University of Wisconsin Hematology

Biology and clinical use of cytokines and hematopoetic growth factors

General

  1. Metcalf D. Hematopoietic cytokines. Blood 2008;111:485
  2. Kaushansky K. Lineage-Specific Hematopoietic Growth Factors. NEJM 2006;354:2034

G-CSF/GM-CSF

  1. Anderlini and Champlin. Biologic and molecular effects of granulocyte colony-stimulating factor in healthy individuals: recent findings and current challenges. Blood 2008;111:1767
  2. Hirsch et al. Effects of granulocyte-colony stimulating factor on chromosome aneuploidy and replication asynchrony in healthy peripheral blood stem cell donors. Blood 2011;118:2602(No evidence that G-CSF, as given to stem cell donors, causes chromosomal instability)
  3. Hercus et al. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood 2009;114:1289
  4. Hartmann et al. Granulocyte colony-stimulating factor in severe chemotherapy-induced febrile neutropenia. NEJM 1997;336:1776
  5. Sung et al. Meta-analysis: Effect of Prophylactic Hematopoietic Colony-Stimulating Factors on Mortality and Outcomes of Infection. Ann Intern Med 2007;147:400(They reduce infection rate but have little effect on survival)
  6. Wan et al. Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Prevention and Treatment of Invasive Fungal Disease in Recipients of Allogeneic Stem-Cell Transplantation: A Prospective Multicenter Randomized Phase IV Trial. J Clin Oncol 2015;33:3999(Growth factor support associated with lower overall mortality)
  7. Beekman and Touw. G-CSF and its receptor in myeloid malignancy. Blood 2010;115:5131(Reviews evidence linking G-CSF administration and leukemogenesis)
  8. Relling et al.  Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment.  Blood 2003;101:3862
  9. Socie et al. Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT). Blood 2007;109:2794(G-CSF administration increased risk of MDS/AML by about 2)

Erythropoietin and erythropoietic drugs

  1. Rizzo et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood 2010116:4045
  2. Henry et al.  Epoetin Alfa.Clinical Evolution of a Pleiotropic Cytokine. Arch Intern Med 2004;164:262
  3. Unger et al. Erythropoiesis-stimulating agents – time for a reevaluation (editorial). NEJM 2010;362:189
  4. Besarab et al. The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin.  NEJM 1998; 339:584 (Raising hemoglobin to normal levels associated with increased mortality in dialysis patients with CHF or ischemic heart disease)
  5. Sano and Goto. Possible Mechanism of Hematocrit Elevation by Sodium Glucose Cotransporter 2 Inhibitors and Associated Beneficial Renal and Cardiovascular Effects. Circulation 2019; 139:1985 (Drugs increase EPO production, with modest rise in Hct)
  6. Remuzzi and Ingelfinger.  Correction of anemia – payoffs and problems (editorial). NEJM 2006;355:2144(Normalization of hemoglobin level in uremia with EPO does not lead to improved cardiovascular outcomes)
  7. Gowanlock et al. Erythropoiesis-stimulating agents in elderly patients with anemia: response and cardiovascular outcomes. Blood Adv 2017;1:1538(Benefit seen in patients with anemia of uncertain etiology and EPO < 200; no significant increase in CV events)
  8. Corwin et al. Efficacy and safety of epoetin alfa in critically ill patients. NEJM 2007;357:965 (EPO did not reduce transfusion requirements; it may have reduced mortality in trauma patients, but caused increased risk of thrombosis. With editorial)
  9. Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia. JAMA 2008;299:914(Increased VTE and mortality risk in patients receiving ESAs)
  10. Heinze et al. Mortality in renal transplant recipients given erythropoietins to increase haemoglobin concentration: cohort study. BMJ 2009;339:b4018 (Mortality increased in ESA recipients with Hgb > 12.5)
  11. Pfeffer et al. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. NEJM 2009;361:2019 (Giving darbepoetin to attain a target Hgb of 13 did not reduce risk of death or cardiovascular events, increased stroke risk)
  12. Rizzo et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood 2008;111:25
  13. Palmer et al. Meta-analysis: Erythropoiesis-Stimulating Agents in Patients With Chronic Kidney Disease. Ann Intern Med 2010;153:23(Targeting Hgb>12 increases risk for stroke, hypertension and vascular device thrombosis, and “probably” for death and cardiovascular events)
  14. Clement et al. The Impact of Selecting a High Hemoglobin Target Level on Health-Related Quality of Life for Patients With Chronic Kidney Disease. A systematic review and meta-analysis. Arch Intern Med 2009;169:1104 (“Targeting hemoglobin levels above 12 grams leads to small and not clinically meaningful improvements in QOL”)
  15. Solomon et al. Erythropoietic Response and Outcomes in Kidney Disease and Type 2 Diabetes. NEJM 2010;363:1146(Dose escalation in poor responders to darbepoetin associated with increased risk of cardiovascular events or death)
  16. Macdougall et al. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis. NEJM 2019;380:447(More aggressive iron replacement diminished ESA requirements)
  17. Collister et al. The Effect of Erythropoietin-Stimulating Agents on Health-Related Quality of Life in Anemia of Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2016;164:472(Targeting higher Hb does not improve quality of life)
  18. Skali et al. Stroke in Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With Darbepoetin Alfa. The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) Experience. Circulation 2011;124:2903(2-fold increased incidence of stroke in patients given darbepoetin)
  19. Ghali et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation 2008;117:526(No improvement in function or quality of life)
  20. Swedberg et al. Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure. NEJM 2013;368:1210(No improvement in outcomes)
  21. Kansagara et al. Treatment of anemia in patients with heart disease: A systematic review. Ann Intern Med 2013;159:746
  22. Casadevall et al. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial.  Blood 2004;104:321 (Treatment was expensive, and did not improve quality of life)
  23. Österborg et al. Impact of epoetin-ß on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study. Br J Haematol 2005;129:1365(no effect on survival vs placebo)
  24. Jaspers et al. Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial. Blood 2014;124:33 (EPO started one month after HSCT hastens RBC recovery and reduces transfusion requirements)
  25. Casadevall N et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. NEJM 2002;346:469
  26. Bennett et al. Pure Red-Cell Aplasia and Epoetin Therapy.  NEJM 2004;351:1403
  27. Stead et al. Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers. Blood 2006;108:1830
  28. Chen et al. Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis. NEJM 2019;381:1001(With editorial)
  29. Chen et al. Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis. NEJM 2019;381:1011(Oral agent non-inferior to EPO; with editorial)
  30. Singh et al. Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis. NEJM 2021;385:2313(with editorial)
  31. Singh et al. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis. NEJM 2021;385:2325(with editorial)
  32. Singh et al. Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients. A Randomized Clinical Trial. JAMA Intern Med 2022;182;592 (Daprodustat non-inferior to darbepoetin)
  33. Chertow et al. Vadadustat in Patients with Anemia and Non–Dialysis-Dependent CKD. NEJM 2021;384:1589 (Oral agent had comparable efficacy to darbepoetin, slightly higher risk of cardiovascular events; with editorial)
  34. Eckardt et al. Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. NEJM 2021;384:1601 (This trial showed noninferiority to darbepoetin with respect to both efficacy and safety; with editorial)

Thrombopoietin and thrombopoietic drugs

  1. Grozovsky et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 2015;21:47(Aging platelets lose sialic acid, then bind to hepatic receptor that promotes TPO production)
  2. Kuter and Begley:  Recombinant human thrombopoeitin: basic biology and evaluation of clinical studies.  Blood 2002:100:3457
  3. Kuter D. New thrombopoietic growth factors. Blood 2007;109:4607