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Hyperferritinemia and acute kidney injury in pediatric patients receiving allogeneic hematopoietic cell transplantation.
Kurokawa, M, Nishiyama, K, Koga, Y, Eguchi, K, Imai, T, Oba, U, Shiraishi, A, Nagata, H, Kaku, N, Ishimura, M, et al
Pediatric nephrology (Berlin, Germany). 2020;(10):1977-1984
Abstract
BACKGROUND Acute kidney injury (AKI) often occurs in pediatric patients who received allogeneic hematopoietic cell transplantation (HCT). We evaluated the risk and effect of HCT-related AKI in pediatric patients. METHODS We retrospectively studied the survival and renal outcome of 69 children 100 days and 1-year posttransplant in our institution in 2004-2016. Stage-3 AKI developed in 34 patients (49%) until 100 days posttransplant. RESULTS The 100-day overall survival (OS) rates of patients with stage-3 AKI were lower than those without it (76.5% vs. 94.3%, P = 0.035). The 1-year OS rates did not differ markedly between 21 post-100-day survivors with stage-3 AKI and 29 without it (80.8% vs. 87.9%, P = 0.444). The causes of 19 deaths included the relapse of underlying disease or graft failure (n = 11), treatment-related events (4), and second HCT-related events (4). Underlying disease of malignancy (crude hazard ratio (HR) 5.7; 95% confidence interval (CI), 2.20 to 14.96), > 1000 ng/mL ferritinemia (crude HR 4.29; 95% CI, 2.11 to 8.71), stem cell source of peripheral (crude HR 2.96; 95% CI, 1.22 to 7.20) or cord blood (crude HR 2.29; 95% CI, 1.03 to 5.06), and myeloablative regimen (crude HR 2.56; 95% CI, 1.24 to 5.26), were identified as risk factors for stage-3 AKI until 100 days posttransplant. Hyperferritinemia alone was significant (adjusted HR 5.52; 95% CI, 2.21 to 13.76) on multivariable analyses. CONCLUSIONS Hyperferritinemia was associated with stage-3 AKI and early mortality posttransplant. Pretransplant iron control may protect the kidney of pediatric HCT survivors.
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Patients Undergoing Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation Exhibit Depleted Vitamin C Status in Association with Febrile Neutropenia.
Carr, AC, Spencer, E, Das, A, Meijer, N, Lauren, C, MacPherson, S, Chambers, ST
Nutrients. 2020;(6)
Abstract
Patients undergoing myeloablative chemotherapy and hematopoietic stem cell transplantation (HSCT) experience profound neutropenia and vulnerability to infection. Previous research has indicated that patients with infections have depleted vitamin C status. In this study, we recruited 38 patients with hematopoietic cancer who were undergoing conditioning chemotherapy and HSCT. Blood samples were collected prior to transplantation, at one week, two weeks and four weeks following transplantation. Vitamin C status and biomarkers of inflammation (C-reactive protein) and oxidative stress (protein carbonyls and thiobarbituric acid reactive substances) were assessed in association with febrile neutropenia. The vitamin C status of the study participants decreased from 44 ± 7 µmol/L to 29 ± 5 µmol/L by week one (p = 0.001) and 19 ± 6 µmol/L by week two (p < 0.001), by which time all of the participants had undergone a febrile episode. By week four, vitamin C status had increased to 37 ± 10 µmol/L (p = 0.1). Pre-transplantation, the cohort comprised 19% with hypovitaminosis C (i.e., <23 µmol/L) and 8% with deficiency (i.e., <11 µmol/L). At week one, those with hypovitaminosis C had increased to 38%, and at week two, 72% had hypovitaminosis C, and 34% had outright deficiency. C-reactive protein concentrations increased from 3.5 ± 1.8 mg/L to 20 ± 11 mg/L at week one (p = 0.002), and 119 ± 25 mg/L at week two (p < 0.001), corresponding to the development of febrile neutropenia in the patients. By week four, these values had dropped to 17 ± 8 mg/L (p < 0.001). There was a significant inverse correlation between C-reactive protein concentrations and vitamin C status (r = -0.424, p < 0.001). Lipid oxidation (thiobarbituric acid reactive substances (TBARS)) increased significantly from 2.0 ± 0.3 µmol/L at baseline to 3.3 ± 0.6 µmol/L by week one (p < 0.001), and remained elevated at week two (p = 0.003), returning to baseline concentrations by week four (p = 0.3). Overall, the lowest mean vitamin C values (recorded at week two) corresponded with the highest mean C-reactive protein values and lowest mean neutrophil counts. Thus, depleted vitamin C status in the HSCT patients coincides with febrile neutropenia and elevated inflammation and oxidative stress.
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3.
Vitamin D deficiency is not associated with graft versus host disease after hematopoietic stem cell transplantation: A meta-analysis.
Chiengthong, K, Cheungpasitporn, W, Thongprayoon, C, Lertjitbanjong, P, Cato, LD, Bathini, T, Ungprasert, P, Mao, MA, Chokesuwattanaskul, R
Journal of evidence-based medicine. 2020;(3):183-191
Abstract
OBJECTIVE Vitamin D status plays an important role in immunoregulation, and a deficiency is believed to be related to Graft Versus Host Disease (GVHD) in patients after hematopoietic stem cell transplantation (HSCT). We aim to study the association between vitamin D deficiency and GVHD after HSCT. METHODS A literature search was conducted utilizing MEDLINE, EMBASE, and The Cochrane Library Database from inception to July 2019. Eligible studies were required to1 be clinical trials or observational studies (cohort, case-control, or cross-sectional studies);2 provide data to calculate the odds ratios (OR) of GVHD in HSCT patients with vitamin D deficiency. Two reviewers independently extracted the data and assessed the risk of bias. Pooled odds ratios (OR) with 95% confidence interval (CI) were estimated using random-effects meta-analysis through the Comprehensive Meta-Analysis 3.3 software. RESULTS In total, 8 observational studies consisting of 1335 HSCT patients were enrolled in this systematic review. Overall, there was no significant association between vitamin D deficiency and acute GVHD (OR = 1.06, 95% CI 0.74-1.53, P > 0.05). There was no significant association between vitamin D deficiency and chronic GVHD (OR = 1.75, 95% CI 0.72-4.26, P > 0.05). Funnel plots and Egger regression asymmetry test were performed and showed no publication bias. CONCLUSION There is not a statistically significant association between vitamin D deficiency and neither acute nor chronic GVHD.
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Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial.
Beelen, DW, Trenschel, R, Stelljes, M, Groth, C, Masszi, T, Reményi, P, Wagner-Drouet, EM, Hauptrock, B, Dreger, P, Luft, T, et al
The Lancet. Haematology. 2020;(1):e28-e39
Abstract
BACKGROUND Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. METHODS We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING medac GmbH.
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5.
Body composition after allogeneic haematopoietic cell transplantation/total body irradiation in children and young people: a restricted systematic review.
Lorenc, A, Hamilton-Shield, J, Perry, R, Stevens, M, ,
Journal of cancer survivorship : research and practice. 2020;(5):624-642
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Abstract
PURPOSE To collate evidence of changes in body composition following treatment of leukaemia in children, teenagers and young adults (CTYA, 0-24 years) with allogeneic haematopoietic stem cell transplant and total body irradiation (HSCT+TBI). METHODS Papers were identified by searching Medline and Google Scholar, reference lists/citations and contacting key authors, with no date or language restrictions. Inclusion criteria were as follows: leukaemia, HSCT+TBI, aged ≤ 24 years at HSCT and changes in body composition (total fat, central adiposity, adipose tissue function, muscle mass, muscle function). Quality was assessed using a brief Newcastle-Ottawa scale. RESULTS Of 900 papers, 20 were included: seven controlled, five uncontrolled studies and eight case reports. Study quality appeared good. There was little evidence of differences in total fat/weight for HSCT + TBI groups (compared to healthy controls/population norms/short stature controls). There was some evidence of significantly higher central adiposity and differences in adipose tissue function (compared to leukaemic/non-leukaemic controls). Muscle mass was significantly lower (compared to healthy/obese controls). Muscle function results were inconclusive but suggested impairment. Case reports confirmed a lipodystrophic phenotype. CONCLUSIONS Early remodelling of adipose tissue and loss of skeletal muscle are evident following HSCT + TBI for CTYA leukaemia, with extreme phenotype of overt lipodystrophy. There is some evidence for reduced muscle effectiveness. IMPLICATIONS FOR CANCER SURVIVORS Body composition changes in patients after HSCT + TBI are apparent by early adult life and link with the risk of excess cardiometabolic morbidity seen in adult survivors. Interventions to improve muscle and/or adipose function, perhaps utilizing nutritional manipulation and/or targeted activity, should be investigated.
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Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan-Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation.
El-Serafi, I, Remberger, M, Ringdèn, O, Törlén, J, Sundin, M, Björklund, A, Winiarski, J, Mattsson, J
Clinical and translational science. 2020;(2):293-300
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Abstract
The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan (Bu) and cyclophosphamide before allogeneic HSCT during 1990-2015. Patients' supportive care was changed in order to reduce the regimen-related toxicities. Norethisterone use was terminated in 1998, therapeutic drug monitoring of Bu was initiated in 2000, and the use of liver supportive drugs, such as ursodeoxycholic acid and N-acetyl-L-cysteine, were started in 2002 and 2009, respectively. In total, 26 patients (7.0%) developed SOS at a median of 19 days after transplantation. Of these 26 patients, 20 died at a median of 119 days after HSCT and 102 days after the diagnosis of SOS. The incidence of SOS decreased over time in accordance with the improvements in supportive care. The highest incidence of SOS was during 1995-1999 (16.2%) compared with 2.3% during 2010-2015. Overall survival for patients with SOS was 62%, 46%, and 27% at 100 days, 1 year, and 5 years after HSCT, respectively, compared with 92%, 77%, and 66% for those who did not develop SOS (P < 0.001). In conclusion, the incidence of SOS and related deaths were significantly decreased over the last years. Our institution pursues massive preventative and personalized measures for SOS. This strategy may also be applicable in other conditioning protocols in order to reduce the incidence of SOS and, hence, improve the clinical outcome.
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Hematopoietic Stem Cell Transplantation in Congenital Dyserythropetic Anemia Type II: A Case Report and Review of the Literature.
Uygun, V, Russo, R, Karasu, G, Daloğlu, H, Iolascon, A, Yeşilipek, A
Journal of pediatric hematology/oncology. 2020;(6):e507-e510
Abstract
Currently, there is no guideline for the treatment of patients with congenital dyserythropoietic anemia (CDA) type II. One approach is to follow-up patients with transfusions, on the basis of individually determined target hemoglobin levels, and iron chelation according to the thalassemia guidelines. In some transfusion-dependent CDA II patients, splenectomy reduces the number of transfusions; however, the only known curative option for CDA II patients is hematopoietic stem cell transplantation (HSCT). Only a few published case reports of allogeneic HSCT in CDA II patients are available. Here, we review the literature and add our data of a CDA II patient who developed transfusion dependence and was cured with HSCT.
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Hepatic focal nodular hyperplasia after pediatric hematopoietic stem cell transplantation: The impact of hormonal replacement therapy and iron overload.
Cattoni, A, Rovelli, A, Prunotto, G, Bonanomi, S, Invernizzi, P, Perego, R, Mariani, AM, Balduzzi, A
Pediatric blood & cancer. 2020;(4):e28137
Abstract
BACKGROUND The advent of techniques for the assessment of iron overload (liver T2*-MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. METHODS We performed a retrospective analysis of the liver T2*-MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. RESULTS Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 ± 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate-to-severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI-T2* values in affected patients were statistically lower than healthy controls (P < .001). CONCLUSIONS We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.
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[Hepatobiliary complications following allogeneic hematopoietic cell transplantation: Recommendations of the Francophone Society of Bone Marrow transplantation and cellular Therapy (SFGM-TC)].
Detrait, M, de Berranger, E, Dulery, R, Ménard, AL, Thépot, S, Toprak, SK, Turlure, P, Yakoub-Agha, I, Guillaume, T
Bulletin du cancer. 2020;(1S):S18-S27
Abstract
Hepatobiliary complications are frequent in the context of allogeneic hematopoietic cell transplantation (allo-HCT) and contribute largely to the morbidity and mortality after transplantation. Within the framework of the ninth workshops of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2018, diagnostic approaches and treatments of hepatobiliary dysfunctions prior to and following transplantation were reviewed according to the analysis of published studies.
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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.
Küpesiz, FT, Hazar, V, Eker, N, Guler, E, Yesilipek, MA, Tuysuz, G, Kupesiz, A
Journal of pediatric hematology/oncology. 2020;(5):e315-e320
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 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.