Pharmacometabolomics for Predicting Variable Busulfan Exposure in Pediatric HSCT Patients

Abstract Optimal dosing for busulfan is important for minimization of systemic toxicity from overexposure and graft failure or relapse from underexposure. Herein, we investigated potential markers for predicting individual variation in the pharmacokinetics of busulfan, and suggested possible mechanism for inter-individual variability by using pharmacometabolomics. Fifty-nine pediatric patients undergoing busulfan-based conditioning chemotherapy for hematopoietic stem cell transplantation were divided into three groups according to the area under the concentration-time curve (AUC) of busulfan; low-, medium-, and high-AUC group. Nontargeted metabolic profiling of baseline urine samples showed that deferoxamine metabolites were abundant, while 2 acylcarnitines and phenylacetylglutamine were significantly lower in high-AUC group, compared with low-AUC group. Higher level of deferoxamine, an iron-chelating agent for the patients with a high serum ferritin level during the conditioning chemotherapy, suggested pharmacokinetic interaction between serum ferritin level and busulfan exposure. Retrospective analysis of the correlation between serum ferritin level and busulfan AUC showed positive correlation in 130 pediatric patients. The optimal busulfan dose to meet the target AUC of 18,750 μg*h/L/day was calculated to be 119.7 ± 30.1 mg/m2 in patients with ferritin < 1,000 ng/mL and 106.1 ± 29.3 mg/m2in patients with ferritin ≥ 1,000 ng/mL (P=0.021). Mechanismly, previous studies have indicated that ferritin, acylcarnitine and phenylacetylglutamine are closely associated with liver function. Increased serum ferritin is thought to be responsible for an increased production of oxygen free radicals and activation of GSH turnover, which means reduction of GSH levels in both plasma and erythrocytes and this depletion seems to be related to the decrease of busulfan metabolism. Down regulation of acylcarnitines is associated with deregulation of mitochondrial fatty acid β-oxidation by hepatic injury. PAGN, a marker of waste nitrogen scavenger, was down-regulated which indicates ammonia-related metabolism could also be involved in busulfan exposure. Hyperammonemia, a clinical condition of elevated ammonia levels, is mainly lead by liver cell damage. Taken together, our findings demonstrate that elevated serum ferritin levels are a potential biomarker correlated with busulfan exposure and provide some evidence that busulfan metabolism seems to decrease in the patients with reduced liver function. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Hematologic Improvement with Iron Chelation using therapy Deferasirox in Patients with Aplastic Anemia: A Subgroup Analysis of KAMS0112 Prospective Study,

Blood ◽

10.1182/blood.v118.21.3424.3424 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3424-3424

Author(s):

Yoo-Hong Min ◽

Sung-Soo Yoon ◽

Hyeoung Joon Kim ◽

Kyoo-Hyung Lee ◽

Jae Hoon Lee ◽

...

Keyword(s):

Platelet Count ◽

Iron Overload ◽

Serum Ferritin ◽

Research Funding ◽

Serum Ferritin Level ◽

Ferritin Level ◽

Iron Chelation ◽

Hemoglobin Level ◽

Hematopoietic Stem ◽

Wbc Count

Abstract Abstract 3424 Patients with aplastic anemia (AA) are suffered from various complications related to bone marrow failure and peripheral cytopenia. Although immunosuppressive therapy or hematopoietic stem cell transplantation has been performed for curative purpose, the majority of patients have been treated only by supportive cares including repeated transfusion. However, because continued transfusion eventually induces iron overload in many tissues and organs, transfusional iron overload and its consequences are another life-threatening problems for AA patients. Previous reports about iron chelation therapy (ICT) have mainly shown its efficiency for decreasing tissue iron and safety. However, improvement in hematopoiesis after iron chelation therapy has been limitedly reported as case reports or trials involving small number of patients without objective tools for measuring tissue iron content. In the KAMS0112 study (a multi-center, open label, prospective study evaluating the efficacy of ICT with deferasirox in transfusional iron overload with myelodysplastic syndrome or AA using quantitative R2-MRI, Ferriscan), a total of 54 patients with AA showing serum ferritin level over 1,000 ng/ml were enrolled from 19 institutes, and further analyzed for the changes in hemogram during ICT as well as efficacy and safely of deferasirox. During the study, the specific treatments for AA, such as immunosuppressive therapy or hematopoietic stem cells transplantation, were not undertaken. During 1 year prior to study, patients received 23.7±16.9 units of red blood cell (RBC) product, and the baseline serum ferritin level and liver iron content (LIC) were 4,164±447 ng/ml and 20.1±12.0 mg Fe/g DW, respectively. Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin level falls below 500 ng/ml, treatment was withheld. In spite of continued transfusional support during the study, serum ferritin level and LIC were significantly decreased after 1 year of ICT with deferasirox (Ds-ferritin=−3,076.7±489.9 ng/ml, p=0.0003; DLIC=−7.73 mg/Fe/g DW, p=0.001). To evaluate the improvement of each parameter in hemogram by ICT, patients with baseline hemoglobin level less than 8.0 g/dl (n=28), with baseline WBC count less than 4/ml (n=43), and with baseline platelet count less than 20/ml (n=31) were selected separately. At the end of study, hemoglobin level and platelet count (8.2±3.0 g/dl and 22.2±31.4/ml, respectively) was significantly increased from the baseline value (6.1±1.1 g/dl, p=0.001; 12.5±12.4/ml, p=0.05, respectively). WBC count was also slightly increased (from 2.1±0.9/ml to 2.3±0.9/ml, p=0.457). Considering the relatively uniform criteria of transfusion, the finding that hemoglobin level and platelet count could increase above 8 g/dl and 20/ml, respectively, after 1 year of deferasirox treatment is clinically significantly. Due to gradual improvement of anemia, requirement of RBC transfusion had continuously decreased during the study period (R2=0.31). This subanalysis of KAMS0112 study demonstrates that ICT using deferasirox can be effective in improving anemia and thrombocytopenia in the transfusional iron overload patients with AA, as well as reducing serum ferritin level and LIC. Further studies might be required to elucidate the mechanism involved in the improvement of hematopoiesis associated with correction of deranged intracellular iron homeostasis. Disclosures: Min: Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Lee:Novartis: Research Funding. Won:Novartis: Research Funding. Shim:Novartis: Research Funding. Kim:Novartis: Research Funding. Seung:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Chung:Novartis: Research Funding. Hyun:Novartis: Research Funding. Jo:Novartis: Research Funding. Jung:Novartis: Research Funding. Sohn:Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Joo:Novartis: Research Funding. Cheong:Novartis: Research Funding.

Download Full-text

Influence of Pretransplantation Serum Ferritin on Children Beta-Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.5520.5520 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5520-5520

Author(s):

Yongsheng Ruan ◽

Xuedong Wu ◽

Xiaoqin Feng ◽

Yuelin He ◽

Chunfu Li

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Ferritin Level ◽

Conditioning Regimen ◽

Thalassemia Major ◽

Hematopoietic Stem

Abstract Objectives: To evaluate the influence of pretransplantation serum ferritin on children β-thalassemia major (β-TM) undergoing allogeneic hematopoietic stem cell transplantation. Methods: A retrospective analysis of 266 HLA-matched children with β-TM from January 2009 and November 2014 was performed. Transplantation conditioning regimen of these children was the NF-08-TM protocol. Median follow-up time was 28 months (3~62months). We observed the relationship between pretransplantation serum ferritin level and transplantation complications which included infection, graft versus host disease(GVHD),veno-occlusive disease(VOD) and death. Results: Transplantation-related death occurred in 18 of 266 patients (6.8%). Five-year overall survival (OS) was found to be 92.8%. Among various complications, only infection was significantly associated with the high serum ferritin level (t=-2.673, P=0.008), especially serum ferritin above 3449.5μg/L(P=0.000). Meanwhile infection was the most common complication and severe infection would be main cause of deaths. Conclusions: NF-08-TM conditioning regimen was the optimization for HLA-matched β-TM patients. High pretransplantation serum ferritin level would bring high infection occurrence. Disclosures No relevant conflicts of interest to declare.

Download Full-text

A Prospective Study of Thyroid Function Status in Patients of Haemoglobin E Beta Thalassemia and Correlation with Serum Ferritin Level

Blood ◽

10.1182/blood.v128.22.4837.4837 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4837-4837

Author(s):

Tuphan Kanti Dolai ◽

Shuvra Neel Baul ◽

Prakas Kumar Mandal ◽

Rajib De ◽

Prantar Chakrabarti

Keyword(s):

Correlation Coefficient ◽

Serum Ferritin ◽

Subclinical Hypothyroidism ◽

Thyroid Dysfunction ◽

Serum Ferritin Level ◽

Conflicts Of Interest ◽

Ferritin Level ◽

Thyroid Status ◽

Beta Thalassaemia ◽

Serum Tsh

Abstract Introduction Haemoglobin E-beta-thalassaemia (EBT) represent approximately 50 per cent of those affected with severe beta thalassemia.The highest frequencies are observed in India, Bangladesh and throughout Southeast Asia. Endocrinopathies are now amongst the common complications of thalassaemia and it is multifactorial in origin. Iron overload in EBT is also multifactorial. This study was undertaken to evaluate the thyroid dysfunction in patients of EBT and its correlation with serum ferritin levels. Methods EBT patients were evaluated prospectively to assess thyroid dysfunction status and correlate it with serum ferritin levels. High performance liquid chromatography was performed with Bio-rad beta thalassaemia short program variant II. Serum ferritin estimation was done with microplate immunoenzymometric assay and thyroid assay for TSH, free T4 and T3 were done by access 2 Immunoassay System, Beckman Coulter. Results 50 patients with EBT were evaluated. The mean age of patients were 19.7 years (range: 12-47). There were 28 males and 22 females. There were 41(82%) and 9(18%) transfusion dependent and transfusion independent patients respectively and 40(80%) were on chelation therapy. In this cohort 22(44%) patients had thyroid dysfunction. Six (12%) and 16(32%) of patients were having hypothyroidism and subclinical hypothyroidism respectively. Mean ± Standard deviation (S.D) of serum ferritin level with hypothyroidism, subclinical hypothyroidism and euthyroidism was 1077 ± 371.8 ng/ml ,1422 ± 1361.0 ng/ml and 1252 ± 664.4 ng/ml respectively with correlation coefficient =0 [Fig 1 and Fig 2]. Serum ferritin levels do not predict thyroid dysfunction in patients of EBT. Male and female have equal preponderance for thyroid dysfunction. Patients with subclinical hypothyroidism were having few symptoms compared to frank hypothyroidism and majority of symptoms in either scenario were masked by thalassemia itself. Earlier age of onset of EBT is associated more with thyroid dysfunction however the association is not statistically significant (p=0.2). There was no association between spleen size and thyroid dysfunction (p=0.7). Conclusions Thyroid dysfunction was seen in 42% of EBT patients. Prevalence of hypothyroidism was found to be higher in EBT patients compared to general population but a definite correlation with the serum ferritin levels could not be established. Figure 1 Mean serum ferritin level and thyroid status Figure 1. Mean serum ferritin level and thyroid status Figure 2 Correlation of serum TSH and ferritin level (correlation coefficient =0) Figure 2. Correlation of serum TSH and ferritin level (correlation coefficient =0) Disclosures No relevant conflicts of interest to declare.

Download Full-text

Non-insulin-dependent diabetes mellitus and elevated serum ferritin level

Journal of Diabetes and its Complications ◽

10.1016/s0002-9610(05)80252-1 ◽

1993 ◽

Vol 7 (4) ◽

pp. 245-249 ◽

Cited By ~ 32

Author(s):

Todd B. Kaye ◽

André T. Guay ◽

Donald C. Simonson

Keyword(s):

Diabetes Mellitus ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Ferritin Level ◽

Elevated Serum ◽

Insulin Dependent Diabetes Mellitus ◽

Insulin Dependent Diabetes ◽

Dependent Diabetes Mellitus ◽

Insulin Dependent

Download Full-text

Association between serum ferritin level and thyroid hormones in hypothyroid pediatric patients

Anatolian Current Medical Journal ◽

10.38053/acmj.971060 ◽

2021 ◽

Vol 3 (4) ◽

pp. 300-302

Author(s):

Ayşegül ALPCAN ◽

Yaşar KANDUR ◽

Serkan TURSUN ◽

Meryem ALBAYRAK ◽

Ayça TÖREL ERGÜR

Keyword(s):

Thyroid Hormones ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Pediatric Patients ◽

Ferritin Level

Download Full-text

The Effect of Chronic Viral Hepatitis on Serum Ferritin Level in Thalassemia Patients

Blood ◽

10.1182/blood-2019-125010 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4819-4819

Author(s):

Natthapat Rujeerapaiboon ◽

Adisak Tantiworawit ◽

Pokpong Piriyakhuntorn ◽

Thanawat Rattanathammethee ◽

Sasinee Hantrakool ◽

...

Keyword(s):

Viral Load ◽

Iron Overload ◽

Viral Hepatitis ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Conflicts Of Interest ◽

Ferritin Level ◽

Iron Concentration ◽

Chronic Viral Hepatitis ◽

The Mean

Background: Serum ferritin is widely used as a marker of iron overload in thalassemia patients. However, the ferritin level is affected by active infections or inflammation. The association between viral hepatitis and serum ferritin level in thalassemia patients is still unclear. This study aimed to determine the effect of chronic viral hepatitis on serum ferritin level in thalassemia patients. Methods: This was a cross-sectional study in thalassemia patients aged ≥15 years-old at Chiang Mai University hospital. We expected that thalassemic patients in our clinic have a mean serum ferritin of 767 ng/mL with a standard deviation of 210 ng/mL. As a result, we have to enroll a total of 28 patients to demonstrate 30% difference of mean serum ferritin when the power was set at 80% with alpha level of 0.05. Information on chronic viral hepatitis, mean serum ferritin and liver iron concentration (LIC) as measured by T2* MRI were collected. Chronic viral hepatitis status was confirmed by either HBV DNA or HCV RNA testing. Patients were categorized to hepatitis and non-hepatitis group. Serum ferritin levels were compared between two groups. LIC measurement was used as a gold standard for iron overload. Subgroup analysis was performed according to iron overload and transfusion requirement status. Categorical and continuous variables were compared using the Chi-squared test and T-test, respectively. The correlation between viral loads and mean serum ferritin levels was analyzed by Pearson's correlation. Result: Of 32 thalassemia patients (25 non-transfusion dependent [NTDT] and 7 transfusion dependents [TDT]), 13 patients had chronic viral hepatitis (7 with hepatitis B and 6 with hepatitis C infections). The LIC between hepatitis and non-hepatitis groups were not significantly different (7.28 [SD 4.7] vs 9.08 [SD 5.2] mg Fe/g, p=0.19). In the higher LIC group (≥ 5 mg Fe/g), the mean serum ferritin level was higher in the hepatitis group than non-hepatitis group (1,776 [SD 488] vs 967 [SD 860] ng/mL, p=0.03). For the lower LIC group (<5 mg Fe/g), the mean ferritin levels were not significantly different between the hepatitis and non-hepatitis groups (646 [SD 224] vs 459 [SD 205] ng/mL, p=0.22). The correlation between the viral load and mean ferritin level in NTDT group showed a significant linear correlation with R=0.7 (p=0.04). Conclusions: We observe a higher serum ferritin level among thalassemia patients who concurrently have chronic viral hepatitis. Chronic viral hepatitis is a possible cause of a falsely high ferritin level in these patient population. Furthermore, the viral load is positively correlated with serum ferritin level. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Elevated Serum Ferritin Levels Are Highly Associated with Diabetes Mellitus and Hypothyroidism in Thalassemia Patients

Blood ◽

10.1182/blood.v120.21.5174.5174 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5174-5174

Author(s):

Sasinee Hantrakool ◽

Adisak Tantiworawit ◽

Ekarat Rattarittamrong ◽

Chatree Chai-adisaksopa ◽

Weerasak Nawarawong ◽

...

Keyword(s):

Diabetes Mellitus ◽

Risk Factor ◽

Iron Overload ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Ferritin Level ◽

Elevated Serum ◽

Major Risk Factor ◽

Maximum Serum ◽

Hemoglobin E

Abstract Abstract 5174 Background: Endocrinopathiesare well recognized serious complications in thalassemia patients with iron overload. Elevated serum ferritin levels reflect severity of iron overload and are associated with relevant clinical outcomes. Increased serum ferritin > 2, 500 μg/dl has been found to predict the development of cardiac function abnormalities but the predicting serum ferritin level for diabetes and hypothyroidism has not been determined. Method: This is a cross sectional and retrospective study to evaluate the correlation between ferritin levels and endocrinopathies (diabetes, hypothyroidism) in thalassemia patients. All thalassemia patients age > 18 years old, during August 2011 and June 2012 were enrolled. The diagnosis and type of thalassemia were reviewed and confirmed. Diabetes and hypothyroidism were diagnosed by fasting blood sugar and thyroid functions test. Serum ferritin was measured at the same period. The medical record was reviewed for age, sex, splenomegaly, history of splenectomy, transfusion requirement, maximum serum ferritin level, mean serum ferritin level and iron chelation history. Result: Among 92 thalassemia patients [35 male (38%) and 57 female (62%)] with a median age of 30. 6 years (range, 18–71). There were 28 (30. 4%) cases of Homozygous β-thalassemia, 45 cases (48. 9%) of β-thalassemia/Hemoglobin E and 18 cases (19. 5%) of Hemoglobin H or AE Bart's disease. Most patients (60. 9%) underwent splenectomy, while only one third of patients (34. 8%) were NTDT (non-transfusion dependent thalassemia) (Table 1). The mean value of random and maximum serum ferritin levels for the whole group were 2, 408 μg/dl (range279–9, 817) and 5, 101 μg/dl (range 279–37, 656), respectively. The prevalence of diabetes mellitus and impaired fasting glucose (IFG) were 9. 8% (9 cases) and 10. 9% (10 cases), respectively. Patients with diabetes had significantly higher mean maximum serum ferritin levels than those with non-diabetes (11, 241 μg/dl vs. 4, 468 μg/dl, (p=0. 0001) (Table 2). The cut-off point of maximum serum ferritin levels > 2, 500 μg/dl was the major risk factor for the development of diabetes complication in this group of patients. Six patients (6. 5%) and 21 patients (22. 8%) had hypothyroidism and subclinical hypothyroidism, respectively. Patients with hypothyroidism had significantly higher mean maximum serum ferritin levels than those with euthyroidism [(7, 638 vs. 4, 117 μg/dl, (p=0. 003)]. From univariate analysis, the cut-off point of maximum serum ferritin levels > 3, 500 μg/dl was the major risk factor associated with hypothyroidism (p=0. 007). Conclusion: Elevated serum ferritin level is a predictor of the development of diabetes mellitus and hypothyroidism in thalassemia patients with iron overload. The maximum serum ferritin levels of greater than 2, 500 and 3, 500 μg/dl are associated with diabetes mellitus and hypothyroidism, respectively. These findings warrant the value of iron chelating therapy to maintain serum ferritin levels below 2, 500 μg/dl to avoid the development of endocrinopathies in patients with thalassemia. Disclosures: No relevant conflicts of interest to declare.

Download Full-text