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One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.
Inati, A, Kahale, M, Sbeiti, N, Cappellini, MD, Taher, AT, Koussa, S, Nasr, TA, Musallam, KM, Abbas, HA, Porter, JB
Pediatric blood & cancer. 2017;(1):188-196
Abstract
BACKGROUND Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT. RESULTS Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
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Impact of non-transferrin-bound iron (NTBI) in comparison to serum ferritin on outcome after allogeneic stem cell transplantation (ASCT).
Hilken, A, Langebrake, C, Wolschke, C, Kersten, JF, Rohde, H, Nielsen, P, Kröger, N
Annals of hematology. 2017;(8):1379-1388
Abstract
The optimal parameters and time points for the measurement of iron overload (IO) in allogeneic stem cell transplantation (ASCT) patients are still under discussion. Hyperferritinemia and IO are poor prognostic factors in ASCT. We hypothesize that non-transferrin-bound iron (NBTI) is possibly a better marker to predict the effect of IO on the outcome than serum ferritin (SF), which however is not specific for IO. The aim of this prospective observational trial was to evaluate the influence of NBTI in comparison to SF on the outcome of ASCT patients [overall survival, bloodstream infections (BSIs), and invasive fungal infections (IFIs)]. We analyzed daily transferrin saturation (TSAT), SF, and NTBI (if TSAT exceeded 70%) in 100 patients who received ASCT during conditioning, and on day 0, +7, and +14 post-ASCT. After a median NTBI level of 0 μmol/l at baseline, the median of the area under the curve (AUC) of NTBI between conditioning and ASCT (d0) increased to 17 μmol*d/l, and between ASCT and day +14 to 56.3 μmol*d/l. Higher NTBI-AUC d0 resulted in a higher risk of BSI (HR 1.042, p = 0.009) and IFI (HR 1.070, p = 0.001) and showed a trend of inferior 1-year survival (65 vs. 76%, p = 0.09). Baseline SF did not influence BSI, but higher levels resulted in more IFI (HR 1.26, p < 0.001). In conclusion, NTBI possibly better predict for a higher risk of bloodstream infections than SF and needs further investigation.
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Association of Nutritional Parameters with Clinical Outcomes in Patients with Acute Myeloid Leukemia Undergoing Haematopoietic Stem Cell Transplantation.
Baumgartner, A, Zueger, N, Bargetzi, A, Medinger, M, Passweg, JR, Stanga, Z, Mueller, B, Bargetzi, M, Schuetz, P
Annals of nutrition & metabolism. 2016;(2):89-98
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INTRODUCTION In acute myeloid leukemia (AML) patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT), there is uncertainty about the extent of influence nutritional parameters have on clinical outcomes. In this study, we investigated the association between initial body mass index (BMI) and weight loss during HSCT on clinical outcomes in a well-characterised cohort of AML patients. METHODS We analysed data of the Basel stem-cell transplantation registry ('KMT Kohorte') including all patients with AML undergoing first allogeneic HSCT from January 2003 to January 2014. We used multivariable regression models adjusted for prognostic indicators (European Group for Blood and Marrow Transplantation risk score and cytogenetics). RESULTS Mortality in the 156 AML patients (46% female, mean age 46 years) over the 10 years of follow-up was 57%. Compared to patients with a baseline BMI (kg/m2) of 20-25, a low BMI <20 was associated with higher long-term mortality (70 vs. 49%, adjusted hazard ratio 1.97, 95% CI 1.04-3.71, p = 0.036). A more pronounced weight loss during HSCT (>7 vs. <2%) was associated with higher risk for bacterial infections (52 vs. 28%, OR 2.8, 95% CI 0.96-8.18, p = 0.059) and fungal infections (48 vs. 23%, OR 3.37, 95% CI 1.11-10.19, p = 0.032), and longer hospital stays (64 vs. 38 days, adjusted mean difference 25.6 days (15.7-35.5), p < 0.001). CONCLUSION In patients with AML, low initial BMI and more pronounced weight loss during HSCT are strong prognostic indicators associated with lower survival and worse disease outcomes. Intervention research is needed to investigate whether nutritional therapy can reverse these associations.
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A double-blind, randomized, controlled trial on N-acetylcysteine for the prevention of acute kidney injury in patients undergoing allogeneic hematopoietic stem cell transplantation.
Ataei, S, Hadjibabaie, M, Moslehi, A, Taghizadeh-Ghehi, M, Ashouri, A, Amini, E, Gholami, K, Hayatshahi, A, Vaezi, M, Ghavamzadeh, A
Hematological oncology. 2015;(2):67-74
Abstract
Acute kidney injury (AKI) is one of the complications of hematopoietic stem cell transplantation and is associated with increased mortality. N-acetylcysteine (NAC) is a thiol compound with antioxidant and vasodilatory properties that has been investigated for the prevention of AKI in several clinical settings. In the present study, we evaluated the effects of intravenous NAC on the prevention of AKI in allogeneic hematopoietic stem cell transplantation patients. A double-blind randomized placebo-controlled trial was conducted, and 80 patients were recruited to receive 100 mg/kg/day NAC or placebo as intermittent intravenous infusion from day -6 to day +15. AKI was determined on the basis of the Risk-Injury-Failure-Loss-End-stage renal disease and AKI Network criteria as the primary outcome. We assessed urine neutrophil gelatinase-associated lipocalin (uNGAL) on days -6, -3, +3, +9 and +15 as the secondary outcome. Moreover, transplant-related outcomes and NAC adverse reactions were evaluated during the study period. Statistical analysis was performed using appropriate parametric and non-parametric methods including Kaplan-Meier for AKI and generalized estimating equation for uNGAL. At the end of the trial, data from 72 patients were analysed (NAC: 33 patients and placebo: 39 patients). Participants of each group were not different considering baseline characteristics. AKI was observed in 18% of NAC recipients and 15% of placebo group patients, and the occurrence pattern was not significantly different (p = 0.73). Moreover, no significant difference was observed between groups for uNGAL measures (p = 0.10). Transplant-related outcomes were similar for both groups, and all patients had successful engraftment. Three patients did not tolerate NAC because of abdominal pain, shortness of breath and rash with pruritus and were dropped from the intervention group before transplantation. However, the frequency of adverse reactions was not significantly different between groups. In conclusion, our findings could not show any clinical benefits from high-dose NAC particularly for AKI prevention in allogeneic hematopoietic stem cell transplantation patients.
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Caphosol(®) mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation. A pilot study.
Svanberg, A, Öhrn, K, Birgegård, G
European journal of oncology nursing : the official journal of European Oncology Nursing Society. 2015;(1):50-3
Abstract
PURPOSE To investigate if adding Caphosol(®), a mouthwash solution, to oral cryotherapy (OC) further protects against oral mucositis (OM), a toxic painful complication to high dose chemotherapy. METHOD The study was a randomised, controlled, study design. Patients ≥16 years scheduled for allogeneic stem cell transplantation were included consecutively and randomised to experimental group receiving OC combined with Caphosol(®) (n = 20) or control group receiving OC only (n = 20). OC was given from start to end of HDCT. Caphosol(®), from day 0 to day 21. RESULT There were no significant differences regarding age or gender between the groups. Mucositis was assessed with the World Health Organisation (WHO) grading scale. Pain was assessed with a 10 cm visual analogue scale (VAS) from 0 = no pain to 10 = worst imaginable pain. Start and duration of therapy with pain relieving drugs, serum C-reactive protein values, and number of days of hospitalisation were collected from the medical records. Data on OM, oral pain, use of i.v. opioids and total parenteral nutrition were collected during 22 days. There was no significant difference between the groups on OM, oral pain, use of i.v. opioids or TPN between the groups. CONCLUSION The study showed no additional effect of combining Caphosol(®) with OC.
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Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants.
Goldberg, JD, Zheng, J, Castro-Malaspina, H, Jakubowski, AA, Heller, G, van den Brink, MR, Perales, MA
Bone marrow transplantation. 2013;(1):99-104
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Palifermin, a recombinant human keratinocyte growth factor, is commonly given to prevent mucositis following autologous transplantation. In the allogeneic hematopoietic stem cell transplant (allo-HSCT) setting, safety and efficacy data are limited. We conducted a retrospective study in 251 patients undergoing allo-HSCT, 154 of whom received peritransplant palifermin. In all patients, palifermin significantly decreased the mean number of days of total parenteral nutrition (TPN, 13 vs 16 days, P=0.006) and patient-controlled analgesia (PCA, 6 vs 10 days, P=0.023), as well as the length of initial hospital stay (LOS, 32 vs 37 days, P=0.014). However, the effect of palifermin was only significant in patients who received a TBI- but not BU-based chemotherapy conditioning regimen. In TBI recipients, palifermin decreased the mean number of days of TPN (13 vs 17 days, P<0.001) and PCA (7 vs 12 days, P=0.033), and the length of stay (32 vs 38 days, P=0.001). Palifermin did not affect GVHD, graft failure or relapse. Therefore, in the largest analysis with this patient population to date, we demonstrate that palifermin is safe in allo-HSCT patients, decreases TPN and PCA use and decreases LOS following TBI-based but not chemotherapy-based allo-HSCT.
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A prospective randomized toxicity study to compare reduced-intensity and myeloablative conditioning in patients with myeloid leukaemia undergoing allogeneic haematopoietic stem cell transplantation.
Ringdén, O, Erkers, T, Aschan, J, Garming-Legert, K, Le Blanc, K, Hägglund, H, Omazic, B, Svenberg, P, Dahllöf, G, Mattsson, J, et al
Journal of internal medicine. 2013;(2):153-62
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BACKGROUND To our knowledge, no randomized toxicity studies have been conducted to compare myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in allogeneic haematopoietic stem cell transplantation (HSCT). METHODS Adult patients ≤60 years of age with myeloid leukaemia were randomly assigned (1 : 1) to treatment with RIC (n = 18) or MAC (n = 19) in this Phase II single-centre toxicity study. RESULTS There was a maximum median mucositis grade of 1 in the RIC group compared with 4 in the MAC group (P < 0.001). Haemorrhagic cystitis occurred in eight of the patients in the MAC group and none in the RIC group (P < 0.01). Results of renal and hepatic tests did not differ significantly between the two groups. RIC-treated patients had faster platelet engraftment (P < 0.01) and required fewer erythrocyte and platelet transfusions (P < 0.001) and less total parenteral nutrition (TPN) than those treated with MAC (P < 0.01). Cytomegalovirus (CMV) infection was more common in the MAC group (14/19) than in the RIC group (6/18) (P = 0.02). Donor chimerism was similar in the two groups with regard to CD19 and CD33, but was delayed for CD3 in the RIC group. Five-year transplant-related mortality (TRM) was approximately 11% in both groups, and rates of relapse and survival were not significantly different. Patients in the MAC group with intermediate cytogenetic acute myeloid leukaemia had a 3-year survival of 73%, compared with 90% among those in the RIC group. CONCLUSION Reduced-intensity conditioning had several advantages compared with MAC, including less mucositis, less haemorrhagic cystitis, faster platelet engraftment, the need for fewer transfusions and less TPN, and fewer CMV infections. Both regimens were tolerated and TRM was low.
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A supersaturated calcium phosphate solution seems to effectively prevent and treat oral mucositis in haematopoietic stem cell transplanted cancer patients - single centre experience.
Wasko-Grabowska, A, Rzepecki, P, Oborska, S, Barzal, J, Mlot, B, Gawronski, K, Wasko, M, Szczylik, C
Journal of B.U.ON. : official journal of the Balkan Union of Oncology. 2012;(2):363-8
Abstract
PURPOSE Oral mucositis (OM) is one of the most frequent and bothersome complications of high-dose chemotherapy with subsequent auto- and allogeneic haematopoietic stem cell transplantation (HSCT). We have assessed the effectiveness of supersaturated calcium phosphate rinse (Caphosol ®) and palifermin (Kepivance®) in the prophylaxis of OM caused by HSCT. METHODS Caphosol® and Kepivance® were prospectively evaluated in OM prophylaxis in 64 patients after HSCT and compared against themselves and an historical control group. RESULTS Grade 3 and 4 OM was not observed in patients treated with Caphosol® and palifermin. None of those patients needed total parenteral nutrition (TPN), too. In the Caphosol® group 40.9% of the patients did not develop OM, and 70% of patients treated with palifermin were free of any kind of OM symptoms. In the control group OM was observed in all cases. CONCLUSION Caphosol® seems to decrease the incidence, severity and duration of OM, the demand for opioids and for TPN. It needs to be tested in randomized trials, because its easy administration and cost-effectiveness may render it a valuable addition to the standard care in the treatment of OM.
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Caspofungin as antifungal prophylaxis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis.
Döring, M, Hartmann, U, Erbacher, A, Lang, P, Handgretinger, R, Müller, I
BMC infectious diseases. 2012;:151
Abstract
BACKGROUND Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) often receive intravenous liposomal amphotericin B (L-AmB) as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS), a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB. METHODS We retrospectively analyzed the safety, feasibility, and efficacy of CAS in our center, and compared the results with L-AmB as antifungal monoprophylaxis in pediatric patients undergoing HSCT. 60 pediatric patients received L-AmB (1 or 3 mg/kg bw/day) and another 60 patients received CAS (50 mg/m2/day) as antifungal monoprophylaxis starting on day one after HSCT. The median ages of patients receiving L-AmB and CAS were 7.5 years and 9.5 years, respectively. RESULTS No proven breakthrough fungal infection occurred in either group during the median treatment period of 23 days in the L-AmB group and 24 days in the CAS group. One patient receiving CAS developed probable invasive aspergillosis. During L-AmB treatment, potassium levels significantly decreased below normal values. Patients treated with L-AmB had more drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge as compared with the CAS group. CAS was well-tolerated and safe in this cohort of immunocompromised pediatric patients, who underwent high-dose chemotherapy and HSCT. CONCLUSION Prophylactic CAS and L-AmB showed similar efficacy in this biggest cohort of pediatric patients after allogeneic HSCT reported, so far. A prospective randomized trial in children is warranted to allow for standardized guidelines.
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Oral chronic graft-vs.-host disease characterization using the NIH scale.
Fassil, H, Bassim, CW, Mays, J, Edwards, D, Baird, K, Steinberg, SM, Williams, KM, Cowen, EW, Mitchell, SA, Hakim, FT, et al
Journal of dental research. 2012;(7 Suppl):45S-51S
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Chronic graft-vs.-host disease (cGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Oral cGVHD is manifested by mucosal, salivary, and/or sclerotic changes that have been linked to pain and poor quality of life. Our aim was to describe the demographic, clinical, and laboratory markers of oral cGVHD in alloHSCT patients (N = 187) enrolled in a cGVHD cross-sectional study at the NIH (#NCT00331968). We propose a meaningful and reproducible measure of disease defined by a cut-off point reflecting clinical minimally detectable change (0-2 = no oral cGVHD, 3-15 = oral cGVHD) on the 15-point NIH cGVHD clinician assessment scale. Forty-four patients had oral cGVHD. Oral cGVHD was associated with a quiescent or de novo type of cGVHD onset (p = 0.05), higher cGVHD severity (p = 0.033), lower albumin (p = 0.0008), higher total complement (p = 0.012), greater bother from foods or oral ulcers and greater mouth pain, and sensitivity (p < 0.0001). Multivariable logistic regression modeling with albumin, mouth pain, and total complement was 74.3% predictive of oral cGVHD and 80.2% predictive of non-oral cGVHD. We propose the use of >2 points on the NIH scale as a reproducible definition of clinically significant oral cGVHD, which may be useful in clinical settings or as eligibility criterion or as an endpoint in clinical trials.