Transfusion therapy for sickle cell disease: what’s new?

Hemolytic transfusion reactions (HTRs) occur in 3% to 5% of transfusions in individuals with SCD and up to 11% of such reactions are fatal. Mitigation is achieved through judicious use of transfusions and provision of RBCs lacking the cognate antigens against which a recipient has alloantibodies.

New SCD-modifying agents (SCDMAs), which increase baseline hemoglobin levels and reduce markers of hemolysis, offer the potential to minimize the need for RBC transfusions in individuals with SCD at high risk of HTRs. Voxelotor (Oxbryta), a HbS polymerization inhibitor, is a Food and Drug Administration–approved SCDMA for ages ≥4 years, which significantly increases hemoglobin levels and reduces markers of hemolysis in individuals with SCD.^2,3 Although unable to directly prevent HTRs, voxelotor, in addition to hydroxyurea, should be considered to improve the baseline hemoglobin in patients at high risk for hemolytic reactions to minimize future RBC transfusions. Pyruvate kinase activators are another class of agents being investigated to reduce hemolysis and increase baseline hemoglobin in individuals with SCD. Phase 2/3 trials of pyruvate kinase activators mitapivat (AG-348) and etavopivat (FT-4202) are ongoing (www.clinicaltrials.gov, #NCT05031780 and #NCT04624659) and may be added to the repertoire of SCDMAs to minimize RBC transfusion in high-risk individuals.

Given that most RBC antibodies in individuals with SCD evanesce over time,^4,5 identification of RBC antibodies when they are present is critical. Equally important is RBC antibody data sharing between hospitals. Since the guidelines were published, the Department of Health & Human Services’ Advisory Committee on Blood and Tissue Safety and Availability has published support for the need of a national RBC antibody registry. Furthermore, there is ongoing research to increase data interoperability and, in the longer term, to require the uniform recording of RBC antibodies using ISBT-128 codes in the electronic medical record.

A DHTR with hyperhemolysis can be a life-threatening transfusion reaction in individuals with SCD.⁶ The 2020 ASH SCD transfusion support guidelines suggested immunosuppressive therapy over no immunosuppressive therapy for DHTRs, including the use of IV immunoglobulin, steroids, rituximab, and/or eculizumab. Since that time, case reports have described individuals with SCD and HTRs successfully treated with an IL-6 receptor antagonist (tocilizumab [Actemra]).^7-10 The binding of tocilizumab to the IL-6 receptor inhibits, among other things, IL-6–mediated macrophage activation. As such, tocilizumab could be considered as a potential therapeutic strategy to recommendation 4; however, further investigation of tocilizumab is warranted. Driven in part by the success of eculizumab in disorders resulting from complement-mediated intravascular hemolysis (eg, cold agglutinin disease and paroxysmal nocturnal hematuria), a range of new inhibitors targeting distinct components of the complement cascade are currently under investigation.¹¹ Although these agents have not been used in treatment of SCD, they may provide additional future treatment options for individuals with SCD suffering from severe DHTRs with hyperhemolysis.

The 2020 ASH SCD transfusion support guidelines suggested red cell exchange (RCE) over simple transfusion for patients requiring chronic transfusion therapy as it minimizes iron accumulation and can improve maintenance of the target HbS percentage. Isovolemic hemodilution (IHD) RCE is a procedure available in which, before the RCE, the patient undergoes an RBC depletion with concurrent volume replacement with normal saline or 5% albumin. The intent of IHD-RCE, also known as depletion exchange, is to decrease the number of RBC units needed to attain the target HbS percentage. The ASH guideline panel was unable to provide a recommendation for IHD-RCE vs conventional RCE because of a lack of evidence suggesting the impact of IHD-RCE on RBC unit utilization was superior.^12,13 Since the 2020 ASH guidelines were finalized, a French study of 50 patients reported a 16% reduction of RBC units when comparing IHD-RCE to standard RCE (average requirement decreased from 13 to 11 units).¹⁴ All patients underwent IHD-RCE every 2 months to maintain the HbS <50% and unit savings were calculated from the RBC unit number required by the instrument software to perform standard RCE. RBC unit savings may occur with IHD-RCE when patients require large volume procedures, but studies are needed to determine blood unit utilization for patients who require RCE to maintain the HbS <30%. In addition, the 2020 ASH guidelines panel highlighted a need for further studies evaluating the safety of IHD-RCE in patients with chronically transfused SCD. Since its report, a single institution study reported on the incidence of RCE adverse events and found no association between the use of IHD-RCE and procedural adverse events.¹⁵ Despite this report, more investigation is needed to determine long-term impact of IHD-RCE compared with conventional RCE on neurologic outcomes.

The 2020 ASH SCD transfusion support guidelines included recommendations on transfusion management during pregnancy. The panel concluded that there was insufficient evidence to recommend prophylactic transfusion rather than standard of care for pregnant women with SCD. However, consideration of prophylactic transfusions at regular intervals was recommended for women with a history of severe SCD-related complications before current pregnancy (including during previous pregnancies), additional features of high-risk pregnancy (eg, additional comorbidities), or women who develop SCD-related complications during the current pregnancy (conditional recommendation based on very low certainty of evidence). Consequently, the panel identified this as a research priority. Currently, there is an ongoing multicenter feasibility trial comparing standard of care with serial prophylactic RBC exchange (to maintain HbS <30%) starting in the first trimester in women with SCD, which intends to assess willingness of pregnant women with SCD to participate in a chronic RCE regimen and to evaluate maternal and fetal outcomes (Transfusion Antenatally in Pregnant Women With SCD [TAPS2]; www.clinicaltrials.gov, #NCT03975894).

The purpose of the 2020 guidelines was to provide evidence-based recommendations for RBC transfusion support in patients with SCD. Because high-quality evidence was not uniformly available for each transfusion topic, the panel’s goal was to provide clinical decision support for shared decision-making by patients and clinicians based on the available evidence. Ongoing clinical trials studying chronic transfusion therapy for pregnant women with SCD, or adults with SCD and pulmonary arterial hypertension (SCD and CardiovAscular Risk–RBC Exchange trial [SCD-CARRE]; www.clinicaltrials.gov, #NCT04084080), will guide future recommendations. As new therapeutics are approved and ongoing clinical trials provide new evidence, guideline monitoring will continue to incorporate new management approaches and highlight top research priorities.

Contribution: All authors wrote the manuscript.

Conflict-of-interest disclosure: R.M.F. has served as an advisory board member for Global Blood Therapeutics (Oxbryta) and Forma Therapeutics (Etavopivat [FT-4202]). The remaining authors declare no competing financial interests.

Correspondence: Stella T. Chou, Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Blvd, Philadelphia, PA 19104; e-mail: chous@chop.edu.