Advancing through challenges: current strategies in sickle cell disease management

Introduction

Sickle cell disease (SCD) is the most common monogenic disease in the world (1). In patients with SCD, a point mutation in the β-globin gene causes the amino acid glutamine to be replaced by valine, generating a hydrophobic hemoglobin molecule, hemoglobin S (HbS) (2). When deoxygenated, HbS polymerizes and causes red blood cell (RBC) sickling, leading to profound anemia, hemolysis, vaso-occlusive crisis (VOC), and end-organ damage; resulting in the noted shorter lifespan (52.6 years) compared to the general population (3). SCD was first described in 1910 by a Chicago-based physician who found abnormally elongated erythrocytes on a blood smear from an anemic dental student from the West Indies (4,5). In subsequent decades, Linus Pauling and other investigators elucidated SCD’s molecular and genetic foundation (6,7). SCD was the first to be defined at this basic level, yet subsequent research advances and approved clinical interventions lagged far behind other genetic illnesses such as cystic fibrosis and hemophilia (8).

This lag in research advancement and meaningful clinical intervention has been recognized as an example of structural racism, limiting resource allocation for disease understanding and management (9). While the medical community quickly began to study and develop treatments for other genetic diseases, in the United States, SCD did not receive the same level of attention (10). Most people with SCD in the U.S. are of African descent, which has historically influenced the quality of healthcare they receive (11,12). It was not until the latter half of the 20th century that significant advocacy and civil rights movements highlighted the need for equitable healthcare provisions and spurred research into treatments. The National Sickle Cell Anemia Control Act in 1972 marked a turning point, leading to the establishment of specialized centers for SCD care (13). Still, challenges remain in addressing the racial disparities in healthcare access and outcomes for SCD patients. It took nearly a century for the first approval of disease modifying therapy [hydroxyurea (HU)] and will take even more to counter the stigma and trauma faced by SCD patients in receiving appropriate care. Awareness and understanding of these historical and ongoing injustices are crucial as part of the broader efforts to provide equitable health services and develop effective treatments for all affected by SCD.

In this review, we examine the currently approved SCD treatments including the use of disease-modifying drugs, the life-altering potential of curative hematopoietic stem cell transplantation (HSCT), and the cutting-edge advances in gene therapy. By integrating insights from these areas, our review seeks to highlight a comprehensive approach that not only manages the symptoms but also addresses the underlying pathology of SCD, paving the way for transformative care in this field.

Role of disease modifying therapies

Increasing fetal hemoglobin (HbF) with HU

HU or hydroxycarbamide, is a small molecule that belongs to a class of compounds called hydroxamic acids (14). HU inhibits ribonucleotide reductase (RR), an enzyme that transforms ribonucleotides to deoxyribonucleotides which are required for DNA synthesis and repair (15,16). HU was first synthesized in 1869 and gained FDA approval in 1967 in treatment of neoplastic disease. Its role in SCD became recognized in the 1980s after an increase in HbF levels was noted in SCD patients after exposure to HU (16-18). Higher levels HbF interfere with the polymerization of deoxygenated HbS molecules, and RBCs with higher percentage of HbF relative to HbS are more deformable and demonstrate better RBC rheology (19). The beneficial effect of HbF was first observed in the 1960’s after patients with SCD and hereditary persistence of HbF (HPFH) demonstrated a milder clinical phenotype (20,21). HU has further therapeutic impact in SCD with reduction of chronic inflammation via decreasing total white blood cells and platelets, the former of particular significance as leukocytosis is a negative prognostic factor for patients with SCD (18,19).

The foundational clinical study to establish the therapeutic effects of HU was the Multicenter Study of Hydroxyurea (MSH) (22). The MSH compared HU versus placebo in a double blind, placebo-controlled, randomized control trial (RCT) from 1992–1995 in 299 adults for 21 months (22). Treatment with HU was shown to reduce the number of crises by 44%, the intensity of crises, the risk of development of acute chest syndrome (ACS), the frequency of RBC transfusions and the number of packed RBC units transfused. HU subsequently gained US Food and Drug Administration (FDA) approval for SCD in 1998 (23). In the nine year open label observational follow up study of the MSH cohort, including 233 of the original 299 SCD patients, there was a 40% reduction in mortality for those continuing HU treatment (24). Extending the MSH cohort follow-up to 17.5 years, there was a persistent mortality benefit for patients taking HU (25). HU is now considered the cornerstone of SCD treatment.

Reducing hemolysis and improving hemoglobin level with the hemoglobin polymerization inhibitor voxelotor

A feature of HbS, but not HbA is the tendency to polymerize under certain physiologic conditions. HbS is the result of a single DNA adenine to thymine base substitution resulting in the replacement of the hydrophilic glutamine with the hydrophobic valine at position six of the beta globin chain. In the deoxygenated state, due to the stoichiometry of the altered beta globin molecule, there is a tendency to attach to adjacent hemoglobin molecules, ultimately forming an insoluble polymer and irreversibly deforming the RBC shape which leads to membrane fragility and hemolysis. RBCs that are deformed this way are recognized morphologically as sickle cells. These cells have shortened survival from intravascular hemolysis, resulting in a constellation of downstream consequences including anemia and pervasive end organ damage (26). Anemia itself is critically associated with adverse clinical outcomes (27,28) and the break-up of erythrocytes and release of hemoglobin, membrane fragments and iron results leads to a cascade of inflammatory processes that damage vessels, impede blood flow and result in ischemic damage to end organ tissues (29).

In 2019, the US Food and Drug Administration approved voxelotor—a first in class hemoglobin polymerization inhibitor (30). This drug selectively binds the N-terminal valine of the alpha globin chain and in so doing, increases oxygen affinity, reducing oxygen offloading and inhibiting polymerization of HbS.

In the randomized, placebo-controlled HOPE trial, oral voxelotor 1,500 mg daily was compared with voxelotor 900 mg daily and placebo in SCD patients twelve years and older (31). More participants receiving 1,500 mg daily of voxelotor versus placebo had a hemoglobin response of at least 1 g/dL [51%, 95% confidence interval (CI): 41–61% vs. 7%, 95% CI: 1–12%, P<0.001]. Similarly, markers of hemolysis (indirect bilirubin, reticulocyte count) improved significantly in the treatment vs. placebo groups. Approximately 2/3 of the participants in each of the groups were also receiving HU, with treatment benefits observed regardless of HU status. Based on these results, the FDA gave approval for the treatment of SCD in adolescents (12 and over) and adults. In a follow-up analysis of the HOPE trial participants, response was shown to be comparable and durable out to 72 weeks of treatment (32). The subsequent HOPE-KIDS 1 trial produced comparable results, expanding the indication for voxelotor to children 4 years and older (33).

The HOPE trials were insufficiently powered to address rates of VOCs or end organ damage. However, there is a current ‘real world’ voxelotor registry that is gathering long-term data on 1,000 voxelotor treated patients (PROSPECT, NCT04930445) and preliminary data was presented at the 2023 annual meeting of the American Society of Hematology (ASH) (34). Further, other reports have indicated fewer transfusions, improvement in leg ulcers, and less frequent VOCs in voxelotor-treated SCD patients (35-37) although reduction in end organ disease remains to be confirmed. Shah and colleagues examined data available in a large insurance claims analysis of 3,128 voxelotor treated SCD patients from 2019 through 2021 and found reduced transfusions, fewer VOCs, less frequent hospitalizations and shorter lengths of stay compared to pre-treatment data (36). Thus, although there have been issues raised, particularly about oxygen offloading by voxelotor bound HbS (38), there is now accumulation of abundant literature reporting real-world experience that voxelotor is both safe and effective in the adjunctive management of SCD. Definitive evidence of efficacy in the context of sickle cell mediated end-organ injury remains to be established. Of note, presently, osivelotor, a next-generation HbS polymerization inhibitor with improved pharmacokinetics compared to voxelotor is under phase 2/3 study with promising results (Table 1) (39).

Reducing vaso-occlusion by p-selectin blockade: crizanlizumab

P-selectin is an adhesive molecule found within the platelet α-granule and the Weibel-Palade bodies of endothelial cells. It facilitates the rolling of blood cells across the endothelial surface and initiates the binding of leukocytes in the bloodstream to platelets, endothelial cells, and other leukocytes at areas of tissue damage and inflammation (49). Given the importance of vaso-occlusion in the pathogenesis of SCD pain crises and end organ damage, P-selectin blockade was an attractive target in SCD. Accordingly, crizanlizumab, a monoclonal antibody that selectively binds P-selectin was the first to be tested for patients with SCD. In 2019, the FDA approved crizanlizumab based on observations from the SUSTAIN trial (50). This was a randomized controlled phase 2 study to evaluate the effect of crizanlizumab on the frequency of pain crisis. Initial results of the 198 enrolled patients were promising, demonstrating a 43% reduction in frequency of VOCs for patients who experienced 2–4 VOCs in the preceding year and 63% reduction in patients experiencing 5–10 VOCs per year (50,51). However, preliminary results from a confirmatory STAND trial reported at the ASH 2023 annual meeting (52) did not demonstrate similar efficacy and this has dampened enthusiasm and limited availability of this drug in some countries (53) including the European Commission who revoked Marketing Authorization for Crizanlizumab throughout the European Union (54). It should be noted that the results of these studies raised concern that the discrepancy in results may reflect pandemic-associated alterations in healthcare utilization and its effect on patient selection. For this reason and based on observation that the drug is clearly effective in some patients, crizanlizumab continues to be available in United States. Furthermore, there is some data that crizanlizumab may reduce the frequency of priapism. The SPARTAN trial demonstrated a 61% reduction in terms of number of priapic events, a finding that did not quite reach statistical significance (P value 0.07) but signaled the need to continue investigating this drug with potential benefit in selected subsets of SCD patients (55). Our clinical experience with crizanlizumab demonstrates its effectiveness varies among patients; it is beneficial for some, yet ineffective for others. Thus, a more precise identification of patient subsets likely to respond to p-selectin inhibition remains a research goal. Additionally, we are anticipating the results from the phase III trial of inclacumab (Table 1), a longer acting p-selectin inhibitor, to further elucidate the efficacy of this class of drugs in mitigating VOCs (42,43).

Transfusion programs remain a mainstay of treatment

Transfusion therapy in primary and secondary stroke prevention

Prior to the development of disease modifying therapies, RBC transfusion was the mainstay of disease management. Transfusion therapy has been used effectively to treat the complications of SCD for nearly 50 years. As early as 1969, a transfusion program was established to reduce the frequency of stroke in SCD patients (56). However with increasing transfusions, the negative impacts of secondary hemochromatosis and alloimmunization became apparent (57). The STOP trial was designed to evaluate the effectiveness of chronic transfusion therapy to reduce the risk of first stroke in children with elevated transcranial doppler velocities (58). It was the first trial to include exchange transfusions in the treatment of SCD, in order to mitigate the known risk of iron overload and demonstrated a 92% lower risk of stroke in the transfusion group over the study period of 26 months. The SWiTCH trial, which was designed to evaluate the non-inferiority of HU (with phlebotomy) compared to continued transfusion and iron chelation in pediatric patients, demonstrated a trend towards increased frequency of stroke in the HU arm, with equivalent iron content and the trial was therefore terminated early (59). The authors concluded “transfusions and chelation remain a better way to manage children with SCD, stroke, and iron overload”. Over time, the accumulated evidence has led to the ASH’s 2020 recommendation in favor of prompt blood transfusion following suspected stroke or transient ischemic attack (TIA) and for initiation transfusion program to maintain a hemoglobin >9.0 g/dL and HbS <30% in the pediatric population (60). While adults are not mentioned in this recommendation, clinical practice has typically been to continue transfusion therapy at these goals for patients with history of stroke. Where available, RBC exchange is commonly used over simple transfusion to avoid the risks of iron overload in patients requiring chronic transfusion therapy.

Transfusion in pregnancy

While not all studies are randomized controlled trials, numerous researchers have presented compelling evidence supporting the efficacy of transfusion therapy in mitigating maternal complications in SCD which includes higher rates of VOCs, ACS and hypertensive disorders of pregnancy, intrauterine growth restriction and fetal demise (61-65). Even with limitations in these studies, the consensus favors prophylactic over demand transfusions in SCD pregnancies. Despite these improved outcomes, concerns over alloimmunization and lack of well-established randomized controlled clinical trials, have led to the lack of definitive recommendations for pregnant SCD patients. At this time, the ASH guidelines suggest an individualized approach to transfusion in pregnant patients at higher risk, given that likely benefit outweighs the associated risks (60). Presently, much work remains to be done in developing a treatment pathway to include RBC transfusion for pregnant SCD patients as patients are taken off DMTs during pregnancy and require aggressive management in light of increased risk of complications.

Perioperative transfusion

The ASH guidelines recommend preoperative transfusion for patients with SCD depending on the surgery’s risk due to increased complications in the perioperative period. Notably, the first RCT found no significant improvement in clinical outcomes between maintaining a preoperative hemoglobin level over 10 g/dL alone versus achieving a more aggressive target of 10 g/dL with HbS under 30% (66). A subsequent RCT in Bahrain showed no differences in peri-operative outcomes, and neither group faced major complications (67). However, the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) multicenter RCT observed reduced complications with prophylactic transfusions, including exchange transfusions to achieve reduced HbS levels (68). Despite limited evidence, the ASH consensus panel still supports preoperative transfusion, considering the potential benefits likely outweigh the risks.

Additional uses of transfusion programs

RBC exchange is urgently recommended for SCD complications such as ACS, hepatic/splenic sequestration, fat embolism syndrome, and multi-organ failure. Observational studies have shown that RBC exchange is safe and effective in improving oxygenation for ACS in pediatric patients, though it’s reserved for severe cases due to limited evidence. Hepatic sequestration, characterized by rapid liver enlargement and hemoglobin drop, and intrahepatic cholestasis, marked by increased direct bilirubin and coagulopathy, have been successfully managed with exchange transfusion (69-71). Splenic sequestration, more common in children with HbSS, may also necessitate exchange transfusion, particularly in adults with HbSC who are at increased risk. Additionally, VOCs progressing to multi-organ failure in SCD patients are effectively treated with exchange transfusion, as recommended by the British Society of Hematology (72). The same guidelines also suggest transfusion therapy to prevent frequent VOC complications, considering the risk of iron overload and the benefits of tailored treatment approaches, especially in patients with frequent hospitalizations.

Alloimmunization in SCD

Transfusion therapy, when meticulously administered with appropriate antigen matching, has demonstrated remarkable efficacy in minimizing complications associated with SCD. The alloimmunization rate among SCD patients has been documented to range between 18% and 30%, in stark contrast to the 2–5% range observed in the general population (73,74). This discrepancy primarily arises from polymorphic RBC antigen disparities given that in Europe and the United States, the majority of SCD patients are of African descent while donors predominantly are Caucasian. Thus the risk of alloimmunization can be safely addressed with extended antigen matching and future development of national data registry of patient’s RBC antigens. This is also an area under ongoing development and optimization given the frequency of RBC transfusions in SCD patients.

Curative and transformative therapies in SCD

Curative approach through HSCT

Bone marrow HSCT is the only cure for SCD (75). Its use was first noted in 1984 after HSCT transplant for a patient with both SCD and acute myelogenous leukemia proved effective for both conditions (76). This lead the way for decades of donor and conditioning regimen modifications to today’s transplant platform. While human leukocyte antigen (HLA) fully matched transplant is most ideal, less than 20% of SCD patients have an available donor (77). There are more than 200 HLA genes impacting antigen recognition and processing (78). For this reason, strategies that incorporate partially matched related donor (e.g., haploidentical) or matched unrelated donors have become more frequently utilized. However, these are associated with higher risks of both rejection and graft-versus-host disease (GVHD) (79). It is important to note that many SCD patients do not have the donor, financial or psychosocial support system in place to pursue transplant. Moreover, HSCT remains inaccessible in Sub-Saharan Africa where resources are limited and SCD is most prevalent.

Understanding gene therapy in SCD

Given the single gene alteration in SCD, gene therapy may be an optimally utilized strategy for transformative therapy. Currently, two treatment strategies have been FDA-approved that include either gene editing to increase HbF or alteration of the beta globin gene to induce modified HbA production. This involves patients undergoing apheresis to dampen inflammation and optimize the bone marrow for stem cell collection. While granulocyte-colony stimulating factor (G-CSF) is contraindicated in SCD due to increased VOC risk, plerixafor, a C-X-C chemokine receptor-4 antagonist has proven to be useful in the mobilization of marrow stem cells from SCD patients (80,81). HSCs are then sent to centralized laboratories for genetic modification, a process that may take several months. In the interim, patients continue to receive disease modifying therapies or transfusion protocol. Once ready for infusion, patients are admitted for chemotherapy with busulfan which is generally well tolerated although side effects include stomatitis, febrile neutropenia and thrombocytopenia (82-84). Once platelet and neutrophil engraftment has occurred successfully, patients are then discharged to their medical home for ongoing care.

Lyfgenia

Lyfgenia, also known as Lovo-cel, is an innovative gene therapy for SCD that involves the use of lovotibeglogene autotemcel. This therapy targets the beta globin gene utilizing a lentiviral vector. The vector is designed for safety with a self-inactivating feature and does not affect regulatory regions or oncogenes. It specifically replaces threonine with glutamine at codon 87 of the beta globin gene, producing a modified anti-sickling hemoglobin (HbA^T87Q) that retains normal oxygen-carrying capacity (83,85,86). This therapy was developed through a series of clinical studies, starting with the proof-of-concept trial HGB-205 and followed by phase 1/2 and phase 3 trials (HGB-206 and HGB-210, respectively) (87-89). The results have shown that Lovo-cel leads to durable and stable engraftment of modified hemoglobin in patients resulting in reduced severe VOCs and improved hemoglobin levels. The FDA approved Lovo-cel in December 2023 based on these positive outcomes. Lovo-cel treatment generally shows good tolerance among patients, with most side effects related to the conditioning regimen. Importantly, there have been isolated cases of serious adverse events such as acute myeloid leukemia and a death due to cardiopulmonary arrest, but these were not directly linked to the therapy itself. Overall, the 60-month follow-up data indicate no occurrences of oncogenesis, graft failure, or other severe adverse effects, highlighting the treatment’s potential for long-term efficacy and safety in managing SCD.

Casgevy

Exagamglogene autotemcel (Exa-cel) leverages CRISPR/Cas9 gene editing technology to target and disrupt the BCL11A erythroid enhancer on chromosome 2, leading to an increase in HbF expression. CRISPR-Cas9, originally a bacterial defense mechanism, enables precise genome editing by introducing specific changes at targeted locations within the DNA (90,91). This is particularly relevant in SCD, where symptoms usually appear in the first year of life as HbF levels decline and adult beta-globin levels rise. The shift from fetal to adult hemoglobin is mediated by BCL11A, a transcription factor that suppresses γ-globin gene expression, thereby reducing HbF production (92). This transition is vital post-birth but problematic in SCD, where sustained HbF could alleviate disease severity. High levels of HbF are associated with minimal or absent SCD symptoms, making BCL11A a prime target for CRISPR/Cas9-based therapies like Exa-cel, which received FDA approval in late 2023.

In a recent phase 3 study, Frangoul and colleagues demonstrated that Exa-cel effectively edited over 70% of BCL11A alleles in peripheral blood within 2 months post-infusion, and nearly 86% in bone marrow by 6 months (82). Additionally, the proportion of F cells—which contain HbF—reached 93% at 6 months, indicating widespread cellular distribution. These genetic modifications led to significant increases in HbF levels, from 36.9%±9.0% at 3 months to 43.9%±8.6% at 6 months post-infusion and maintained near 40% at 48.1 months follow-up. Hemoglobin levels also rose, showing sustained improvement to near-normal ranges over the same period. There was a marked reduction in hemolysis, evidenced by lower lactate dehydrogenase levels and reticulocyte counts. Out of 44 patients treated with Exa-cel, 30 had adequate follow-up data for evaluation. Impressively, all 30 avoided hospitalizations for managing VOCs for at least 12 months, and 29 remained free of any VOCs during that time. Only one patient required hospitalization due to a severe VOC and that was triggered by parvovirus B19 infection. Patient-reported outcomes also improved, particularly in metrics assessed by the ASCQ-Me questionnaire, specifically designed for SCD (93). Exa-cel’s safety profile was comparable to that of other gene therapies, with most adverse reactions related to the conditioning regimen, including busulfan induced stomatitis. Tragically, one patient died following a coronavirus disease 2019 (COVID-19) infection, exacerbated by pre-existing lung conditions and potentially compounded by busulfan-induced lung injury. No hematological malignancies were reported, underscoring the therapy’s safety.

It is important to recognize that despite the promising potential of gene therapy in SCD, not every patient will qualify nor will every patient want it. Gene therapy is among the most expensive treatments available, with the HSC manufacturing alone costing $2–3 million (94). This financial burden is particularly daunting as many SCD patients are reliant on public health insurance and this could widen existing disparities in patient care. Beyond financial barriers, many healthcare institutions lack the necessary infrastructure and expertise to effectively administer and monitor gene therapies. Despite efforts to expand SCD specialty care, including over 95 recognized SCD centers (94), challenges persist in technological, clinical, and psychological readiness for these advanced treatments. These issues underscore the broader challenges in making gene therapies accessible and affordable for those most in need. Addressing these barriers require continued optimization and prioritization of new disease-modifying therapies (DMTs) for SCD. By enhancing DMT development and improving access to specialized multidisciplinary care, we can better serve a larger population of SCD patients while preparing healthcare centers to safely implement gene therapies. This dual approach is crucial for ensuring equitable access to effective treatments that enhance quality of life and health outcomes for all SCD patients. This understanding has fueled the many ongoing efforts to develop new targets for SCD treatment as further outlined below and summarized in Table 1.

Future directions

Pyruvate kinase (PK) activators

PK activators, approved for the treatment of PK deficiency have emerged as a novel drug class to treat SCD as well. The PK activators of clinical interest in SCD include mitapivat and etavopivat and in order to appreciate their role in SCD, one must understand their mechanism of action. PK is one of the major enzymes in the glycolytic pathway that converts glucose to pyruvate (95). RBCs lack mitochondria and thus glycolysis and anaerobic respiration are the major source of adenosine triphosphate (ATP), the universal currency of free energy in biological systems (95,96). Glycolysis also produces the reduced form of nicotinamide adenine dinucleotide (NADH), which RBCs utilize to reduce methemoglobin, a byproduct of reactive oxygen species, back to hemoglobin. Two-three disphosphoglycerate (2,3-DPG) is also generated upstream to PK via the Rapoport-Luebering pathway, and is used to regulate oxygen affinity of hemoglobin by stabilizing the deoxy (T) quaternary structure of hemoglobin (97,98). Increased levels of 2,3 DPG, low intracellular pH, and high levels of CO₂ stimulate rightward shift of the oxygen dissociation curve. The p50, or the point at which hemoglobin is half-saturated with oxygen, is used as a marker for oxygen affinity as higher P50 is associated with rightward shifts of the dissociation curve. The P50 of HbS is increased when it is in the deoxygenated state and is directly correlated with the proportion of HbS polymers, contributing to sickling once HbS polymers aggregate (99). Without polymer formation, HbS oxygen affinity is normal (100). Although PK has several isoforms, the PK-R variant is responsible for about 50% of ATP produced in RBCs (98). PK activators bind to the PK-R enzyme allosterically away from the pocket of phosphoenolpyruvate, the immediate precursor pyruvate, and activate the enzyme by stabilizing the active conformation. Activation of PK-R leads to increased intracellular ATP availability and decreased intracellular concentrations of 2,3-DPG (96,101). Increased ATP availability has been associated with maintenance of RBC membrane activity, cellular hydration, RBC deformability and protection from oxidative damage (102).

Mitapivat, the first in-class activator of PK, was FDA approved in February 2022 for patients with PK deficiency after a phase III clinical trial demonstrated treatment was associated with increase in hemoglobin of up to 1.5 g/dL in 40% of patients treated (103). Given the physiologic benefits of PK activation, PK activators were investigated in SCD initially in vitro with whole blood from a patient with SCD (etavopivat) followed by phase I trials of mitapivat and etavopivat in SCD patients (104,105). In both trials, treatment was associated with increased hemoglobin response^, reduced hemolysis and favorable safety profile. Of the six ongoing clinical trials with PKA, the largest are phase II/III trials that are called HIBISCUS (etavopivat) (NCT04624659) and RISE-UP (mitapivat) (NCT05031780) as demonstrated in Table 1 (40,41).

Complement inhibition

Complement activation has been implicated in the pathophysiology of SCD as markers of complement activation (such as C5b-9) are increased in SCD patients at steady state and during VOC (106,107). Studies have implicated overactivation of the alternate pathway triggered by hypoxia followed by reperfusion of sickled RBCs with subsequent lysis of these cells. In HbSS mice, infusion of the anaphylatoxin C5a induced stasis, inflammation and up-regulation of Weibel-Palade body p-selectin and von Willebrand factor (108). Moreover, complement has been implicated in delayed hemolytic transfusion reaction (DHTR), and thus the ASH 2020 guidelines on transfusion recommend immunosuppressive therapy (including the C5 complement inhibitor eculizumab) in patients with DHTR and ongoing hyper-hemolysis or in those at high risk for DHTR with acute need for transfusion (109). As outlined in Table 1, a phase IIa trial (NCT05565092) is underway on a monoclonal antibody (ALXN1820) that inhibits properdin, an endogenous activator of the alternate complement pathway, to evaluate the safety and tolerability of this agent in patients with SCD (44,45). Another phase IIa clinical trial (NCT05075824) investigating the C5 inhibitor is crovalimab with a primary end point of evaluating VOCs that is ongoing (46,47).

Iron restriction

Cell free heme and hemoglobin, produced as a consequence of intravascular hemolysis, induces severe oxidative stress. Cell free heme also scavenges free nitric oxide, promoting vasoconstriction with activation of platelets and coagulation factors with implications for the pathogenesis of pulmonary hypertension in SCD. Cell free heme also activates adhesion molecules and induces leukocyte activation and migration, which in turn are involved in the pathogenesis of the VOC (110,111). Restricting iron suppresses HbS production, and thus in case reports, iron restriction was associated with less crisis in one patient and more rapid healing of a leg ulcer in another (112). Vamifeport (VIT-2763) is a small molecule that, like hepcidin, blocks ferroportin and thus blocks intestinal iron absorption and iron export from the liver and macrophages. In Townes mice, vamifeport induced iron-restricted erythropoiesis (as evident by reduction of mean corpuscular hemoglobin concentration) with subsequent reduction in spleen weight, markers of hemolysis, and mean cellular volume without affecting absolute reticulocyte count or serum hemoglobin (110). In a phase I trial in 72 healthy volunteers, treatment with vamifeport reduced serum iron and transferrin saturation with comparable safety profile compared to placebo (113). A phase IIa, double-blind RCT on vamifeport administration in patients with SCD with a primary end point of reduction in hemolysis markers was recently completed (NCT04817670) although results are not yet published (Table 1). Lastly, a human derived hemopexin, CSL889 is currently being investigated in treating acute VOC via improvement in heme toxicity (Table 1, NCT05075824) (48).

Conclusions

Despite its global prevalence, SCD remains understudied and underfunded. Many patients continue to suffer due to inadequate access to essential healthcare services, with the largest affected populations residing in third-world countries where medical resources are scarce. The increased morbidity and mortality rates associated with SCD as indicated in the literature are primarily based on patient data and observations in a setting of poor access to care and a lack of DMTs. However, the landscape of treatment options has evolved; we now have more tools in our toolbox than ever before. As a result, it is crucial that the care for each patient with SCD be individualized, incorporating these newer options to better address their unique needs and improve their quality of life. In our practice, HU is offered to SCD patients with all genotypes especially when complications and organ changes are present. After HU optimization, if anemia persists with hemolysis, patients are offered voxelotor to minimize hemolysis and improve hemoglobin. And those with ongoing VOCs, we trial crizanlizumab. Despite the results of the STAND trial, we find crizanlizumab works for some patients. However, future directions should include a pathway to identify which patients would benefit most from crizanlizumab and it is reassuring to know that efforts are under way in this regard. Furthermore, it is important to recognize while donor pool limits hematopoietic stem cell transplantation, this remains the only curative option at this time for SCD. However, single gene editing or addition as with gene therapy has resulted in a promising pathway for transformative therapies. What remains to be optimized is the process of receiving gene therapy, patient preparedness, candidate selection as well as financial cost to the patient and society. Nonetheless, gene therapy offers a very exciting pathway for patients in the coming years. For those patients not wanting gene therapy or not a fit, we need to continue to build our toolbox for SCD management. This is incredibly important given the largest burden of disease is in the poorest areas of the world that are unlikely to have access to transplant or gene therapy for decades to come. Thus, the ongoing clinical trials in identifying other therapeutic targets in SCD remain paramount to disease control and addressing the global health crisis of SCD. Despite of advances made in SCD, patient utilization of disease modifying therapies remains suboptimal (114). The reasons are multifactorial, but we believe the growth of dedicated sickle cell centers with clinicians who can individualize treatment strategies are essential in overcoming inherent barriers to care. The incorporation of specialized sickle cell care with ongoing new disease modifying strategies can greatly improve the outcome for patients burdened with this debilitating disease (115).

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-14/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-14/coif). W.B.E. serves as an unpaid editorial board member of Annals of Blood from February 2024 to January 2026. W.B.E. also receives grants from Inova Adult Sickle Center, consulting fees/honoraria from Pfizer and Pharmacosmos, and support for attending meetings and/or travel from Inova Health Systems. S.A. receives funding support for an investigator-initiated study from Pfizer for a project involving Voxelotor and serves on Pfizer’s speakers bureau. S.A. also served on a single meeting with Agios on 11/22/2023 in an advisory/consulting capacity and serves on the board for nonprofit community-based organization in sickle cell disease called HemoGLOWBIN. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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