am glad to hear about the increased awareness of curative therapy as a treatment option in Dr Kanter’s setting. Additionally, strategies such as nonmyeloablative therapy and haploidentical human leukocyte antigen–matched donors have resulted in more people being able to receive curative treatment.
Regarding voxelotor and crizanlizumab, at our SCD center that provides medical care for children and adults, we developed a systematic approach to determine who should be offered treatment with these newly US Food and Drug Administration (FDA)–approved agents. With voxelotor, we have been focused predominantly on the adults who have hemoglobin levels of less than 6 g/dL, as very few children have hemoglobin levels that meet those criteria. We have also started offering voxelotor to those who are heavily alloimmunized, recognizing that the blood bank can identify a subgroup of patients in whom a standard transfusion would be extremely difficult due to red blood cell alloantibodies. In addition, we have treated children and adults who have religious objections to blood transfusions with voxelotor. Specifically, we have used voxelotor to increase hemoglobin levels prior to surgery. Based on the American Society of Hematology guidelines, prior to surgery, recommended care is to increase the hemoglobin level to greater than 9.0 g/dL but less than 11 g/dL with simple transfusions. Voxelotor enables us to approach a presurgery goal of a hemoglobin level of greater than 9.0 g/dL with or without preoperative transfusions.
Regarding crizanlizumab, we have found that this therapy is helpful to our patients who have been on hydroxyurea, are adherent to the medication, and still have multiple episodes of severe acute vaso-occlusive pain events. This therapy has been extremely helpful in our adolescent and young adult population, particularly those who might be less inclined to be adherent with their hydroxyurea or those with compound heterozygous SCD who are not eligible to take hydroxyurea.
As has been the case for kidney disease and heart disease in the general population, individuals with SCD have multiple FDA-approved drugs available to them. Further, families are increasingly asking our team for the best evidence regarding their optimal combination of FDA-approved SCD treatments. Ultimately, the answer to this question is within the National Heart, Lung, and Blood Institute purview to fund clinical trials that compare outcomes with FDA-approved multimodal therapies for SCD.
Associate Professor of Pediatrics
“We are currently in the era of multimodal therapy. This is especially relevant when we have patients who take hydroxyurea but continue to have breakthrough sickle cell complications.”
We recently were presented with the case of a very heavily alloimmunized patient who came to us from an outside hospital after having another delayed hemolytic transfusion reaction, and we were exploring all avenues to avoid transfusion. As a result, one of the treatments we initiated was voxelotor, in addition to management with immunosuppression and erythropoietin. We have observed beneficial effects with the use of voxelotor among patients relatively quickly after treatment initiation. Voxelotor provides another means of increasing hemoglobin levels without transfusion for alloimmunized patients whom we cannot transfuse safely.
We are currently in the era of multimodal therapy. This is especially relevant when we have patients who take hydroxyurea but continue to have breakthrough sickle cell complications. We can now add crizanlizumab or voxelotor to their outpatient management, which has been shown to be effective. In fact, we currently have several adolescent patients who are on both hydroxyurea and voxelotor. While pill burden is an important consideration, I do think that we are in the age of multimodal therapy, as mentioned previously, and that we should consider the best combination for each individual.
Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-439. doi:10.1056/NEJMoa1611770
Bernaudin F, Dalle J-H, Bories D, et al; Société Française de Greffe de Moelle et de Thérapie Cellulaire. Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France. Haematologica. 2020;105(1):91-101. doi:10.3324/haematol.2018.213207
Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656-2701. doi:10.1182/bloodadvances.2020001851
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DeBaun MR, Jordan LC, King AA, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020;4(8):1554-1588. doi:10.1182/bloodadvances.2019001142
Howard J, Ataga KI, Brown RC, et al. Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2021;8(5):e323-e333. doi:10.1016/S2352-3026(21)00059-4
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Vichinsky E, Hoppe CC, Ataga KI, et al; HOPE Trial Investigators. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519. doi:10.1056/NEJMoa1903212