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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 1886-1893 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.002 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 TrialFrom the Departments of Hematology-Oncology, Biostatistics, and Surgery, St Jude Children's Research Hospital; College of Medicine, University of Tennessee Health Science Center, Memphis, TN; and Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. Address reprint requests to Victor M. Santana, MD, Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105-2794; e-mail: Victor.Santana{at}stjude.org
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 CONCLUSION: The addition of EPO to the G-CSF regimen provides no benefit for patients receiving intensive induction chemotherapy for high-risk neuroblastoma.
The successful treatment of high-risk neuroblastoma remains a major challenge in pediatric oncology—less than one-third of patients who receive current therapy will survive longer than 5 years.1,2 Several investigators have demonstrated that dose intensification increases response rates to induction chemotherapy for neuroblastoma,3-5 and intensive induction regimens are now standard among contemporary treatment protocols. However, dose intensification results in significant pancytopenia, with its attendant risks and costs. Complicating this therapy-induced toxicity is the frequent occurrence of metastatic invasion of the bone marrow, a finding seen at the time of diagnosis of at least two thirds of high-risk neuroblastoma cases.6 Neuroblastoma cells shed gangliosides, which inhibit myelopoiesis and erythopoiesis in vitro7 and probably contribute to the substantial hematologic problems experienced by these patients. Recombinant hematopoietic growth factors have frequently been used to hasten hematopoietic recovery during treatment, and in certain clinical situations their use has resulted in fewer infectious complications, transfusions, and treatment delays.8,9 Recombinant human granulocyte colony-stimulating factor (G-CSF) promotes proliferation and maturation of myeloid progenitors,10 and it is now routinely used in pediatric oncology treatment protocols to shorten the duration of chemotherapy-induced neutropenia. When given during induction chemotherapy for advanced neuroblastoma, G-CSF also reduces treatment delays and the duration of intravenous antibiotic use.11 In addition to neutropenia, anemia is a significant problem for patients with neuroblastoma. The causes of anemia include not only chemotherapeutic toxicity and metastatic marrow involvement, but also blood loss, nutritional deficiencies, and chronic inflammation. Erythropoietin (EPO) is an endogenous growth factor that controls the body's response to anemia by regulating the proliferation and maturation of erythroid progenitors.12 Administration of recombinant human EPO increases the hematocrit in a dose-dependent manner,13 and for adult and pediatric patients receiving certain chemotherapy regimens, EPO can reduce the number of RBC transfusions required.14-18 The use of EPO in adult patients with cancer may even improve quality of life.14,19 Although children receiving intensive induction chemotherapy for high-risk neuroblastoma require frequent RBC transfusions, the combined use of EPO and G-CSF after chemotherapy for neuroblastoma or other pediatric malignancy has not been evaluated in a randomized trial. Early preclinical studies suggested that this combination may produce adverse effects by causing stem-cell competition and cross-lineage inhibition of early hematopoietic cell development.20-23 However, in a recent clinical trial of ovarian cancer treatment, the addition of EPO not only increased the median hematocrit, but also enhanced the ability of G-CSF to reduce post-treatment neutropenia after the first cycle of chemotherapy.24 Other clinical trials have shown these agents to have a synergistic effect when used to treat myelodysplastic syndrome25 and severe aplastic anemia.26 We designed a study whose primary purpose was to evaluate the efficacy of EPO in reducing blood transfusion requirements and stimulating hematopoiesis in pediatric patients with high-risk neuroblastoma. We randomly and prospectively assigned 38 patients with high-risk neuroblastoma to receive treatment with G-CSF alone or treatment with G-CSF + EPO after each of six cycles of intensive induction chemotherapy. Our cohort of uniformly treated pediatric patients who received EPO in a prospective trial is the largest to date. Here we describe the effects of this cytokine combination not only on these patients' RBC transfusion requirements, but also on neutropenia and thrombocytopenia during induction therapy.
Patients From January 1992 to January 1997, 38 patients with newly diagnosed neuroblastoma of Pediatric Oncology Group stage C or D (International Neuroblastoma Staging System, 2b, 3, 4) were enrolled on the NB91 protocol at St Jude Children's Research Hospital (Memphis, TN). All patients were at least 1 year old and had histologic proof of metastatic neuroblastoma. Bone marrow involvement was assessed by conventional histologic methods (including immunostaining for chromogranin A and synaptophysin). No other methods were used to quantify or measure the amount of residual marrow disease. During the study period, three additional patients older than 1 year with newly diagnosed neuroblastoma of similar stages were seen at St Jude but not enrolled on the protocol; two were in poor clinical condition and required emergency treatment, and there was considerable diagnostic uncertainty regarding the third patient at the time empiric therapy was started. The study was approved by the institutional review board, and informed parental permission for all enrolled patients was obtained according to institutional guidelines.
Chemotherapy and Stem-Cell Rescue
Hematopoietic Growth Factors and Supportive Care During induction therapy, all 38 patients received G-CSF (Neupogen; Amgen, Thousand Oaks, CA) subcutaneously at 10 µg/kg per day. G-CSF administration started 24 hours after a cycle of chemotherapy and continued until 2 days before the start of the next cycle of chemotherapy. On day 6 of the first cycle, patients were randomly assigned to receive (n = 18) or not receive (n = 20) recombinant EPO (Epoetin alfa, Procrit; Ortho Biotech Products, LP, Raritan, NJ). Patients whose hemoglobin concentration was  8 g/dL before the start of induction chemotherapy received packed RBC transfusions to achieve a hemoglobin concentration > 8 g/dL. EPO was given subcutaneously, daily, initially at 200 U/kg, starting on day 6 of cycle 1 and continuing until 48 hours before the start of cycle 2. In subsequent cycles, EPO was given 24 hours after completion of chemotherapy. If the hemoglobin concentration remained less than 10 g/dL, EPO was administered daily, but if the hemoglobin concentration was  10 g/dL, EPO was given thrice weekly (Monday, Wednesday, and Friday) to maintain a hemoglobin concentration between 10 g/dL and 13 g/dL. If the hemoglobin concentration exceeded 13 g/dL, EPO was not administered until the concentration decreased below 13 g/dL. Patients having evidence of iron deficiency (widened RBC distribution and transferrin saturation < 15%) received oral iron supplementation with ferrous sulfate (2 mg/kg per day).
Patients in either treatment arm received RBC transfusions only when their hemoglobin concentration was
Statistical Methods and Study Design The primary end point was the effectiveness of EPO in decreasing each patient's total RBC transfusion requirements (cc/kg). Fifteen patients per treatment arm were deemed sufficient to detect a decrease of 25% in the total transfusion requirement using a one-sided alternative with a type I error rate of 5% and power of 80%. We expected to detect a decrease of approximately 25% (21 mL/kg, if the average were 82 mL/kg, as we found in a previous study) in the transfusion requirement. The survival period was defined as the interval from the time of diagnosis to the time of last contact or death from any cause. The progression-free survival period was defined as the interval from the time of diagnosis to the time of last contact, relapse, disease progression, or death from any cause. The method of Kaplan and Meier was used to estimate the probabilities of survival and progression-free survival, and the exact log-rank test was used to compare the distributions of survival probability. Fisher's exact test was used to identify differences between groups with respect to categoric variables, and the exact Wilcoxon rank sum test was used to compare continuous response variables between groups. When comparing continuous measures (eg, days of neutropenia or total RBC transfusion requirements), we also computed an adjusted measure accounting for each patient's time at risk. Differences in total RBC transfusion requirements and the number of RBC transfusions between treatment groups were further explored by using a repeated measures mixed model to account for correlation among multiple observations of the same subject.27
Patient Characteristics The characteristics of the 38 patients enrolled on the study are listed in Table 2. Most patients (25 of 38 [66%]) were male, and 74% were white. The treatment groups did not significantly differ in terms of age (P = .99), baseline hemoglobin concentration (P = .99), or disease stage (P = .41). There was no significant difference between the treatment groups when age (P = .94) or baseline hemoglobin concentration (P = .26) was analyzed as a continuous variable.
The results of laboratory studies at diagnosis are listed in Tables 3 and 4. The median baseline hemoglobin concentration, baseline platelet count, and reticulocyte count did not significantly differ between the two treatment groups. Baseline EPO concentrations were available for only eight patients (median concentration, 51.75 mU/mL; range, 19 to 625 mU/mL).
Twenty-four (63%) of 38 patients had bone marrow involvement at diagnosis. The percentages of patients in each group who had marrow involvement were similar at diagnosis (60% of G-CSF group, 67% of G-CSF + EPO group; P = .74), after four cycles of chemotherapy (P = .70), and after induction (P = .99).
Compliance in Obtaining Laboratory Values
RBC Transfusion Requirements
The median total RBC transfusion requirement per patient, measured from the date of enrollment onto the study to the end of induction therapy, was 106.6 mL/kg (range, 66.6 to 202.9 mL/kg) for the G-CSF group and 161.0 mL/kg (range, 92.0 to 243.6 mL/kg; P = .005) for the G-CSF + EPO group. This difference was significant even when accounting for the duration of induction therapy (P = .007). In addition, patients who received G-CSF + EPO were given more transfusions (258 transfusions) than those who received G-CSF alone (207 transfusions), and the median total number of transfusions per patient during the six cycles of induction therapy was higher in the G-CSF + EPO group (13.5 transfusions) than in the G-CSF group (9.5 transfusions). When the analysis was restricted to transfusions given for a hemoglobin concentration A repeated measures analysis showed no significant difference in minimum hemoglobin concentration between patients given G-CSF alone and those given G-CSF + EPO (P = .082). However, patients given G-CSF + EPO had lower average minimum hemoglobin concentrations during five of the six cycles of induction therapy (Fig 1).
We also calculated the median difference between hemoglobin concentrations at the start and end of induction therapy for 17 patients treated with G-CSF alone and 13 treated with G-CSF + EPO. The second (after therapy) hemoglobin concentration was that obtained no more than 7 days before or after the last day of induction therapy. The median decrease was 0.8 g/dL for those who received G-CSF alone and 0.1 g/dL for those given G-CSF + EPO (P = .35). We found no significant difference in reticulocyte counts at the start and end of induction therapy between the two treatment groups. Because hemoglobin response may lag 4 weeks or more behind initiation of EPO treatment, we assessed hemoglobin concentrations between weeks 4 and 7 of induction. The highest concentration occurred at a median of 5 weeks; the median increase was 1.3 g/dL above baseline. However, there was no evidence of a difference in maximum hemoglobin response between the two groups (P = .41).
Iron Laboratory Assessments and Supplementation
Duration and Sequelae of Neutropenia
Platelet Transfusion Requirements
Time Required to Complete Induction Therapy
Response to Chemotherapy for Neuroblastoma
Patient Outcome
Addition of EPO to G-CSF for patients receiving intensively timed induction chemotherapy with cyclophosphamide, doxorubicin, etoposide, and cisplatin for high-risk neuroblastoma resulted in patients having increased, rather than decreased, RBC transfusion requirements. This finding was surprising and deserves careful analysis. Assessment of similar regimens has suggested that frequent complications may result from treatment-related pancytopenia. Indeed, all patients on the current study required blood and platelet transfusions during induction therapy, and febrile neutropenia developed after 92 (39%) of 233 cycles of chemotherapy, despite the administration of G-CSF. There are several possible explanations for our unexpected results. First, the two treatment groups may have had some important differences. Although hemoglobin concentrations were not significantly different between the groups at enrollment (median, 8.85 v 9.35 g/dL for the G-CSF and G-CSF + EPO groups, respectively; P = .26), the power of this observation is limited by the size of the study. To control for a possible difference in baseline hemoglobin levels, we compared RBC transfusion requirements and numbers of transfusions between groups, stratified by hemoglobin concentration at enrollment. Both end points were significantly different (P < .01). Unfortunately, baseline erythropoietin concentration—a possible predictor of responsiveness to EPO therapy18,28—was unknown for many patients; the two groups may have differed on this variable. Other factors that may contribute to anemia, such as documented infections or hemorrhage, were not significantly different between groups. Alternatively, iron deficiency anemia, a possible consequence of EPO administration,29 may have developed in the EPO-treated group. Although patients were not initially given iron supplementation, they were observed for laboratory evidence of iron deficiency and treated if necessary. While this is a theoretical concern when using EPO, we did not see this complication during this study. No patient on study required or was supplemented with iron. However, differences between treatment groups may have been smaller if we had given iron routinely at the start of EPO therapy, as done in some studies.17,18 It is unknown how cytokine dose and scheduling affects RBC production. On the basis of knowledge available at the time this treatment protocol was initiated in 1991, we administered EPO in a schedule similar to that used for G-CSF (200 U/kg, daily, starting 1 day after each chemotherapy cycle and continuing until 2 days before the next cycle) but different from that currently recommended (150 U/kg per dose, thrice weekly, throughout chemotherapy).30,31 Because EPO may take several weeks to increase the hematocrit, even in healthy persons, its intermittent use may have reduced its efficacy. However, our cumulative EPO dose is greater than that resulting from the continual administration of 150 U/kg doses thrice weekly, despite intermittent administration. Our dose of G-CSF of 10 mcg/kg/d is twice the current standard,8,9 and it is unknown whether the higher dose contributed to anemia. Another possible cause of the greater transfusion requirement of the G-CSF + EPO group is the development of anti-EPO antibodies. High-specificity, low-affinity antibodies to EPO have been reported in patients receiving long-term EPO therapy for renal failure.32 Although the relevance of these antibodies to recombinant EPO use is unclear, red-cell aplasia has been reported in patients with systemic lupus erythematosus33 and renal disease.34 No anti-EPO antibodies were detected in a recent analysis of EPO-treated myelodysplastic syndrome,35 and we are unaware of any other reports of anti-EPO antibody formation in patients with cancer. However, the use of certain recombinant products to treat postchemotherapeutic thrombocytopenia has resulted in antibody formation and lower platelet counts,36 and these problems remain a possible, albeit unlikely, complication of cytokine administration. How the presence of metastatic bone marrow disease affects the response to hematopoietic growth factors is unknown. The overall incidence of bone marrow involvement is much higher with neuroblastoma than with other pediatric solid tumors, and induction therapy fails to clear the marrow of disease in up to 10% of high-risk patients.1 Given the inhibitory effects of neuroblastoma cells on hematopoiesis,7,37 cytokine use may be less effective in patients with neuroblastoma than in patients with other solid tumors that metastasize less frequently to the marrow. However, the presence of residual marrow disease as assessed in our study is unlikely to have contributed to the noted differences. We found no significant difference between groups in the number of patients with marrow involvement at diagnosis, after four cycles of chemotherapy, or after induction therapy. The most likely explanation for our observed lack of benefit of EPO involves the kinetics of erythropoiesis following an intensive regimen of chemotherapy. Concentrations of endogenous EPO typically remain high for several days after a cycle of intensive chemotherapy,38 and few EPO-responsive erythroid progenitors may be present until late in the recovery phase.39 When chemotherapy is myelosuppressive and intensively timed, as in our study, the 17 to 20 days between cycles of chemotherapy may be insufficient time for exogenous EPO to act optimally. Indeed, the intensity of therapy may be the primary determinant of EPO benefits seen after less myelosuppressive regimens16-18 but not after high-dose chemotherapy and subsequent autologous stem-cell transplantation.39-41 Because we used relatively large doses of cytokines in this study, we were concerned that stem-cell competition may occur. Preclinical studies have shown that EPO given at high-doses can inhibit production of neutrophils21 and platelets.22 Further, when large doses of G-CSF and EPO are given concurrently to mice, cross-inhibition of granulopoiesis and erythropoiesis occurs.23 Nevertheless, we saw no evidence that stem-cell competition worsened the neutropenia or thrombocytopenia in our patients. EPO receptors have been identified on various types of solid tumor cells, including cultured neuroblastoma cells,42 thus the use of EPO could, potentially, accelerate tumor growth. We saw no evidence supporting this possibility; the probabilities of progression-free and overall survival were similar between groups. Indeed, concurrent administration of EPO and G-CSF was well tolerated—no patient needed to discontinue cytokine therapy because of side effects.
The use of EPO has become more attractive in light of recent American Society of Clinical Oncology (ASCO) recommendations concerning adults receiving chemotherapy for a solid tumor whose hemoglobin concentration is
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Victor M. Santana, Amgen.
Supported in part by United States Public Health Service Cancer Center Support (CORE) Grant CA-21765; Childhood Solid Tumor Program Project Grant CA-23099; Amgen Inc; and the American Lebanese Syrian Associated Charities. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341:1165-1173, 1999 2. Katzenstein MH, Cohn SL: Advances in the diagnosis and treatment of neuroblastoma. Curr Opin Oncol 10:43-51, 1998[Medline] 3. Cheung N-K, Heller G: Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. J Clin Oncol 9:1050-1058, 1991[Abstract] 4. Pearson AD, Craft AW, Pinkerton CR, et al: High-dose rapid schedule chemotherapy for disseminated neuroblastoma. Eur J Cancer 28A:1654-1659, 1992 5. Bowman LC, Hancock ML, Santana VM, et al: Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: The St. Jude Children's Research Hospital experience, 1962 to 1988. J Clin Oncol 9:1599-1608, 1991[Abstract] 6. DuBois SG, Kalika Y, Lukens JN, et al: Metastatic sites on stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 21:181-189, 1999[CrossRef][Medline]
7. Sietsma H, Nijhof W, Dontje B, et al: Inhibition of hemopoiesis in vitro by neuroblastoma-derived gangliosides. Cancer Res 58:4840-4844, 1998 8. Wagner LM, Furman WL: Haemopoietic growth factors in paediatric oncology: a review of the literature. Paediatr Drugs 3:195-217, 2001[CrossRef][Medline]
9. American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 12:2471-2508, 1994
10. Lord BI, Bronchud MH, Owens S, et al: The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor. Proc Natl Acad Sci U S A 86:9499-9503, 1989 11. Michon JM, Hartmann O, Bouffet E, et al: An open-label, multicentre, randomized Phase 2 study of recombinant human granulocyte colony-stimulating factor (filgrastim) as an adjunct to combination chemotherapy in paediatric patients with metastatic neuroblastoma. Eur J Cancer 34:1063-1069, 1998
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13. Goodnough LT, Monk TG, Andriole GL: Erythropoietin therapy. N Engl J Med 336:933-938, 1997 14. Henry DH, Abels RI: Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: Results of double-blind and open-label follow-up series. Semin Oncol 21:21-28, 1994 (suppl 3)[Medline] 15. Ludwig H, Sundal E, Pecherstorfer M, et al: Recombinant human erythropoietin for the correction of cancer associated anemia with or without concomitant cytotoxic therapy. Cancer 76:2319-2329, 1995[CrossRef][Medline] 16. Leon P, Jiminez M, Barona, et al: Recombinant human erythropoietin for the treatment of anemia in children with malignant solid tumors. Med Pediatr Oncol 30:110-116, 1998[CrossRef][Medline] 17. Porter JC, Leahey A, Polise K, et al: Recombinant human erythropoietin reduces the need for erythrocyte and platelet transfusions in pediatric patients with sarcoma: A randomized, double-blind, placebo-controlled trial. J Pediatr 129:656-660, 1996[CrossRef][Medline] 18. Bolonaki I, Stiakaki E, Lydaki E, et al: Treatment with recombinant human erythropoietin in children with malignancies. Pediatr Hematol Oncol 13:111-121, 1996[Medline] 19. Crawford J, Cella D, Cleveland CS, et al: Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 95:888-895, 2002[CrossRef][Medline]
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21. Christensen RD, Lietchy KW, Koenig JM, et al: Administration of erythropoietin to newborn rats results in diminished neutrophil production. Blood 78:1241-1246, 1991
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23. de Haan G, Engel C, Dontje B, et al: Mutual inhibition of murine erythropoiesis and granulopoiesis during combined erythropoietin, granulocyte colony-stimulating factor, and stem cell factor administration: In vivo interactions and dose-response surfaces. Blood 84:4157-4163, 1994
24. Pierelli L, Perillo A, Greggu S, et al: Erythropoietin addition to granulocyte colony-stimulating factor abrogates life-threatening neutropenia and increases peripheral blood progenitor cell mobilization after epirubicin, paclitaxel, and cisplatin combination chemotherapy: Results of a randomized comparison. J Clin Oncol 17:1288-1295, 1999
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28. Ludwig H, Fritz E, Leitgeb C, et al: Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood 84:1056-1063, 1994 29. Van Wyck DB: Iron management during recombinant human erythropoietin therapy. Am J Kidney Dis 14:9-13, 1989 (2 Suppl 1)[Medline]
30. Rizzo JD, Lichtin AE, Woolf SH, et al: Use of Epoetin in patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20:4083-4107, 2002 31. Feusner J, Hastings C: Recombinant human erythropoietin in pediatric oncology: A review. Med Pediatr Oncol 39:463-468, 2002[CrossRef][Medline] 32. Castelli G, Famularo A, Semino C, et al: Detection of anti-erythropoietin antibodies in haemodyalisis patients treated with recombinant human erythropoietin. Pharmacol Res 41:313-318, 2000[CrossRef][Medline] 33. Tzioufas AG, Kokori SI, Petrovas CI, et al: Autoantibodies to human recombinant erythropoietin in patients with systemic lupus erythematosus: Correlation with anemia. Arthritis Rheum 40:2212-2216, 1997[Medline] 34. Prabkhar SS, Muhfelder T: Antibodies to recombinant human erythropoietin causing pure red cell aplasia. Clin Nephrol 47:331-335, 1997[Medline] 35. Voulgari PV, Hatzimichael EC, Tsiara S, et al: Investigation for the presence of anti-erythropoietin antibodies in patients with myelodysplastic syndrome. Eur J Haematol 66:31-36, 2001[CrossRef][Medline]
36. Li J, Yang C, Xia Y, et al: Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98:3241-3248, 2001
37. Shurin GV, Shurin MR, Bykovskaia S, et al: Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Res 61:363-369, 2001 38. Lazarus HM, Goodnough LT, Goldwasser E, et al: Serum erythropoietin levels and blood component therapy after autologous bone marrow transplantation: Implications for erythropoietin in this setting. Bone Marrow Transplant 10:71-75, 1992[Medline] 39. Locatelli F, Zecca M, Pedrazzoli P, et al: Use of recombinant human erythropoietin after bone marrow transplantation in pediatric patients with leukemia: Effect on erythroid repopulation in autologous vs. allogeneic transplants. Bone Marrow Transplant 13:403-410, 1994[Medline]
40. Chao NJ, Scriber JR, Long G, et al: A randomized study of erythropoietin and granulocyte colony-stimulating factor (G-CSF) versus placebo and G-CSF for patients with Hodgkin's and Non-Hodgkins lymphoma undergoing autologous bone marrow transplantation. Blood 83:2823-2828, 1994 41. Vannucchi AM, Bosi A, Ieri A, et al: Combination therapy with G-CSF and erythropoietin after autologous bone marrow transplantation for lymphoid malignancies: A randomized trial. Bone Marrow Transplant 17:527-531, 1996[Medline] 42. Wollman Y, Westphal G, Blum M, et al: The effect of human recombinant erythropoietin on the growth of a human neuroblastoma cell line. Life Sci 59:315-322, 1996[CrossRef][Medline]
43. Cascinu S, Fedeli A, Del Ferro E, et al: Recombinant human erythropoietin treatment in cisplatin-associated anemia: A randomized, double-blind trial with placebo. J Clin Oncol 12:1058-1062, 1994 44. Thatcher N, De Campos ES, Bell DR, et al: Epoietin alpha prevents anemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 80:296-302, 1999 45. Rothmann SA, Paul P, Weick JK, et al: Effect of cis-diamminedichloroplatinum on erythropoietin production and hematopoietic progenitor cells. Int J Cell Cloning 3:415-423, 1985[Medline] Submitted December 30, 2003; accepted February 27, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
