Regular Iron Chelation Therapy Research Articles

Improvements in Health-Related Quality of Life after Exagamglogene Autotemcel in Patients with Transfusion-Dependent Beta-Thalassemia

Background: Transfusion-dependent β-thalassemia (TDT), an inherited hematological disorder which requires life-long, chronic red blood cell transfusion (RBC) and regular iron chelation therapy, has a substantial negative impact on health-related qualify of life (HRQoL). Exagamglogene autotemcel (exa-cel) is a one-time, non-viral, ex vivo CRISPR-Cas9 gene-edited cell therapy in phase 3 clinical trials that has been shown to eliminate the need for RBC transfusions and achieve transfusion independence. Here, we report HRQoL data from a pre-specified interim analysis of the exa-cel CLIMB TDT-111 study. Methods: CLIMB TDT-111 is an ongoing, 24-mo, phase 3 trial of a single dose of exa-cel in patients aged 12-35 years with TDT and a history of ≥100 mL/kg/year or ≥10 U/year of packed RBC transfusions for 2 years prior to screening. Changes in patient-reported outcome (PRO) measures including EuroQol Quality of Life Scale 5 dimensions 5 levels of severity (EQ-5D-5L, including descriptive system and visual analog scale [VAS]) and Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT, including FACT-General [FACT-G] and bone marrow transplant subscale [BMTS]) for adults and the EuroQol Quality of Life Scale 5 dimensions youth (EQ-5D-Y) and Pediatric Quality of Life Inventory (PedsQL) for adolescents were assessed through month 24 as a secondary endpoint in the trial. Data are presented as of 16 January 2023 for the 24 adults (aged ≥18-35 years) and 11 adolescents (aged ≥12 to < 18 years) who had been followed for ≥16 months after exa-cel infusion. Results: Clinically meaningful improvements, exceeding the minimal clinically important difference (MCID) thresholds, were observed in all PRO measures in adults. Baseline mean EQ-5D-5L health utility US index score (n=24, mean [SD]: 0.85 [0.18]) was near the general population norm and in line with baseline scores previously reported for adult patients with TDT. By month 24, both EQ-5D-5L health utility US index scores and EQ VAS scores showed substantial improvement (mean [SD] changes at month 24 [n=15]: 0.12 [0.26] and 10.2 [20.9] points; MCIDs 0.078 and 7 to 10, respectively). FACT-G Total Score improved from baseline by month 12 and was sustained through month 24 (mean [SD] change at month 24 [n=15] 10.3 [17.0] points; MCID 3 to 7), with improvements observed in all 4 subscales (physical, social/family, emotional, and functional well-being). BMTS score improved by month 12 and was sustained through month 24 (mean [SD] change at month 24 [n=15] 6.8 [4.7] points; MCID 2 to 3). For adolescents, EQ VAS scores improved through month 18 (mean [SD] change from baseline 4.8 [6.1] points). Total PedsQL score improved by month 6 and was sustained through month 18 (mean [SD] change from baseline [n=7] 14.1 [9.2] points; MCID 4.36). Physical functioning and psychosocial health scores, sub-components of PedsQL, both showed sustained improvement through month 18 (mean [SD] change [n=7] 19.2 [9.1] and 11.4 [10.9] points; MCID of 6.66 and 5.30 points, respectively). Improvement in psychosocial score was observed in all 3 subscales (social, emotional, and school functioning). Conclusion: Adults and adolescents infused with exa-cel reported sustained and clinically meaningful improvements in their HRQoL, with improvements observed across different instruments and domains, including physical, emotional, social/family and functional well-being and overall health status. These results demonstrate the broad clinical benefits of exa-cel in patients with TDT.

Cognitive Status In Thalassemia

Background: Thalassemia is one of the most common chronic and genetic hematological disorder. This chronic disease challenges the individual at the physical, emotional, cognitive level and disrupts the quality of life because of persistent anemia and hypoxia. The aim of study is to assess the cognitive status in thalassemia.
 Material and methods: This is a cross-sectional observational type of study that was performed in Autism and Child Development Center of Chattagram Maa Shishu–O–General Hospital. Children aged 6 to 16 years with thalassemia of different catagories were enrolled as study subjects. Study period was six months. Cognitive status of this study subject was assessed by WICS-IV equipment.
 Results: Among the 50 study subjects, Hb E b thalassemia was the most common type of thalassemia 39(78%). 2(4%) patient took oral chelating agent, 18 (36%) were under injectable, 20(40%) were found taking both oral and injectable and 10(20%) were observed not under any iron chelation therapy. Regular iron chelation therapy was found in 22(44%) cases.10(20%) cases had normal intelligence,19(38%) cases had mild mental retardation and 21 (42%) had moderate mental retardation. Among the 10 patients who do not use any chelation therapy,8(80%) patients had moderate retardation and 2(20%) had mild mental retardation. On the other hand, among the 40 patients who were having iron chelation therapy, 10(25%) patients showed normal level of intelligence, 17(42.5%) had mild mental retardation and 13(32.5%) had moderate mental retardation. In different score of WISC-IV, it was found that working memory and processing speed were poorer than verbal comprehension and perceptual reasoning in different type of thalassemia. This study also showed poor cognition is more prominent in thalassemia major and Hb E beta thalassemia.
 Conclusion: Cognitive status of the study subjects who take regular iron chelation therapy is much better than those who do not take iron chelation therapy. Hence, iron chelation therapy is proved to have better cognitive outcome for thalassemia patients with iron overload.
 Chatt Maa Shi Hosp Med Coll J; Vol.22 (1); January 2023; Page 57-61

Evaluation of diastolic dysfunction in multi-transfused thalassemia patients

Background: An important complication of thalassemia is iron deposition in the cardiac tissue resulting in degeneration, fibrosis and dysfunction. Cardiac disease is the primary cause of death. Aims and objectives were to detect early cardiac involvement in patients with transfusion dependent thalassemia by conventional doppler echocardiography and tissue doppler imaging while they are still asymptomatic. Methods: 150 patients in the age group of 2-18 years who were receiving regular and frequent blood transfusions were enrolled in this study. Institutional ethical clearance was taken. After informed consent, 2D echocardiography was performed on all the patients. Previous blood reports reviewed. Various parameters like mitral flow pattern, LVEF and Tricuspid regurgitant jets were taken into account to diagnose cardiac dysfunction. Results analysed by standard statistical tests. Results: Out of 150 patients, 58% were males and 42% were female patients. The 13 (8.6%) patients were diagnosed as having diastolic dysfunction. Out of 150, majority (86.6%) were below the age of 15 years, 81.33% children were diagnosed as having thalassemia before the age of 2 years, 97% patients were on regular iron chelation therapy, 32% patients had pre-transfusion Hb <7 gm/dl, 78.66% patients had S. ferritin levels >2500 ng/ml and more number of males (7.33%) have undergone splenectomy than females. Conclusions: Diastolic dysfunction on Doppler echocardiography is an early sign of myocardial dysfunction in patients with beta thalassemia.

Contribution Factors on Long- term and Short- term Survival of Thalassemia Major Patients

Introduction: Thalassemia major is an important health problem in Mediterranean countries that causes many psychological and economic problems. This study aimed to evaluate the effective factors on long- and short-term survival of thalassemia major patients using mixture and non-mixture cure survival models based on Generalized Gompertz distribution. The Generalized Gompertz distribution has flexible curve of failure rate that may be appropriate for different situation of survival analysis.
 Methods: In this retrospective cohort study, medical records of 300 thalassemia major patients referring to Zafar's thalassemia clinic during 1994-2017 in Tehran, Iran were reviewed. Mixture and non-mixture cure survival models based on Gompertz and Generalized Gompertz distributions were performed to estimate the effective factors on long- term and short- term survival of Thalassemia Major Patients. The Akaike Information Criteria (AIC) was used to compare the models. Analysis was performed using SAS software version 9.4.
 Results: The mean (±SD) survival time was 32.21 (±7.47) years. The censorship rate was 78.30%. In both of the mixture and non-mixture cure models, Generalized Gompertz distribution, as compared to the standard Gompertz had the lower Akaike criteria that was 200.8. Based on this model, iron deposition in liver at mild and moderate levels had a significant effect on the long-term survival of these patients.
 Conclusion: Based on Akaike Information criteria, considering the Generalized Gompertz mixture cure model has the best fit for the data of thalassemia major disease in which patients are long-term survivors. In order to analyze the survival of patients with thalassemia major, since iron deposition in liver at mild and moderate levels had a significant effect on the long-term survival of these patients; it is recommended to apply a regular iron chelation therapy for extra iron excretion.

Influencing factors of iron metabolism assessment in patients with myelodysplastic syndrome: A retrospective study

目的分析骨髓增生异常综合征（MDS）患者铁代谢评估的影响因素。方法181例MDS患者接受磁共振成像（MRI）和（或）能谱CT（DECT）对肝脏和心脏铁浓度的检测，其中41例患者在2次检查期间接受了规律铁螯合治疗（ICT）。同步检测调整铁蛋白（ASF）、红细胞生成素（EPO）、心功能、肝转氨酶、肝炎抗体、外周血T细胞极化等指标，并收集患者是否合并骨髓纤维化、脾大、环孢素A使用等信息进行比较分析。结果MRI组、DECT组肝铁浓度均与ASF呈正相关（r分别为0.512、0.606，P值均<0.001），MRI组心铁浓度与ASF仅呈弱相关（r＝0.303，P<0.001），而DECT组心铁浓度与ASF无明显相关性（r＝0.231，P＝0.053）。输血依赖显著影响患者肝和心铁浓度［MRI组：LIC：（28.370±10.706）mg/g对（7.593±3.508）mg/g，t＝24.30，P<0.001；MIC：1.81对0.95，z＝2.625，P<0.05，DECT组：肝VIC：（4.269±1.258）g/L对（1.078±0.383）g/L，t＝23.14，P<0.001：心VIC：1.69对0.68，z＝3.142，P<0.05］。重度以上铁过载组患者EPO浓度明显高于轻中度铁过载组及正常组（P值均<0.001）；MDS伴环状铁粒幼红细胞（MDS-RS）患者与和其他MDS低危组患者相比，肝铁浓度明显增高［DECT组：3.80（1.97,5.51）g/L对1.66（0.67,2.94）g/L，P＝0.004；MRI组：13.7（8.1,29.1）mg/g对11.6（7.1,21.1）mg/g，P＝0.032］。而年龄、骨髓纤维化、脾大、T细胞极化、环孢素A的使用、肝转氨酶、肝炎抗体阳性等因素对铁代谢无明显影响。结论MDS患者肝铁浓度与ASF呈正相关，心铁浓度与ASF无明显相关性。输血依赖、EPO浓度、合并RS是铁代谢的影响因素。

Dysregulated Neutrophil Iron Homeostasis in β-Thalassemia Impairs Phagocytosis and Reactive Oxygen Species Production

IntroductionBeta thalassemia is an inherited disorder characterised by ineffective erythropoiesis leading to anemia and secondary iron overload. Neutrophils are the first line of innate immune defence against infection is dysfunctional in thalassemia patients. Iron is required for the oxidative response of neutrophils to allow the production of reactive oxygen species (ROS). However, the role of iron contributing to the neutrophil dysfunction is unclear. This is the first study to characterise the neutrophil iron metabolism in β-thalassemia and its association with oxidative burst capacity, phagocytosis, and systemic iron homeostasis.MethodSixteen thalassemia patients and fourteen healthy individuals were recruited in the department of Haematology, Christian Medical College, Vellore, India. Neutrophils were purified from human whole blood collected in EDTA tube, using neutrophil magnetic isolation kit (Miltenyi Biotec). Purified population (>95%) was confirmed by the presence of the surface marker CD62L evaluated using flow cytometry. Haematological parameters were analysed according to standard methods. Serum ferritin, iron, soluble transferrin receptor were measured using immunoassay. Serum hepcidin was measured using ELISA. Neutrophil RNA was isolated using trizol method and was reverse transcribed into complementary DNA using QIAGEN kit. The relative quantification of iron related genes were measured using real-time PCR. In oxidative burst assay, neutrophils were incubated with dihydrorhodamine 123 (DHR) and stimulated with Phorbol 12-Myristate 13-Acetate (PMA). Respiratory burst of the cell was analysed by flow cytometry. Phagocytosis and acidification capacity of human neutrophils were quantified using the pHrodo Green Staphylococcus aureus BioParticles kit (Thermo Fisher). Acquisition was performed using the Beckman Coulter(Navios) flow cytometer and analysed using kaluza software. Statistical analysis was performed using SPSS software.ResultsWe investigated a cohort of β thalassemia Major (n=5), intermedia (n=6) and sickle beta thalassemia (n=5) patients who were on regular iron chelation therapy. The demographic and biochemical parameters are tabulated in Table 1. Serum iron, ferritin levels and transferrin saturation were significantly increased in thalassemia cohort as compared to healthy donors (Fig1a). There was no significant association between ferritin and hepcidin levels. The percentage of neutrophils in thalassemia was significantly reduced incomparision to healthy donors (p=0.032). Oxidative burst capacity of neutrophils from thalassemia major and intermedia patients were significantly decreased (p=0.002) compared to healthy donors upon stimulation with PMA (Fig1b). Neutrophil phagocytosis capacity indicated by the relative amounts of phagocytized fluorescein S.aureus particles were significantly lower in thalassemia patients compared with controls, after 15min/30min incubation (Fig1c). The recognition capacity of neutrophils towards bioparticles significantly decreased at 45-minute incubation in patients (p=0.017) (Fig1d). Serum iron overload and transferrin saturation had negative association with neutrophil phagocytosis capacity (r=-0.714; p=0.045 & r=-0.857; p=0.014), respectively. Neutrophil iron related gene expression was analysed and found significantly lower expression of FPN 1A (FPN1 containing iron regulatory element (IRE)), DMT1B without IRE region and IRP2 respectively (p=0.029, p=0.029 & p=0.016) (Fig1e). FPN1B without IRE region was upregulated in thalassemia patients (p=0.016). Serum ferritin had positive correlation with FPN1B (r=0.786; p=0.036). Soluble transferrin receptor had negative association with DMT1A (containing IRE region) and IRP2 respectively (r=-0.900; p=0.037 and r=-0.750; p=0.052).Aberrant neutrophil function was found in all thalassemia patients. Although oxidative burst activity was decreased in thalassemia major and intermedia patients, sickle β-thalassemia patients had normal burst activity. Systemic iron status had inverse correlation with phagocytosis capacity of neutrophils. Dysregulation of iron transporters in neutrophils was indicated by decreased expression of DMT1 and augmented FPN1B expression, despite systemic iron overload. These findings have to be explored in a larger cohort to elucidate the clinical significance. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A study on quality of life among thalassemic children aged 8 to 18 years

Background: The assessment of quality of life in children, especially in those with chronic illness such as thalassaemia, is particularly important. It differs from other forms of medical assessment in that it focuses on the individuals’ own views of their well-being and other aspects of life, giving a more holistic view of well-being.Methods: Hospital based descriptive, observational study was conducted on 200 school-age children. Two tools were used to collect the necessary data. The first was a structured interview questionnaire sheet including socio-demographic data of children and their parents as well as medical history. The second tool was a standardized tool (Pediatric Quality of Life Inventory TM Version 4.0).Results: The results of the present study revealed that the quality of life of school-age children with Thalassemia Major was affected. According to child’s report regarding total QOL score 30% of children had good score compared to 35% in parent’s report, while 65% had fair score compared to 60% in parent’s report. Emotional functioning scored the lowest followed by physical then school and social functioning. Regarding compliance with treatment, 91% of the studied children had regular blood transfusion therapy. In addition, 81% of the studied children were compliant with iron chelation therapy.Conclusions: Thalassemia has a negative impact on perceived physical, emotional, social and school functioning in thalassemia patients. There was a significant association between the total quality of life and compliance with blood transfusion and regular iron chelation therapy in both child and parent report.

Adherence to Iron Chelation Therapy and Its Determinants.

Background: Thalassemia is a chronic disease requiring lifelong treatment. The adherence to regular iron chelation therapy is important to ensure complication-free survival and good quality of life.The study aim to assess the adherence to iron chelation therapy (ICT) in patients with transfusion-dependent thalassemia (TDT), evaluate various causes of non-adherence and study the impact of non-adherence on the prevalence of complications secondary to iron overload. Materials and Methods: Patients with TDT on ICT for > 6 months were enrolled in the study. Hospital records were reviewed for demographic details, iron overload status, treatment details, and the prevalence of complications. A study questionnaire was used to collect information on adherence to ICT, knowledge of patients, and the possible reasons for non-adherence. Results: A total of 215 patients with a mean age of 15.07+7.68 years and an M: F ratio of 2.2:1 were included in the study. Non-adherence to ICT was found in 10.7% of patients. Serum ferritin levels were significantly higher in the non-adherent group (3129.8+1573.2 µg/l) than the adherent population (2013.1+1277.1 µg/l). Cardiac as well as severe liver iron overload was higher in the non-adherent patients. No correlation was found between disease knowledge and adherence to ICT. Difficulties in drug administration and many medicines to be taken daily were statistically significant reasons for non-adherence. There was no difference in the co-morbidities arising due to the iron overload in the two groups. Conclusion: Nearly 11% of patients with TDT were non-adherent to ICT. Non-adherence results in higher iron overload.

Conventional audiometric screening for detection of drug induced hearing loss in thalassemics: a pilot study

Background: Drug induced hearing impairment is likely in subjects undergoing multiple blood transfusions which necessitates timely detection and rehabilitation, especially in the pediatric age group.Methods: A total 30 thalassemic patients undergoing regular iron chelation therapy with Desferrioxamine and Deferasirox were included in this prospective study. Follow up studies were conducted after 12 months of chelation therapy i.e. after 1 year thus spanning a total duration of 1 years.Results: The most common age group was 4-8 years (46%) followed by 8-12 years (20%). Male patients outnumbered female patients in the ratio of 2.75:1 constituting 73% of study population oral Deferasirox (80%) followed Desferrioxamine (13.3%) and a combination therapy (6.6%). The distribution shows shift of pure tone average in higher thresholds with continuation of therapy.Conclusion: Despite Desferrioxamine doses usually felt to be low risk for ototoxicity (less than 40 mg/kg/day), found a high rate of ototoxicity in our patients using pure tone audiometry (23%).

Clinical Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Transfusion-Dependent β-Thalassemia Treated at the Bambino Gesù Children's Hospital, Rome, Italy

β-thalassemia is one of the most common monogenic blood disorders worldwide, and is highly prevalent in Mediterranean countries. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been the only curative treatment for transfusion-dependent β-thalassemia (TDT; the most severe disease form) for many years, but it is limited by donor availability and has a significant risk of morbidity and mortality. We conducted a chart review of patients with β-thalassemia who underwent allo-HSCT (N=80) at the Bambino Gesù Children's Hospital, Rome, Italy, between March 2011 and August 2018. Median (range) age at allo-HSCT was 5.5 (0.3-20.0) years [&amp;lt;12 years: n=70 (87.5%), ≥12-18 years: n=7 (8.8%), ≥18 years: n=3 (3.8%)] and all patients but one had TDT [n=79 (98.8%)]. Prior to allo-HSCT, patients received a median (range) of 17.4 (4-52) transfusions per year (n=64) and had a median (range) serum ferritin concentration of 1217 (135-9123) ng/mL and a median (interquartile range) hemoglobin level of 10.3 (9.3-11.4) g/dL. All patients had received regular iron chelation therapy prior to transplantation. In total, 18 (22.5%), 28 (35.0%), and 34 (42.5%) patients received allo-HSCT from human leukocyte antigen (HLA)-identical sibling donors, HLA-haploidentical donors, and unrelated donors (fully matched donor: n=28, donor with a single HLA disparity: n=6), respectively. Of these donors, 42 (52.5%) were carriers for thalassemia-associated mutations. In total, 53 (66.3%) donors and 35 (43.8%) recipients were cytomegalovirus-positive. Bone marrow was the stem cell source in 51 cases (63.8%), while 28 patients received an alphabeta T-cell depleted peripheral blood haploidentical HSCT (35.0%); the remaining child (1.3%) received both bone marrow and cord blood from the same related donor. All patients continued to receive transfusions immediately after allo-HSCT; however, only 7 (8.8%) received a transfusion in the 3 to 12-month post-transplantation period (2 due to underlying disease; 5 due to other reasons including GI bleeding). Median (range) time to reach transfusion-free status was 3.8 (1.1-47.8) weeks. Median (interquartile range) hemoglobin levels at 6 and 12 months after allo-HSCT were 10.9 (10.2-11.9) and 11.9 (10.6-13.0) g/dL, respectively. The cumulative incidences of primary and secondary graft failure were 10.0% and 12.5% at 24 months (HLA-identical donor: 0% and 11.1%, haploidentical donor: 17.9% and 3.6%, unrelated donor: 8.8% and 20.6%). Eleven out of 14 patients experiencing graft failure were successfully rescued with a second allograft, while 2 patients were not retransplanted due to parental decision and 1 patient died after the engraftment of the second allograft. Eight patients developed grade II-IV acute graft-versus-host disease (GVHD) and one patient developed moderate chronic GVHD. Cumulative incidence rates of grades II-IV and III-IV acute GVHD were 12.7% and 8.0% at 24 months (HLA-identical donor: 0% and 0%, haploidentical donor: 7.3% and 0%, unrelated donor: 23.8% and 18.8%). Three patients (3.8%) died of transplant-related causes (1 case each of hemophagocytic lymphohistiocytosis, sepsis, and multi-organ failure [the patient receiving the second allograft]) with a median (range) time from transplantation to death of 8.7 (3.7-11.0) months. Of these patients, all had been transplanted from an unrelated donor and 2 had reached sustained full-donor chimerism. The probability of overall and event-free (event defined as either death or primary/secondary graft failure) survival was 96.2% and 81.2% at 24 months (HLA-identical sibling donor: 100% and 88.9%, haploidentical donor: 100% and 78.6%, unrelated donor: 91.2% and 79.4%). The probability of thalassemia-free survival (event defined as either death or primary/secondary graft failure not rescued by a second allograft) was 93.7% at 24 months (HLA-identical sibling donor: 100%, haploidentical donor: 92.9%, unrelated donor: 91.2%). In this large single-center cohort of children with predominantly TDT, allo-HSCT led to beneficial outcomes for most patients, resulting in the discontinuation of transfusions with 93.7% of patients being thalassemia-free. Nevertheless, HSCT is still associated with GVHD, graft failure, and mortality, and only 22.5% of patients had an HLA-identical sibling donor, illustrating a key limitation of allo-HSCT. Emerging research is addressing such barriers to treatment. Disclosures Merli: Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Algeri:Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria. Gruppioni:Bluebird bio: Employment, Equity Ownership. Kommera:Bluebird bio: Employment, Equity Ownership. Maa:Bluebird bio: Employment, Equity Ownership. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

Serum Neutrophil Gelatinase-Associated Lipocalin as a Biomarker for Early Renal Dysfunction in Adult Egyptian Patients with b-Thalassemia Major

AbstractBackground: Renal dysfunction in thalassemia may occur before the occurrence of any symptoms, Induction of NGAL after kidney injury precedes the elevation of classical markers for kidney damage, which made it a promising marker for renal dysfunction in b-thalassemia, major.Aim of the Work: To assess value of serum NGAL in patients with b-thalassemia major as an early marker of renal impairment.Patients and Methods: The present study enrolled 70 subjects and they were classified into two main groups:•Group (I): 20 apparently healthy normal volunteers.•Group (II): 50 multi-transfused b-thalassemia major patients.Which subdivided according to chelation therapy into two subgroups:•Subgroup (I): On regular iron chelation therapy.•Subgroup (II): Without chelation therapy.Results: In our study serum NGAL was significantly elevated in group II compared to control group. Also in our study, we found a direct correlation between NGAL and urea, creatinine, eGFR, ferritin, transferrin saturation while there was inverse correlation between NGAL and hemoglobin, b2- microglobulin.Conclusion: NGAL could be considered as early predictor of renal dysfunction in thalassemia.

Chelation-induced ototoxicity in thalassemic patients: Role of distortion-product otoacoustic emissions and various management parameters

Context and Aims: A limited number of studies have been conducted for the assessment of hearing loss in thalassemic patients on regular chelation therapy and even fewer studies were conducted using otoacoustic emissions (OAEs). The present study was conducted to assess the prevalence of ototoxicity in multiple transfused thalassemic patients on regular iron chelation therapy (with desferrioxamine [DFO] and deferasirox), to compare the efficacy of OAEs (distortion-product OAEs [DPOAEs]) with that of pure tone audiometry (PTA) for hearing assessment and to correlate ototoxicity with age, mean hemoglobin (Hb), serum ferritin levels, dose and duration of chelation therapy, and therapeutic index Settings and Design: This was a prospective, observational study conducted in a tertiary care hospital. Subjects and Methods: Thirty thalassemic patients undergoing regular iron chelation therapy with DFO and deferasirox were included in this prospective study. Hearing assessment was done using otoscopy, tympanometry, PTA, and DPOAEs between January 1, 2010, and June 30, 2010. Follow-up studies were conducted after 12 months of chelation therapy using the same tests. Patients with and without ototoxicity were compared with respect to age, mean Hb, serum ferritin levels, dose and duration of chelation therapy, and therapeutic index. Statistical Analysis Used: Statistical analysis was carried out using the Student's t-test for normally distributed data and Pearson Chi-square test for categorical data. For nonparametric variables, Mann–Whitney and Wilcoxon tests were applied. Results: Using DPOAEs, 36% of patients were detected having a hearing deficit at the start of the study which increased to 46% at the end of study, whereas using PTA, the detection of hearing loss was 10% and 23%, respectively. DPOAE analysis showed a statistically significant decrease in the signal to noise ratio after 1 year of therapy at 4000 Hz, 5714 Hz, and 8000 Hz with maximum number of patients showing abnormality at 5714 Hz. The analysis revealed no significant difference between the affected and unaffected groups with respect to age, sex, height, weight, serum ferritin level, mean Hb, cumulative dose, mean daily dose and duration of chelation, or therapeutic index. Conclusions: Despite DFO doses usually felt to be low risk for ototoxicity (<40 mg/kg/day), we found a high rate of ototoxicity in our patients using DPOAEs (46%). No variables were identified that reliably predict ototoxicity. We impress on the need for regular audiological screening using DPOAEs for early detection of ototoxicity.

Prospective Changes of Cardiac and Hepatic Iron and Cardiac Function in Low and Intermediate-1 Risk MDS Patients

Background: In patients with myelodysplastic syndrome (MDS) no longitudinal studies on myocardial and hepatic iron and on cardiac function and fibrosis are available in literature. So, the aim of our study was to assess the changes in cardiac and hepatic iron overload and the morpho-functional cardiac parameters by Magnetic Resonance Imaging (MRI) in MDS patients enrolled in the MIOMED (Myocardial Iron Overload in MyElodysplastic Diseases) study who performed the follow-up (FU) MRI at 12 months.Methods: MIOMED is an observational, MRI multicentre study in low and intermediate-1 risk MDS patients who have not received regular iron chelation therapy. Out of the 51 MDS patients enrolled, 48 underwent the baseline MRI exam and 28 performed the MRI FU. This analysis was limited to patients who performed both the MRIs. Mean age was 72.8±7.6 years and 8 patients were females. MIO was assessed using a multislice multiecho T2* approach. Hepatic T2* values were assessed in a homogeneous tissue area and converted into liver iron concentration (LIC). Biventricular function parameters were quantified by cine sequences. Myocardial fibrosis was evaluated by late gadolinium enhancement (LGE) acquisitions.Results: The FU MRI was not performed for the following reasons: 4 deaths and 16 patient refusal.At baseline only one patient showed cardiac iron overload (global heart T2*=14.8 ms) but he recovered at the FU (global heart T2*=28.8 ms). He was not transfused. Out of the 27 patients without significant cardiac iron at the baseline, 26 maintained the same status at the FU while one showed cardiac iron (global heart T2*=12.3 ms).Thirteen patients (8 transfusion-dependent - TD) had hepatic iron overload (MRI LIC≥3mg/g/dw) at the baseline.For this subgroup, the baseline and the FU LIC values were, respectively, 14.9±12.0 mg/g/dw and 20.1±16.1 mg/g/dw. The increase in MRI LIC values was not significant (P=0.196). Out of the 11 patients with a baseline MRI LIC<3 mg/g/dw, two (13.3%) showed hepatic iron at the FU. Only one patient was TD but both patients had not received any chelation therapy.Serum ferritin levels were comparable at both the MRIs (923±618 vs 1168±1004 ng/ml; P=0.150).Due mainly to technical reasons, biventricular function was assesses at both baseline and FU MRIs in 22 patients. At baseline 6 patients showed a reduced left ventricular ejection fraction (LVEF) and 4 of them recovered at the FU. All patients had a baseline global heart T2*>20 ms (one with 2 segmental T2* values<20 ms). At baseline 5 patients showed a reduced right ventricular EF (RV EF) and all recovered at the FU. One patient with normal LV EF at baseline showed pathological LV EF at the and 2 patients with normal RV EF at baseline showed reduced RV EF at the FU (one patient suffered from pulmonary hypertension). At the FU we detected a significant increase in the LV end-diastolic volume index (EDVI) (mean difference: 6.5±11.3 ml/m2; P=0.015) as well as in the RV EDVI (mean difference: 7.8±9.3 ml/m2; P=0.002). The change in the LV mass index between the 2 MRIs was not significant.For 18 patients the presence of myocardial fibrosis was investigated at both baseline and FU MRIs, and this subgroup was considered. Eight patients had myocardial fibrosis at the baseline. One patient showed a subendocardial ischemic pattern and seven patients showed a non-ischemic pattern and myocardial fibrosis was detected for all of them also at the FU. At the FU one new occurrence of non-ischemic myocardial fibrosis was detected.Conclusion. The new occurrences of cardiac iron, reduced cardiac function, increased LV and RV EDVI and myocardial fibrosis and the worsening in MRI LIC values suggest the need of performing periodic MRI scans, in order to better manage these patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresOliva:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Speakers Bureau.

Myocardial Tissue Characterization By Cardiac MR Imaging In Myelodysplastic Syndromes

IntroductionMagnetic Resonance Imaging (MRI) provides unique insight regarding tissue characterization in the heart. We reported the baseline MRI findings at the end of the recruitment in the MIOMED (Myocardial Iron Overload in MyElodysplastic Diseases) study. In particular, we evaluated the distribution of iron overload in the whole left ventricle (LV) and he presence of myocardial fibrosis in patients with myelodysplastic syndromes (MDS); the association with LV function was also investigated. No data are available in the literature about this issue. MethodsMIOMED is an observational, MRI multicentre study in low and intermediate-1 risk MDS patients who have not received regular iron chelation therapy. Out of the 51 MDS patients enrolled, 48 underwent the baseline MRI exam. Mean age was 71.7±8.5 years and 17 patients were females. MIO was assessed using a multislice multiecho T2* approach. Biventricular function parameters were quantified by cine sequences. Myocardial fibrosis was evaluated by late gadolinium enhancement acquisitions. ResultsWe found 27 (56.3%) patients with no MIO (all 16 segmental T2* values >20 ms). The remaining patients showed an heterogeneous MIO (some segments with T2* values >20 ms and other segments with T2* values <20 ms) and of them 2 (9.5%) showed a global T2* value <20 ms, indicating significant MIO. A reduced LV ejection fraction (EF) was found in the 29.5% of cases and a reduced RV EF in the 23.3%. There was not a significant association between heart T2* values and LV EF.Myocardial fibrosis was detected in the 35.9% of the patients. Three patients showed an ischemic pattern and one of them had a transmural fibrosis in the LV apical region. Out of the 3 patients with an ischemic pattern, only one patient had a positive history for a previous myocardial infarction. The majority of the patients had two or more foci of myocardial fibrosis, involving more frequently the septal segments. Patients with myocardial fibrosis were significantly older (75.4±7.9 vs 68.9±7.6 yrs; P=0.019). Global heart T2* and LV volumes were not significantly different between patients with and without fibrosis. The LV EF was lower in fibrotic patients but the statistical significance was not reached (58.4±11.7 vs 64.8±8.9 %; P=0.067). ConclusionsAlthough a significant heart iron was found only in two cases, nearly half the patients had abnormal T2* values in at least one myocardial segment. This finding underlines the importance to use a multislice approach in order to perform an early diagnosis and prevent a more diffuse iron distribution by chelation therapy. This goal could be critical in patients with myocardial fibrosis that seems to be a relative common findings in the old MDS patients. In fact, an underlying heart damage as represented by fibrosis could make the hearts of the old MDS patients more sensitive to lower levels of accumulated iron. Disclosures:No relevant conflicts of interest to declare.

MRI Survey In Transfusion-Dependent and Non-Transfusion-Dependent MDS Patients

IntroductionSeveral studies have shown cardiac diseases as causes of death in myelodisplastic (MDS) patients receiving transfusions. So iron overload may be considered an independent negative prognostic factor. There are few and rather contradictory studies using Magnetic Resonance Imaging (MRI) in the evaluation of myelodysplastic syndromes. We report the baseline MRI findings at the end of the recruitment in the MIOMED (Myocardial Iron Overload in MyElodysplastic Diseases) study. In particular, we investigated myocardial iron overload (MIO), hepatic iron overload and biventricular functional parameters in MDS patients, outlying the differences between transfusion dependent and non transfusion dependent patients. MethodsMIOMED is an observational, MRI multicentre study in low and intermediate-1 risk MDS patients who have not received regular iron chelation therapy. Out of the 51 MDS patients enrolled, 48 underwent the baseline MRI exam. Mean age was 71.7±8.5 years and 17 patients were females. Hepatic T2* values were assessed in a homogeneous tissue area and converted into liver iron concentration (LIC). MIO was assessed using a multislice multiecho T2* approach. Biventricular function parameters were quantified by cine sequences. ResultsThe mean global heart T2* was 38.7±8.3 ms while the mean LIC was 7.6±8.8 mg/g/dw. Global heart T2* values were not significantly correlated with LIC or serum ferritin levels while a significant association between LIC and serum ferritin was detected (R=0.689; P<0.0001).Thirty-two (66.6%) patients were non-transfusion dependent while 16 patients were transfusion-dependent. The two groups were homogeneous for age, sex and hemoglobin levels but transfusion-dependent patients had significantly higher serum ferritin levels (1612±864 vs 711±430; P<0.0001). The percentage of patients with detectable hepatic iron (LIC≥3 mg/g/dw) was significantly higher in the transfusion-dependent group (Figure 1, left). Mean LIC was 14.4±11.1 mg/g/dw in the transfusion-dependent group and 4.2±4.6 mg/g/dw in the non-transfusion-dependent group (P<0.0001). A significant heart iron (global heart T2* value <20 ms) was found in two patients, in both patients an heterogeneous pattern (some segments with T2* values >20 ms and other segments with T2* values <20 ms) was detected. Out of two patients with significant heart iron one patient was not transfused and he did not show significant hepatic iron (LIC=2.12 mg/g/dw). The other one patient was regularly transfused and he received sporadically (less than two weeks/month) chelation treatment with deferoxamine in the 2 years before the MRI. The global heart T2* (Figure 1, right), the pattern of iron burden and the number of segments with T2*<20 ms were comparable between the two groups. Biventricular end-diastolic volume index, biventricular ejection fraction and left ventricular (LV) mass index were comparable between the two groups. [Display omitted] ConclusionsAs expected, regularly transfused MDS patients showed significantly higher levels of hepatic iron overload, that, however, was present in almost the 30% of non-transfusion-dependent patients, mainly due to increased intestinal iron and augmented erythropoiesis. MIO is not frequent in MDS patients and it is not correlated with LIC and serum ferritin levels. Conversely, MIO can be present also in non-transfusion dependent patients and in absence of detectable hepatic iron. These data remark the importance to check directly for heart iron with a more sensitive segmental approach avoiding to estimate heart iron burden from indirect indicators such as LIC, serum ferritin or transfusion state. Disclosures:No relevant conflicts of interest to declare.

Iron Chelation Therapy and Mobilization of Hematopoietic Peripheral Progenitors in Patients with β-Thalassemia Major

AbstractAbstract 5178Several reports established an association between iron chelation therapy with deferasirox and hematopoietic improvement in patients with myelodysplastic syndromes. Data in β-thalassemia major (TM) patients is absent. We evaluated levels (frequency and aboslute number) of several hematopoietic peripheral progenitors (HPP: Colony Forming Unit-Granulocyte/Macrophage [CFU-GM], Erythroid Burst-Forming Unit [BFU-E], Colony Forming Unit-Granulocyte, Erythrocyte, Macrophage, Megakaryocyte [CFU-GEMM], and Long Term Culture-Initiating Cells [LTC-IC]) in 26 TM patients (median age 28. 5 years, 42. 3% males) and 12 age-matched controls. All TM patients had to be using the same iron chelator for at least 6 months with >80% compliance. The levels of all HPP were significantly higher in TM patients than controls, and varied between splenectomized and nonsplenectomized patients (lower CFU-GM and BFU-E, and higher LTC-IC in splenectomized patients). Patients using deferasirox (n=9) showed significantly higher levels of BFU-E compared with both deferoxamine (n=10) and deferiprone (n=7) treated patients (p<0. 01). After adjusting for age, sex, splenectomy status, serum ferritin changes, the association between higher BFU-E levels and deferasirox compared with deferoxamine or deferiprone therapy remained statistically significant (R2=0. 698, p=0. 006). Mobilization of BFU-E in TM patients receiving regular iron chelation therapy depends on the type of chelator used, independent of iron status. Disclosures:Forni:Novartis Pharmaceuticals: Research Funding; Ferrokin: Research Funding. Musallam:Novartis Pharmaceuticals: Honoraria.

Manual erythroexchange for chronic transfusion therapy in patients with sickle cell syndromes unresponsive to hydroxyurea: A long‐term follow‐up

Between 1981 and 2010, we have treated 40 patients requiring chronic transfusion with periodic manual erythrocyte exchange and autologous plasma rescue (MEEX). Here, we present retrospective, long-term (median 22, range 14–29 years) follow-up data for a subset of seven patients with sickle cell syndromes who did not respond to hydroxyurea (HU). Patient characteristics are listed in Supporting Information, Tables I and II. MEEX was accomplished by using a single venous access and infusing 500 ml of isotonic solution (for adults) and removing 500 ml blood (range 400–600 ml according to the patient's weight and the physician's discretion). The rescue process involves centrifugation of the collected blood product and reinfusion of autologous plasma. This is followed by another 500 ml phlebotomy and the infusion of 2–3 units of packed Rh-matched, leuko-filtered, plasma-depleted red cells, with the aim of lowering HbS levels to around 40%. For pediatric patients, the bleeding volume is smaller (5–10 cc/Kg) and the volumes of infused saline and packed Rh-matched, leuko-filtered, plasma-depleted red cells are equal to the phlebotomy volumes, without plasma rescue. The interval between each MEEX procedure for these seven patients ranged from 45 to 90 days to maintain at all times HbS concentrations below 60–70% and the median number of procedures was 133 (range 85–204). None of the seven patients experienced acute complications of sickle cell disease (SCD), such as acute chest syndrome, splenic sequestration, stroke, bone necrosis, or priapism, or long-term complications such as renal failure, cerebrovascular or retinal damage, or pseudoxanthoma-like manifestations. None of the seven patients experienced alloimmunization and all but one patient had normal liver iron concentrations [assessed by superconducting quantum interference device, magnetic iron detector, magnetic resonance imaging (MRI), or biopsy]. This patient, who started the program at the age of 26 years with iron overload due to previous transfusions, required regular iron chelation therapy. Cardiac function tests indicated that all subjects had a left ventricular ejection fraction of >60% and cardiac T > 20 mms (measured by MRI). There was no evidence of pulmonary arterial hypertension on echocardiography. During the observation period, five patients required hospitalization (four with acute cholecystitis and one due to venous occlusive crisis). Only one patient requires chronic analgesia (to relieve pain caused by pre-existing femur head necrosis). Automated EEX (AEEX) ensures lower postprocedural HbS levels (30% HbS vs. 40% with our MEEX protocol) because it makes use of two distal ports to increase the volume of red cells removed. However, the larger number of transfused units in AEEX exposes the patient to a higher transfusional risk. In addition, the automated procedure is significantly more expensive than the manual one, as indicated in Table I. Previous studies have indicated that EEX is a safe and efficacious alternative to both HU and simple transfusions for preventing complications of SCD and improving patients' quality of life [1, 2]. Our results with MEEX confirm previous findings including that if MEEX is started before significant iron overload occurs, the need for chelation therapy may be obviated [3]. Given the relative simplicity and the lower cost, MEEX should be considered for chronic transfusion therapy in developing countries [4]. The authors thank Jane Tricker and Dr. Silvia Caviglia for editorial assistance in the preparation of this article. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Complete Hematopoietic Recovery after Continuous Iron Chelation Therapy in a Patient with Severe Aplastic Anemia with Secondary Hemochromatosis

A 16-yr-old male patient with hemochromatosis due to multiple packed red blood cell transfusions was referred to our emergency center for the treatment of severe aplastic anemia and dyspnea. He was diagnosed with aplastic anemia at 11-yr of age. He had received continuous transfusions because an HLA-matched marrow donor was unavailable. Following a continuous, approximately 5-yr transfusion, he was noted to develop hemochromatosis. He had a dilated cardiomyopathy and required diuretics and digitalis, multiple endocrine and liver dysfunction, generalized bleeding, and skin pigmentation. A total volume of red blood cell transfusion before deferoxamine therapy was about 96,000 mL. He received a regular iron chelation therapy (continuous intravenous infusion of deferoxamine, 50 mg/kg/day for 5 days q 3-4 weeks) for approximately seven years after the onset of multiple organ failures. His cytopenia and organ dysfunctions began to be gradually recovered since about 2002, following a 4-yr deferoxamine treatment. He showed completely normal ranges of peripheral blood cell counts, heart size, and liver function two years ago. He has not received any transfusions for the last four years. This finding suggests that a continuous deferoxamine infusion may play a role in the immune regulation in addition to iron chelation effect.

A Case of SAA with Secondary Hemochromatosis: Can Continuous Iron Chelation Reverse Both Bone Marrow and Multiple Organ Failures?.

A 24-year-old male patient with hemochromatosis due to multiple packed red blood cell transfusions, was referred to our emergeny center for a treatment of severe aplastic anemia and dyspnea. He was diagnosed with aplastic anemia at the age of 11 and had developed a transfusional hemochromatosis after 5 years of multiple blood transfusions. He had dilated cardiomyopathy with ejection fraction of 4 % requiring diuretics and digitalis, multiple endocrine dysfunctions (hypothyroidism, hypoparathyroidism with hypocalcemia, cataract, and intracranial calcifications, diabetes, and gonadal dysfunction), liver dysfunction, generalized bleeding, and skin pigmentation (Fig.1-left). A total volume of packed red blood cell transfusion before deferoxamine therapy was about 96,000 ml and the number of transfused units of platelet concentrates were innumerable. He had received regular iron chelation therapy (continous intravenous infusion of deferoxamine, 50 mg/kg/day for 5 days q 3–4 weeks) for 7 years after multiple organ failures. His cytopenias and organ dysfunctions (heart, liver and skin) began to recover progressively in 2002, after four years of deferoxamine therapy. He had had complete normal ranges of his peripheral blood cell counts, heart size, and liver function two years ago (Fig.1-right & Fig.2). He has not received any transfusions for the last four years. This finding suggests that continuous deferoxamine infusion may play a role in immune regulation in addition to iron chelation effect. [Display omitted] [Display omitted]