Myelotoxicity Under Hydroxyurea/Siklos In Sickle Cell Patients: Experience of the University Hospital of Guadeloupe Regarding 4 Clinical Cases

Introduction

Sickle cell disease is the most common genetic disorder in the world and constitutes a significant public health problem, particularly in populations of African and Afro-Caribbean origin [1]. It is characterized by the presence of an abnormal hemoglobin, hemoglobin S (HbS), which causes chronic hemolysis and vaso-occlusive complications that can considerably impair the quality of life and prognosis of patients [2].

Hydroxyurea (Siklos) is currently the main disease-modifying therapy for sickle cell disease. Its efficacy is based in particular on increasing fetal hemoglobin (HbF), reducing vaso-occlusive crises, and decreasing hospitalizations [3].

However, despite its well-established therapeutic benefits, hydroxyurea can cause hematological adverse effects, primarily myelotoxicity, which can manifest as severe aregenerative anemia, neutropenia, and/or thrombocytopenia [4].

Managing these complications can be complex, particularly in patients with comorbidities or pre-existing bone marrow failure. In the French overseas territories, especially Guadeloupe, where the prevalence of sickle cell disease is high, data on Siklos-induced anemias remain limited [5].

Through this series of clinical cases observed at the University Hospital of Guadeloupe, we report the diagnostic, therapeutic and evolutionary aspects of sickle cell patients who presented with severe anemia under hydroxyurea.

General Objective

To describe the diagnostic aspects and management of hydroxyurea-induced myelotoxicity in sickle cell patients followed at the University Hospital of Guadeloupe.

Specific Objectives

To describe the clinical and biological characteristics of patients with anemia while taking Siklos.

To identify factors that may contribute to the development of hematological toxicity.

To describe the therapeutic approaches used in the management of these complications.

To analyze the clinical and biological evolution after treatment adjustment.

Methodology

This is a retrospective descriptive case series study conducted at the University Hospital of Guadeloupe. We included sickle cell patients followed in the sickle cell care unit who experienced hematological toxicity attributed to hydroxyurea (Siklos) during the period from 2023 to 2026. Clinical, biological and therapeutic data were collected from medical records

Observation

Clinical Case 1

A 28-year-old female patient with sickle cell disease (SS), with a baseline hemoglobin of 8-9 g/dL and a hemoglobin of 10.5-11 g/dL while on Siklos, had two previous blood transfusions and two previous episodes of acute chest syndrome. She was taking Siklos 1750 mg (26 mg/kg) daily, which she had started one year prior, and Speciafoldine 5 mg daily. All her vaccinations were up to date.

She consulted us in December 2025 for shortness of breath, physical asthenia, and lower back and right leg pain, rated 5/10, which had been present for 5 days. She had been treated at home with Acupan 30 mg and paracetamol 1 gram. Further medical history showed no fever, cough, or myotonic pain.

At our examination, she weighed 66 kg with a BMI of 26.11 kg/m², her blood pressure was normal (102/55 mmHg), her heart rate was normal (75 beats per minute), her oxygen saturation was 100%, and her temperature was 37°C.

She was lucid and coherent, her palpebral conjunctivae were slightly pigmented, and her bulbar conjunctivae were subicteric. Her superficial cervical lymph nodes were not enlarged. Chest: The chest was symmetrical and ample, with no signs of respiratory distress. The first and second heart sounds were audible and regular. Vocal fremitus was well transmitted, lung sounds were preserved, and there was a pure bilateral breath sound.

Her abdomen was not distended; it was soft and compressible, without organomegaly, and non-tender.

The ENT examination was unremarkable. We considered the possibility of anemia due to Siklos, given the normochromic, non-regenerative macrocytic anemia and iron deficiency.

We treated her as follows:

immediate discontinuation of Siklos for 15 days;

Tardyferon 80 mg: 1 tablet every other day;

Aranesp: two 150 µg injections 48 hours apart;

Acupan 30 mg tablets: 1 tablet every 6 hours;

Paracetamol 1 g: 1 tablet every six hours.

The patient returned on day 5 with persistent shortness of breath despite taking erythropoietin.

The patient returned on day 5 with persistent shortness of breath despite taking erythropoietin. At our examination, vital signs were normal: BP 144/51 mmHg, HR 89 bpm, oxygen saturation 99%, respiratory rate 15 breaths per minute.

We considered the possibility of poorly tolerated anemia and ordered a follow-up blood test. We then prepared two units of red blood cell concentrates compatible with extended phenotyping and scheduled a blood transfusion for day 7. We continued with Tardyferon tablets; Siklos was reintroduced 15 days later at a dose of 750 mg with laboratory monitoring every 15 days for two months.

Clinical Case 2

A 65-year-old woman with sickle cell disease (SS), weighing 63 kg, with a baseline hemoglobin level between 7-8 g/dL, experienced numerous vaso-occlusive crises in childhood, hearing loss, bilateral osteonecrosis of the femoral head, and a history of anemia while taking Siklos six years prior, requiring several transfusions with iron overload. She also presented with microalbuminuria and an ACR of 12. She has been taking Siklos 1000 mg (15 mg/kg) for four years, along with Speciafoldine, Twystan, and Aranesp 300 µg every 15 days.

She presented to the emergency department in November 2025 with physical asthenia and dyspnea on minimal exertion. On examination, she was asthenic, tachycardic at 120 bpm, and had conjunctival pallor. The rest of the examination was unremarkable. We initially suspected severe anemia and set aside three phenotyped and compatible packed red blood cells (PRBCs).

Ultimately, she was transfused with two PRBCs and the Siklos was immediately discontinued. We reintroduced it weeks later. She continued taking Aranesp and Spiafoldine. On day 22, we observed an increase in hemoglobin and reticulocyte count.

The patient then presented to the emergency department three months later in 2026 with severe anemia and was transfused with two PRBCs. Siklos was discontinued and later reintroduced at a dose of 750 mg, then increased to 1000 mg one month later. Aranesp was administered subcutaneously at a dose of 150 µg ,twice weekly.

Clinical Case 3

A 62-year-old patient with sickle cell disease (SB0), weighing 65 kg, with a baseline hemoglobin of 8/dL and an alpha mutation, a history of transfusion, centrilobular emphysema, IgA gammopathy, nephropathy, and a smoking habit (5-6 cigarettes per day), was taking Triatec, Speciafoldine 5 mg, and Siklos 1250 mg (19 mg/kg), which was started in 2020 due to worsening proteinuria.

He consulted us in 2025 for physical asthenia and exertional dyspnea that had appeared two days prior, without any signs of infection or other complaints.

On examination, we noted primarily mild pallor of the skin and mucous membranes. Given his non-regenerative macrocytic anemia while taking Siklos, along with mild thrombocytopenia, we considered the possibility of myelotoxicity. We stopped the Siklos and gave Aranesp 300 mg in two doses per week and checked 20 days later and resumed the Siklos, decreasing to 1000 then 250 mg per day.

Clinical Case 4

75-year-old female with sickle cell disease (SS), weighing 68kg, with a baseline hemoglobin of 8-9g/dl, with proteinuria nephropathy, sickle cell retinopathy, hypertension, bilateral osteonecrosis of the humeral head, myocardial infarction with worsening of her anemia, the reason for her being put on Siklos + Aranesp since 2022; Severe OSA, treated with oxygen therapy, Siklos 500 mg daily (8 mg/kg), Aranesp 150µg daily, Speciafoldine, Corvasal 2M 3 times daily (1 tablet), and Kardegic 1 sachet daily.

The patient consulted us in June 2024 for physical asthenia. Clinical examination revealed a normal oxygen saturation (100%), normal blood pressure (133/66 mmHg), a normal heart rate (85 bpm), and slightly discolored eyelid conjunctivae.

Laboratory tests showed normochromic, normocytic, non-regenerative anemia with neutropenia, indicating bicytopenia, likely due to Siklos.

The patient received a transfusion of one unit of packed red blood cells, Siklos was temporarily discontinued, and the Aranesp dose was increased to 300 µg per week. Siklos was reintroduced one month later at a dose of 250mg per day.

Discussion

Our work highlights the occurrence of severe, aregenerative anemias associated with myelotoxicity under hydroxyurea (Siklos) in sickle cell patients followed at the University Hospital of Guadeloupe. Although hydroxyurea is currently the standard disease-modifying therapy for sickle cell disease, its use remains limited by the occurrence of hematological adverse effects, primarily dose-dependent myelosuppression [2].

In our observations, all four patients presented with macrocytic, aregenerative anemia with a decreased reticulocyte count, consistent with bone marrow toxicity induced by hydroxyurea/Siklos. This macrocytosis is a classic biological effect of the treatment, secondary to the inhibition of DNA synthesis of erythroid precursors [4]. However, in our cases, the significant drop in hemoglobin associated with the decrease in reticulocytes indicated clinically significant bone marrow toxicity requiring therapeutic adjustment.

The first clinical case illustrates severe anemia in a young patient with a significant decrease in hemoglobin to 6 g/dL and reticulocytopenia, despite an inflammatory profile not suggestive of an acute infectious or hemolytic complication. The progressive correction after temporary discontinuation of Siklos, administration of erythropoietin, and blood transfusion strongly supports a drug-induced toxicity. This observation is consistent with data in the literature showing that the myelotoxicity of hydroxyurea is generally reversible after discontinuation of treatment [3].

Furthermore, this first case highlights the diagnostic difficulty associated with iron metabolism abnormalities in sickle cell patients. Despite elevated ferritin, the decreased transferrin level, coupled with severe anemia, led to the consideration of functional iron deficiency. In sickle cell patients, the interpretation of iron markers remains complex due to the chronic inflammatory context, transfusion episodes, and hemolysis [1].

The second clinical case is particularly remarkable due to the extreme severity of the anemia, with a hemoglobin level of 2.9 g/dL associated with a significant drop in reticulocytes. This patient presented several factors likely to increase the toxicity of hydroxyurea: advanced age, a history of hematological toxicity with Siklos, early renal failure, and post-transfusion iron overload. Advanced age is recognized as a vulnerability factor to drug-induced myelosuppression due to decreased bone marrow reserve and pharmacokinetic changes [6]. Moreover, the presence of moderate chronic kidney disease may have contributed to drug accumulation. Since Siklos is partially eliminated renally, reduced clearance exposes patients to an increased risk of hematological toxicity [7]. This observation underscores the importance of close monitoring in elderly patients or those with renal insufficiency.

The third case illustrates the difficulty of therapeutic management in patients with multiple comorbidities. In this Sβ0-thalassemia sickle cell patient, the presence of nephropathy, pulmonary emphysema, and chronic active smoking could also contribute to impaired erythropoiesis. Nevertheless, the biological improvement after temporary discontinuation of Siklos and dose reduction reinforces the hypothesis of drug toxicity.

In all our observations, several biological elements were consistently observed: marked macrocytosis, reticulocytopenia, and improvement after treatment interruption. These characteristics are consistent with the hematological toxicity criteria described in international recommendations [5].

One of the key findings of this series highlights the importance of regular biological monitoring in patients receiving hydroxyurea/Siklos. Current guidelines recommend frequent complete blood counts, particularly during the initiation and dose titration phases [8]. Insufficient monitoring could lead to serious, life-threatening hematological complications.

Our cases also underscore the value of individualized treatment. In some patients, especially the elderly or frail, the maximum tolerated dose may be significantly lower than the standard doses usually used. In our observations, the gradual resumption of low-dose treatment after hematological recovery allowed us to maintain the therapeutic benefit of Siklos while limiting the recurrence of toxicity.

Finally, this series serves as a reminder of the complexity of managing sickle cell patients on hydroxyurea. In cases of severe anemia, it remains essential to rule out other common causes such as aplastic crisis, hyperhemolysis, vitamin deficiency, infection, or splenic sequestration before concluding that drug toxicity is the cause [9].

Despite the small sample size, this study is valuable because it describes real-life clinical situations observed in a sickle cell disease expert center in an overseas territory. It highlights the need for rigorous multidisciplinary monitoring and personalized adjustment of hydroxyurea treatment Tables 1-5).

Leucocytes	Valeur j1	J2	J5	J7(TS)	J21
Hématie	1,51 Tera(3,8-5,8)	1,810 Tera/l	1,44Tera/l	2,2 Tera/l	2,43T/l
Leucocyte	2,7 Giga/l(4-10)	2,95Giga	3,1Giga	3,7Giga	4,72Giga
Hémoglobine	6,4 g/dl(11,5-16,5)	7,7g/dl	6g/dl	8,2g/dl	9,4g/dl
Hématocrite	18,8% ( 37-47%)	22,6%	18,5%	24,5%	28,5%
VGM	124,5fl (80 -100)	124,9fl	128,5fl	Double population	117,3fl
TCMH	42,4 pg(27-32)	42,5pg	41,7pg	37,3pg	38,7pg
CCMH	34 g/dl( 32-36)	34,1 g/dl	32,4g/dl	33,5g/dl	33g/dl
Plaquette	200Giga/l(150-500)	193 Giga/l	177Giga/l	145Giga/l	224G/l
Réticulocytes	33 Giga/l( 50-150)	45 Giga/l	54Giga/l	84 Giga/l	123G/l
Folate sérique	40 nanogramme/ml (3,1-20,5)	38nanogramme/ml	34nanogramme/ml	19nanogramme/ml	17,7ng/ml
Ferritine	440nanogramme/ml ( 20-200)	438nanogramme/ml	412nanogramme/ml	398nanogramme/ml	390nanogramme/ml
Vitamine B12	246 pg/ml(189-883)	250pg/ml	270picog/ml	280pg/ml	300pg/ml
Transferrine	1,9 g/l(2-3,6)	1,9g/l	1,8g/l	1,9g/l	1,6g/l
Fer sérique	28,1 micromole /l( 5,83-34,5)	28micromole/l	25micromol/l	17,7micromol/l	29microl/l
Coefficient de saturation de T	59 %( 20-40)	58%	50%	48%	42%
LDH	395 UI/l( 135-214)	367UI/l	328Ui/l	315Ui/l	529Ui/l
Bilirubine totale	10micromol/l	9,5Microl/l	5micromol/l	15micromol/l	17micromol/l
Bilirubine conjuguée	2,6mg/l	2,5mg/l	4mg/l	5micromol/l	6micromol/l
CKD -EPI	112ml/’	110ml/’	115ml/’	120ml/’	117ml/’

Table 1: Biological assessment of the first observation.

Table 2: Biological assessment of the second observation.

Table 3: Biological assessment of the third observation.

Table 4: Biological assessment of the fourth observation.

Table 5: Summary biological assessment of four clinical cases.

Conclusion

Hydroxyurea (Siklos) remains the cornerstone disease-modifying therapy for sickle cell disease and significantly reduces vaso-occlusive complications. However, its use may be associated with clinically significant hematological toxicity, particularly severe aregenerative anemia secondary to bone marrow suppression.

This case series highlights the heterogeneous presentation of hydroxyurea-induced myelotoxicity, ranging from isolated severe anemia to bicytopenia, particularly in elderly patients and those with multiple comorbidities. Temporary discontinuation of treatment, supportive care including erythropoietin and blood transfusion when indicated, and subsequent dose adjustment resulted in favorable clinical and hematological outcomes in all patients.

These observations emphasize the importance of regular hematological monitoring, individualized dose titration, and early recognition of toxicity signs. In patients presenting with severe anemia while receiving hydroxyurea, alternative causes must be carefully excluded before attributing the event to drug toxicity.

Further studies involving larger cohorts are needed to better identify risk factors for hydroxyurea-induced myelotoxicity and to optimize monitoring strategies in patients with sickle cell disease.

Limitations of the Study

This study has some limitations. First, it is a series of clinical cases with a small sample size, limiting the generalizability of the results. Second, its retrospective nature exposes the study to a risk of missing data and heterogeneity in biological monitoring.

Furthermore, the absence of pharmacological measurement of hydroxyurea prevents formal confirmation of drug accumulation. Certain associated comorbidities, particularly renal insufficiency or chronic inflammatory conditions, may also have contributed to the occurrence of the observed cytopenias.

Nevertheless, this series has several strengths. It describes situations rarely reported in the Caribbean literature and highlights important practical issues concerning the monitoring of Siklos in real-world settings. It also underscores the need for an individualized approach in frail sickle cell patients.

Lessons Learned From The Three Clinical Cases

Hydroxyurea can cause potentially serious, severe, non-regenerative anemia in patients with sickle cell disease.

Macrocytosis associated with reticulocytopenia is a major indicator of drug-induced myelotoxicity in the context of good adherence to treatment.

The hematological toxicity of Siklos is generally reversible after temporary discontinuation and dose adjustment.

Elderly patients, patients with renal insufficiency, or those with a history of hematological toxicity require close monitoring regardless of the time elapsed since the start of treatment.

Regular monitoring of complete blood counts (CBC) and reticulocyte counts is essential during hydroxyurea treatment.

Management should be individualized to maintain therapeutic benefit while minimizing toxicity.

In the event of severe anemia during Siklos treatment, other causes of anemia in sickle cell patients must be systematically ruled out.

Algorithm for the management of anemia under hydroxyurea in sickle cell patients.

1. Clinical suspicion

Sickle cell patient on Siklos presenting with: asthenia, pallor, worsening anemia, dyspnea.

2. Initial laboratory workup

Complete blood count (CBC).

Reticulocytes, Bilirubin, LDH, CRP.

Ferritin,Serum creatinine,Hemoglobin electrophoresis.

3. Look for signs of hematological toxicity

Consider myelotoxicity if:

Macrocytosis, Reticulocytopenia, Possible neutropenia, Possible thrombocytopenia.

4. Rule out differential diagnoses

Viral aplastic crisis, Hyperhemolysis, Splenic sequestration Severe infection, Vitamin deficiency, Renal failure.

5. Therapeutic management

If moderate toxicity, Reduce Siklos dose.

Close monitoring, If severe toxicity Temporarily discontinue Siklos, Blood transfusion if Necessary hydration,vitamin supplementation, erythropoietin as indicated.

6. Monitoring

Complete blood count (CBC) reticulocytes, renal function, clinical progress.

7. Resumption of therapy

Gradual resumption of Siklos, dose adjusted to the patient's profile, regular monitoring.

Acknowledgements

The authors thank the team of the cross-functional unit for the management of sickle cell disease at the University Hospital of Guadeloupe for their support in the care of sickle cell patients.

Ethical Statement

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Clinical data were collected anonymously and confidentially. Information that could identify patients was removed to preserve their confidentiality. Access to medical data was limited to the investigators involved in the study, and no personal information was disclosed. Informed consent was obtained from the patient before the use of clinical data.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding

This study was conducted without external funding. The authors self-funded the work.

Author Contributions

All authors participated in patient care, data collection, and the writing and revision of the manuscript. All authors read and approved the final version of the manuscript.

Declaration of the use of artificial intelligence

Artificial intelligence (ChatGPT, OpenAI) was used as a writing assistance tool for grammar and language correction, sentence rephrasing, improvement of the scientific writing style, manuscript structuring, and abstract preparation. All outputs generated by the artificial intelligence tool were carefully reviewed and validated by the authors. The authors retain full responsibility for the accuracy, integrity, and scientific content of the manuscript, as well as for the conclusions presented in this work.

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