Transfusion-associated Iron Overload Research Articles

Association between Transfusion-Related Iron Overload and Liver Fibrosis in Survivors of Pediatric Leukemia: A Cross-Sectional Study.

Patients who receive frequent blood transfusions are at an elevated risk of developing hepatic fibrosis due to iron overload in the liver. In this study, we evaluated the effectiveness of transient elastography (TE) (FibroScan®) for assessing liver fibrosis in patients with pediatric cancer. We enrolled 106 consecutive cases of acute leukemia in individuals under 21 years of age. The participants were followed for 2 years. Based on their serum ferritin (SF) levels, the patients were divided into two groups: group 1 (SF≥300 ng/mL) and group 2 (SF<300 ng/mL). A liver FibroScan® was performed, and a p-value of less than 0.05 was considered statistically significant. Among the various parameters in the liver function test (LFT), alkaline phosphatase was significantly higher in a subgroup of patients aged 5-8 years in group 2 compared to those in group 1. The indices of liver fibrosis determined by TE, including the FibroScan score, controlled attenuation parameter score, steatosis percentage, and meta-analysis of histological data in viral hepatitis score, as well as indirect serum markers of liver fibrosis such as the aminotransferase (AST)/alanine aminotransferase (ALT) ratio, Fibrosis 4 score, and AST to platelet ratio index, did not differ significantly between the two groups. The association between the TE results and LFT parameters was only significant for ALT. Transfusion-associated iron overload does not have a significant correlation with severe liver fibrosis. FibroScan® is not a sensitive tool for detecting early stages of fibrosis in survivors of pediatric leukemia.

Adverse events of red blood cell transfusions in patients with sickle cell disease

Blood transfusion is a common medical intervention for patients with sickle cell disease (SCD) and disease related complications. While patients with SCD are at risk for all transfusion related adverse events defined by the National Healthcare Safety Network (NHSN) Biovigilance Component Hemovigilance Module Surveillance Protocol, they are uniquely susceptible to certain adverse events. This review discusses risk factors, mitigation strategies, and management recommendations for alloimmunization, hemolytic transfusion reactions, hyperviscosity and transfusion-associated iron overload in the context of SCD.

Assessment of Liver Fibrosis by Transient Elastography in Children and Young Adults With Sickle Cell Disease With and Without Iron Overload.

Transfusion-associated iron overload may cause liver fibrosis. We compared transient elastography (TE) and aspartate aminotransferase-platelet ratio index (APRI), noninvasive markers for hepatic fibrosis, to liver histology in children and young adults with sickle cell disease (SCD) who were iron overloaded (cohort 1). Age-matched subjects with SCD but without iron overload (cohort 2) were enrolled for APRI and TE assessments. Nineteen subjects ages 10 to 21 years were transfused for a mean of 9.67 years, had a mean serum ferritin of 4899±2849 ng/mL, and a liver iron concentration of 15.56±10.12 mg/g dry liver weight by R2-magnetic resonance imaging. Mean APRI was 0.33±0.13 in cohort 1 and 0.27±0.10 in cohort 2. The mean liver stiffness measures (LSM) in cohort 1, assessed by TE, was 8.46±3.95 kPa, ranging from 3.5 to 14.6 kPa (expected normal <7 kPa). Cohort 2 had a mean LSM of 5.72±1.74 kPa (4.6 to 8.7 kPa). There was a good correlation between LSM and histologic fibrosis (t value 6.94, P<0.0001). There was no significant correlation between APRI and histologic fibrosis and between APRI and LSM. A high LSM suggests liver fibrosis in children and adults with SCD with iron overload and may merit histologic confirmation especially if persistent.

Busulfan-fludarabine- or treosulfan-fludarabine-based myeloablative conditioning for children with thalassemia major.

Significant advances in supportive care for patients with transfusion-dependent thalassemia major (TDT) have improved patients' life expectancy. However, transfusion-associated iron overload remains a significant barrier to long-term survival with good quality of life. Today, allogeneic hematopoietic stem cell transplantation (HSCT) is the current curative standard of care. Alongside selection of the best available donor, an optimized conditioning regimen is crucial to maximize outcomes for patients with TDT undergoing HSCT. The aim of this retrospective analysis was to investigate the role of busulfan-fludarabine-based and treosulfan-fludarabine-based conditioning in TDT patients undergoing HSCT. We included 772 patients registered in the European Society for Blood and Marrow Transplantation (EBMT) database who underwent first HSCT between 2010 and 2018. Four hundred ten patients received busulfan-fludarabine-based conditioning (median age 8.6years) and 362 patients received treosulfan-fludarabine-based conditioning (median age 5.7years). Patient outcomes were retrospectively compared by conditioning regimen. Two-year overall survival was 92.7% (95% confidence interval: 89.3-95.1%) after busulfan-fludarabine-based conditioning and 94.7% (95% confidence interval: 91.7-96.6%) after treosulfan-fludarabine-based conditioning. There was a very low incidence of second HSCT overall. The main causes of death were infections, graft-versus-host disease, and rejection. In conclusion, use of busulfan or treosulfan as the backbone of myeloablative conditioning for patients with TDT undergoing HSCT resulted in comparably high cure rates. Long-term follow-up studies are warranted to address the important issues of organ toxicities and gonadal function.

Mobilization of Auto-Stem Cells in the Thalassemia Major and Relationship with Iron Overload

Objectives: The hematopoietic stem cells transplantation (HSCT) is the only curable treatment in current for thalassemia major (TM).The quantity of auto stem cell of TM patients are very important for rescue the patients in case of failure of HSCT, and auto stem cells of TM will be used as target cells for gene therapy (GT) in the near future. Iron overload (IOL) can damage the hematopoiesis of TM. How to collect the auto stem cells in TM patients? How about the affects of iron overload in the mobilization and collection of auto stem cell? The aim of this study was to analyze quantity of auto stem cells in the TM and the affects of iron overload (IOL). Methods: We retrospectively analyzed a total of 134 patients and 25 normal donors undergoing PBSCs collection between January 2012 and December 2019. Patients with serum ferritin levels over 1,000 ng/mL and with a history of red blood cell transfusions prior to stem cell collection were defined as a group having transfusion-associated iron overload (IOL). In total one hundred and thirty-four patients and twenty-five donors were subcutaneous administrated G-CSF (Granulocyte Colony Stimulating Factor) 10 mg/kg/d Injection for 5 days, PBSCs was collected using a large volume leukapheresis (LVL) procedure. The data of WBC, MNC and CD34+ in product were analyzed by SPSS 20 software. Results: In 134 patients, median age is 8.60 range: (1-17),and 25 Normal donors, median age is 7.5 range: (1-18). The results demonstrated that cells either in patients with thalassemia or normal donors were effectively mobilized by G-CSF (10 mg / kg/d),as these children showed a marked increase in white blood cells and MNC cells in peripheral blood, reaching a peak in 4 to 5 days after the injection of G- CSF alone. Comparison of the MNC [(6.7±3.5) ×10⁸/kg vs (7.2±4.77) ×10⁸/kg] and CD34+cells [(10.29±4.5)×10⁶/kg vs (10.9±6.8)×10⁶/kg] in collected product in TM patients and normal donors groups revealed no significant difference. There was no significant difference between different Ferritin level (Mild, Intermediate and Severe) on WBC, MNC, and CD34+ in each group at the time point studied. But there was significant difference on MNC number (Normal liver iron (7.73±2.69)×10⁸/kg, Mild liver iron overload (7.66±4.64)×10⁸/kg, Intermediate (6.18± 2.84) ×10⁸/kg compared to Severe liver iron (4.45±3.34)×10⁸/kg, P=0.039. Significant difference was also can be seen in number of MNC of product in patients with intermediate cardiac iron overload compared to normal cardiac iron overload and mild cardiac iron overload (2.76±0.97) ×10⁶/kg vs(6.86±3.39) ×10⁶/kg and (6.88±3.72)×10⁶/kg, P=0.030. There was a statistically significant difference positive correlation between median age (P=0.011) and MNC/Kg (P=0.030). Conclusion:The quantity of mobilization of PBSC in TM patients had no significant difference compare to normal donor. The MNC in product was statistically decreased in intermediate cardiac iron overload and severe liver iron overload (IOL) subgroup. It indicated that iron overload (IOL) in organs may negatively relate to proliferation and mobilization of stem cells in TM. Further quality study of PBSC such as stem cell culture and ability of proliferation should be more evaluated. The sufficient quantity and high quality auto stem cell from TM patient can be more used in the future. Disclosures No relevant conflicts of interest to declare.

No child with a transfusion-dependent haemoglobinopathy left unchelated: are we there yet?

Haemoglobinopathies such as thalassaemias and sickle cell disease pose substantial clinical and public health challenges across the world. 1 Shah FT Sayani F Trompeter S Drasar E Piga A Challenges of blood transfusions in β-thalassemia. Blood Rev. 2019; 37100588 Crossref PubMed Scopus (33) Google Scholar The Global Burden of Disease Study 2017 2 GBD 2017 Disease and Injury Incidence and Prevalence CollaboratorsGlobal, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018; 392: 1789-1858 Summary Full Text Full Text PDF PubMed Scopus (3032) Google Scholar estimates a prevalence of 411 000 and incidence of 106 300 new cases per year globally of clinically significant thalassaemias. Because most patients with β-thalassaemia major require regular blood transfusions for the treatment of severe anaemia, often starting within the first 2 years of life, most of these patients have transfusion-associated iron overload with its long-term sequelae. Allogeneic haematopoietic stem-cell transplantation is the only potentially curative therapeutic option; however, this treatment is limited by accessibility issues and its associated morbidity and mortality. Therefore, iron chelation therapy to mitigate the effects of transfusion-associated iron overload has been a standard of care in the treatment of transfusion-dependent haemoglobinopathies. 1 Shah FT Sayani F Trompeter S Drasar E Piga A Challenges of blood transfusions in β-thalassemia. Blood Rev. 2019; 37100588 Crossref PubMed Scopus (33) Google Scholar , 3 Di Maggio R Maggio A The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major. Br J Haematol. 2017; 178: 676-688 Crossref PubMed Scopus (16) Google Scholar Iron chelation therapy has been shown to improve outcomes, and the oral iron chelators deferiprone and deferasirox seem to be more effective and lead to greater compliance than the parenteral deferoxamine. 4 Pennell DJ Berdoukas V Karagiorga M et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood. 2006; 107: 3738-3744 Crossref PubMed Scopus (388) Google Scholar , 5 Pennell DJ Porter JB Piga A et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA). Blood. 2014; 123: 1447-1454 Crossref PubMed Scopus (82) Google Scholar , 6 Ladis V Chouliaras G Berdoukas V et al. Survival in a large cohort of Greek patients with transfusion-dependent beta thalassaemia and mortality ratios compared to the general population. Eur J Haematol. 2011; 86: 332-338 Crossref PubMed Scopus (43) Google Scholar Although data for patients as young as 2 years are available for deferasirox, there are few high-quality randomised studies in paediatric patients receiving deferiprone. Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trialIn paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. Full-Text PDF

Increased incidence of infection in patients with myelofibrosis and transfusion-associated iron overload in the clinical setting.

Transfusion-associated iron overload may lead to increased risk of infection, but its role in myelofibrosis (MF) has been scarcely explored. We evaluated 106 consecutive patients with primary or secondary MF. Up to 38% of patients were transfusion-dependent (TD) with a median of 14 RBC units received. Median observation time was 36months (range 3-203). Forty-five percent of patients experienced one or more infectious episodes for a total of 69 infectious events, 13 (19%) of which were severe. The 60-month cumulative incidence of infection was 64.1 ± 6.5%. TD patients showed a higher incidence of infection (HR = 2.13, p = 0.019). Transfusion burden was markedly greater in TD patients with infectious complication (median 24 RBC units vs 15 RBC units; p = 0.012). The 60-month overall survival was 40 ± 5.9%. Lower International Prognostic Scoring System (IPSS) risk (p < 0.0001) and ruxolitinib (p = 0.027) were significantly correlated with higher survival. This real-world study showed increased infections in patients with higher transfusion burden. It may therefore be interesting to further investigate the role of iron chelation in improving infection-free survival in MF patients.

Increased Incidence of Infection in Patients with Myelofibrosis and Transfusion-Associated Iron Overload: A Monocentric Experience

Background. Transfusion-associated iron overload may increase the risk of infections both increasing bacterial or fungal growth and leading to the production of free iron that impairs immune system response. Anemia and transfusion dependency (TD) represent well known prognostic factors of survival in patients with myelofibrosis (MF). Compared to myelodysplastic syndrome (MDS), the role of iron overload on infection in MF has been scarcely explored. Methods. We identified consecutive adult patients diagnosed at our Centre with primary or secondary MF, between 1998 and 2018. Patients were stratified in 2 groups according to transfusion dependence defined as having received &gt;2 unit of red blood cells (RBC) over 3 months. The total number of RBC units infused was also collected. All infections were recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE). Results. A total of 106 patients, median age 72 years (range 44-89) were retrospectively evaluated. A diagnosis of primary MF was performed in 75 of cases (71%), post Essential Thrombocythemia myelofibrosis (PET-MF) in 27 (25%) and post Polycythemia Vera myelofibrosis (PPV-MF) in 4 (4%). Splenomegaly was present in 83 patients (78%) and 30 (28%) reported constitutional symptoms.According to the IPSS, 43 patients (40 %) were classified at low or intermediate-1 risk, and 63 (60 %) at intermediate-2 or high risk. Molecular analysis was performed in 76 patients (72%): 54 of 76 patients (71%) were positive for the JAK2V617F mutation, 10 (13%) for CALR mutation, 4 (5%) for MPL, and 8 (11%) were negative for all tested mutations. Over time, 56 patients (53%) received hydroxyurea or other cytoreductive treatment, and 23 (22%) ruxolitinib. Overall, 39 patients (37%) were transfusion dependent with a median of 14 RBC units received during follow-up (range 4-199). The median serum ferritin level in the TD cohort was 840 ng/mL (range 130-12.129). Median observation time was 36 months (range 3-203). At last follow-up, 48 patients (45%) presented one or more infectious episodes. Total infectious events were 69 and 13 of them (19%) were defined as severe (grade 3-4 CTCAE). Anatomical site of infections was the respiratory tract in 28 (41%) of cases, gastro-intestinal in 22 (32%), gynecological-urological in 8 (11%), sepsis in 2 (3%), unspecified in the remaining cases. When detected, the etiological agents were bacterial in 8 (12%), viral in 5 (7%) and fungal in 4 (6%). The 60-month cumulative incidence of infection from diagnosis of MF was 64.1±6.5%. TD patients showed a higher incidence of infection (99±8.8% vs 53.3±8%, p=0.007) (Figure 1). In multivariate analysis no association was found between infection incidence and primary vs secondary MF, splenomegaly, age &gt;65 years, ruxolitinib treatment; only transfusion dependencemaintained a significant association (p=0.019; HR=2.13; 95% C.I.=1.13-4.01). Among the 39 TD patients, the transfusion burden was significantly higher in those with infectious complication (median 24 RBC units vs 15 RBC units; p=0.012). The 60-month overall survival was 40±5.9%. Lower IPSS-risk (p&lt;0.0001) and ruxolitinib treatment (p=0.027) were significantly associated with higher survival. Conclusions. This retrospective monocentric real-life study showed an increased risk of infections in MF patients with higher transfusion burden. The role of iron chelation in improving infection free survival in patients with MF and iron overload should be further investigated. Figure 1 Disclosures No relevant conflicts of interest to declare.

Wheatgrass Extract (Mugineic Acid): An Inexpensive and Effective Iron Chelator in Patients with Myelodysyplastic Syndromes

Background: Patients with red blood cell (RBC) transfusion-dependent myelodysplastic syndromes (MDS) and congenital anemias are at risk of transfusional hemosiderosis and organ injury from reactive iron species. Available iron chelating drugs in the US are either inconvenient for administration (parenteral deferoxamine) or are costly (oral deferasirox or deferiprone - median cost for these drugs exceeds $13,000-$18,000/month, Master S et al Blood 2016; 128:4858). Additionally, available chelators frequently have adverse effects including gastrointestinal (GI) upset or renal insufficiency. Wheatgrass, a food supplement prepared from the cotyledons of the Triticum aestivum Common Wheat plant, is sold either as a freeze-dried powder or as a juice extracted from the fresh leaves of the plant. Recently wheatgrass was found to contain high concentrations of the hexedentate iron chelator mugineic acid, a phytosiderophore that has comparable efficacy to deferasirox (ICL670) in a murine model of iron overload, and which may be a clinically meaningful iron chelator (Das et al J Biochem 2016; 160:163, Mukhopadhyay S et al JCO 2009; 15S:7012). Methods: Twelve patients with transfusion-dependent MDS (n=11) or congenital dyserythropoietic anemia (n=1) self-administered wheatgrass that they either grew themselves in potting soil or in an agricultural setting (n=3), procured from a juice bar (n=7), or obtained in powder form from a nutritional supplement store (n=2). Three patients also had known HFE variants. Seven patients had previously taken deferasirox and 2 patients had also received deferoxamine, but either did not tolerate these drugs or did not achieve adequate chelation. For patients using wheatgrass in the juice form, approximately 30 mL of juice was obtained from the leaves and stems of ~7 day-old wheatgrass. Serum ferritin was monitored over a period of at least 3 months. Serial hepatic T2* MRI was performed in 2 patients, one of whom also continued to take deferasirox. Results: The serum ferritin of patients at baseline was 2370 ng/mL (range, 1553-6089 ng/mL). The median decrement in serum ferritin in patients taking wheatgrass was 834 ng/mL (range of reduction, 251 to 1774 ng/mL). 3 patients reported worsening in GI upset or diarrhea but only 1 patient discontinued wheatgrass due to these effects; other adverse events were not observed. Two patients who grew their own wheatgrass noted mold outbreaks in the culture and switched to wheatgrass obtained from a juice bar. 1 patient noted a reduction in transfusion needs (of uncertain connection to wheatgrass administration), and the hepatic iron concentration measured by MRI decreased in both patients who were assessed radiographically. Conclusion: Mugineic acid in wheatgrass has iron chelating activity in patients with transfusion-associated iron overload. The annual cost of daily wheatgrass supplement from an urban juice bar (~$1500) is approximately 10% of the monthly cost of deferasirox or deferiprone in the US and less than 1% of the annual cost. Formal trials of wheatgrass or of purified mugineic acid in iron-overloaded patients with MDS or congenital anemias are indicated. Disclosures Steensma: H3 Biosciences: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Equity Ownership; Onconova: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy.

Clinical outcomes of transfusion-associated iron overload in patients with refractory chronic anemia.

BackgroundThe purpose of this study was to evaluate the clinical outcomes of transfusion-associated iron overload in patients with chronic refractory anemia.MethodsClinical manifestations, main organ function, results of computed tomography (CT), endocrine evaluation, and serum ferritin levels were analyzed retrospectively in 13 patients who were transfusion-dependent for more than 1 year (receiving >50 units of red blood cells) to determine the degree of iron overload and efficacy of iron-chelating therapy.ResultsSerum ferritin levels increased to 1,830–5,740 ng/mL in all patients. Ten patients had abnormal liver function. The CT Hounsfield units in the liver increased significantly in eleven patients, and were proportional to their serum ferritin levels. Skin pigmentation, liver dysfunction, and endocrine dysfunction were observed in nine patients with serum ferritin >3,500 ng/mL, eight of whom have since died. Interestingly, serum ferritin levels did not decrease significantly in nine transfusion-dependent patients who had received 15–60 days of iron-chelating therapy.ConclusionTransfusion-dependent patients may progress to secondary iron overload with organ impairment, which may be fatal in those who are heavily iron-overloaded. The CT Hounsfield unit is a sensitive indicator of iron overload in the liver. Iron chelation therapy should be initiated when serum ferritin is >1,000 ng/mL and continued until it is <1,000 ng/mL in transfusional iron-overloaded patients.

Pharmacogenetic Study of Deferasirox, an Iron Chelating Agent

Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing −1774 del and/or −24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79–28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7–43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34–150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.

Iron chelation therapy in patients with transfusion‐dependent myelodysplastic syndrome

Iron chelation therapy in patients with transfusion‐dependent myelodysplastic syndrome

The Role of Iron Chelation Therapy for Patients With Myelodysplastic Syndromes

The appropriate role of iron chelation therapy in the management of patients with myelodysplastic syndromes (MDS) is currently controversial. Some investigators interpret data to indicate that careful attention to iron parameters, with early initiation of iron chelation in patients with evidence suggesting transfusion-associated iron overload, is an important component of high-quality MDS patient care. Other physicians are more skeptical, noting that chelation can be cumbersome or costly, has associated risks, and has not yet been shown to reduce morbidity or mortality in the MDS setting. This article reviews the extent to which iron chelation therapy might be either an important clinical intervention in MDS or a distraction from more pressing clinical concerns.

Transfusion‐associated iron overload as a predictive factor for poor stem cell mobilization in patients with haematological malignancies

Transfusion-associated iron overload is often observed in patients with haematological malignancies. We analysed the effect of iron overload, indicated by high serum ferritin level, on the mobilization of CD34(+) peripheral blood stem cells (PBSCs). We evaluated the association between the serum ferritin level prior to PBSC collection and the number of CD34(+) cells collected through leukapheresis in 51 patients with various haematological malignancies. Patients with serum ferritin level over 1000 ng mL(-1) were defined as high-ferritin group. Comparing the good (> or =1 x 10(6) per kg CD34(+) cells) and poor (<1 x 10(6) per kg CD34(+) cells) mobilizing groups, there was no difference in disease status, previous chemotherapies and white blood cell count at the first day of apheresis. However, there was a significant difference in the median units of red blood cell transfused between the good and poor mobilizer (2 vs. 8 units; P = 0.012). Serum ferritin level was notably higher in the poor mobilizer (1670 +/- 1320 ng mL(-1)) compared with the good mobilizer (965 +/- 705 ng mL(-1), P = 0.035). The cumulative number of CD34(+) cells per kg collected during the whole procedure was significantly lower in the high-ferritin group (5.5 +/- 4.7 x 10(6) per kg vs. 13.1 +/- 9.1 x 10(6) per kg, P = 0.01). Multivariate analysis revealed that serum ferritin level remained as an independent predictive factor for poor PBSC mobilization. Our study indicated that transfusion-associated iron overload is a predictive factor for poor PBSC mobilization. Iron chelation therapy prior to apheresis may be required to collect sufficient numbers of PBSCs in the iron overload patients.

Transfusion-Associated Iron Overload as an Adverse Risk Factor for Transplantation Outcome in Patients Undergoing Reduced-Intensity Stem Cell Transplantation for Myeloid Malignancies

Transfusion-associated iron overload could be an important risk factor in myeloablative hematopoietic stem cell transplantation. However, few studies have evaluated the effect of iron overload in reduced-intensity stem cell transplantation (RIST). We evaluated 38 patients with myeloid malignancies, 16 with and 22 without iron overload, who received RIST. We used pretransplant serum ferritin as a marker of iron overload. There was a positive correlation between the number of transfused packed red blood cells and pretransplant serum ferritin levels (21.5 units and 1,578.7 μg/l in the iron overload group vs. 12 units and 739.3 μg/l in the iron non-overload group; p <0.01). Engraftment day and chimerism analysis were not affected by iron overload (p = 0.71 and 0.47, respectively). There were no differences in treatment-related mortality (p = 0.94), veno-occlusive disease (p = 0.99), acute and chronic graft versus host disease (p = 0.58 and 0.99, respectively) according to iron overload. There was a significant difference in disease-free and overall survival (35.8 and 27% in the iron overload group vs. 80.6 and 54.6% in the iron non-overload group; p = 0.01 and 0.03, respectively). We conclude that transfusion-associated iron overload is an adverse risk factor in RIST for myeloid malignancies. The clinical outcomes according to iron overload in RIST were different in myeloablative hematopoietic stem cell transplantation. A serial follow-up of serum ferritin level and judicious iron chelation therapy will be needed to manage the side effect of iron overload in RIST and improve transplantation outcomes.

Prognostic Impact of Elevated Serum Ferritin in Patients Undergoing Myeloablative Stem Cell Transplantation.

Patients undergoing allogeneic stem cell transplantation (alloSCT) for hematologic malignancies are often highly transfused, and thus at risk for transfusion-associated iron overload. In other settings, such as thalassemia or hemochromatosis, iron overload has been associated with organ toxicity, particularly hepatotoxicity, as well as with an increased susceptibility to infection. Since hepatic and infectious complications are frequent and life-threatening in patients undergoing alloSCT, iron overload could potentially be an important contributor to treatment-related morbidity and mortality after transplantation. We studied 935 consecutive patients who underwent myeloablative alloSCT at our institution between 1997 and 2005. A pre-transplant serum ferritin level, which we used as a surrogate measure of iron load, was available for 600 of the 935 patients (64%). The median ferritin level was 864ng/ml. The percentage of patients with serum ferritin ≥1000ng/ml was 47%. This percentage varied significantly between disease types, being lowest (6%) in patients with CML and highest (79%) in patients with AML. A ferritin level ≥1000ng/ml was associated with significantly worse overall and disease-free survival, as shown in the figure. [Display omitted] This was confirmed in proportional hazards models using the following covariates: age, type and stage of disease, cytogenetic risk group for AML and MDS, conditioning regimen, HLA match, graft source, GVHD prophylaxis regimen, CMV serostatus, gender, prior transplant, and year of transplantation. In this model, the hazard ratio for mortality associated with ferritin ≥1000ng/ml was 1.7 (95%CI=1.3 to 2.4, p=0.0005). In competing risks regression analysis, using the same covariates, an elevated serum ferritin was associated with a significant increase in non-relapse mortality (NRM) (HR=1.6, p=0.02), but not with a significant increase in the risk of relapse. The greatest impact of elevated serum ferritin on survival and NRM was in patients with MDS (HR for mortality=3.0, p=0.001). Because serum ferritin is an acute phase reactant, we performed the same analyses using pre-transplant albumin level as an additional covariate that could reflect general inflammatory state. Although albumin level was of independent prognostic significance, its inclusion in the multivariate models did not alter the conclusions. Finally, in logistic regression analyses, elevated serum ferritin was associated with a non-significant increase in the risk of veno-occlusive disease (OR=1.6, p=0.09), but not in an increased risk of acute GVHD (OR=0.9, p=0.4) or specifically of acute liver GVHD (OR=1.2, p=0.5).Conclusions: in patients undergoing myeloablative alloSCT, and particularly in those with MDS, an elevated serum ferritin is associated with significantly higher NRM, as well as significantly lower disease-free and overall-survival. Our results could be helpful in estimating prognosis for patients who are candidates for myeloablative alloSCT. They also pave the way for prospective trials on the impact of iron overload and on the possible beneficial role of iron chelation in this patient population.

Pyridoxine responsive sideroblastic anemia in a boy with mitral valve prolapse

Sideroblastic anemia is a rare, heterogeneous group of disorders characterized by hyperferremia, microcytic hypochromic anemia, and bone marrow erythroid hyperplasia with the presence of numerous ringed sideroblasts. We describe herewith the case of a rare coincidence of sideroblastic anemia and mitral valve prolapse with resultant regurgitation in a 2-year-old boy. In addition to the inherent propensity for the development of cardiac dysfunction in sideroblastic anemia due to transfusion-associated myocardial iron overload and chronic anemia, a coincidence of MVP will further increase the likelihood of the morbidity or mortality of th patient. in this patient. After response to pyridoxine, the patient remains in good condition with stable hemoglobin levels

Deferasirox (ICL670; Exjade®), a Novel Orally Available Iron Chelator for Correction of Transfusion-Associated Iron Overload

Cerebral ischaemia triggers various physiological processes, some of which have been considered deleterious and others beneficial. These processes have been characterized in one influential model as being part of a transition from injury to repair processes. We argue that another important distinction is between dysregulated and regulated processes. Although intervening in the course of dysregulated processes may be neuroprotective, this is unlikely to be true for regulated processes. This is because from an evolutionary perspective, regulated complex processes that are conserved across many species are likely to be adaptive and provide a survival advantage. We argue that the neuroinflammatory cascade is an adaptive process in this sense, and contrast this with a currently popular theory which we term the maladaptive immune response theory. We review the evidence from clinical and preclinical pharmacology with respect to this theory, and deduced that the evidence is inconclusive at best, and probably falsifies the theory. We argue that this is why there are no anti-inflammatory treatments for cerebral ischaemia, despite 30 years of seemingly promising preclinical results. We therefore propose an opposing theory, which we call the adaptive immune response hypothesis.

Transfusion-associated iron overload.

Iron overload develops mainly via two mechanisms, by a defect in the regulation of iron absorption (hereditary hemochromatosis) or by parenteral route (chronic red cell transfusion for anemic patients without blood loss) especially in patients with different categories of refractory anemias, and in anemic patients with chronic infection, alcohol excess, and malignancies. The accurate assessment of body iron is indispensable for the correct diagnosis and for finding the optimal treatment schedule for each individual patient. Liver biopsy with quantitative iron determination and histochemistry is still the reference method for the assessment of body iron status for patients with iron overload. New noninvasive measurements (hepatic magnetic susceptibility, CT, and magnetic resonance imaging) are still investigational procedures. It is important to decrease the need for transfusion by judicious use of red cell concentrates, make more widespread use of erythrocytapheresis, determine the red blood cell phenotype of the patient before the onset of a regular transfusion regimen, treat concomitant hepatitis infections, consider splenectomy to diminish red blood cell requirements, and early on consider allogeneic bone marrow transplantation for thalassemic patients who have HLA-identical siblings. It is advisable to screen for the hereditary hemochromatosis gene before starting any kind or regular red blood cell transfusion therapy, and to avoid if possible, the risk of free radical release by transfusional iron overload during the physiologically hypercoagulable state of pregnancy and its effects on the highly proliferative tissues of the fetus.