Journal of Clinical Oncology The Official Journal of the American Society of Clinical Oncology
Vol 8, No 6
June 1990
EDITORIAL
Recombinant Erythropoietin Therapy in Cancer Patients
AS
STATED so persuasively a recent review by Gasson and Golde,' in "The hemopoietins may effect a revolution in medicine as profound as the introduction of antibiotics a half a century ago." Clearly, recombinant hematopoietic growth factors are likely to play a major and expanding role in the management of patients with cancer. The administration of recombinant myeloid cytokines (granulocyte colony-stimulating factor, granulocyte-macrophage colonystimulating factor, and, perhaps, interleukin-3) are likely to expand both the scope and safety of chemotherapeutic and marrow transplant programs, enabling an earlier recovery of granulocytes and monocytes and, perhaps, platelets following chemotherapy-induced myelosuppression. As the report by Oster et a12 in this issue of the Journal of Clinical Oncology demonstrates, recombinant human erythropoietin (rhEpo) may also be a significant contributor to the management of patients with cancer. They describe six patients with hematologic malignancies who responded to "pharmacologic" doses of rhEpo with a significant improvement in hemoglobin levels and a decrease in transfusion requirements. Erythropoietin (Epo) is the primary regulator of erythropoiesis in humans and other mammals. This regulation is based on an elegant "negativefeedback" servo-mechanism, whereby hypoxia is sensed in the kidney, resulting in increased production of Epo by the kidney. In response to an elevated level of Epo in the plasma, the red cell mass expands. If hypoxia is corrected, Epo production in the kidney will be suppressed. Thus, Epo is a bona fide hormone secreted from the kidney and transported via the plasma to a distant site, the bone marrow. In contrast, the
cells producing other hemopoietins are generally in close proximity to their target cells. The cloning of the Epo gene 3'4 has permitted large-scale production of human Epo. No significant structural differences between the recombinant and native molecules have been reported. After intravenous infusion, both the native and the recombinant molecules have a half-life in the plasma of about 5 hours. In comparison to the other recombinant hemopoietins, rhEpo has the highest degree of specificity and safety. In humans, it appears to act almost exclusively on committed erythroid progenitor and precursor cells, allowing these cells to proliferate and enter into terminal erythroid maturation, thereby expanding the production of new RBCs. Epo binds to a unique membrane protein that has recently been cloned and expressed. 5 Epo receptor mRNA has been detected only in erythroid progenitor and precursor cells. The Epo receptor is a member of a recently recognized family of growth factor receptors. It has sequence homology with receptors for granulocyte-macrophage colonystimulating factor, interleukin-3, interleukin-4, interleukin-6, interleukin-7, and with the 0 subunit of the interleukin-2 receptor. Very little is known about the molecular events following the binding of Epo to its receptor that lead to proliferation and differentiation of erythroid cells. Once rhEpo became available for clinical trials, the first application was obvious: the treatment of anemia of uremia,6-8 which, compared with other types of anemias, is associated with markedly decreased levels of Epo. The responses of these uremic patients exceeded even the most optimistic expectations. Indeed, barring coexistent iron deficiency or some other mechanism
Journalof Clinical Oncology, Vol 8, No 6 (June), 1990: pp 949-951
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
949
950
H. FRANKLIN BUNN
suppressing erythropoiesis, the anemia of uremia can be "cured" by the administration, either intravenously or subcutaneously, of rhEpo. To date, thousands of dialysis and predialysis patients have benefited from treatment, with minimal toxicity. The correction of their anemia has been accompanied by improvement in both exercise tolerance and quality of life. 9 Bolstered by this remarkable success, clinical investigators are now turning to other (nonrenal) types of anemias that might benefit from therapy with rhEpo. In these nonuremic patients, the endogenous levels of plasma Epo increase on a logarithmic scale in proportion to the degree of anemia.'o Therefore, it seemed likely that patients with severe anemia, who already have an extremely high level of endogenous hormone, would probably not respond to additional administration of high doses of rhEpo. Nevertheless, the specificity and safety of rhEpo has justified the search for clinical applications beyond the anemia of uremia. Investigators first turned to other common types of chronic anemias: those due to chronic inflammation and malignancy. Means et al" recently showed that the anemia associated with chronic rheumatoid arthritis could be partially corrected by high doses of rhEpo. In like manner, patients with acquired immune deficiency syndrome and anemia due in part to zidovudine therapy have been shown to benefit from rhEpo if their baseline plasma Epo level was low.1 2 A small number of patients with myelodysplastic anemias have been treated with rhEpo. Overall, the response rate in this latter group of patients appears to be rather low, probably owing to impaired hematopoiesis. Patients with malignant tumors commonly have a mild to moderate normochromic-normocytic anemia. In common with other "anemias of chronic inflammation," the serum iron and total iron-binding capacity are low, and the serum ferritin is high, indicating a block in the transfer of iron from stores to the erythroid precursor cells. In occasional cancer patients, the anemia is much more severe, due to either blood loss, marrow infiltration by tumor, or on occasion hemolysis, either microangiopathic or autoimmune. There is sound rationale for the administration of Epo to patients with uncomplicated
anemia of malignancy. Their bone marrows generally have adequate pools of erythroid progenitor and precursor cells that are capable of orderly erythropoiesis. Moreover, many,' 3 6' but not all,'0 reports suggest that patients with the anemias of chronic inflammation,13-16 including malignancy,' 3 '16 have somewhat lower levels of Epo in comparison to patients with other types of anemia of similar severity. If so, the case for rhEpo therapy becomes stronger. Although the anemia in patients with cancer is seldom a dominant factor in their overall symptoms and morbidity, a safe and effective way to increase the red cell mass may add significantly to their overall performance status. The results that Oster et a12 have obtained from patients with hematologic malignancies indicate that this may be the case. It will clearly be important to extend this study to the much larger groups of patients with anemias secondary to solid malignant tumors. It may be that patients with solid tumors may respond even better to rhEpo, to the extent that their marrow is free of infiltrating tumor. Therapy with rhEpo may have a more compelling rationale in cancer patients receiving chemotherapy. Patients treated with cisplatin have been shown to have unexpectedly low levels of Epo in their plasma," and, accordingly, have responded well to rhEpo therapy.'8 For unclear reasons, patients who receive extensive cytotoxic chemotherapy, such as for acute leukemia or marrow transplantation, develop a prompt rise in plasma Epo levels followed by a fall.'9-21 These changes cannot be fully explained by fluctuations in hemoglobin level. It may be that chemotherapeutic agents impose some degree of toxicity on the cell in the kidney responsible for Epo production. Appropriate concern is reverberating about the safety of blood transfusions. For this reason as well as the considerations outlined above, there is sound rationale for the use of rhEpo to support and stimulate erythropoiesis in selected cancer patients before and during chemotherapy. H. Franklin Bunn Brigham and Women's Hospital HarvardMedical School Boston, MA
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
951
EDITORIAL REFERENCES 1. Gasson DW, Golde JC: Hormones that stimulate the growth of blood cells. Sci Am 259:62-70, 1988 2. Oster W, Herrmann F, Gamm H, et al: Erythropoietin (Epo) for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 8:956-962, 1990 3. Jacobs K, Shoemaker C, Rudersdorf R, et al: Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313:806-810, 1985 4. Lin F-K, Suggs S, Lin C-H, et al: Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 82:7580-7584, 1985 5. D'Andrea AD, Lodish H, Wong GC: Expression cloning of the murine erythropoietin receptor. Cell 57:277-285, 1986 6. Eschbach JW, Egrie JC, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. N Engl J Med 316:73-80, 1987 7. Winearls CG, Oliver DO, Pippard MJ, et al: Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 2:1175-1178, 1986 8. Eschbach JW, Abdulhadi MH, Browne JK, et al: Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 111:992-1000, 1989 9. Evans RW, Rader B, Manninen DL: The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. JAMA 263:825-830, 1990 10. Erslev AJ, Wilson J, Caro J: Erythropoietin titers in anemic, nonuremic patients. J Lab Clin Med 109:429-433, 1987 11I.Means RT Jr, Olsen NJ, Krantz SB, et al: Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: Clinical and in vitro studies. Arthritis Rheum 32:638-642, 1989 12. Erythropoietin (EPO) Study Group, Rudnick SA:
Human recombinant erythropoietin (r-HuEPO): A doubleblind, placebo-controlled study in acquired immunodeficiency syndrome (AIDS) patients with anemia induced by disease and AZT. Proc Am Soc Clin Oncol. 8:2, 1989 (abstr) 13. Ward HP, Kurnick JE, Pisarczyk MJ: Serum level of erythropoietin in anemias associated with chronic infection, malignancy, and primary hematopoietic disease. J Clin Invest 50:332-335, 1971 14. Baer AN, Dessypris EN, Goldwasser E, et al: Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol 66:559-564, 1987 15. Hochberg MC, Arnold CM, Hogans BB, et al: Serum immunoreactive erythropoietin in rheumatoid arthritis: Impaired response to anemia. Arthritis Rheum 31:1318-1321, 1988 16. Miller CB, Jones RJ, Piantadosi S, et al: Decreased erythropoietin (EPO) response associated with the anemia of malignancy. Proc Am Soc Clin Oncol 8:182, 1989 (abstr) 17. Rothmann SA, Paul P, Weick JK, et al: Effect of cis-diamminedichloroplatinum on erythropoietin production and hematopoietic progenitor cells. Int J Cell Cloning 3:415423, 1985 18. Henry DH, Rudnick SA, Bryant E, et al: Preliminary report of two double blind, placebo controlled studies using human recombinant erythropoietin (rHuEpo) in the anemia associated with cancer. Blood 74:6a, 1989 (abstr) 19. Birgegard G, Wide L, Simonsson B: Marked erythropoietin increase before fall in Hb after treatment with cytostatic drugs, suggest mechanism other than anaemia for stimulation. Br J Haematol 72:462-466, 1989 20. Piroso E, Erslev AJ, Caro J: Inappropriate increase in erythropoietin titers during chemotherapy. Am J Hematol 32:248-254, 1989 21. Schapira L, Antin JH, Eder JP, et al: Determination of serum erythropoietin levels in patients undergoing bone marrow transplantation (BMT). Blood 74:243a, 1989 (abstr)
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Vol 8, No 6
June 1990
EDITORIAL
Recombinant Erythropoietin Therapy in Cancer Patients
AS
STATED so persuasively a recent review by Gasson and Golde,' in "The hemopoietins may effect a revolution in medicine as profound as the introduction of antibiotics a half a century ago." Clearly, recombinant hematopoietic growth factors are likely to play a major and expanding role in the management of patients with cancer. The administration of recombinant myeloid cytokines (granulocyte colony-stimulating factor, granulocyte-macrophage colonystimulating factor, and, perhaps, interleukin-3) are likely to expand both the scope and safety of chemotherapeutic and marrow transplant programs, enabling an earlier recovery of granulocytes and monocytes and, perhaps, platelets following chemotherapy-induced myelosuppression. As the report by Oster et a12 in this issue of the Journal of Clinical Oncology demonstrates, recombinant human erythropoietin (rhEpo) may also be a significant contributor to the management of patients with cancer. They describe six patients with hematologic malignancies who responded to "pharmacologic" doses of rhEpo with a significant improvement in hemoglobin levels and a decrease in transfusion requirements. Erythropoietin (Epo) is the primary regulator of erythropoiesis in humans and other mammals. This regulation is based on an elegant "negativefeedback" servo-mechanism, whereby hypoxia is sensed in the kidney, resulting in increased production of Epo by the kidney. In response to an elevated level of Epo in the plasma, the red cell mass expands. If hypoxia is corrected, Epo production in the kidney will be suppressed. Thus, Epo is a bona fide hormone secreted from the kidney and transported via the plasma to a distant site, the bone marrow. In contrast, the
cells producing other hemopoietins are generally in close proximity to their target cells. The cloning of the Epo gene 3'4 has permitted large-scale production of human Epo. No significant structural differences between the recombinant and native molecules have been reported. After intravenous infusion, both the native and the recombinant molecules have a half-life in the plasma of about 5 hours. In comparison to the other recombinant hemopoietins, rhEpo has the highest degree of specificity and safety. In humans, it appears to act almost exclusively on committed erythroid progenitor and precursor cells, allowing these cells to proliferate and enter into terminal erythroid maturation, thereby expanding the production of new RBCs. Epo binds to a unique membrane protein that has recently been cloned and expressed. 5 Epo receptor mRNA has been detected only in erythroid progenitor and precursor cells. The Epo receptor is a member of a recently recognized family of growth factor receptors. It has sequence homology with receptors for granulocyte-macrophage colonystimulating factor, interleukin-3, interleukin-4, interleukin-6, interleukin-7, and with the 0 subunit of the interleukin-2 receptor. Very little is known about the molecular events following the binding of Epo to its receptor that lead to proliferation and differentiation of erythroid cells. Once rhEpo became available for clinical trials, the first application was obvious: the treatment of anemia of uremia,6-8 which, compared with other types of anemias, is associated with markedly decreased levels of Epo. The responses of these uremic patients exceeded even the most optimistic expectations. Indeed, barring coexistent iron deficiency or some other mechanism
Journalof Clinical Oncology, Vol 8, No 6 (June), 1990: pp 949-951
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
949
950
H. FRANKLIN BUNN
suppressing erythropoiesis, the anemia of uremia can be "cured" by the administration, either intravenously or subcutaneously, of rhEpo. To date, thousands of dialysis and predialysis patients have benefited from treatment, with minimal toxicity. The correction of their anemia has been accompanied by improvement in both exercise tolerance and quality of life. 9 Bolstered by this remarkable success, clinical investigators are now turning to other (nonrenal) types of anemias that might benefit from therapy with rhEpo. In these nonuremic patients, the endogenous levels of plasma Epo increase on a logarithmic scale in proportion to the degree of anemia.'o Therefore, it seemed likely that patients with severe anemia, who already have an extremely high level of endogenous hormone, would probably not respond to additional administration of high doses of rhEpo. Nevertheless, the specificity and safety of rhEpo has justified the search for clinical applications beyond the anemia of uremia. Investigators first turned to other common types of chronic anemias: those due to chronic inflammation and malignancy. Means et al" recently showed that the anemia associated with chronic rheumatoid arthritis could be partially corrected by high doses of rhEpo. In like manner, patients with acquired immune deficiency syndrome and anemia due in part to zidovudine therapy have been shown to benefit from rhEpo if their baseline plasma Epo level was low.1 2 A small number of patients with myelodysplastic anemias have been treated with rhEpo. Overall, the response rate in this latter group of patients appears to be rather low, probably owing to impaired hematopoiesis. Patients with malignant tumors commonly have a mild to moderate normochromic-normocytic anemia. In common with other "anemias of chronic inflammation," the serum iron and total iron-binding capacity are low, and the serum ferritin is high, indicating a block in the transfer of iron from stores to the erythroid precursor cells. In occasional cancer patients, the anemia is much more severe, due to either blood loss, marrow infiltration by tumor, or on occasion hemolysis, either microangiopathic or autoimmune. There is sound rationale for the administration of Epo to patients with uncomplicated
anemia of malignancy. Their bone marrows generally have adequate pools of erythroid progenitor and precursor cells that are capable of orderly erythropoiesis. Moreover, many,' 3 6' but not all,'0 reports suggest that patients with the anemias of chronic inflammation,13-16 including malignancy,' 3 '16 have somewhat lower levels of Epo in comparison to patients with other types of anemia of similar severity. If so, the case for rhEpo therapy becomes stronger. Although the anemia in patients with cancer is seldom a dominant factor in their overall symptoms and morbidity, a safe and effective way to increase the red cell mass may add significantly to their overall performance status. The results that Oster et a12 have obtained from patients with hematologic malignancies indicate that this may be the case. It will clearly be important to extend this study to the much larger groups of patients with anemias secondary to solid malignant tumors. It may be that patients with solid tumors may respond even better to rhEpo, to the extent that their marrow is free of infiltrating tumor. Therapy with rhEpo may have a more compelling rationale in cancer patients receiving chemotherapy. Patients treated with cisplatin have been shown to have unexpectedly low levels of Epo in their plasma," and, accordingly, have responded well to rhEpo therapy.'8 For unclear reasons, patients who receive extensive cytotoxic chemotherapy, such as for acute leukemia or marrow transplantation, develop a prompt rise in plasma Epo levels followed by a fall.'9-21 These changes cannot be fully explained by fluctuations in hemoglobin level. It may be that chemotherapeutic agents impose some degree of toxicity on the cell in the kidney responsible for Epo production. Appropriate concern is reverberating about the safety of blood transfusions. For this reason as well as the considerations outlined above, there is sound rationale for the use of rhEpo to support and stimulate erythropoiesis in selected cancer patients before and during chemotherapy. H. Franklin Bunn Brigham and Women's Hospital HarvardMedical School Boston, MA
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
951
EDITORIAL REFERENCES 1. Gasson DW, Golde JC: Hormones that stimulate the growth of blood cells. Sci Am 259:62-70, 1988 2. Oster W, Herrmann F, Gamm H, et al: Erythropoietin (Epo) for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 8:956-962, 1990 3. Jacobs K, Shoemaker C, Rudersdorf R, et al: Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313:806-810, 1985 4. Lin F-K, Suggs S, Lin C-H, et al: Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 82:7580-7584, 1985 5. D'Andrea AD, Lodish H, Wong GC: Expression cloning of the murine erythropoietin receptor. Cell 57:277-285, 1986 6. Eschbach JW, Egrie JC, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. N Engl J Med 316:73-80, 1987 7. Winearls CG, Oliver DO, Pippard MJ, et al: Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 2:1175-1178, 1986 8. Eschbach JW, Abdulhadi MH, Browne JK, et al: Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 111:992-1000, 1989 9. Evans RW, Rader B, Manninen DL: The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. JAMA 263:825-830, 1990 10. Erslev AJ, Wilson J, Caro J: Erythropoietin titers in anemic, nonuremic patients. J Lab Clin Med 109:429-433, 1987 11I.Means RT Jr, Olsen NJ, Krantz SB, et al: Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: Clinical and in vitro studies. Arthritis Rheum 32:638-642, 1989 12. Erythropoietin (EPO) Study Group, Rudnick SA:
Human recombinant erythropoietin (r-HuEPO): A doubleblind, placebo-controlled study in acquired immunodeficiency syndrome (AIDS) patients with anemia induced by disease and AZT. Proc Am Soc Clin Oncol. 8:2, 1989 (abstr) 13. Ward HP, Kurnick JE, Pisarczyk MJ: Serum level of erythropoietin in anemias associated with chronic infection, malignancy, and primary hematopoietic disease. J Clin Invest 50:332-335, 1971 14. Baer AN, Dessypris EN, Goldwasser E, et al: Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol 66:559-564, 1987 15. Hochberg MC, Arnold CM, Hogans BB, et al: Serum immunoreactive erythropoietin in rheumatoid arthritis: Impaired response to anemia. Arthritis Rheum 31:1318-1321, 1988 16. Miller CB, Jones RJ, Piantadosi S, et al: Decreased erythropoietin (EPO) response associated with the anemia of malignancy. Proc Am Soc Clin Oncol 8:182, 1989 (abstr) 17. Rothmann SA, Paul P, Weick JK, et al: Effect of cis-diamminedichloroplatinum on erythropoietin production and hematopoietic progenitor cells. Int J Cell Cloning 3:415423, 1985 18. Henry DH, Rudnick SA, Bryant E, et al: Preliminary report of two double blind, placebo controlled studies using human recombinant erythropoietin (rHuEpo) in the anemia associated with cancer. Blood 74:6a, 1989 (abstr) 19. Birgegard G, Wide L, Simonsson B: Marked erythropoietin increase before fall in Hb after treatment with cytostatic drugs, suggest mechanism other than anaemia for stimulation. Br J Haematol 72:462-466, 1989 20. Piroso E, Erslev AJ, Caro J: Inappropriate increase in erythropoietin titers during chemotherapy. Am J Hematol 32:248-254, 1989 21. Schapira L, Antin JH, Eder JP, et al: Determination of serum erythropoietin levels in patients undergoing bone marrow transplantation (BMT). Blood 74:243a, 1989 (abstr)
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
