Receiving Iron Chelation Therapy Research Articles

Analysis of the Risk of Infection Stratified By Absolute Neutrophil Counts during Deferiprone-Associated Severe Neutropenia or Agranulocytosis

Introduction Patients with transfusional iron overload receiving iron chelation therapy with deferiprone may experience a decrease in absolute neutrophil counts (ANC) that range from mild (ANC <1.5 x 10 9/L) to severe neutropenia/agranulocytosis (typically defined as ANC <0.5 x 10 9/L), and which put them at risk for infections. In patients taking deferiprone, the risk of infection and/or mortality associated with ANC of <0.2 or <0.1 x 10 9/L is unknown. Our objective was to analyze data from patients taking deferiprone in clinical trials and the postmarketing setting to determine the incidence and severity of infection stratified by ANC levels. s Methods The clinical trial setting involved patients with systemic iron overload who had thalassemia, sickle cell disease, or other anemias and received deferiprone across 15 clinical trials. Data associated with episodes of severe neutropenia/agranulocytosis in patients who had been treated with at least 1 dose of deferiprone were reviewed. For the postmarketing setting, all individual case safety reports since the first market approval of deferiprone on August 25, 1999 to August 31, 2021, were reviewed; cases coded to agranulocytosis were extracted; cases without any reported ANC were removed; and cases with at least 1 ANC value were analyzed. Obtaining confirmed ANC value was not always possible in the postmarketing setting. All infections occuring within ±2 weeks of agranulocytosis onset were identified, graded for severity, and classified as serious, including fatal or life-threatening. Serious events were defined as any event that resulted in death, was life-threatening, required hospitalization or prolonged existing hospitalization, caused disability or permanent damage, caused congenital anomaly, or was classified as an important medical event. Infection events associated with ANC values were categorized into 3 groups based on the nadir ANC (all x 10 9/L): Group A, ANC ≥0.2 to <0.5; Group B, ANC ≥0.1 to <0.2; or Group C: ANC <0.1. Results A total of 977 patients with systemic iron overload received deferiprone in sponsored clinical trials. Among those, 9 patients were in Group A, 3 in Group B, and 10 in Group C. Of the 12 patients in Groups A and B, none had serious, severe, or fatal infections ( Table 1). Three of the 10 (30.0%) patients in Group C experienced serious or severe infections that included (1) parvovirus infection accompanied by diarrhea, a maculopaular rash, and pyrexia resulting in hospitalization; (2) a severe but nonserious respiratory tract infection with esophageal candidiasis in a patient with a history of neutropenia prior to initiating deferiprone; and (3) a fatal case of Pseudomonal sepsis in a patient who had a history of multiple cardiac and pulmonary comorbidities. Deferiprone was permanently discontinued in all 3 patients. From postmarketing data, of a total of 238 adverse reactions that were coded as agranulocytosis, 176 had at least 1 ANC value. Among those, 65 reactions were in Group A, 20 in Group B, and 91 in Group C. Among the reactions in Group A, 5/65 (7.7%) had serious infections and 3 of them (4.6%) had fatal outcomes due to sepsis ( Table 2). Among the reactions in Group B, 2/20 (10.0%) had serious infections, with a fatal outcome in one of them (5.0%); the death was from sepsis and the life-threatening infection involved pneumonia with multiple pulmonary complications. Among the reactions in Group C, 12/91 (13.2%) had serious infections and 8 of them (8.8%) had fatal outcomes; the 8 deaths were associated with sepsis. The 4 serious non-fatal infections involved sepsis; pancytopenia with ANC nadir of 0 accompanied by oropharyngeal pain, fever, and diarrhea that required hospitilization; angioinvasive mucormycosis; and disseminated herpes simplex accompanied by sepsis, resulting in hospitalization. Conclusion Patients receiving deferiprone who become neutropenic are generally at a higher risk of infections or mortality with lower neutrophil levels (ie, ANC <0.2 or <0.1 x 10 9/L compared with ANC ≥0.2 to <0.5 x 10 9/L). Our findings are consistent with the recently published guidelines from the European Hematology Association and the European Network for Innovative Diagnosis and Treatment of Chronic Neutropenias that used agranulocytosis to describe events with ANC of ≤0.2 x 10 9/L in association with a high risk of severe and life-threatening infections.

Effects on hearing after long-term use of iron chelators in beta-thalassemia: Over twenty years of longitudinal follow-up

ObjectiveThe role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. MethodsWe retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. ResultsA total of 42 adult TDT patients (18 male, 24 female; age range: 41–55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. ConclusionThis study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients.

Economic and clinical burden of managing transfusion-dependent β-thalassemia in the United States

AimsTo describe clinical complications, treatment use, healthcare resource utilization (HCRU), and costs among patients with transfusion-dependent β-thalassemia (TDT) in the United States.Materials and methodsMerative MarketScan Databases were used to identify patients with β-thalassemia between 1 March 2010, and 1 March 2019. Patients were eligible for inclusion with ≥1 inpatient claim or ≥2 outpatient claims for β-thalassemia and ≥8 red blood cell transfusions (RBCTs) during any 12-month period after and including the date of the first qualifying β-thalassemia diagnosis code. Matched controls consisted of individuals without β-thalassemia. Clinical and economic outcomes of patients were assessed during ≥12 months of follow-up, defined as the period from the index date (i.e. the first RBCT) to either the end of continuous enrollment in benefits, inpatient death, or 1 March 2020.ResultsOverall, 207 patients with TDT and 1035 matched controls were identified. Most patients received iron chelation therapy (ICT) (91.3%), with a mean of 12.1 (standard deviation [SD] = 10.3) ICT claims per-patient-per-year (PPPY). Many also received RBCTs, with a mean of 14.2 (SD = 4.7) RBCTs PPPY. TDT was associated with higher annual ($137,125) and lifetime ($7.1 million) healthcare costs vs. matched controls ($4183 and $235,000, respectively). Annual costs were driven by ICT (52.1%) and RBCT use (23.6%). Patients with TDT had 7-times more total outpatient visits/encounters, 3-times more prescriptions, and 33-times higher total annual costs than matched controls.LimitationsThis analysis may underestimate the burden of TDT, as indirect healthcare costs (e.g. absenteeism, presenteeism, etc.) were not included. Results may not be generalizable to patients excluded from this analysis, including those with other types of insurance or without insurance.ConclusionsPatients with TDT have high HCRU and direct healthcare costs. Treatments that eliminate the need for RBCTs could reduce the clinical and economic burden of managing TDT.

Assessment of Iron Chelation Therapy Adherence in Patients with Thalassemia Major in Babylon Province

Abstract BACKGROUND: Thalassemia is severe public health problem in Iraq and other nearby countries, represents about 75% of all hemogloniopathy with prevalence and incidence 36/100.000 and 34/100.000 respectively. beta thalassemia major represented 67% of all types of thalassemia. In the absence of treatment, it cause bony deformities and hepatosplenomegaly. Bone marrow transplant is the only curative treatment, but it is restricted to only a few patients. As a result, the majority of patients also receive iron chelation therapy along with routine blood transfusions. Failure of chelation can result in endocrinopathies, cardiomyopathy, and hepatic failure, iron chelation therapy requires careful monitoring and high adherence to obtain acceptable therapeutic outcomes. The main factor causing morbidity and mortality in thalassemia is iron excess. Adherence is a complicated phenomenon that involves interconnected elements linked to each patient’s condition, therapy, and environment as well as psychological elements. OBJECTIVE: We assessed the adherence to iron chelation therapy in thalassemia major patients in Babylon province in Iraq and trying to identify the factors leading to poor adherence. MATERIALS AND METHODS: This is cross sectional study performed over the course of two months on 100 patients with β-thalassemia major registered at hereditary blood disease center, in Babylon, Iraq, using deferasirox as chelation agent by direct interview using a predesigned questionnaire. RESULT: Mean age was (14.93± 6.85) years, (61%) of patients were males. The great majority (97%) were single. (59%) of patients were below bachelor. (96%) were unemployed and about half of patients (51%) were rural. Number of affected family members range from 0 to 4, with only one affected member rank one. (92%) of them not use chronic medication other than chelating therapy and folic acid. Disease complication other than organomegaly present in 14% of patients, that include hepatitis C infection, delayed growth, diabetes mellitus and hypothyroidism. More than three-quarters of patients (79%) have good adherence for chelation therapy, were 21 patients have poor adherence, mostly secondary to gastrointestinal side effect (nausea, vomiting, stomach discomfort and bitter taste), or non-specific causes (disinterest, forgetfulness, feeling hassled and taking other medication). The mean duration from diagnosis was 13.6 years, transfusion duration was 13.4 years, transfusion frequency was about 23 days and chelating duration was 10.7 years. Mean of packed cell volume (PCV) was 22%, while mean of serum ferritin was 4342mg/ dl. There was significant association between mean PCV of patients and their adherence to chelating therapy P value was (0.009), other variable show non-significant association. CONCLUSION: Thalassemia major patients in Babylon governorate have good level of adherence to iron chelation therapy which was nearly comparable or even better than adherence rates in other Middle East countries. Despite that, the chelation is inadequate due to logistic issues.

MPN-291 Management of PMF-Associated Anemia in Armenia. Data for the 10-Year Period Between 2010-2020.

Primary myelofibrosis (PMF) is Philadelphia-chromosome-negative myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, cytopenias, constitutional symptoms, hepatosplenomegaly, and extramedullary hematopoiesis. PMF-associated anemia is usually treated with androgens, danazol, erythropoiesis-stimulating agents (ESAs), immunomodulatory drugs (such as thalidomide, lenalidomide, pomalidomide), corticosteroids, and red blood cell (RBC) transfusions. The aim of our retrospective study was to evaluate the management of PMF-associated anemia in Armenia. The medical records of all patients diagnosed with PMF in Hematology Center in Armenia were analyzed retrospectively from 01/01/2010 to 12/31/2020. Between 2010-2020 the total number of patients was 238, 112 (47.1%) of which were alive by the time of data collection. Median age was 60 (28-88). Female patients were 102 (42.86%). At the time of diagnosis, 48 (42.86%) patients had anemia (Hb<12g/dL) of which 12 (10.71%) mild anemia (Hb 11-11.9g/dL); 20 (17.86%) moderate anemia (Hb 8-10.9g/dL); 16 (14.28%) severe anemia (Hb<8g/dL). Erythropoietin level was estimated only in one patient. In the majority of patients, anemia has correlated with chronic transfusions. At different stages of treatment, 23 (20.53%) patients were transfusion-dependent, 4 (3.57%) received androgens, 14 (12.5%) prednisone and 1 patient lenalidomide. Among all transfusion-dependent patients, no one has received iron chelation therapy. None of the patients underwent an allogeneic hematopoietic stem cell transplantation (HSCT) because it is not available in the Republic of Armenia. Treatment restrictions are due to financial reasons. Our work showed that due the significant diagnostic and therapeutic limitations in our country led to Inferior outcomes. The method of correlation of anemia in PMF patients is chronic transfusions, which also impairs the quality of life of patients.

A natural history of lower-risk myelodysplastic syndromes with ring sideroblasts: an analysis of the MDS-CAN registry

Patients with lower-risk (LR) myelodysplastic syndromes (MDS) with ring sideroblasts (RS) have better prognosis than those without RS, but how they fare over time is not fully understood. This study’s objective was to assess the natural history of LR MDS with RS ≥5% using MDS-CAN registry individual data. Kaplan–Meier estimates and generalized linear mixed models were used to describe time-to-event outcomes and continuous outcomes, respectively. One hundred and thirty-eight patients were enrolled; median times from diagnosis to enrollment and follow-up were 6.6 and 39.6 months, respectively. Within 5 years of enrollment, 65% of patients had ≥1 red blood cell transfusion dependence episode. Within 5 years of diagnosis, 59% developed iron overload, 38% received iron chelation therapy, 14% progressed to acute myeloid leukemia, and 42% died. Patients exhibited inferior health-related quality of life trends. These first real-world data in LR MDS-RS in Canada indicate a high level of morbidity and mortality over a 5-year period. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02537990

P1517: REAL-WORLD COMPLICATION BURDEN AND DISEASE MANAGEMENT IN TRANSFUSION-DEPENDENT ADULTS WITH ΒETA-THALASSEMIA (Β-THAL) IN GREECE: FINAL RESULTS OF THE EPIDEMIOLOGICAL CROSS-SECTIONAL ULYSSES STUDY

Background: Despite improved prognosis, patients with transfusion-dependent β-thal commonly experience treatment and disease complications. Aims: To assess the prevalence and severity of treatment and disease complications, capture disease management, and identify predictors of complications in a representative sample of patients with transfusion-dependent β-thal in routine settings in Greece. Methods: ULYSSES is an epidemiological, multicenter, retrospective cross-sectional study of adults diagnosed with β-thal ≥12 months before enrollment who received ≥6 red blood cell (RBC) units (excluding elective surgery) with no transfusion-free period ≥35 days in the 24 weeks before enrollment. Hemoglobinopathies S/β- and α-thalassemia were excluded. Primary data were collected at a single visit and through chart review. Results: From Oct 21, 2019 to June 15, 2020, a total of 201 eligible patients were enrolled by 12 major thalassemia centers; 64.2% were female, median age was 45.7 years (interquartile range [IQR], 40.2–50.5; 75.6% >40 years), mean (standard deviation [SD]) time since diagnosis was 42.9 (7.8) years.Overall, 44.3% were β+β+, 36.8% β+β0, 13.4% β0β0, and 5.5% carried β+, δβ-Sicilian, Corfu δ0β+, Turkish (δβ)0, and hemoglobin Lepore combinations. The most common β-globin mutations were IVS1-nt110 G>A (63.7%), Codon 39 C>T (25.4%), and IVS1-nt6 T>C (22.9%). Median (IQR) age at diagnosis and RBC transfusion initiation was 0.8 (0.4–2.8) and 1.3 (1.0–5.0) years, respectively. During the 48 weeks prior to enrollment, patients received a mean (SD) of 34.2 (9.5) RBC units from a median (IQR) of 23.0 (18.0–28.0) RBC transfusion events. Before enrollment, all patients had received iron chelation therapy (ICT), started at a median (IQR) age of 6.4 (3.2–12.9) years (median [IQR] exposure 35.6 [30.0–40.0] years), and 53.2% had received other therapies, including folic acid (48.3%); 53.2% had a splenectomy at a median (IQR) age of 22.0 (14.0–29.0) years. From diagnosis to enrollment, patients developed 1443 cumulative complications (median 6 [range, 1–55]; 585 ongoing at enrollment; 19.6% [237/1211] known Grade ≥3). Disease-related complications related to β-thal were experienced by all patients (total 1089 [median 5 (range, 1–21)]; 22.1% were Grade ≥3). Over half of patients (53.2%) experienced complications related to treatment (total 354; [median 1 (range, 0–35)]; 13.0% Grade ≥3; Figure), of which 43.4% (n=273), 25.4% (n=73), and 2.0% (n=8) were related to RBC transfusions, ICT, or other treatments, respectively. Of patients 18–40 years, 36.7%, 30.6%, and 16.3% experienced ≥1 treatment-related, RBC transfusion,or ICT complication, respectively, compared with 58.6%, 48.7%, and 28.3% of those >40 years. The 48-week pre-enrollment hospitalization rate due to disease or treatment complications was 0.076 per patient-year (95% confidence interval [CI], 0.045–0.128). Medical/surgical history (odds ratio[OR], 5.16; 95% CI, 1.91–13.92; P=0.001), splenectomy (OR, 2.86; 95% CI, 1.16–7.02; P=0.022), and >24 transfusion events in 48 weeks prior to enrollment (OR, 2.78; 95% CI, 1.15–6.74; P=0.023) were associated with increased odds for developing treatment-related complications. In contrast, splenectomy was associated with lower odds (OR, 0.27; 95% CI, 0.08–0.89; P=0.031) of having either treatment- or disease-related complications. Image:Summary/Conclusion: Real-world data generated by ULYSSES underscore the substantial complication burden of patients with transfusion-dependent β-thal routinely managed in Greece, which worsens with advanced age. †First and second author have contributed equally.

ASSESSMENT OF THE AUTONOMIC AND PERIPHERAL NERVE FUNCTION IN PATIENTS WITH THALASSAEMIC SYNDROME IN A TERTIARY CARE HOSPITAL - A CROSS SECTIONAL STUDY

INTRODUCTION: β-thalassaemia is an inherited disorder of haemoglobin characterized by an absence or reduced synthesis of the β-globin chain. The net result is an excess of α-chains, which precipitate and destroy the red cell precursors, leading to anaemia, skeletal changes, splenomegaly and numerous other complications. Treatment is by regular blood transfusion coupled with iron chelation therapy to prevent iron accumulation and organ damage. AIM: To assess the autonomic and peripheral nerve function in patients with thalassaemic syndrome. MATERIALAND METHODS: Patients attending the Thalassaemia Clinic of Medical College Hospital, Kolkata. Indoor patients from Medicine st th ward and Institute of Haematology and Transfusion Medicine wards of Medical College Hospital, Kolkata from 1 May 2008 to 30 April 2009. After inclusion patients were divided into following groups: Group1 (THAL1): Patients requiring regular blood transfusion and are either receiving inadequate iron chelation or no iron chelation at all. Group2 (THAL2): Patients who require regular blood transfusion and are receiving adequate iron chelation. Group3 (THAL3): Patients who do not require regular blood transfusion RESULT: The median value of distal latency of right common peroneal nerve is slightly increased in all 3 groups. The normal value should be &lt; 4.55ms, thus increase in distal latency is seen in all 3 groups. The median values of distal latency of left common peroneal nerve as well as distal latency of common peroneal nerve as a whole is within normal limits. Distal latency of common peroneal nerve (p value=0.012). Proximal latency of left common peroneal nerve(p value=0.013). Proximal latency of common peroneal (p value=0.001) CONCLUSION: There is demyelinating type of neuropathy of right common peroneal nerve of all the groups. This indicates presence of motor peripheral neuropathy in patients of thalassaemia. All other latencies and amplitudes of both motor and sensory nerves are within normal limits. There were statistically increased motor latencies in patients receiving iron chelation therapy with adequate chelation when compared to the other groups, although the overall latency was within acceptable limits of the laboratory standards. This may be due to subclinical affection of the motor nerves in the form of demyelination. Therefore, the role of toxic effects of iron chelator on peripheral nerves needs to be studied further.

Comparison of Visual Evoked Potential in Thalassemia Patients Receiving Iron Chelation Therapy

Patients of thalassemia require iron chelation therapy for the treatment of iron overload in the form of desferrioxamine (DFO), combination of DFO and deferiprone and oral deferiprone only. One of the side effects of DFO is ocular toxicity. Present study was conducted to elicit the subclinical effects of DFO on visual pathways by doing Visual Evoked Potential (VEP). Forty five patients of thalassemia major were divided into three groups (I, II &amp;III) based on their iron chelation therapy as desferrioxamine, combination of desferrioxamine&amp; deferiprone and only deferiprone respectively. VEP was recorded in each group and comparison was done. In VEP P100 was significantly prolonged in the group of thalassemia patients receiving DFO and combination of DFO and deferiprone suggesting vulnerability to ocular toxicity of DFO. We can suggest that in patients receiving chronic DFO therapy, VEPs may be considered to monitor the toxic effects of DFO on visual system. Keywords: Thalassemia, iron chelation, visual evoked potential.

Rusfertide (PTG-300), a Hepcidin Mimetic, Maintains Liver Iron Concentration in the Absence of Phlebotomies in Patients with Hereditary Hemochromatosis

▪Introduction: Patients with hereditary hemochromatosis (HH) require continued phlebotomies to limit end-organ damage. Approximately 25% of patients in maintenance felt receiving phlebotomies was “inconvenient” or “very inconvenient” (Brisott et al, 2011). Patient compliance with phlebotomies generally declines with time (Hicken et al, 2003), and therapeutic phlebotomies may not be medically suitable for some HH patients. Rusfertide, a peptide mimetic of hepcidin, is an effective regulator of iron distribution and utilization that has demonstrated control of iron in an animal model of HH.Methods: We conducted an open-label, dose-finding efficacy study that investigated subcutaneous rusfertide in HH patients on a stable phlebotomy regimen of 0.25 to 1 phlebotomy per month for at least 6 months. Patients with clinical laboratory abnormalities and those receiving iron chelation therapy or erythrocytapheresis were excluded. Subjects received individually titrated rusfertide doses once or twice a week to maintain transferrin saturation (TSAT) below 45% and were followed for 6 months. Study measures included TSAT, serum iron, transferrin and ferritin, liver iron concentration (LIC) measured by MRI, and adverse events (AEs).Results: Sixteen subjects (10 male/6 female) were enrolled. Mean age and weight were 62.5 years and 88.1 kg, respectively. LIC values were maintained at pre-study levels, with minimal use of phlebotomies during the duration of the study (Figure 1A). Average pre-study phlebotomy rate was 0.27 phlebotomies/month compared to 0.03 phlebotomies/month during the study (p<0.0001; Figure 1B). There was a dose- and concentration-dependent decrease in serum iron and TSAT (Figure 2A and 2B). Transferrin levels were relatively constant over the course of the study. There were no notable changes in hematological parameters such as hematocrit, erythrocytes, leucocytes, or platelets. Rusfertide was generally well tolerated. Adverse events reported in 2 or more subjects included diarrhea, fatigue, injection site reactions (erythema, induration, pain, pruritis), dizziness, and headache.Conclusions: Rusfertide demonstrated a pharmacodynamic effect in reducing TSAT and serum iron, with corresponding significant reduction in the number of phlebotomies, and with LIC maintained at pre-study levels with minimal use of phlebotomies. These data indicate rusfertide was well tolerated in patients with HH and controls LIC, supporting development of rusfertide as a potential treatment for HH. [Display omitted] DisclosuresKowdley: PTG: Consultancy, Research Funding. Modi: Protagonist Therapeutics: Current Employment. Valone: Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gupta: Protagonist Therapeutics: Current Employment.

Perception of Parents of Thalassemic Child to Thalassemia in Pakistan.

BackgroundThalassemia is an inherited blood disorder characterized by reduced hemoglobin synthesis. Aim of our study is to assess the parental knowledge of thalassemia patients and their awareness regarding treatment and preventive measures against thalassemia.MethodsIt is an observational study done at Ali Zaib Foundation Thalassemia Center in Sahiwal, Pakistan, in May 2019. One hundred parents were enrolled in this study and a subjective questionnaire was used to collect data through direct structured survey method over a period of 30 days.ResultsThere were parents of 62 (62%) male patients and 38 (38%) female patients, with a median age of 8.5 ± 6.2 years. Forty-three (43%) parents were illiterate while eight (8%) parents were highly educated. Sixty-six (66%) patients were born to parents with consanguineous marriages. Eighty-two (82%) parents were aware of thalassemia, 72 (72%) were aware of the risk of thalassemia due to cousin marriages, 76 (76%) parents were aware of the importance of prenatal diagnosis (PND), while 88 (88%) believed that a PND was beneficial. Fifty-two (52%) parents knew about thalassemia treatment, 80 (80%) were aware of the importance of blood screening, and 14 (14%) patients were receiving iron chelation therapy. Seventy-eight (78%) parents were aware of thalassemia prevention. All parents believed that the public requires awareness of the importance of premarital screening and PND.ConclusionParental awareness regarding β-thalassemia, its treatment and prevention is fair but far from ideal. Premarital screening, provision of accurate information to the public by professionals, and adequate screening and PND of at-risk families can significantly reduce the rates of thalassemias.

Iron Overload in Lower International Prognostic Scoring System Risk Myelodysplastic Syndromes Patients Receiving Red Blood Cell Transfusions: Relation to Infection and Possible Benefit of Iron Chelation Therapy

Background: Analyses in lower risk myelodysplastic syndromes (MDS) suggest inferior survival in patients (pts) with transfusional iron overload (IOL). Some studies suggest an increased incidence of infections and infection related mortality in transfused MDS pts. Reducing IOL with iron chelation therapy (ICT) appears to give clinical benefit. The literature suggests that IOL can predispose to bacterial, fungal and viral infections, as organisms use iron for metabolism and cell division, and IOL can adversely affect neutrophil function. There are no clinical studies examining infection risk in MDS pts with IOL in the non-stem cell transplant (SCT) setting, and whether this risk can be attenuated with ICT.Methods: We performed a retrospective analysis of pts with a bone marrow biopsy confirmed diagnosis of lower International Prognostic Scoring System (IPSS) risk MDS receiving red blood cell (RBC) transfusions. Pts were identified from the clinical database and charts reviewed. Clinical data extracted included baseline characteristics, serum ferritin level (SF), treatment, and infectious episodes requiring antibiotics, antifungal or antiviral medications. Statistical analyses were performed using SPSS for Windows, version 24.Results: Of 182 transfused MDS pts, 138 were lower IPSS risk. 44 pts were excluded for: not transfused as lower risk, n=19; higher IPSS risk, or received hypomethylating agent or SCT, n=13; and inadequate information, n=12. The median (range) age at first RBC transfusion was 72.5 (31-93) years and 78 (57%) pts were male. 59 pts received ICT: deferasirox (DFX), n=45 (76.3%); deferoxamine (DFO), n=13 (22.0%); and deferiprone, n=1 (1.7%); and 79 did not receive ICT. Median (range) time from 1st RBC transfusion to ICT was 22.5 (1.4-209) months and duration of ICT 13 (1-75) months. Clinical factors differing between ICT and non-ICT pts, respectively, were (median [range]): age at 1st RBC transfusion, 67 (31-88) and 75 (43-93) years; number of RBC units (U) transfused while lower risk, 76 (10-675) and 24 (2-200); number of RBCU/4 weeks, 2.2 (0.5-9.1) and 2.0 (0.1-5.4); SF 914 (49-15608) and 266 (12-5009) ng/mL; and other treatments received, 18 (30.5%) and 5 (6.3%); p</=0.04 for all. Factors not differing between groups were: gender; French American British or World Health Organization MDS diagnosis; marrow blast count; IPSS or IPSSR cytogenetic risk; IPSS or IPSSR risk; neutrophil count at first RBC transfusion or at first infection; and causes of death, p=NS for all. Infections included: bacterial, n=88; viral; fungal; and mycobacterial; n=2 each. In ICT and non-ICT pts, respectively, infections while lower IPSS risk were (number [%]): pts, 23 (40.0%) and 22 (27.8%); episodes (median [range]), 2 (1-6) and 2 (1-5); hospitalizations, 16 (27.1%) and 8 (10.1%); and infectious deaths, 0 (0%) and 1 (1.3%), p=NS for all. In ICT pts, infections occurred pre-ICT in 9 (15.3%); on DFX, n=10 (22.2%), and on DFO, n=4 (30.8%), p<0.0001. Median overall survival (OS) from 1st RBC transfusion while lower IPSS risk was not reached at 105, and 50.1 months for ICT and non-ICT pts, respectively, p=0.01. ICT remained significant for OS in a multivariate analysis (MVA) including: ICT; IPSS cytogenetic risk; and hospitalization for infection; (all p</=0.06 in univariate analysis), p=0.003, hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.2-0.7, and lost significance when number of RBCU received (p<0.0001) was added to the MVA. However, OS was significantly superior for ICT pts receiving >20 and >50 RBCU (p=0.02, and <0.0001, respectively). Median time to first infection (TTI) was 27 and 7.8 months for ICT and non-ICT pts, respectively, p<0.0001 (Figure 1). ICT remained significant for TTI in an MVA including: age; IPSS cytogenetic risk; marrow blast count; and number of RBCU received (p=0.03, HR 0.3, 95% CI 0.09-0.9). For TTI, marrow blast count was also significant in the MVA (p=0.04). TTI remained significantly longer for ICT pts with blast count <5% (p=0.004).Conclusions: In this retrospective, non-controlled analysis, for lower IPSS risk MDS patients receiving RBC transfusions, receiving iron chelation therapy was associated with superior overall survival. Though number and type of infections were similar between groups and despite similar neutrophil counts, time to first infection was significantly longer in ICT patients. These results should be confirmed in larger, prospective analyses. [Display omitted] DisclosuresLeitch:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau; Abbvie: Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Long-Term Effects of Iron Chelating Agents on Ocular Function in Patients with Thalassemia Major.

BackgroundThe aim of this study is to evaluate eye structures and function in patients receiving iron chelating therapy and to assess whether a correlation exists between the onset of ocular alterations and the intake of iron chelating drugs.MethodsA prospective cohort study was performed. Eighty-eight patients, composed of children and adults with thalassemia major (TM) who are taking or had taken iron chelating drugs (deferoxamine, deferiprone or deferasirox), have been initially enrolled in the study. The final sample featured 80 patients, including 18 children and 62 adults. These subjects received an eye examination to evaluate intraocular pressure (IOP), best corrected visual acuity (BCVA), the presence of refractive defects, cornea, anterior chamber, lens, fundus oculi, visual field and mean retinal nerve fiber layer (RNFL) thickness. Logistic regression model analysis was performed in order to assess any correlation. In addition, a literature search regarding the relation between iron chelating drugs and ocular adverse events was carried out to compare the results obtained with the evidence in the literature.ResultsLogistic regression did not report a significant correlation between the intake of iron chelating drugs and the onset of anterior ocular segment alterations, lens opacities, retinal diseases, optical neuropathies, astigmatism, visual field and RNFL thickness defects. Logistic regression returned a statistically significant correlation between myopia and iron chelation therapy (p-value 0.04; OR 1.05) and also between presbyopia and total duration of therapy with deferoxamine (p-value 0.03; OR 1.21). Although intraocular pressure levels remained within the normal range, a significant correlation with the length of deferoxamine therapy has been found (p-value 0.002; association coefficient −0.12). A negative correlation between deferiprone and presbyopia has also been observed.ConclusionIron chelation therapy is not associated with severe visual function alterations. Limitation of deferoxamine treatment can help prevent ocular complications. Deferiprone and/or deferasirox may be preferable, especially in patients over age 40 years.

The Importance of Cardiac T2* Magnetic Resonance Imaging for Monitoring Cardiac Siderosis in Thalassemia Major Patients.

Objective: Cardiac T2* magnetic resonance imaging (MRI) has recently attracted considerable attention as a non-invasive method for detecting iron overload in various organs in thalassemia major patients. This study aimed to identify the prevalence of cardiac siderosis in thalassemia major patients and evaluate cardiac T2* MRI for monitoring cardiac siderosis before and after patients receive iron chelation therapy and its relation to serum ferritin, left ventricular ejection fraction, and liver iron concentration. The information gathered would be used for the direct monitoring, detection, and treatment of complications early on. Methods: A total of 119 thalassemia major patients were recruited in the present study. The cardiac T2* MRI was compared to serum ferritin levels, liver iron concentration (LIC), and left ventricular ejection fraction. All patients were classified into four groups based on their cardiac siderosis as having normal, marginal, mild to moderate, or severe cardiac iron overload. At the follow-up at years one, three, and five, the cardiac T2* MRI, LIC, serum ferritin, and left ventricular ejection fraction (LVEF) were determined. Results: The prevalence of cardiac siderosis with cardiac T2* MRI ≤ 25 ms was 17.6% (n = 21). There was no correlation between cardiac T2* MRI and serum ferritin, liver iron concentration, and LVEF (p = 0.39, 0.54, and 0.09, respectively). During one year to five years’ follow-up periods, cardiac T2* MRI (ms) in patients with severe cardiac siderosis had significantly improved from 8.5 ± 1.49 at baseline to 33.9 ± 1.9 at five years (p < 0.0001). Patients with severe, mild-moderate, marginal, and no cardiac siderosis had median LIC (mg/g dw) of 23.9 ± 6.5, 21.6 ± 13.3, 25.3 ± 7.7, and 19.9 ± 5.5 at baseline, respectively. Conclusions: This study supports the use of cardiac T2* MRI to monitor cardiac iron overload in patients who have had multiple blood transfusions. Early diagnosis and treatment of patients at risk of cardiac siderosis is a reasonable method of reducing the substantial cardiac mortality burden associated with myocardial siderosis. Cardiac T2* MRI is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy.

Oxidative status in the β-thalassemia syndromes in Sri Lanka; a cross-sectional survey

In the β-thalassemias, oxidative stress, resulting from chronic hemolysis, globin chain imbalance, iron overload and depleted antioxidant defences, likely contributes to cell death, organ damage, anemia, hypoxia and inflammation. We assessed variations in these parameters in β-thalassemia syndromes in Sri Lanka.Between November 2017 and June 2018, we assessed children and adults attending two thalassemia centres in Sri Lanka: 59 patients with HbE β-thalassemia, 50 β-thalassemia major, 40 β-thalassemia intermedia and 13 HbS β-thalassemia. Median age was 26.0 years (IQR 15.3–38.8), 101 (62.3%) were female and 152 (93.8%) of Sinhalese ethnicity. Methemoglobin, plasma hemoglobin, heme and ferritin were measured as sources of oxidants; plasma total antioxidant capacity, haptoglobin, hemopexin and vitamins C and E assessed antioxidant status; plasma thiobarbituric acid reactive substances and 8-hydroxy–2′–deoxyguanosine assessed oxidative damage; hemoglobin, plasma erythropoietin and transferrin receptor assessed anemia and hypoxia and plasma interleukin-6 and C-reactive protein assessed inflammation. Fruit and vegetable intake was determined by dietary recall. Physical fitness was investigated using the 6-min walk test and measurement of handgrip strength.Oxidant sources were frequently increased and antioxidants depleted, with consequent oxidative damage, anemia, hypoxia and inflammation. Biomarkers were generally most abnormal in HbE β-thalassemia and least abnormal in β-thalassemia intermedia but also varied markedly between individuals with the same thalassemia syndrome. Oxidative stress and damage were also more severe in splenectomized patients and/or those receiving iron chelation therapy. Less than 15% of patients ate fresh fruits or raw vegetables frequently, and plasma vitamins C and E were deficient in 132/160 (82.5%) and 140/160 (87.5%) patients respectively. Overall, physical fitness was poor in all syndromes and was likely due to anemic hypoxia.Studies of antioxidant supplements to improve outcomes in patients with thalassemia should consider individual patient variation in oxidative status both between and within the thalassemia syndromes.

EQ-5D-3L health state utility values in transfusion-dependent thalassemia patients in Malaysia: a cross-sectional assessment

PurposeThere is a gap of information describing the health state utility values (HSUVs) of transfusion-dependent thalassemia (TDT) patients in Malaysia. These values are useful in the assessment of health-related quality of life (HRQoL), economic evaluations and provide guidance to disease management decisions. The objective of this study was to estimate and derive HSUVs associated with the treatment and complications of TDT patients in Malaysia using the EQ-5D-3L instrument.MethodsA cross-sectional survey using the EQ-5D-3L instrument was conducted between May to September 2018 across various public hospitals in Malaysia. Using a multi-stage sampling, patients diagnosed with TDT and receiving iron chelating therapy were sampled. The findings on the EQ-5D-3L survey were converted into utility values using local tariff values. A two-part model was used to examine and derive the HSUVs associated with the treatment and complications of iron overload in TDT.ResultsA total of 585 patients were surveyed. The unadjusted mean (SD) EQ-5D-3L utility value for TDT patients were 0.893 (0.167) while mean (SD) EQ VAS score was 81.22 (16.92). Patients who had more than two iron overload complications had a significant decline in HRQoL. Patients who were on oral monotherapy had a higher utility value of 0.9180 compared to other regimen combinations.ConclusionLower EQ-5D-3L utility values were associated with patients who developed iron overload complications and were on multiple iron chelating agents. Emphasizing compliance to iron chelating therapy to prevent the development of complications is crucial in the effort to preserve the HRQoL of TDT patients.

Beta-thalassemia major of late diagnosis revealed by pregnancy: a double atypical observation

The diagnosis of beta thalassemia major is most often made in childhood, the discovery in adults is exceptional. We report an observation of a transfusion-dependent form of beta thalassemia diagnosed following a pathological pregnancy. A 30-year-old patient was being managed for transfusion-refractory anemia following a pregnancy with a 28-week amenorrhea abortion. The patient had anemic syndrome, hemolytic jaundice, splenomegaly and craniofacial dysmorphia. Biology noted microcytic hypochromic anemia with a hemoglobin level of 6.3 g/dl and significant erythroblastosis and an electrophoretic profile of major beta-thalassemia. Radiography of the skull showed cortical hypertrophy with a protrusion of the frontal bone and diffuse osteoporosis. The patient received iron chelation therapy combined with a transfusion regimen of red blood cell concentrate and folic acid. This observation illustrates a double atypia of symptomatic major beta thalassemia with transfusion need discovered late and exceptional spontaneous pregnancy in this field.

Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome

Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome

Prescribing patterns and drug-related problems (DRPs) in transfusion-dependent paediatric thalassemia patients: A prospective interventional study from a tertiary care hospital in India.

BackgroundEach year nearly 10,000 children with thalassaemia major are born in India, but among them, very few are optimally managed mainly in urban regions even though the Government of India has incorporated their care and treatment in the 12th Five-Year Plan. Data on prescribing patterns and drug-related problems (DRPs) in paediatric thalassaemia patients in India are limited.MethodsIn this prospective interventional study, the medications prescribed were recorded after reviewing the treatment charts, thalassaemia register, thalassaemia card, nurses’ notes, as well as discharge summaries. When DRPs and/or medication errors were identified, the same was discussed with the concerned health care professionals and suitable suggestions were made at the earliest.ResultsOut of the enrolled 54 patients, only 94% (n = 51) of the patients received iron chelation therapy with deferasirox and/or deferiprone, Folic acid tablet was prescribed for 100% of the patients (n = 54). Five percent of patients (n = 3) had undergone splenectomy and was prescribed with amoxicillin prophylactically. There were a total of 16 DRPs and 15 medication errors were identified and suitable measurements were taken to solve these problems.ConclusionsThe prescribing patterns, DRPs and medication errors in transfusion-dependent paediatric thalassaemia patients were discussed in this study. Our study was effective in identifying and solving the DRPs and medication problems that occurred in thalassaemia patients.

Urinary neutrophil gelatinase-associated lipocalin as a marker of kidney injury in Egyptian patients with thalassemia

EnBackgroundRenal disease is a long-term complication that should be recognized in thalassemia, especially with the rise in the average age of this population. Proper assessment of renal function abnormalities in thalassemia can be challenging because of the increased use of iron chelators, which themselves can affect renal function. There is a trend toward earlier detection of glomerular and tubular abnormalities, using early biomarkers of renal dysfunction. However, conflicting data make conclusive correlations difficult to achieve and strong diagnostic statistical parameters for these biomarkers are still lacking. Examples include albumin/creatinine ratio which can predict the initial signs of glomerular impairment, serum cystatin-C, and serum or urinary β-2 microglobulin have received attention as better tools to assess sensitive changes in glomerular filtration rate (GFR) and creatinine clearance in thalassemia as compared with serum creatinine and eGFR. Neutrophil gelatinase-associated lipocalin (NGAL) excretion in urine occurs when there is proximal tubular injury that disrupts NGAL reabsorption or increases NGAL synthesis. Significant correlations between the levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL) and the degree of proteinuria in patients with chronic renal disease from diverse etiologies have been reported.AimThe study was to assess the markers of renal injury in β-thalassemia (β-TM) patients and to detect the significance of urinary albumin/creatinine ratio and uNGAL levels, as markers of kidney injury in Egyptian patients with thalassemia.Materials and methodsThis case–control study was conducted on 40 β-TM patients and 45 age-matched and gender-matched healthy controls, 27 women and 13 men, with a mean age of 29±9 years and for controls 28±5 years.The majority of enrolled patients (22) were thalassemia intermediate. One-third of the patients were receiving iron chelation therapy, 78.6% on deferasirox, and 21.4% on deferiprone. All patients were subjected to through history taking, physical examination, and routine laboratory investigation. Tests were done for the diagnosis of thalassemia and to identify the type of thalassemia. Type and dose of Iron chelation therapy was recorded treatment: type and dose of chelation. Measurement of uNGAL and calculation of uNGAL/creatinine ratio were done. eGFR was calculated according to the original modification of diet in renal disease equation eGFR (ml/min/1.73 m2). Chronic kidney disease was defined and graded according to KDIGO 2012.ResultsThe results show that there is a statistically significant difference between cases and controls regarding uNGAL level as median was 498.0 ng/ml for cases compared with controls 423.3 ng/ml with a P value of 0.034. There is a statistically significant difference between cases and controls regarding uNGAL/creatinine ratio as the median was 481.75 ng/mg for cases compared with 333.79 with a P value of 0.003. There is no significant correlation between uNGAL (ng/ml) and dose of iron chelator, duration of iron chelator, eGFR, hemoglobin (Hg) level, serum ferritin, and albumin/creatinine ratio. There is no significant correlation between uNGAL/creatinine ratio (ng/mg) and eGFR, Hg level, serum ferritin, and albumin/creatinine ratio. eGFR was significantly higher (hyperfiltration) in cases compared with controls, with a median of 169.8 ml/min/1.73 m3 compared with 119.6 ml/min/1.73 m3, with a P value of less than 0.001. There was a statistically significant difference between cases and controls regarding albumin/creatinine ratio (µg/mg creatinine) as the median was 29.4 µg/mg creatinine for cases compared with controls 10.0 µg/mg creatinine with a P value of less than 0.001.ConclusionThis study showed that assessment of albumin/creatinine ratio, uNGAL, and uNGAL/creatinine ratio, can be regarded as potential early biomarkers of renal dysfunction in β-TM patients.