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1.
Impact of Iron overload and Iron Chelation with deferasirox on outcomes of patients with severe aplastic anemia after allogeneic hematopoietic stem cell transplantation
Pan, T., Ji, Y., Liu, H., Tang, B., Song, K., Wan, X., Yao, W., Sun, G., Wang, J., Sun, Z.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these transfusions can result in an excess of iron in the body tissues, which can negatively impact the success of the transplant. OBJECTIVES This study aimed to examine the impact of pre-transplant iron overload (IO) on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with severe aplastic anemia (SAA). It also investigated whether iron chelation (IC) therapy was necessary to enhance transplantation outcomes in SAA patients by providing guidelines for determining when excess iron should be chelated. STUDY DESIGN The study consisted of two parts: Cohort 1, which was retrospective and conducted from April 2012 to December 2018, divided SAA patients receiving their first allo-HSCT into two groups based on their pre-transplant serum ferritin (SF) levels: the iron overload (IO) group (SF >1000 ng/ml, n=17) and the non-IO group (SF ≤ 1000 ng/ml, n=48). Cohort 2 was a prospective clinical trial conducted from January 2019 to July 2020. It involved SAA patients diagnosed with IO who were treated with iron chelation (IC) therapy using deferasirox (DFX) at a dose of 10-30 mg/kg. Patients were separated into two groups based on their pre-transplant SF levels: the IC success (IC(success)) group (SF ≤ 1000 ng/ml, n=18) and the IC failure (IC(failure)) group (SF >1000 ng/ml, n=28) groups. All participants were evaluated for the correlation between pre-transplant SF levels and transplantation outcomes. A P-value of less than 0.05 was considered statistically significant. RESULTS There was no significant difference in the speed of engraftment for the three lineages or in the incidence of 100-day grade II-IV acute graft-versus-host disease (aGVHD), grade III-IV aGVHD, or 3-year chronic GVHD between the two groups in both cohorts. However, in cohort 1, it was noteworthy that 1-year OS (83.3% vs. 41.2%, p < 0.001) and 3-year OS (83.3% vs. 35.3%, p < 0.001) were significantly worse in the IO group. Furthermore, 180-day TRM (14.6% vs. 47.1%, p = 0.005) and 1-year TRM (16.7% vs. 52.9%, p = 0.002) were significantly higher in the IO group. The IO group was significantly associated with inferior 3-year OS in both univariate and multivariate analyses. In cohort 2, it was found that 1-year OS (42.9% vs. 88.9%, p = 0.003) and 3-year OS (42.9% vs. 83.3%, p = 0.007) were significantly better in the IC(success) group, while 180-day TRM (11.1% vs. 39.3%, p = 0.040) and 1-year TRM (11.1% vs. 57.1%, p = 0.003) were significantly lower in the IC(success) group. These differences were confirmed in both univariate and multivariate analyses. CONCLUSIONS The study involving two cohorts showed that pre-HSCT iron overload has a negative impact on transplantation outcomes in SAA patients. Chelating excess iron with a serum ferritin level below 1000 ng/ml was found to be necessary and could potentially improve the outcomes.
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2.
Iron overload following hematopoietic stem cell transplantation: Prevalence, severity and management in children and adolescents with malignant and non-malignant diseases
Cattoni, A., Capitoli, G., Casagranda, S., Corti, P., Adavastro, M., Molinaro, A., Gennaro, F. D., Bonanomi, S., Biondi, A., Galimberti, S., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Iron overload (IOL) is a frequently reported complication following hematopoietic stem cell transplantation (HSCT) which has been extensively assessed in the field of hemoglobinopathies, but has not been thoroughly characterized after HSCT in pediatric malignancies. OBJECTIVES Our aim was to assess prevalence, severity, risk factors and management of IOL, as defined by means of biochemical (serum ferritin) and radiological tools (T2*-MRI), in a cohort of pediatric patients transplanted for either malignant or benign diseases. STUDY DESIGN Monocentric, retrospective, observational study. All the 163 patients alive and in continuous remission 24 months after HSCT, out of the 219 consecutive children and adolescents transplanted at our Institution between 2012 and 2018, were included in the study. IOL was classified into four categories, i.e. absent, mild, moderate and severe. RESULTS Of the 163 patients, 73% had some degree of IOL, which was mild, moderate and severe in 37%, 29% and 7%, respectively. Moderate/severe IOL was more frequent among patients diagnosed with a malignant versus benign disease (43% vs 19%; p 0.0065). Ferritin trend lines showed a "bell-shaped" distribution, with the highest levels being recorded during the first 6 months after HSCT, followed by a spontaneous reduction. Both pre-HSCT (1659 versus 617 ng/mL, p<0.001) and maximum post-HSCT (2473 ng/mL versus 1591 ng/mL, p<0.001) median ferritin levels were statistically higher among patients with malignancies. Radiological assessment of IOL confirmed a more severe degree in malignant compared to benign disorders (median T2*-MRI 4.20 msec, IQ: 3.0-6.40 versus 7.40, IQ: 4.90-11.00, respectively - p 0.008). T2* levels were associated with the number of transfusions performed (p 0.0006), with a steeper drop in T2* values for the first 20 transfusions and a milder slope subsequently. T2* and ferritin values showed a statistically significant negative exponential relationship (p<0.0001), though ferritin levels ≥1000 ng/mL showed a poor specificity (48%) and positive predictive value (53%) in discriminating moderate-to-severe from absent-mild IOL as assessed by T2*-MRI, but high sensitivity (92%) and negative predictive value (91%). In a multivariable model, >20 transfusions (OR 4.07, 95% CI 1.61-10.68, p 0.003) and higher pre-HSCT ferritin levels (p<0.001) were associated with the risk of developing moderate-to-severe IOL. A sibling donor (OR 0.29, 95% CI 0.10-0.77, p 0.015) and a non-malignancy (OR 0.27, 95% CI 0.08-0.82, p 0.026) were protective factors. Phlebotomies (66%), low-dose oral chelators (9%) or a combined approach (25%) were started at a median of 12 months after HSCT in 78% of the patients with IOL. Six% of the patients treated exclusively with phlebotomies (median 14, significantly higher in patients >40 kg) discontinued them due to poor venous accesses, lack of compliance or hypotension, whereas 39% of patients treated with chelators developed mild renal or hepatic side effects which resolved upon tapering or discontinuation. CONCLUSIONS Patients with malignancies showed statistically higher pre- and post-HSCT ferritin levels and lower T2*. High ferritin recorded upon T2*-MRI showed unsatisfactory diagnostic accuracy in predicting IOL, thus, T2*-MRI should be regarded as a key element to confirm IOL after HSCT in patients with elevated ferritin levels. IOL treatment is feasible after HSCT.
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3.
Iron Chelation with Deferasirox suppresses the Appearance of LPI during Conditioning Chemotherapy prior to Allogeneic Stem Cell Transplantation
Essmann, S., Heestermans, M., Dadkhah, A., Janson, D., Wolschke, C., Ayuk, F., Kröger, N. M., Langebrake, C.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND During conditioning chemotherapy prior to allogeneic haematopoietic stem cell transplantation (HSCT) non-transferrin-bound iron and its chelatable form, labile plasma iron (LPI), regularly appear in the blood of patients at high levels of transferrin saturation (TfS). As these free iron species potentially favour infection and mediate transplant-associated toxicities, chelation therapy could be an approach to improve outcome after transplantation. However, data addressing iron chelation in the immediate peri-transplantation period are sparse. OBJECTIVE To investigate the influence of iron chelation with deferasirox during conditioning chemotherapy on the appearance of LPI, the incidence of infection and toxicities and its tolerability in the peri-transplantation period. STUDY DESIGN We conducted a single-center, prospective, observational study in 25 adult, iron-overloaded (serum ferritin > 1000 µg/l) patients with planned allogeneic HSCT after myeloablative, busulfan-based conditioning chemotherapy. Patients received iron chelation with deferasirox (14 mg/kg) from the start of conditioning until day 3 after transplantation. Iron parameters including LPI were obtained at chelator's trough level daily until d0 and on d4, d7 and d14. Data regarding infection (bacteraemia or invasive fungal disease) and toxicity as well as the tolerability of deferasirox was collected until the end of the follow-up period on d28. Data was analysed descriptively. RESULTS TfS levels exceeded 70 % in median on 6 days (4-10 days) and in 63.6 % (36.4-90.9 %) of the samples per patient. Although, in 19 of 25 patients (76 %) no elevated LPI values were detected during the intake of deferasirox despite high TfS levels. Only six patients (24 %) showed mildly increased LPI values (≤ 0.5 units) during the intake of deferasirox, three of whom presented with elevated LPI values before the start of conditioning. Deferasirox was well tolerated and no aggravation of toxicities was observed. Infection occurred in five patients (20 %), comprising three of the six patients with elevated LPI values despite chelation therapy. CONCLUSION In the present study, we demonstrate that iron chelation with deferasirox safely suppresses the appearance of LPI and might decrease the incidence of infection, while the impact on transplant-associated toxicities remains to be elucidated.
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4.
Efficacy and Safety of Iron Chelation Therapy After Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Thalassemia Patients: A Retrospective Observational Study
Kupesiz, F. T., Sivrice, C., Akinel, A., Kintrup, G. T., Guler, E., Kupesiz, A.
Journal of pediatric hematology/oncology. 2022;44(1):e26-e34
Abstract
BACKGROUND Studies on the increased body iron load in patients with thalassemia major have thoroughly demonstrated the problems caused by iron overload. In patients who undergo hematopoietic stem cell transplantation (HSCT) as curative therapy, iron overload continues long after transplantation. There are few pediatric studies on chelation therapy in the posttransplant period. In this study, we present the outcomes of our patients who received posttransplant oral chelation therapy. PATIENTS AND METHODS This retrospective observational study evaluated the outcomes of pediatric patients with thalassemia major who used oral chelation therapy after allogeneic HSCT at the Akdeniz University Pediatric Bone Marrow Unit between January 2008 and October 2019. RESULTS Deferasirox therapy was initiated in 58 pediatric patients who underwent HSCT for thalassemia. Pretreatment mean serum ferritin was 2166±1038 ng/mL. Treatment was initiated at a mean of 12±6.7 months after transplantation and continued for a mean of 15.7±11.5 months. At treatment discontinuation, the mean serum ferritin was 693±405 ng/mL and the mean reduction was -1472.75±1121.09 ng/mL (P<0.001 vs. posttreatment). Serum ferritin was below 500 ng/mL in 52% of the patients at treatment discontinuation. Manageable side effects such as nausea, vomiting, liver enzyme elevation, and proteinuria were observed in 17% of the patients, while one patient developed ototoxicity. CONCLUSIONS Deferasirox therapy effectively reduces iron overload in the posttransplant period. Studies evaluating the effects of early treatment on the graft may help to establish guidelines for posttransplant chelation therapy. Clear guidelines are needed regarding when to initiate and discontinue treatment.
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5.
Long-term effect of hematopoietic stem cell transplantation on the quality of life of patients with β-thalassemia major in Guangxi, China--A cross-sectional study
Zhai, L., Liu, Y., Huo, R., Pan, Z., Zhang, Y., Li, Z., Li, F., Fan, J., Wei, W.
Current stem cell research & therapy. 2022
Abstract
OBJECTIVE The purpose of our study was to compare the quality of life (QOL) of patients with hematopoietic stem cell transplantation (HSCT) for more than 2 years for β-thalassemia major (β-TM) with that of β-TM patients with conventional therapy (blood infusion and iron chelation) and that of the general population. METHODS This was a cross-sectional comparative study on the QOL of 225 β-TM patients treated with blood transfusion and iron-chelation therapy, 133 β-TM patients who had undergone HSCT or 270 age- and sex-matched healthy individuals from Guangxi, China. Child-self and parent-proxy reports of the PedsQL 4.0 Generic Core Scales were used to prospectively evaluate QOL. RESULTS The incidence of acute GVHD was 14.3% (grade III-IV in 4.5% of patients), and that of chronic GVHD was 3.8%. This was lower than that of previous studies since the inclusion of anti-thymocyte globulin(ATG)ATG. Patients who underwent transplantation from a voluntary donor had higher QOL scores and lower rates of acute GVHD, chronic GVHD and comorbidities than those receiving stem cell sources from an HLA mismatched related donor (haploidentical donor). Transplants with PBSCs or UCBT, PBSCT+BMT, BMT, or BMT+UCBT as stem cell sources did not have any impact on QOL. The QOL of β-TM patients was very similar to that of the general population. More complications (P<0.001), shorter posttransplantation time (P<0.001) and older age at HSCT (P=0.01) were associated with poorer child QOL (P=0.020). Additional analyses investigating QOL β-TM patients receiving conventional treatment with β-TM revealed poorer outcomes than the cohort of transplanted patients. CONCLUSION β-TM patients can be cured by HSCT and regain QOL as good as that of the general population. β-TM patients are suggested to undergo HSCT as soon as possible to avoid complications related to iron overload and blood infusion.
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6.
Iron Chelation with Deferasirox increases Busulfan AUC during Conditioning Chemotherapy prior to Allogeneic Stem Cell Transplantation
Essmann, S., Dadkhah, A., Janson, D., Wolschke, C., Ayuk, F., Kröger, N. M., Langebrake, C.
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND The negative effects of iron overload due to repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with an iron chelator. However, in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) chelation therapy is often postponed until the late posttransplant period because of potential drug interactions. OBJECTIVE To systematically investigate the influence of iron chelation with deferasirox on the pharmacokinetics of intravenous busulfan in adult patients in the context of routine therapeutic drug monitoring (TDM) prior to HSCT. STUDY DESIGN We conducted a single-center, prospective, observational study in 25 adult patients with planned allogeneic HSCT after myeloablative, busulfan-based, TDM-guided conditioning chemotherapy. Busulfan was administered i.v. over 3 h with an initial dose of 3.2 mg/kg once daily (based on AIBW in overweight patients). Four consecutive dosages were planned to achieve a cumulative area under the curve (AUC) of 80 mg*h/l. Patients received deferasirox for transfusional iron overload as per approval from the start of conditioning until d3 after transplantation. Model-based calculation of the busulfan area under the curve (AUC) was carried out by means of Bayesian prediction based on a population pharmacokinetic model after the first or second dose of busulfan and dose adjustments were performed accordingly. RESULTS Calculated median cumulative AUC before dose adjustment was 93.7 mg*h/l (65.1 - 151.4 mg*h/l), which was considerably above the target AUC of 80 mg*h/l ± 10 %. Median dose adjustment was -17.1 % (-50.0 - 18.2 %) and patients ultimately received busulfan with a median cumulative dose of 10.60 mg/kg (6.38 - 15.62 mg/kg). A busulfan dose reduction was necessary in 19 patients (76 %) whereas a dose increase was only necessary in one patient. After dose adjustment the median AUC was 79.7 mg/L*h (62.5 - 84.2 mg/l*h). Median busulfan clearance was 0.134 l/h/kg (0.084 - 0.203 l/h/kg), which is significantly lower than the average clearance of 0.2 l/h/kg reported in the literature, while volume of distribution was not altered. CONCLUSIONS We were able to demonstrate, that TDM is the key point to facilitate a safe co-administration of both medications, since the intake of deferasirox leads to a considerable increase in the busulfan AUC of about 35 - 40 %. The reason for the increase in busulfan AUC is a reduction in busulfan clearance by about one third, therefore a lower initial dose of busulfan followed by TDM could be considered in this case.
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7.
Outcome of iron reduction therapy in ex-thalassemics
Aboobacker, F. N., Dixit, G., Lakshmi, K. M., Korula, A., Abraham, A., George, B., Mathews, V., Srivastava, A.
PloS one. 2021;16(1):e0238793
Abstract
There is limited data on iron reduction therapy (IRT) after successful allogeneic haematopoietic stem cell transplantation (aHSCT) for patients with thalassemia major (TM). We present the long term outcome of IRT in 149 patients with TM who underwent aHSCT during January, 2001-December, 2012. The median age was 7 years (range:1-18) and 92 (61.7%) belonged to Pesaro class 3 with a median ferritin at aHSCT of 2480ng/ml (range:866-8921). IRT was reinitiated post-aHSCT at a median of 14 months (range:5-53) post aHSCT with phlebotomy alone in 10 (6.7%) patients or iron chelation alone in 60 (40.3%) patients while 79 (53%) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month) was as follows: 87 (range:33-195), 130 (range:17-1012) and 147 (range:27.7-1427) in the phlebotomy, chelation and combination therapy groups, respectively (p = 0.038). With a median follow up of 80 months (range:37-182), target ferritin level of <300ng/ml was achieved in 59(40%) while a level <500ng/ml was achieved in 88 patients (59%) in a median duration of 41 months of IRT (range: 3-136). Patients in class III risk category and higher starting serum ferritin levels (>2500ng/ml) were associated with delayed responses to IRT. Our data shows that IRT may be needed for very long periods in ex-thalassaemics to achieve target ferritin levels and should therefore be carefully planned and initiated as soon as possible after aHSCT. A combination of phlebotomy and iron chelators is more effective in reducing iron overload.
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8.
Iron overload during the treatment of acute leukemia: pretransplant transfusion experience
Yokus, O., Herek, C., Cinli, T. A., Goze, H., Serin, I.
International journal of hematologic oncology. 2021;10(3):Ijh36
Abstract
BACKGROUND Recent studies have shown the increased risk of mortality in cases with acute leukemia and iron overload. We aimed to determine the status of iron overload in patients with acute leukemia. MATERIALS & METHODS Patients diagnosed with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) between January 2015 and December 2019 were included in the study. RESULTS At 6 months, there were statistically more patients with serum ferritin >1000 in the AML group compared to the ALL group (p = 0,011). CONCLUSION Iron overload occurs earlier in patients with AML; the difference disappears after 6 months of treatment. It is the correct point to emphasize that iron overload is an important factor of pretransplant morbidity, especially in AML cases.
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9.
Retrospective Evaluation of Relationship Between Iron Overload and Transplantation Complications in Pediatric Patient Who Underwent Allogeneic Stem Cell Transplantation Due to Acute Leukemia and Myelodysplastic Syndrome
Kupesiz, F. T., Hazar, V., Eker, N., Guler, E., Yesilipek, M. A., Tuysuz, G., Kupesiz, A.
Journal of pediatric hematology/oncology. 2020
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is a curative therapy option for hematologic malignancies. Iron overload is common in this patient group and can impact short-term and long-term nonrelapse mortality. STUDY DESIGN Retrospective observational cohort study. AIMS To evaluate the effect of iron load on early and late HSCT outcomes in patients with acute leukemia and myelodysplasia in order to assess the necessity of reducing iron load. PATIENTS AND METHODS Sixty patients who underwent HSCT in pediatric stem cell transplantation unit between 2000 and 2012 were evaluated retrospectively. The patients were divided into those with pretransplantation serum ferritin levels above and below the median value of 1299 ng/mL. RESULTS Forty-two (70%) of the patients were male, mean ages of the low and high ferritin groups were 85.43+/-9.42 and 118.56+/-10.04 months, respectively. Acute graft-versus-host disease (GVHD) within the first 100 days and acute liver GVHD were significantly more common in the high ferritin group (P<0.011 for both). Ferritin level was not associated with rates of engraftment syndrome, veno-occlusive disease, early/late infection, relapse, or overall and disease-free survival. CONCLUSIONS In our study, significant result especially in terms of acute liver GVHD, was important to emphasize the need to be more careful in terms of acute liver GVHD risk in early liver pathologies in patients with high levels of ferritin after transplantation. In future large studies may be helpful to explain the relationship between acute liver GVHD and high ferritin levels.
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10.
Transfusional iron overload in patients receiving autologous stem cell transplantation: An underestimated problem requiring further consideration
Bauduer, F., Recanzone, H.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2020;:102837