TO THE EDITOR:
The American Society of Hematology (ASH) 2020 guidelines for transfusion support for
individuals with sickle cell disease (SCD)
1
included recommendations on specific indications and administration of transfusion,
as well as screening, prevention, and management of alloimmunization, delayed hemolytic
transfusion reactions (DHTRs), and iron overload. The ASH Guideline Monitoring Expert
Working Group conducted an updated literature search that did not identify new studies
that would change the current recommendations.
No randomized control trials or systematic reviews that would impact the current recommendations
were identified. However, since publication, additional therapeutics for SCD that
could impact clinical transfusion practice have been approved by the US Food and Drug
Administration or reported.
1.
Voxelotor (Oxbryta): Hemoglobin S (HbS) polymerization inhibitor that was shown in
a phase 3 randomized, placebo-controlled trial involving participants with SCD to
significantly increase hemoglobin levels and reduce markers of hemolysis. For recommendation
3, which addresses immunosuppressive therapy for patients with SCD with a history
of multiple or life-threatening DHTRs, one should consider voxelotor as a preventive
maintenance therapy to improve the baseline hemoglobin of patients at high risk of
DHTR if red cell transfusion is required.
2
2.
Tocilizumab (Actemra): Monoclonal antibody directed against interleukin 6 (IL-6) receptor.
Case reports have described individuals with DHTRs who have shown marked improvement
after targeted anti–IL-6 receptor therapy, suggesting that blockade of macrophage
activation may be an effective treatment strategy for ongoing DHTR. Tocilizumab could
be added as a potential therapeutic strategy to recommendation 4 that suggests immunosuppressive
therapy (IV immunoglobulin, steroids, rituximab, and/or eculizumab) over no immunosuppressive
therapy in patients with SCD with a DHTR and ongoing hyperhemolysis.
Red blood cell (RBC) transfusion remains a critical component of care for patients
with SCD. Despite improvements to optimize RBC antigen matching, minimize iron overload,
and to transfuse judiciously, individuals with SCD may still experience adverse effects.
As this issue of Blood Advances describes, the ASH 2020 Guidelines for Management
of Sickle Cell Disease: Transfusion Support
1
continue to be relevant, without sufficient new data to recommend revision or retirement.
Several recently approved therapeutics provide alternatives or adjunctive therapy
related to the ASH recommendations for transfusion support, and there are multiple
ongoing efforts and studies relevant to SCD and transfusion therapy which we summarize
here.
Prevention of HTRs in high-risk patients (recommendation 3)
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.
Management of severe DHTRs with hyperhemolysis (recommendation 4)
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, 8, 9, 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.
RCE with or without IHD for chronically transfused patients with SCD (recommendation
7)
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.
Transfusion management during pregnancy (recommendation 8)
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).
Conclusion
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.
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.