জিম্বাবুয়ে বনাম ভারত

Hydroxyurea and transfusion together: a step forward in defining the value of combination therapy in severe sickle cell disease

জিম্বাবুয়ে বনাম ভারত
Hydroxyurea and transfusion together: a step forward in defining the value of combination therapy in severe sickle cell disease


Individuals with sickle cell disease (SCD) face a lifelong burden of both acute and chronic complications that contribute to substantial morbidity and reduced life expectancy (1). Chronic blood transfusion (CT) and hydroxyurea (HU) are two of the most established disease-modifying therapies for SCD. HU is the primary SCD-specific pharmacotherapy, and CT is usually reserved for treatment escalation and is offered to patients with more severe disease, especially for stroke prevention. Although studies have examined the benefits of HU or CT monotherapy in reducing SCD complications, the clinical value of combining these two key therapies remains limited. In this context, Nickel et al. present the results of the first prospective clinical trial specifically designed to assess the safety and clinical benefit of adding HU to patients with SCD receiving simple CT therapy for primary and secondary stroke prevention (2).

Stroke is a devastating complication of SCD (3). Landmark clinical trials conducted over the past three decades have deepened our understanding of cerebrovascular risk factors and helped decrease the burden of overt stroke. The cumulative incidence of stroke in high-resource countries has dropped from 10% to 1%, thanks to the implementation of screening transcranial Doppler (TCD) and the initiation of CT in individuals with abnormal cerebral blood flow velocity on TCD, a reliable biomarker of stroke risk (4-6). The option to safely transition from CT to HU for primary stroke prevention is available only to a subset of patients—those without high-grade vasculopathy and with a sustained HU response (7). CT remains the primary approach for secondary stroke prevention in patients not treated with hematopoietic stem cell transplant (8). However, CT does not entirely prevent cerebrovascular injury; in the TWITCH study, three individuals without underlying vasculopathy on the CT arm experienced a transient ischemic attack, and one developed new vasculopathy (7). Moreover, CT therapy does not seem to fully halt cerebrovascular injury progression, as studies show recurrence of cerebral insults—strokes or silent infarcts—in patients with cerebral vasculopathy or Moyamoya disease, despite maintaining pre-transfusion hemoglobin S (HbS) levels below 30% and appropriate hemoglobin levels (9-11). Additionally, CT carries risks such as alloimmunization and iron overload, while also presenting cost, accessibility, and availability challenges in both low- and high-resource settings (12-14). Given this background, two key questions remain: first, how can we intensify non-curative therapy for patients on CT monotherapy, and second, how can we safely reduce their transfusion burden?

The article by Nickel and colleagues (2) aims to address these issues by evaluating the clinical benefits of combining dose-escalated HU therapy and CT. The primary objectives of this study were to assess the safety and feasibility of combining hydroxyurea and transfusion (HAT) therapy, and to determine whether HAT reduces transfusion requirements. Secondary objectives included examining the effect of HU on biomarkers that indicate the progression of central nervous system (CNS) disease and those associated with vascular damage. Eligible participants were individuals aged 2 to 25 years with SS/Sβ0 thalassemia who had been on CT (simple transfusions) for primary or secondary stroke prevention for at least 1 year. Exclusion criteria included poor adherence to CT (defined as HbS >45% any time in the prior year or transfusion interval >5 weeks), treatment with HU in the previous year, pregnancy, and presence of abnormal laboratory values at the time of enrollment [defined absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or serum creatinine more than twice the upper limit for age]. Nine participants who previously received CT completed 1 year of combination therapy (HU and CT) at the target dose, defined as achieving an ANC below 4×109/L and pre-transfusion goals of Hb 10–11 g/dL and HbS 30–45%. Notably, 66% of this cohort experienced a blood volume reduction of over 10 mL/kg/year with combination therapy compared to previous CT monotherapy. This decrease in blood volume was associated with better HU adherence and increased levels of fetal hemoglobin (HbF). When comparing pre-transfusion labs while on CT versus during combination therapy, a significant increase in hemoglobin and a decrease in hemolysis markers were observed on combination therapy. Interestingly, the median pre-transfusion HbS level was significantly higher among participants on combination therapy than among those on CT alone, likely due to the lower transfusion volume and a more liberalized pre-transfusion S% of 30–45% with HAT (Table 1).

Table 1

Clinical studies evaluating the effects of hydroxyurea and transfusion therapy, alone or in combination, for sickle cell disease

Study type Patient group n (age, indication) Treatment regimen Treatment duration HbS% HbF% Hb levels (g/dL) Clinical outcomes# Inflammatory profile/markers
Prospective, phase 2, (NCT03644953), Nickel et al., 2025 (2) n=14 (median age 11.3yr, on CT for stroke prevention) HU added to existing CT 1 yr (n=9) Pre-HU 27.3 (22.4, 30.0) Pre-HU 0.7 (0.4, 1.3), Pre-HU 8.9 (8.5, 9.2), 1. Median reduction in RBC transfusion volume of 19.4 mL/kg/yr (n=8 of 9)* WBC (K/mcL): Pre-HU 14.7; Post-HU 8.3**
Post-HU 31.7 (25.5, 40.8)* Post-HU 4.6 (1.4, 14.6)** Post-HU 9.4 (9.0, 9.5)* 2. No evidence of CV disease progression ANC (K/mcL): Pre-HU 7.19; Post-HU 3.78**
3. Only 1 SAE possibly attributed to HU (splenic sequestration in 1 patient) Reduction in BDNF, PDGF-AA, PDGF-AA/BB, sVCAM-1, PAI-1, and TNF-α levels after HU (n=7)*
Retrospective, Brousse et al., 2013 (15) n=7 (10–17 yr, progressive CV disease receiving CT) HU added to existing CT 3-4 yr of HU+CT Pre-HU 26 Pre-HU 2 Pre-HU 8.8 No further strokes. WBC (×109/L): Pre-HU 12.4; Post-HU 11
Post-HU 21* Post-HU 2.8 (n=4) Post-HU 9.6* 6 of 7 with stabilization of CV disease. ANC (×109/L): Pre-HU 6.5; Post-HU 5.7
TAMMV (cm/s): Pre-HU 220; Post-HU 190 (n=5)
No toxicities
Cross-sectional, Nickel et al., 2015 (16) n=114 SCD & 29 age-matched controls (11.7–13.9 yr) HU alone (n=23); CT alone (n=68); CT+HU (n=6); no Rx (n=17) HU alone 34.7 mo; CT alone 59.6 mo; CT+HU: CT 68.1 mo & HU 17.1 mo CT alone 22.4 (19.8); CT+HU 40.9 (13.6) HU alone 9.5 (1.0); CT alone 9.6 (0.8); CT+HU 9.9 (1.4); no Rx 8.8 (1.2); controls 13.2 (1.1) N/A WBC and ANC are lower in CT+HU vs. CT alone
Retrospective, Delicou et al., 2016 (17) n=30 (mean age 45.5 yr) HU alone (n=10); Chronic ET (n=10), HU+ET combination (n=10) 5 yr HU alone*: 77.8±5.5; ET*: 48.8±9.10; HU+ET* 34.8±5.05 HU alone, 11.1±3.42; ET 1.86±0.57; HU+ET 8.55±3.07 HU alone: enrollment 9.06±0.91, end 9.08±0.77; ET*: enrollment 8.47±1.39, end 10.44±1.13; HU+ET*: enrollment 9.51±1.28, end 10.99±0.98 Combined HU+ET treatment showed better outcomes than HU or ET for annual crisis rate, acute chest syndrome, stroke, anemia, pulmonary hypertension and liver function N/A
Retrospective, Forte et al., 2022 (18) n=49 adult SCD patients on CT and CVAD 29 CT+HU: Relative rate reduction of VTE with HU+CT: 20.5 (6.4–65.3)
Automated exchange 33 (67%) No thromboprophylaxis: 17 Relative rate reduction of VTE with thromboprophylaxis: 4 (1.2–12.6)
Thromboprophylaxis: 12
Cross-sectional, Dembele et al., 2023 (19) n=88 SCD (2–18 yr, with CV disease on ET) ET alone (n=48); ET+HU (n=40) 3.72–4.81 yr of ET, at least 6 mo of HU ET alone: 35.3 (30.4–41.2); ET+HU: 35 (29–38.4) N/A ET alone: 9.1 (8.7–9.5); ET+HU: 8.6 (8.4–9.2) Lower WBC, ANC, and retic counts in ET+HU vs. ET alone.
ET+HU: decreased Mac-1, LFA-1, plasma elastase
Cross-sectional, Terrigno et al., 2025 (20) n=54 pediatric SCD patients (ages 8–21) HU (n=40); CT (n=14) CT for at least 6 mo HU 79 (77.35–82.5); CT 37.6 (27.4-37.6)**** HU 14.05 (11.8–16.45); CT 4.6 (3.5–6.5)**** HU 8.7 (7.95–9.35); CT 9.4 (8.7–9.9)* ANC (×103/μL): HU 2443; CT 5275***
Aged neutrophils (×103/μL): HU 465; CT 2823****
HU group: lower levels of CXCL10, CCL2, CCL4, IFN-γ and IL10

CT reduces the HbS fraction by lowering the percentage of circulating sickle cells and, over time, can suppress the body’s natural sickle erythropoietic drive. Reducing transfusion volume comes with the risk of higher pre-transfusion HbS levels exceeding 30%. The main concern about raising the pre-transfusion HbS threshold above 30% is the uncertain potential for worsening cerebrovascular injury over time. While it’s possible that the negative effects of higher HbS could be offset by the benefits of increased HbF’s rheological properties, further research is needed. One blood conservation strategy previously examined involves maintaining a higher pre-transfusion hemoglobin threshold of less than 50% for secondary stroke prevention in individuals who had maintained HbS levels below 30% for at least 3–4 years (4,21,22). While no recurrent ischemic strokes or transient ischemic attack events were observed in these small cohort studies, most excluded patients with cerebral vasculopathy or Moya-Moya disease (21,22). Conversely, Nickel et al. included patients with vasculopathy. Using their combined (HU and CT) therapy approach, more than half of their cohort reduced the annual blood volume transfused by roughly the amount given in one session (~10 mL/kg), with only a slight increase in median pre-transfusion HbS to 31.7% (IQR 25.5, 40.8), and without any new or worsening cerebral ischemic events or vasculopathy. These findings, while limited by the small sample size and short study duration of one year, are cautiously reassuring. However, an annual reduction of 10 mL/kg in transfusion volume accounts for a small fraction of total transfused blood and may not sufficiently justify tolerating higher S% without further careful study. In previously published small retrospective studies comparing combination therapy with CT monotherapy, both approaches either achieved similar improvements in hemoglobin (~10 g/dL) along with a decrease in HbS below 30% or showed a markedly better hematological response with combination therapy (15,17) (Table 1). However, unlike Nickel et al., none of these studies aimed specifically at reducing transfusion volume with combination therapy. A modestly higher HbS percentage might be more acceptable in patients receiving CT to prevent vaso-occlusive complications such as recurrent acute pain crises and acute chest syndrome. Adding HU could also be more feasible in patients on CT who undergo exchange transfusions, where HbS% and hemoglobin targets can be more easily maintained, and concerns about potential toxicity from combining chelation agents with HU are reduced.

HU significantly reduces inflammation by lowering blood cell counts (including total white blood cells, neutrophils, and platelets) and plasma pro-inflammatory cytokine levels. It also suppresses the pro-adhesive subset of neutrophils that are expanded in SCD (20,23). While CT has notable disease-modifying effects, several reports indicate residual inflammation that can be reduced with the addition of HU (Table 1). One factor contributing to this is the higher number of total neutrophils, especially aged neutrophils (CD62low/CD184high), which are particularly effective at driving vaso-occlusion and inflammation (19). This inflammatory milieu could potentially continue to promote endothelial activation and vascular injury despite maintaining a low HbS level. Nickel et al. demonstrate that adding HU to CT lowers WBC and ANC as well as plasma levels of pro-inflammatory cytokines, including BDNF, sVCAM-1, and PDGF-AA (2,16). Elevated levels of these cytokines in SCD patients have been linked to a history of stroke and higher TCD velocities (24,25). Notably, Dembélé et al. found no differences in plasma levels of pro-inflammatory cytokines TNF-α, IL-8, and IL-1β between SCD patients receiving CT (exchange transfusions) and untreated SCD patients (19). They also surprisingly observed no differences in the proportion of aged neutrophils across different treatment groups (CT vs. HU vs. CT + HU). However, they did not account for potential confounding factors such as age, race, ANC, or iron overload. Conversely, Terrigno et al., in age- and race-matched cohorts, reported significantly lower counts of total and aged neutrophils, along with reduced levels of several cytokines, in patients treated with HU compared to those on CT, after considering iron burden (20).

Overall, the risks of adding HU to CT appear minimal, and its beneficial effects on circulating blood cells (sickle red cells, white cells, and platelets), blood rheology, and overall inflammatory profile in SCD make it a treatment approach worth serious consideration. Additionally, in SCD patients on CT, with central venous access and thromboprophylaxis, concurrent HU therapy is associated with a lower risk of venous thromboembolism (18). Prospective studies specifically examining this combination are needed in patients with underlying cerebral vasculopathy and other clinical settings. This strategy could be relevant in cases of progressive injury despite CT monotherapy, such as chronic cardiovascular damage—the leading cause of early mortality—manifested by worsening myocardial fibrosis, abnormal diastolic function, and increased tricuspid regurgitant velocity despite CT or HU monotherapy (26-28). Combining these two disease-modifying therapies to enhance therapeutic benefit while minimizing their individual side effects warrants further research. Initial studies should focus on adding HU to CT without changing pre-transfusion HbS targets, using well-designed protocols with meaningful clinical endpoints. Nickel et al. are to be commended for their prospective study design, careful selection of relevant biomarkers of cerebrovascular disease, and demonstration of the feasibility of this promising approach.

Acknowledgments

None.

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

Peer Review File: Available at

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at P.R. received consulting fees from Pfizer. D.M. received consulting fees from Terumo, Novartis, and Pfizer; grants from PCORI, ASH, and NHLBI; and is on the Executive Committee of NASCC. The other author has 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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Cite this article as: Rai P, Capellera-Garcia S, Manwani D. Hydroxyurea and transfusion together: a step forward in defining the value of combination therapy in severe sickle cell disease. Ann Transl Med 2026;14(5):77. doi: 10.21037/atm-2026-0069



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