Delayed Granulocyte Colony-Stimulating Factor (G-CSF) Administration after Chemotherapy Reduces Total G-CSF Doses without Affecting Neutrophil Recovery in a Randomized Clinical Study in Children with Solid Tumors
Pediatr Hematol Oncol. 2020;:1-11
The use of G-CSF after myelotoxic chemotherapy accelerates neutrophil recovery reducing the risk of febrile neutropenia. Current guidelines recommend initiating G-CSF 24 hours after myelotoxic chemotherapy. However, the optimal timing of post-chemotherapy G-CSF administration has not been elucidated. Our previous work in murine models demonstrated that the reappearance of myeloid progenitors does not occur in bone marrow until 3-4 days after completion of chemotherapy suggesting that delayed G-CSF administration may be equally efficacious compared to current practice. We conducted a prospective, randomized, crossover study to compare the absolute neutrophil count (ANC) recovery after chemotherapy and a delayed G-CSF administration to a standard G-CSF administration schedule with early G-CSF start. A total of 21 children with solid tumors who received 2 identical cycles of myelotoxic chemotherapy were randomized to start receiving G-CSF either 24 hours after completion of chemotherapy or on the day that their ANC dropped below 1,000/mm(3). There was no significant difference in the time to neutrophil recovery (ANC > 1,000/mm(3) post nadir) between the two G-CSF administration schedules: 16.0 +/- 0.5 days in the standard group compared to 16.7 +/- 0.4 days in the delayed group (p = 0.36). The total number of G-CSF doses given, however, was significantly less in the delayed group: 6.7 +/- 0.6 compared to 10.5 +/- 0.6 doses in the standard group (p < 0.0001). Our data show that a delayed administration of post chemotherapy G-CSF resulted in a significant reduction in the number of G-CSF injections without compromising the G-CSF effects on neutrophil recovery.
Efficacy and safety of thrombopoietin receptor agonists in children with chronic immune thrombocytopenia: a meta-analysis
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.
Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial
The Lancet Child & Adolescent Health. 2018;2((1)):25-34.
Purpose: No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children's Oncology Group designed a randomized therapeutic trial. Patient and Methods: Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293). Results: Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject. Conclusion: This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG+ constitutes a back-bone upon which to build additional therapy.
The efficacy of recombinant human erythropoietin in treatment chemotherapy induced anemia in children diagnosed with a solid cancer
Iranian Journal of Pediatric Hematology & Oncology. 2014;4((4):):151-9.
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
Pharmacokinetics and pharmacodynamics of intravenous epoetin alfa in children with cancer
Pediatric Blood & Cancer. 2006;47((5):):572-9.
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.
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
Journal of Thrombosis and Haemostasis. 2006;24((22):):3583-9.
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.
Hemoglobin response and improvements in quality of life in anemic children with cancer receiving myelosuppressive chemotherapy
The Journal of Supportive Oncology. 2005;3((6, Suppl 4):):10-11.
A single institutional experience: is epoetin alpha effective in anemic children with cancer?
Pediatric Hematology and Oncology. 2004;21((1):):1-8.
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.
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
Journal of Clinical Oncology. 2004;22((10):):1886-93.
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.
Pharmacokinetics (PK) of intravenously (IV) administered epoetin alfa in pediatric patients receiving myelosuppressive chemotherapy
Journal of Clinical Oncology. 2004;22((14_suppl)):8552.
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].