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A randomized controlled trial to explore the safety and efficacy of irradiated buffy-coat granulocytes in pediatric patients with febrile neutropenia
Ramachandran, M., Gupta, A. K., Meena, J. P., Upadhyay, A. D., Coshic, P., Lodha, R., Seth, R.
American journal of blood research. 2023;13(5):152-161
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Abstract
BACKGROUND Transfusion of granulocytes obtained by apheresis is beneficial in febrile neutropenia (FN) but expensive and time-consuming. Buffy-coat-derived granulocytes could be an alternative. We studied the efficacy and safety of the administration of irradiated buffy-coat-derived granulocytes along with the standard of care in pediatric high-risk (HR) FN. METHODS Sixty children ≤18 years with malignancy and chemotherapy-induced HR FN were randomized to either the granulocyte transfusion (GT) arm which received irradiated buffy-coat derived granulocyte transfusion along with the standard treatment or the standard treatment (ST) arm. RESULTS Baseline characteristics, day-to-defervescence, antibiotic duration, hospital stay, and mortality were comparable between the groups. A significant difference was seen in days to achieve absolute neutrophil count (ANC) >500/mm(3) in the 2 groups: 4.5 days (3-6.5) in the GT arm v/s 8 days (4-11) in the ST arm (P=0.01). CONCLUSION Buffy-coat-derived granulocyte transfusion was safe and led to early hematological recovery but was not associated with survival benefits. Future studies with earlier initiation in the intended dose could be undertaken to generate more evidence.
PICO Summary
Population
Children with malignancy and chemotherapy-induced high-risk febrile neutropenia (n= 60).
Intervention
Irradiated buffy-coat derived granulocyte transfusion along with the standard treatment (GT arm, n= 30).
Comparison
Standard treatment, including: antimicrobials, blood component support, and G-CSF as per the protocol (ST arm, n= 30).
Outcome
Baseline characteristics, day-to-defervescence, antibiotic duration, hospital stay, and mortality were comparable between the groups. A significant difference was seen in days to achieve absolute neutrophil count >500/mm(3) in the 2 groups: 4.5 days (3, 6.5) in the GT arm versus 8 days (4, 11) in the ST arm.
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Efficacy and safety of thrombopoietin receptor agonists in children with chronic immune thrombocytopenia: a meta-analysis
Guo J C, Zheng Y, Chen H T, Zhou H, Huang X H, Zhong L P, Zhou H B, Huang Y, Xie D L, Lou Y L
Oncotarget. 2018;9((6)):7112-7125.
Abstract
Background and Aim: Thrombopoietin receptor agonists (TPO-RAs) have been shown to be safe and effective for adults with chronic immune thrombocytopenia (ITP). The aim of this meta-analysis is to assess the efficacy and safety of thrombopoietin receptor agonists for children with chronic ITP. Materials and Methods: Clinical randomized controlled trials (RCTs) evaluating the efficacy and safety of TPO-RAs in pediatric ITP patients published up to June 2017 were retrieved from PubMed, Cochrane Library, and Embase databases. Relevant data were extracted, and the Physiotherapy Evidence Database scale was used to assess the methodological quality. Stata/SE 12.0 was used to perform a meta-analysis. Results: Seven RCTs were included, with 238 patients and 107 patients in the TPO-RA group and the control group, respectively. Assessing efficacy, better results were found in the TPO-RA group for the rate of overall platelet response, durable response, and rescue medication needed. Furthermore, the TPO-RA group yielded superior results in the incidence of clinically significant bleeding events but had a comparable result in the incidence of any bleeding events and severe bleeding events. No significant difference was found between the two groups in health-related quality of life and parental burden. Assessing safety, no significant difference was found between the two groups in the incidence of any adverse events and severe adverse events. Conclusions: TPO-RAs are effective and safe agents for the treatment of chronic ITP in pediatric patients. Eltrombopag appears to be better than romiplostim in terms of the rate of rescue medication needed and clinically significant bleeding events.
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The efficacy of recombinant human erythropoietin in treatment chemotherapy induced anemia in children diagnosed with a solid cancer
Hiradfar A, Banihosseinian M
Iranian Journal of Pediatric Hematology & Oncology. 2014;4((4):):151-9.
Abstract
BACKGROUND Recombinant human erythropoietin (rHuEPO) treatment can increase hemoglobin levels and decrease transfusion requirements. This study aims to investigate how blood transfusion influences Hemoglobin levels in patients receiving rHuEPO for 12 weeks. MATERIALS AND METHODS This was a case-control study of 60 patients less than 15 years with anemia and a solid tumor in any location between February 2013 and March 2014. Median age of the patients were 6.27+/-0.58 years (range, 0.9-14 years). The patients were randomly assigned in two groups of rHuEPO receiving group and control group. 29 Patients in rHuEPO group received 150 IU/kg/dose rHuEPO subcutaneously, 3 times a week, for 12 weeks. The number of patients received transfusion during the treatment period was compared in the preceding 12 weeks. Also, adverse events (AE) were recorded at the 4(th), 8(th), and 12(th) weeks. RESULTS Mean hemoglobin levels, before and after study, in rHuEPO group were 8.85+/-1.01 g/dl and 9.90+/-0.29 g/dl, respectively (p<0.001) and in control group were, 9.00+/-0.09 g/dl and 7.81+/-0.23 g/dl, respectively (p=0.25). Among 60 patients initially eligible the present study, 57 (29 in rHuEPO group and 28 in control group) completed study course.There was a significant decrease in transfusion requirements in the rHuEPO receiving group (p=0.004). 5 (17.2%) patients in the rHuEPO group needed a blood transfusion, whereas 15 (53.6%) patients needed a transfusion in the control group. rHuEPO occasioned hypertension in one patient at 4(th) week that caused to end the treatment. All other AE were transient, which did not reoccur after the transient discontinuation of the medication (p<0.05). CONCLUSIONS Results showed that the rHuEPO (150 IU/kg/day, 3 times a week) was effective in increasing hemoglobin levels as well as decreasing blood transfusion requirements in children with anemia following intensive chemotherapy. IS 2008-8892
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Double-blind, placebo-controlled study of quality of life, hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy
Razzouk BI, Hord JD, Hockenberry M, Hinds PS, Feusner J, Williams D, Rackoff WR
Journal of Thrombosis and Haemostasis. 2006;24((22):):3583-9.
Abstract
PURPOSE To evaluate the effects of once-weekly epoetin alfa (EPO) on health-related quality of life (HRQOL), hemoglobin (Hb), transfusions, and tolerability in children with cancer. METHODS Anemic patients 5 years to 18 years of age receiving myelosuppressive chemotherapy for nonmyeloid malignancies, excluding brain tumors, received intravenous EPO 600 units/kg to 900 units/kg or placebo once-weekly for 16 weeks. Patients and parents completed the pediatric health-related quality-of-life generic scales (GS) and cancer-specific scales (CS). RESULTS One hundred eleven patients received EPO and 111 patients received placebo. Mean final values for GS total score (P = . 763 among patients; P = . 219 among parents) and CS domain scores (P > or = . 238; P > or = . 081, respectively) were not significantly different between treatment groups. EPO-treated patients had greater increases in Hb overall (P = . 002) and were more likely to be transfusion free after 4 weeks (38. 7% v 22. 5%; P = . 010). Change in Hb was correlated with change in PedsQL-GCS total score in the EPO group (r = 0. 242; P = . 018), but was not in the placebo group (r = 0. 086; P = . 430). Adverse events were comparable between treatment groups. CONCLUSION This study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL was detected between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group. Additional studies are warranted to assess HRQOL when anemia is managed optimally in children with cancer.
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Pharmacokinetics and pharmacodynamics of intravenous epoetin alfa in children with cancer
Freeman BB, Hinds P, Iacono LC, Razzouk BI, Burghen E, Stewart CF
Pediatric Blood & Cancer. 2006;47((5):):572-9.
Abstract
BACKGROUND Epoetin alfa (EPO, PROCRIT) pharmacokinetics and pharmacodynamics were evaluated in children with malignant solid tumors receiving chemotherapy. PROCEDURE Children initially received IV EPO 600 IU/kg (max dose 40,000 IU) or placebo once weekly for 16 weeks. Dose was increased to 900 IU/kg (max dose 60,000 IU) for patients not achieving a 1 g/dl increase in hemoglobin by study week 3 or 4. Serial PK samples were collected for 24 hr after the first study dose, and after the 10th or 11th dose. Serum EPO concentrations were analyzed using an ELISA assay, and pharmacokinetics were evaluated using compartmental methods. RESULTS Twelve children participated; six (median age 15. 2 years; range 9. 3-18. 6 years) were randomized to receive EPO. All children required dosage increases to 900 IU/kg due to no response. The median (range) apparent EPO AUC0-24 and clearance (CL) were 67. 1 IU/ml. hr (13. 8-102. 6) and 0. 26 L/hr/m2 (0. 19-1. 08), respectively. After the 10th or 11th EPO dose in four of these six EPO patients, the median (range) apparent AUC0-24 and CL of EPO was 126. 5 IU/ml. hr (107. 3-161. 1) and 0. 21 L/hr/m2 (0. 15-0. 25), respectively. No significant correlations were observed between pharmacokinetic parameters and pharmacodynamic effects. CONCLUSIONS EPO disposition in our patients was similar to other pediatric patient populations or adults receiving IV EPO. Interesting but insignificant trends were noted in pharmacodynamic effects.
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A double-blind, placebo-controlled study of once-weekly epoetin alfa in children with cancer undergoing myelosuppressive chemotherapy
Razzouk BI, Hockenberry M, Hinds PS, Rackoff W, Hord JD
Journal of Clinical Oncology. 2004;22((14_suppl)):8527.
Abstract
8527 Background: This study was designed to assess the effect of epoetin alfa (EPO) on hemoglobin (Hb) and quality of life (QOL) in children with cancer receiving myelosuppressive chemotherapy (CT). METHODS This was a double-blind, placebo (PBO)-controlled study of pts aged 5-18 y with malignant solid tumors (ST), Hodgkin's lymphoma (HL), acute lymphocytic leukemia (ALL), or non-Hodgkin's lymphoma (NHL) and Hb <12 g/dL. Pts were stratified by tumor type (ST/HL or ALL/NHL) and randomized 1:1 to receive IV EPO 600 U/kg or PBO weekly for 16 wks. Primary end point was pt-reported Peds Quality of Life Inventory (PedQL-ITM) Total Score; secondary endpoints included parent-reported PedsQL-I and pt- and parent-reported PedsQL Cancer Module (PedsQL-CM: Cognitive Problems, Communication, Nausea, Pain and Hurt, Physical Appearance, Procedural Anxiety, Treatment Anxiety, Worry), Hb, and transfusions. QOL was assessed using age-specific (5-7 y, 8-12 y, 13-18 y) versions of each tool. RESULTS 222 pts (111 EPO, 111 PBO) were included in the intent-to-treat analysis: 27 HL, 98 ST, 75 ALL, and 22 NHL. Neither the pt- nor parent-reported PedsQL-I Total Score was significantly different between groups at last value. A significant improvement was seen in the pt-reported PedsQL-I Total Score in pts 5-7 y (EPO, n = 13; PBO, n = 32) receiving EPO vs PBO (P =.043). Pt- and parent-reported Cognitive Problems scores were improved in ALL/NHL pts receiving EPO vs PBO (P=.026 and P=.014, respectively), but no other PedsQL-CM domain. Mean Hb change at last value was not significantly different between groups. Repeated-measures analysis of Hb showed an improvement favoring EPO (P =.012). More pts treated with EPO vs PBO were transfusion free (36% vs 23%; P=.038). Death, serious adverse event, and discontinuation rates were similar in both groups. CONCLUSIONS IV EPO was well tolerated in pediatric cancer pts. Although few differences between QOL scores were detected, there was significant improvement in QOL in pts aged 5-7 y and improved Cognitive scores in ALL/NHL pts. EPO pts had greater increases in Hb and a significant reduction in transfusions vs PBO. [Table: see text].
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Pharmacokinetics (PK) of intravenously (IV) administered epoetin alfa in pediatric patients receiving myelosuppressive chemotherapy
Freeman BB, Iacono LC, Hinds PS, Razzouk BI, Stewart CF
Journal of Clinical Oncology. 2004;22((14_suppl)):8552.
Abstract
8552 Background: The disposition of epoetin alfa (EPO, PROCRIT) has not been well characterized in children. Therefore, we evaluated EPO PK in children with malignant solid tumors undergoing myelosuppressive chemotherapy. METHODS Children in this study were treated at a single center, but were enrolled in a multicenter double-blind, placebo controlled study of EPO. Children received IV EPO 600 IU/kg (max dose 40,000 IU) once weekly for 16 weeks. Serial PK studies were conducted after first EPO dose, and after ninth or tenth EPO dose. Plasma samples were obtained prior to EPO injection and at 0.25, 0.5, 1, 3, 6, 8, and 24 hours after EPO. Plasma EPO concentrations were analyzed using an ELISA assay, with a calibration curve ranging from 0.025 to 0.200 IU/mL. A two-compartment model was fit to the data using maximum likelihood estimation (ADAPT II). RESULTS 13 children were enrolled in the study, of whom 6 (median age 15.2 yrs; range 9.3-18.6 yrs) were randomized to receive EPO. Results from PK studies performed after the first EPO dose (n=6 patients) revealed a median (range) apparent AUC0-24 and clearance (CL) of 70.1 IU/mL*hr (17.29-108.0) and 0.25 L/hr/m2 (0.13-0.87), respectively. The median (range) apparent elimination rate constant (ke) after the first EPO dose was 0.12 h-1 (0.06-0.14). Subsequent PK analysis performed after the ninth or tenth EPO dose in 4 patients showed a median (range) apparent AUC0-24 and CL of 146.2 IU/mL*hr (116.0-172.9) and 0.11 L/hr/m2 (0.02-0.17), respectively. The median (range) apparent EPO ke in these 4 patients was 0.092 h-1 (0.0089-0.11). CONCLUSIONS After multiple EPO doses, an increase in the median apparent EPO AUC0-24 was observed, whereas the median apparent EPO CL decreased by approximately half. The cause of these differences is currently being investigated. Future analyses will relate PK results with pharmacodynamic measures of hematopoeisis and quality of life. Study supported by Ortho Biotech Products, LP, and ALSAC. [Table: see text].
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Combined use of erythropoietin and granulocyte colony-stimulating factor does not decrease blood transfusion requirements during induction therapy for high-risk neuroblastoma: a randomized controlled trial
Wagner LM, Billups CA, Furman WL, Rao BN, Santana VM
Journal of Clinical Oncology. 2004;22((10):):1886-93.
Abstract
PURPOSE To evaluate the efficacy of recombinant erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) in reducing blood transfusion requirements and stimulating hematopoiesis in children with high-risk neuroblastoma. PATIENTS AND METHODS Thirty-eight patients given six cycles of intensive induction chemotherapy for high-risk neuroblastoma were randomized to receive G-CSF (n=20) or G-CSF + EPO (n=18). Cytokines were given subcutaneously each day, starting 24 hours after each chemotherapy cycle and continuing until 48 hours before the start of the next cycle. The primary end point was the effect of EPO on total red cell transfusion requirements during induction therapy. RESULTS Patients who received G-CSF + EPO had a higher red cell transfusion requirement (median, 161. 0 mL/kg) than did those who received G-CSF alone (median, 106. 6 mL/kg; P =. 005). In addition, among patients given transfusions for hemoglobin < or = 8 g/dL, those in the G-CSF + EPO group received more red cell transfusions than did those given G-CSF alone (median per patient, 10 v 8, respectively; P =. 044). The two treatment groups had similar cumulative durations of neutropenia, incidences of febrile neutropenia, platelet transfusion requirements, and numbers of platelet transfusions; they also received induction chemotherapy for similar durations and had similar probabilities of progression-free survival and overall survival. CONCLUSION The addition of EPO to the G-CSF regimen provides no benefit for patients receiving intensive induction chemotherapy for high-risk neuroblastoma.
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A single institutional experience: is epoetin alpha effective in anemic children with cancer?
Yilmaz D, Cetingül N, Kantar M, Oniz H, Kansoy S, Kavakli K
Pediatric Hematology and Oncology. 2004;21((1):):1-8.
Abstract
The authors aimed to investigate the efficacy of epoetin-alpha on hemoglobin levels and red cell transfusion requirement in children with both hematologic malignancy (HM, n = 27) and solid tumors (ST, n = 14). Epoetin-alpha was given (150 U/kg or 250 U/kg, thrice weekly) for 12 weeks. Epoetin alpha significantly increased the hemoglobin levels at the 2nd and 3rd months of therapy (p <. 05). At the 3rd month, the patients required less red cell transfusion. At the dose of 150 U/kg, only three patients with HM, but none of the ST patients, required red cell. However, none required red cell transfusion after 2nd month on epoetin alpha 250 U/kg. Epoetin-alpha administration increases hemoglobin levels and decreases red cell transfusion requirement in children with malignancy.
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Is epoetin alfa a treatment option for chemotherapy-related anemia in children?
Buyukpamukcu M, Varan A, Kutluk T, Akyuz C
Medical & Pediatric Oncology. 2002;39((4):):455-8.
Abstract
BACKGROUND The efficacy and safety of epoetin alfa in ameliorating cancer- or chemotherapy-related anemia and reducing red blood cell (RBC) transfusion requirements have been demonstrated in numerous trials in adult patients. However, limited information is available about recombinant human erythropoietin (rHuEPO, epoetin alfa) as a treatment option in pediatric cancer patients. PROCEDURE To gain more information about the efficacy and safety of epoetin alfa in the treatment of chemotherapy-induced anemia in children with solid tumors receiving either platinum- or nonplatinum-containing chemotherapy, an 8-week randomized trial was conducted. Epoetin alfa 150 IU/kg was given 3 times a week for 8 weeks to 17 patients; 17 control patients received standard of care. RESULTS Transfusions, administered if the hemoglobin (Hb) level dropped to below 6 g/dL, were necessary for only one patient in the epoetin alfa group, as compared with eight patients in the control group (change in Hb from 8.5-10.21 g/dL in the epoetin alfa group vs. 8.48-8.41 g/dL in the control group). CONCLUSIONS The data from this study suggest that this dosing regimen of epoetin alfa is effective and safe in pediatric cancer patients with chemotherapy-related anemia. Further studies with epoetin alfa in more children with different chemotherapy regimens are needed. Copyright 2002 Wiley-Liss, Inc.