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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 4  |  Page : 237-248

Drug therapy in patients with severe forms of sickle cell anemia: A nonrandomized clinical trial of combining l-carnitine with hydroxycarbamide therapy


1 Department of Internal Medicine, Clinical Hematology Unit, Assiut University Hospital Unit of Bone Marrow Transplantation, South Egypt Cancer Institute, Faculty of Medicine, Assiut University, Assiut, Egypt
2 Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt

Date of Submission08-Mar-2022
Date of Decision17-Apr-2022
Date of Acceptance20-Apr-2022
Date of Web Publication18-Oct-2022

Correspondence Address:
Dr. Safaa A A. Khaled
Department of Internal Medicine, Clinical Hematology Unit, Assiut University Hospital Unit of Bone Marrow Transplantation, South Egypt Cancer Institute, Faculty of Medicine, Assiut University, Assiut
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_23_22

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  Abstract 

BACKGROUND AND AIM: Combining Hydroxycarbamide (hydroxyurea) therapy and L-Carnitine (HU+LC) was proved effective and tolerable in patients with thalassemia intermedia; however, its role in sickle cell anemia (SCA) was not investigated. This study aimed to assess various aspects of treatment with HU + LC in adult patients with severe forms of SCA.
PATIENTS AND METHODS: Ninety-one adult SCA patients were recruited, then distributed into four treatment groups: Group 1 – 37 patients treated with HU + LC; Group 2 – 16 patients treated with HU; Group 3 – 18 patients treated with LC; and Group 4 – 20 patients received supportive treatment only. Their baseline data were recorded then reassessed 8–12 weeks later. Their compliance was assessed subjectively.
RESULTS: Patients were nearly matched as regards gender, age, baseline hematologic, and biochemical data. Compared to baseline, HU + LC treatment significantly increased hemoglobin and reduced reticulocytes, white blood cells, mean corpuscular hemoglobin concentration, and lactate dehydrogenase (LDH). Compared with other lines, HU + LC significantly reduced number of painful episodes, blood transfusions, and in hospital days per year. Adding LC to HU improved patient compliance, with mild side effects. Residence, side effects, baseline hemoglobin (Hb), and Hb F% affected patients' compliance. Both gender and age did not show any influence on response to treatment while side effects, compliance, baseline Hb, and LDH displayed a significant effect.
CONCLUSION: Combining LC with HU for the treatment of adult SCA patients showed superior hematologic and clinical effectiveness. The response was more obvious in severe cases. However, health education about the combination is needed to improve patients' compliance and therapeutic responses.
Trial registration:
Clinical Trials.gov, NCT05081349. https://clinicaltrials.gov/ct2/show/NCT05081349.

Keywords: Hydroxycarbamide, L-carnitine, sickle cell anemia, severe forms


How to cite this article:
A. Khaled SA, M. Ashry IE. Drug therapy in patients with severe forms of sickle cell anemia: A nonrandomized clinical trial of combining l-carnitine with hydroxycarbamide therapy. J Appl Hematol 2022;13:237-48

How to cite this URL:
A. Khaled SA, M. Ashry IE. Drug therapy in patients with severe forms of sickle cell anemia: A nonrandomized clinical trial of combining l-carnitine with hydroxycarbamide therapy. J Appl Hematol [serial online] 2022 [cited 2022 Dec 4];13:237-48. Available from: https://www.jahjournal.org/text.asp?2022/13/4/237/358708


  Introduction Top


Sickle cell anemia (SCA) is a type of congenital hemolytic anemia that is caused by amino acid substitution at position 6 of the beta subunit of the adult hemoglobin molecule, resulting in the production of abnormal S hemoglobin. The abnormal hemoglobin (Hb) causes loss of erythrocyte elasticity and sickling subsequently hemolysis, vaso-occlusive phenomenon, inflammation, and end-organ damage. SCA is prevalent in African continent; moreover, the disease haplotype is of the severe form in some African countries. According to the WHO, SCA is responsible for nearly 13% of pediatric deaths in those younger than 5-year-old in certain countries at Africa.[1],[2],[3] In Egypt, the SCA haplotype was found to be mostly Benin haplotype which was found to be presented with a more severe form of the disease with a higher incidence of disease complications and organ damage.[4]

Supportive care, folic acid, and adequate management of sickling crises are the main stay of therapy of mild forms of SCA, those with <3-episodes annually. Prophylaxis against malaria is also recommended in some African countries. Moreover, SCA patients should receive pneumococcal vaccine to guard against infection in those who developed autosplenectomy.[5]

Hydroxycarbamide is an anticancer drug that was proved for the treatment of patients with myeloproliferative neoplasms, melanoma, and ovarian carcinoma. The Food and Drug Administration (FDA) approved hydroxycarbamide for the treatment of severe forms of adult SCA in 1998, it acts by enhancing the production of Hb F. Accordingly, it keeps erythrocytes more rounded and prevents sickling. By its myelosuppressive effect, hydroxycarbamide reduces production of reticulocytes, neutrophils and platelets; all contribute to the inflammatory component of SCA. Thus, it reduces the incidence of painful episodes up to 50%.[6],[7],[8]

L-carnitine is a natural product of the human body that is composed of amino acids and it helps producing energy from fat and is considered a dietary supplement similar to iron and other vitamins. Red meat and fish are L-carnitine-rich foods, while vegetarian diets have very little amount. It could be supplied orally for those with increased demand or with deficient internal levels as those with hyperthyroidism, pregnancy, cardiovascular disorders, and dialysis patients. Moreover, it helps weight reduction, improves exercise tolerance, and brain functions. It was found safe on long-term use, with minimal side effects as nausea and gastric discomfort.[9],[10]

Studies reported the therapeutic effect of the combination of L-carnitine and hydroxycarbamide in patients with β-thalassemia intermedia.[11],[12] This was the first study that investigated the combination in patients with SCA. The study aimed to assess response (efficacy) to treatment either hematologic or clinical, and investigated factors affecting response as patient characteristics and disease characteristics. Moreover, the study was directed to explore the combination side effects and patients' compliance with treatment. Another objective was to assess patients' outcome during the study.


  Patients and Methods Top


Study design, settings, and patients

This was a nonrandomized clinical trial that included patients with SCA who were attending/admitted to the Clinical Hematology Unit, Assiut University Hospital (AUH), from August 2017 to June 2020. Those who were attending the private sector at AUH were also included. Patients were grouped into Group 1: Those who received hydroxycarbamide and L-carnitine either as first or second-line treatment, Group 2 patients treated with hydroxycarbamide alone (first or second line) Group 3 treated with L-carnitine alone (first or second line). Another historical group (Group 4) who received supportive treatment only was recruited from hospital records from January 2014 to July 2017.

Diagnosis of sickle cell anemia and baseline assessment of the study patients

SCA was proved by reviewing hospital files and records for old patients, while the diagnosis was ascertained by complete blood count (CBC) and high-performance liquid chromatography (HPLC) for the new cases. Baseline assessment of patients at the start of the study included clinical history, physical examination including splenic size, CBC, reticulocyte count, liver function tests (LFT), renal function tests (RFT), pregnancy test (for females in childbearing period), HPLC, and lactic dehydrogenase enzyme lactate dehydrogenase (LDH).

Patients' selection criteria

Inclusion criteria for Groups 1 and 2 patients

  • Patients with frequent painful crisis
  • Patients with severe complications as acute chest syndrome, leg ulcers, and priapism
  • Patients with severe anemia Hb <7 g/dl
  • Noncompliance to transfusion therapy or development of auto or alloimmunization.


Patients' exclusion criteria for Groups 1 and 2 were as follows:

  • Pregnancy or unwilling for birth control
  • History of blood or red blood cell (RBCs) transfusion over the past 3-months
  • Hepatic or renal impairment
  • Presence of co-morbid chronic infection or inflammation (unrelated to the disease as SLE or rheumatoid arthritis)
  • History of hypersensitivity to hydroxycarbamide or L-Carnitine.


Those who were excluded from Groups 1 and 2 were assigned to Group 3.

Treatment and assessment of therapeutic response in the study patients

Group 1 patients were treated with the combination of hydroxycarbamide (500 mg capsules); at a dose of 10 mg/kg/day and L-Carnitine (250 mg tablets); at a dose 10 mg/kg/day, for 8–12 weeks. They were kept on regular follow-up at the outpatient clinic every 2–4 weeks. During these follow-up visits, monitoring of response was done by clinical examination, CBC, total and differential white blood cells (WBCs) count, reticulocyte count, bilirubin, RFT, and LFT. Dose escalation by 5 mg/kg/day every 4 weeks till reaching the maximum tolerated dose (MTD) was also considered. The MTD in our patients was mostly 20 mg/kg/day. Patients were considered responding if they show an increment in CBC parameters Hb, MCV, mean corpuscular hemoglobin concentration (MCHC), and reduction of leukocyte, platelet, reticulocyte count, and LDH. Reduction of painful episodes per year, admission days, and number of transfusions per year were also considered good responses to treatment. These clinical parameters were estimated from patients' hospital records 1 year before and after inclusion in the study, and from patients' clinical history.

Group 2 and Group 3 patients were treated with hydroxycarbamide and L-carnitine alone, respectively, with similar dosing schedule as in Group 1. Group 4 was those patients who received supportive treatment only in the form of on-demand packed RBCs transfusions, folic acid 5 mg, and deltavit B12 tablets orally twice daily. Patients who received the combination as second-line treatment to supportive therapy were included in Group 4 at first and Group 1 later on; this was applied in any patient in a given group. In all groups, supportive care and management of acute crisis were prescribed as indicated.

Assessment of patients' compliance and complications of treatment

We followed others and assessed our patients' compliance to treatment subjectively through direct interview with the patient during every follow-up visits.[13] During these visits, patients were asked about various forms of noncompliance, adherence to medications, and duration of noncompliance. Further questions were asked to clarify factors that could cause noncompliance in the study patients.

The assessment of the combination side effects was done by clinical and laboratory investigations every time the patient comes for follow-up at the outpatient clinic. LFTs, blood urea nitrogen, and serum Creatinine (Cr) were done after 8 weeks of treatment.

Serological tests for blood-borne infections were done for all the study patients, also direct and indirect antiglobulin tests were done to assess the development of erythrocyte allo- or auto-immunization in the study groups.

Ethical considerations

As hydroxycarbamide was FDA approved for SCA, the study protocol and design were consistent with the World Medical Association (WMA) Declaration of Helsinki for studies in humans. Furthermore, the study protocol was approved by the Research Ethical Committee at Faculty of Medicine, Assiut University. The study was discussed with all patients, highlighting drug benefits, possible side effects, way of monitoring of response, and the need for birth control. Patients' oral and written consent was obtained before enrollment in the study. Confidentiality and the option to withdraw from the study at any time were addressed.

Statistical analyses

Both SPSS V21 (IBM SPSS, v.21, statistical software, California, USA) and Graphpad Prism V8 software packages were used for statistical analysis of the study data. For description, numerical variables were expressed as mean ± standard deviation (SD), median, range, minimum, maximum, and standard error (SE) while categorical variables as numbers and percentage. The Chi-square test was used to compare qualitative variables among the study groups when the expected values not <5, otherwise, the Fisher-Freeman-Halton exact test was used. For quantitative variables, the One Way ANOVA test of variance and the post hoc Tukey high-speed diesel (HSD) test were used. The paired sample t-test was used to compare quantitative parameters before and after treatment in the study groups. Correlations were performed using Pearson's correlation co-efficient for quantitative variables and the Chi-square test if they are qualitative. Significance was considered when P < 0.05.


  Results Top


Baseline demographic and clinical characteristics of the study groups

[Table 1] shows that the study included a total of 91 SCA patients who were assigned into four treatment groups. Group 1 (n = 37): HU + LC, Group 2 (n = 16): HU alone, Group 3 (n = 18): LC only, and Group 4 (n = 20): Supportive care only. Their ages ranged from 17 to 57 years, and the median was 28 years. Males represented 84.6% of the study sample, and the male-to-female ratio was 5.5/1. The four treatment groups were age- and gender-matched P = 0.5 and 0.155, respectively; also, there was no significant difference between the four groups as regards other demographic characteristics except for social environment P = 0.02.
Table 1: Baseline demographic and clinical characteristics and levels of fetal hemoglobin and S hemoglobin in four groups of patients with sickle cell anemia included in the study (total n=91)

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Clinically, manifestations of anemia followed by vaso-occlusive crisis were the most common presentations 33% and 26.4%, respectively. Modest significant difference in presenting complaint was detected among the four groups as shown in [Table 1]. Furthermore, no significant difference was noted in disease complications among the study groups, as shown in [Supplement Table S1], except for aplastic crisis, leg ulcers, and heart failure with higher incidence in Group 4 (45%), Group 4 (40%), and Group 2 (50%), respectively.



[Table 2] and [Table 3] and [Supplement Table S2] and [Supplement Table S3] reveal no statistically significant differences among the study groups as regards baseline hematologic and biochemical parameters, except for higher RBCs count in Group 1 compared with Group 4 (P = 02).
Table 2: Baseline hematologic profile of the study groups (total n=91)

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Table 3: Baseline biochemical profile of the study groups (total n=91)

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Effect of hydroxycarbamide and L-carnitine treatment on hematologic parameters, compared with the other treatment lines in the study sickle cell anemia patients

[Figure 1] illustrates the effect of the 4 lines of treatments on the study groups. It revealed that treatment with the combination HU + LC significantly increased mean hemoglobin from 7.86 ± 2.45 to 9.88 ± 2.8 (P < 0.0001). Compared to baseline, reticulocytes level dropped significantly in the same group (from 6.7 ± 4.8 to 3.8 ± 2. 2, P < 0.001). Albeit, similar findings were reported in the HU group, Hb increased from 7.2 ± 3.07 to 9.1 ± 2.05 (P < 0.0001) and reticulocytes reduced from 5.7 ± 2.3 to 3.3 ± 1.7, (P = 0.012). However, the mean reticulocyte difference was higher in the HU + LC group compared with the HU group (4.7 vs. 2.1). Reticulocytes were maintained in the other groups.
Figure 1: Effect of different lines of treatment on hematologic parameters of the study patients. (a) Mean corpuscular volume (b) Mean corpuscular hemoglobin concentration (c)Mean corpuscular volume (d) Mean corpuscular hemoglobin concentration (e) Red cell distribution width (f) platelets count (g) Reticulocytes count (h) Lactate dehydrogenase (i) White blood cells count (j) Red blood cells count. HU + LC, HU, LC, S. The I bars indicate standard deviations. *P < 0.05, **P < 0. 01, ***P < 0.001

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Therapy with the supportive measures only significantly increased mean Hb from 6.5 ± 2.3 to 7.8 ± 2.2 (P < 0.0001), unlike LC alone that induced insignificant changes in Hb levels after treatment from 8.03 ± 1.8 to 8.01 ± 1.7 (P = 0.953).

Considering RBCs indices; HU + LC therapy significantly reduced MCHC (P = 0.03) and increased Hematocrit (%) (P=0.04) while no significant change was noted in MCV and RDW or even RBCs count (P=0.54; 0.7) respectively. On the contrary, significant reduction of MCV was noted in HU group and significant increase in hematocrit and RBCs count (P < 0.0001; P < 0.001) respectively.

Highly significant decrease was observed in white blood cell count of the HU group from 12.09 ± 3.928 to 7.18 ± 2.8 after the 3 months' treatment period (P < 0.0001), also therapy with HU + LC significantly reduced WBCs also, from 11.25 ± 4.40 to 9.9 ± 3.07, P = 0.034.

Apart from modest reduction in WBCs (P = 0.04), therapy with LC alone did not change hematologic parameters of patients compared with baseline values. Likewise, therapy with supportive measures only, produced a significant increment in Hb (P < 0.0001), RBCs count (P = 0.009), and platelet count only (P = 0.025), without affection of other parameters.

No change in platelet counts was noted after treatment in either group; except for significant increase in those treated with supportive measures (mean ± SD 200 ± 141.9 vs. 328 ± 201.2).

LDH was significantly reduced in HU + LC, HU, and supportive line groups from 1011 ± 188 to 383 ± 67, 1498 ± 267 to 512 ± 102, and 915 ± 97 to 425 ± 36, respectively (P < 0.0001), while no change was noted in LC group. However, the highest mean difference was in the HU group followed by the HU + LC group, and finally the supportive group.

Clinical effectiveness and the hemoglobin change of hydroxycarbamide and L-carnitine treatment compared with the other treatment lines of the study sickle cell anemia patients

[Figure 2]a shows that treatment with the combination of Hydroxyurea and L-carnitine significantly decreased the mean number of blood transfusions, the number of painful episodes and days spent in hospital per year. It markedly reduced the number of blood transfusions (P < 0.0001) when compared to supportive treatment after the 3 months' treatment period. However, no significant difference was observed when compared with reduction induced by either HU or L-carnitine alone. Patients treated with the combination showed the least frequent transfusions the year after the treatment regimen (P < 0.0001). After treatment, the drop produced by L-carnitine in the number of blood transfusions was more significant (P = 0.0007) than that produced by HU alone (P = 0.0078). Conversely, mean transfusions significantly increased in the group treated with supportive measures only (mean ± SD 4.3 ± 1.8 vs. 6.4 ± 2.3, P = 0.001.
Figure 2: (a) Clinical effectiveness of Hydroxyurea + L-carnitine combination therapy versus other lines of treatment in four groups of the study SCA patients, (b) and (c) Comparison of hemoglobin change caused by Hydroxyurea + L-carnitine combination therapy versus other lines of treatment in four groups of the study SCA patients. N. B. HU = Hydroxyurea, LC = L-carnitine, S = Supportive. Paired sample t-test was used. The I bars indicate standard deviations. *P < 0.05, **P < 0. 01, ***P < 0.001, **** and ####P < 0.0001. For hemoglobin change One way ANOVA test of variance and Post hoc Tukey HSD multiple comparison tests, were used

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Comparing the number of pain episodes before and after treatment regimen, SCA patients treated with the combination suffered least (P = 0.0003) from pain episodes when compared with those treated with supportive measures (P = 0.0271) or HU alone (P = 0.027). L-carnitine did not produce any change in pain episodes' numbers. In addition, therapy with HU + LC significantly cut short in hospital days compared with HU alone (mean ± SD 17.6 ± 1.1 vs. 10.7 ± 0.9, P = 0.000 for the combination, and 16 ± 5.7 vs. 9.6 ± 3.1, P = 0.001 for HU only). Astonishingly, it was noted that treatment with LC or supportive measures alone prolonged in hospital days (mean ± SD 12.4 ± 7.6 vs. 15.6 ± 10.3, P = 0.008 for the L-carnitine group, and 13.1 ± 4.7 vs. 15.6 ± 7.8, P = 0.012 for the supportive group).

Hemoglobin change after treatment was estimated for each group separately. [Figure 2]b and [Figure 2]c and [Supplement Table S4] show that the highest change was in Group 1 (HU + LC) and the lowest was in Group 3 (LC) (2.019 ± 1.889 vs. −0.01667 ± 1.191). Significant differences in hemoglobin change were noted when comparing Groups 1 (HU + LC) and 2 (HU) with Group 3 (LC) only.



Patients' compliance and side effects of hydroxycarbamide and L-carnitine treatment of the study sickle cell anemia patients compared with the other lines of treatment

[Table 4] shows that about 75% of SCA patients who used hydroxycarbamide alone in this study were noncompliant to it while adding L-carnitine to hydroxycarbamide reduced noncompliance to 73%. The median duration off therapy was 12 days for the HU + LC group, and the mean duration of noncompliance was shorter in the combination group compared with HU alone (11.4 vs. 13.4, P = 0.923). Reasons for noncompliance with therapy included literacy, forgetfulness, fear of medication side effects, duration of the treatment period, lack of accessibility, cost and income, and improved symptoms. On the contrary, 35% only and 0% of supportive and LC groups, respectively, were noncompliant.
Table 4: Patients' compliance to different treatment modalities and the reported treatment side effects in the study sickle cell anemia patients (total n=91)

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Four of 16 patients (25%) used hydroxyurea experienced side effects such as anorexia and nausea and another 25% suffered from vomiting and gastric upset. Twenty-one out of 37 (56%) who used HU + LC experienced nausea and 8 (22%) suffered from vomiting [Table 4]. Furthermore, adding L carnitine to HU increased the percentage of subjects suffering from elevated liver enzymes from 6% to 8%. No decline in absolute leukocyte count was noted in all treatment groups. Bone marrow suppression was not observed either.

One-third of those treated with L-carnitine acquired HCV infection, and half of the HU group developed erythrocyte allo- and autoimmunization. On the other hand, 25% of those who received supportive treatment developed allo- and autoimmunization.

Factors affecting patients' compliance and response to treatment on sickle cell anemia patients included in the study

Using Hb change as an indicator of response to treatment the study assessed factors affecting response to treatment and patients' compliance. [Table 5] shows that, in all patients, there were no significant effects of patients' gender or age on compliance or treatment response, while residence exerted significant effect on compliance where 37.8% and 26.7% of compliant patients were from Assiut and Sohag Governorates, respectively. Treatment side effects had the most obvious effect on patients' compliance and treatment response where nearly 69% of compliant patients experienced no side effects. Of disease complications, only heart failure had significant effect on compliance and treatment response, 37% of noncompliant patients had heart failure. Clinically, both in hospital days and painful episodes showed a significant positive correlation with response to treatment and patients' compliance. Hematologically, [Table 5] shows significant negative correlations of patients' compliance with baseline hemoglobin and Hb F %, and insignificant negative correlation with baseline Hb S %. Notably, treatment response showed significantly negative and positive correlations with baseline hemoglobin and LDH, respectively.
Table 5: Factors affecting patients' compliance and response to treatment in the study sickle cell anemia patients (n=91)

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Outcome of sickle cell anemia patients treated with HU + LC compared with other lines of treatment

One patient (2.7%) of those who received HU + LC therapy died during the study. Congestive heart failure (CHF) was reported as the cause of death in this case. On the other hand, two patients (10%) of Group 4 patients who received supportive measures only died. CHF was the cause of death in one case and stroke in the other one, as illustrated in [Figure 3].
Figure 3: Outcome of patients treated with Hydroxyurea + L-carnitine combination therapy versus other lines of treatment in four groups of the study SCA patients, (a) patients' outcomes; (b) cause of death. N. B. HU = Hydroxyurea; LC = L-carnitine; S = Supportive

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  Discussion Top


SCA is a type of hereditary hemolytic blood dyscrasias; it is inherited as an autosomal recessive disorder. SCA exerts economic burden on the societies, health-care services, patients, and their families due to disease course of exacerbations and crises that warrant hospital admissions and RBCs transfusions.[3] Supportive care is the main stay of therapy of mild forms of SCA; however, HU is the main therapy for those with frequent painful episodes and hospital admissions. In Western countries, HU is the standard treatment of SCA, this concept could not be applied in countries where SCA is not uncommon. The treatment of SCA with HU has been extensively investigated, nevertheless, there are limited or no information about the value of adding LC to HU therapy in patients with SCA.[14],[15] This study scrutinized various aspects of therapy with HU and LC in SCA, the study focused on adults unlike most researches on hemoglobinopathies that focused on the pediatric age groups.

The study included 91 adult patients with SCA, they were grouped into four treatment groups; the first was treated with the combination HU + LC, the second with HU only, the third group was treated with LC only, and the fourth group received supportive care only. Their data were collected through medical history, clinical examination, laboratory investigations, and radiologic assessment. The analysis of their demographic and clinical data showed perfect matching between the study groups as regard age and gender. Moreover, no differences were noted among the study groups as regards clinical presentation and disease complications except for aplastic crisis and heart failure. The four groups were nearly matched as regard baseline hematologic and biochemical profiles.

The study assessed the effect of HU + LC therapy on hematologic parameters of SCA patients compared with other lines. In accordance with others, this study showed that HU treatment induced increment of mean Hb and reduction of WBCs and reticulocytes. Moreover, the study revealed better responses when LC was added to HU, mainly considering the reduction of reticulocytes. However, neither HU alone nor the combination affected platelet count significantly. Both leukocytosis and reticulocytosis were found to play an important role in VOC in patients with SCA.[16] Unlike other studies,[17] this study reported reduction in MCV as a response to HU therapy, adding LC reduced MCHC as well. These conflicting results could be explained by the shorter duration of the current study.

In the current study, LDH, an indicator of ongoing hemolysis, was reduced significantly in those treated with the combination. This effect was much more apparent when HU was used alone. Interestingly, treatment with LC alone did not affect pretreatment LDH levels, which mean that LC has nothing to do with hemolysis.

This study proved the findings of others that therapy with HU in SCA patients, reduces pain episodes, blood transfusions, and in hospital days.[18],[19],[20] Moreover, the study reported that combining LC with HU enhances all these effects. An interesting finding was that treatment with LC alone reduces the need to blood transfusions without significant effect on pain episodes; however, when LC was added to HU both effects were obtained.

Therapy with HU + LC showed better compliance compared with HU alone; moreover, it produced the best clinical improvement. The effectiveness of treatment with hydroxyurea is related to compliance with daily use and patients should be regularly counseled as such.[21] The reasons of noncompliance assessed in the study were unintentional, and the majority of them are not the result of conscious decision-making on the part of the patient; literacy, forgetfulness, fear of medication side effects, duration of the treatment period, lack of accessibility, cost and income, and improved symptoms. Among participants in the study, the second most common cause leading to unintentional noncompliance was forgetting to take the medication, a key barrier that has been well recognized and described in the literature.[22],[23] Although LC side effects were not reported as a cause of noncompliance in this study, added to HU side effects may explain the higher incidence of side effects in the combination group. Another explanation is the well-known patients' better tolerance to monotherapy compared with multiple medications.[13]

In this study, hydroxyurea and L-carnitine treatment caused anorexia and nausea in 22% and 25% of patients, respectively, and their co-administration raised the percentage to 56%. Nausea and vomiting were reported as adverse effects of hydroxyurea.[24] However, it was reported that L-carnitine preparations administered orally can occasionally cause heartburn or dyspepsia.[25] Hydroxyurea only treatment and its combination with L-carnitine elevated liver enzymes in 6% and 8% of patients, respectively. Hallam and Kolesar observed acute elevation of liver enzymes with hydroxyurea therapy contrary to the effect of L-carnitine reported by Yousefi Rad et al., in 2019 as it reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) levels only when these aminotransferases are raised or when the duration of supplementation lasts at least 3 months.[26],[27] The possible explanation of these conflicting results could be the shorter duration of the current study.

In this study, hematologic toxicity of HU was not obvious. This may be due to the low dose of HU that was found to produce no or little hematologic toxicity.[28] However, this finding may be misleading due to the short duration of the study and the low patients' compliance to HU.

Although patients' compliance to supportive measures was acceptable in this study, however, this line was associated with the incidence of allo- and auto-immunization and inferior efficacy.

Treatment with LC alone was tolerable and safe. However, it has little hematologic and inferior clinical efficacy. An amazing finding was the ability of LC to reduce the need for blood transfusions, reduce hospital admissions, and decrease total leukocytic count.

The study went further and assessed factors affecting patients' compliance and response to treatment, astonishingly neither patient's gender nor age has significant effects. Expectedly medication side effects and disease complications had significant effect on both compliance and treatment response. A practically important finding was the significant negative correlation between the Hb change and the baseline Hb and LDH values which meant that HU either alone or combined with LC would be better treatment option for severe forms of SCA. Another worthwhile finding is the effect of patients' compliance on treatment response. Accordingly, prescribing the combination should be accompanied by a health education program about its pharmacokinetic and pharmacodynamic properties.

Although this study reported a lower mortality rate in those treated with HU + LC. However, this could be a deceiving finding due to the short duration of the study, where multiple other factors could contribute in this outcome.

Now, an important question is how L-carnitine improved hematologic and clinical effectiveness of HU and reduced noncompliance and incidence of serious complications?

Our study revealed that L-carnitine represents an effective adjuvant therapy to HU that potentially ameliorates clinical symptoms and compliance to therapy in severe SCA patients. L-carnitine could have improved hematological effects of HU through various mechanisms; LC is a scavenger of free radicals upregulates antioxidant enzymes, superoxide dismutase, and catalase, thus protects the RBCs from oxidative stress.[29] In addition, L-carnitine was proved to play a role in hemopoiesis and reduce the need to erythropoietin. Moreover, L-carnitine supplementation for 3-month was reported to reduce erythrocyte deformability in patients with renal anemia under hemodialysis, this effect could be highly beneficial in patients with SCA.[30]

Another important question is what are the advantages and disadvantages of combining L-carnitine with HU for treatment of SCA? Regarding disease morbidity and mortality, the combination reduces the need for blood transfusions and frequent hospital admissions. Thus could reduce the incidence of blood-borne and nosocomial infections in those patients.[31] Moreover, LC was proved to be a cardioprotective agent in many researches,[32] accordingly adding LC to HU for the treatment of SCA could minimize cardiovascular complications, the leading cause of death in those patients. Regarding safety and tolerability of the combination, LC is a natural product with a wide range of safety and minimal side effects.[33]

Considering economic burden of a disease, LC is a cheap widely available drug, adding it to HU will add little cost to patient's prescription. Importantly, the combination, HU + LC, minimizes economic burden of SCA through reducing incidence of VOC, hospital admissions, and transfusions. This could be reflected directly on the patients, their families and health authorities, or indirectly through reducing work off days.

The main disadvantage of combining LC with HU for the treatment of SCA could be a higher rate of incompliance due to multiple medications. Incompliance can affect hematologic and clinical efficacy of the combination. This could be solved by adequate patient consultation or perhaps through combining LC and HU in one form (one capsule) in the near future. This would enhance compliance not only in SCA but also in thalassemia intermedia.


  Conclusions and Future Work Top


Our findings concluded that co-administration of L-carnitine with hydroxycarbamide is a relatively tolerable, safe, and effective line of therapy in patients with severe forms of SCA. Treatment with HU and LC reduces frequency of blood transfusions, in hospital days, and number of painful episodes per year, as such it cuts the economic burden of SCA in a given society. Moreover, the study displayed better response to the combination on severe cases.

Based on the results of this study, we recommended a wide-scale, long-term follow-up studies to assess the role of the combination HU + LC in reducing SCA sequel and complications particularly cardiovascular and cerebrovascular ones, as HU alone was found relatively ineffective in protection of recurrent stroke.[34]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts for interest.



 
  References Top

1.
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376:2018-31.  Back to cited text no. 1
    
2.
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