THERAPEUTIC REVIEW

Hemopoietic Growth Factors: A Review Jacob M. Rowe, MD, and Aaron P. Rapoport, MD

The hemopoietic growth factors are peptide hormones that are known to be responsible for the in vitro and in vivo proliferation of bone marrow progenitor cells into mature differentiated cells. These cytokines have had a major impact on the management of patients with cytopenias and have been extensively used as an adjunct to the management of patients with hematologic malignancies, with or without prior intensive chemcitherapy. Other potential uses, being rigorously studied, include the potential mobilization of stem cells as well as recruitment phase-specific cells into the cell cycle, thus providing a more sensitive environment for targeting specific chemotherapeutic agents.

emopoietic growth factors are peptide hormones H that have dramatically altered the management of patients with cytopenias. These cytokines have added a new dimension to dose-intensive marrowsuppressive treatment regimens, with a potential that has yet to be fully realized. Although the major therapeutic benefit relates to the potential of these cytokines to ameliorate cytopenias, the possibility of altering the phase specificity of cycling cells is an exciting new therapeutic option that is being intensively studied for its therapeutic potential in the treatment of malignant disorders. This review, which is by no means all-inclusive, focuses on the common clinical entities in which the use of hemopoietic growth factors has been established or at least appears to have significant clinical potential. The underlying pathology is discussed as well as an assessment of the likely future directions. BACKGROUND The development of the glycoprotein hormones that constitute the hemopoietic growth factors encompass work begun by Carnot and Deflandre' soon after the turn of the century. In early classical experiments these researchers induced erythrocytosis in rabbits after infusing them with plasma from anemic rabbits.' Further progress was necessarily delayed From the Hematology Unit, University of Rochester School of Medicine and Dentistry, Rochester, New York. Address for reprints: Jacob M. Rowe, MD, University of Rochester Medical Center, Hematology Unit, Box 610, 601 Elmwood Avenue, Rochester, NY 14642.

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from the SAGE Social Science Collections. All Rights Resewed.

and had to await the development - almost 60 years later - of the appropriate culture systems and techniques in which hemopoietic progenitor cells could be grown in vitro. Initial work was described by scientists working independently in Israel and Australia, where in vitro colonies of blood cell precursors, known as colony-forming units (CFUs), were grown from suspensions that contained individual cells from mouse and subsequently from human bone marrow containing early progenitor At the onset it was recognized that for appropriate growth of CFUs, the presence of appropriate feeder layers containing critical elements from the hemopoietic microenvironment were required. It was soon clear that the type of colonies and progenitor cells that could be produced would be determined by manipulating the contents of these microenvironmental elements. The identification of hematopoietic growth factors, or colony-stimulating factors (CSFs)followed this earlier work and formally recognized the ability of these growth factors to stimulate the formation of colonies of cells that had been derived from individual bone marrow progenitors. At this point it became clear (Figure 1)that specific humoral CSFs are necessary for the adequate growth of myeloid, erythroid, lymphoid, and megakaryocytic lineages4v5The early 1970s also saw further refinement of the techniques for growing colonies of human progenitor cells, leading in 1977 to the identification of the first CSF. Macrophage-CSF (M-CSF or CSF-1) was the first CSF to be purified and clearly identified on the basis of its biologic activity after it was shown that this cytokine could stimulate the proliferation of cells of the mononuclear phagocytic series only.6

HEMOPOIETIC GROWTH FACTORS

n /

/

000

Figurc:. Physiologic e,fects of some CSFs

Besides macrophage colony-stimulating factor (MCSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) as well as erythropoietin and interleukin-3 have all been purified, their coding sequences cloned, and the products produced on a large scale through recombinant DNA technology (Table I). Although these five factors have been studied in clinical trials, other cytokines, including interleukin-1, -2, -3, -4, and -6, as well as the various interferons and tumor necrosis factors, also are being studied and have enormous potential. Nevertheless, most of published phase I, 11, and I11 clinical trials involve erythropoietin, GM-CSF, and G-CSF (Table 11), and this review is confined mostly to clinical data for these cytokines.

man proteins were partially purified, leading to molecular cloning of the complementary DNA (cDNA) sequences encoding human GM-CSF and G-CSF.'-'' Human GM-CSF is a 127-amino-acid glycoprotein whose gene has been mapped to the long arm of chromosome 5.8.11Interestingly, the loss of one copy of the genes for GM-CSF and CSF-1 (macrophage colony-stimulating factor), may contribute to the hematologic abnormalities encountered in the 5q- myelodysplastic syndrome." Human G-CSF is a 177amino-acid glycoprotein whose gene has been localized to the long arm of chromosome 17.9.'0*'3In contrast to the retinoic acid receptor a gene, which also has been mapped to 17q, no rearrangement of the human G-CSF gene is seen in acute promyelocytic leukemias bearing the 15;17 chromosomal transl~cation.'~-'~ The biologic effects of GM-CSF and G-CSF depend on binding to specific surface receptors. The GMCSF receptor is a heterodimer consisting of a and ,f3 subunits, and the G-CSF receptor appears to be monomeric, although different isoforms may exist.'618 The GM-CSF and G-CSF receptors are members of a newly described class of hematopoietic receptors that share certain structural feature^.'^*^^ Other members of this family include the erythropoietin receptor, the prolactin receptor, and the interleukin-2 (IL-2) receptor beta chain. It is also noteworthy that functional receptors for GM-CSF and G-CSF have been detected in a variety of nonhematopoietic tissues such as human placenta, and small cell carcinoma.16"21-23 Although the ability of GM-CSF and G-CSF to stimulate proliferation of normal and leukemic marrow progenitors is well e s t a b l i ~ h e d , ' *a~growing ~ - ~ ~ body of evidence suggests that these factors also activate mature effector cells both in vitro and in vivo. Some of the effects of the colony-stimulating factors (CSFs)

TABLE I Human CSFs CSF

BIOLOGY OF GROWTH FACTORS Granulocyte-macrophage colony-stimulating factor (GM-CSF)and granulocyte colony-stimulating factor (G-CSF)are among the substances required by bone marrow progenitor cells for in vitro (and presumably in vivo) growth and differentiation.' Based on their colony-stimulating properties, the murine and hu-

THERAPEUTIC REVIEW

M-CSF GM-CSF G-CSF

IL-3 Erythropoietin

Predominant Cell Origin

Macrophage, fibroblast T-cell macrophage. fibroblast Macrophage, fibroblast T cell Kupfer and pertibular kidney cells

Predominant Cell Stimulated

Macrophage Neutrophil, macrophage eosinophil Neutrophil. eosinophil basophil Neutrophil, macrophage Erythrocyte

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TABLE II Human CSFs Produced by Recombinant DNA CSF

GM-CSF

Vector

Yeast

Generic/Proprietary Names

Sargramostim/PRoKINE LEUKINE

G-CSF Erythropoietin

E. Coli E. Coli Mammalian cells

Molgramosstim/LEuCoMAx FilgraStim/NEUPOGEN Epoietin alpha/EPOGEN PROCRIT

Manufacturer

Hoeschst-Roussel lmmunex Sandoz/Sc hering Amgen Amgen Ortho

are “direct,” requiring no other stimuli, whereas ACUTE LEUKEMIA others are “indirect” and require additional stimuli such as chemotactic factors, ionophores, or immune Enormous interest has developed in the potential use seri Fnr full expression or detection. Direct effects of cytokines, specifically GM-CSF and G-CSF, in an include the ability of GM-CSF to induce the expreseffort to reduce the period of neutropenia. Because sion of the c-fos proto-oncogene as well as the genes one of the causes of death in leukemia is protracted for IL-1, IL-6, G-CSF, CSF-1, and tumor necrosis facaplasia related to chemotherapy, if indeed this petor a.2629Other direct effects include enhancement riod can be shortened and infections reduced, the of neutrophil survival, tyrosine phosphorylation of clinical potential for the use of this agent is enorintracellular substrates, modulation of surface phemous, let alone the cost effectiveness that may result notype (upregulation of CDllb, CD35, CD18; downfrom a shorter hospital stay. regulation of leukotriene B, receptor, IL-8 receptor, Additionally, the potential of GM-CSF and G-CSF and leukocyte adhesion molecule), and enhanced to induce cells into the S-phase of the cycle, thus biosynthesis of leukotriene B, and platelet-activating making them more susceptible to phase-specific f a ~ t o r . ~ ’Indirect - ~ ~ effects include enhanced killing agents such as cytosine arabinoside, has led to inof micro-organisms in the presence of opsons, entriguing preclinical and clinical experiments athanced antibody-dependent cell-mediated cytotoxictempting to actually mobilize leukemic blast cells ity toward HL-60 and lymphoid cell lines, and eninto the phase of a cycle where they would be more hanced oxidative metabolism in the presence of cheresponsive to the action of cytotoxic agents. m o a t t r a c t a n t ~ . ~The ~ - ~ *indirect or “priming” effects Because of the potential for cytokine stimulation of the CSFs may be physiologically advantageous to of acute leukemia,4547there was initially great hesithe host in that full activation of effector cells may be tation in conducting clinical trials with GM-CSF or restricted primarily to sites of inflammation and inG-CSF in acute leukemia. It is for this reason that jury. In general, fewer effects of G-CSF on neutrophil initial clinical trials using GM-CSF were not conactivation have been reported. In addition, elevated ducted for acute leukemia where, ultimately, it may serum levels of G-CSF but not GM-CSF are seen in prove to be of greatest clinical benefit. It is not surthe setting of infection^.^^.^^ These observations are prising therefore that when clinical trials finally did consistent with the notion that in vivo G-CSF may be get underway, these were initially in elderly pamore important as a neutropoietin, and GM-CSF tients, where the risk of death from marrow aplasia may function mainly as a neutrophil recruiter and was so high that this outweighed the potential risk activator. from stimulating leukemia cells. The first such trial The signaling pathway connecting receptor bindwas conducted in 1988:’ and recently the results ing by the CSFs to progenitor cell proliferation and were formally p ~ b l i s h e dIn . ~this ~ trial, GM-CSF was effector cell activation remains poorly understood. given to patients over 65 years of age with de novo Possible important second messenger systems inacute myelogenous leukemia as well as to patients in clude the guanosine-triphosphate-binding proteins second relapse. Standard induction therapy was fol(G-proteins), tyrosine kinases, the serine threonine lowed by a bone marrow examination 4 days after kinase c-raft and the enzyme systems responsible for completion of this therapy. If the nadir bone marrow generation of platelet-activating factor, leukotriene to be free of leukemia, GM-CSF was adB,, and phosphatidic a ~ i d . ~ ~ . ~ ~ * ~ ~ appeared ~ ~

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ministered at a dose of 250 pg/m2/day as a continuous infusion. Thirty patients received GM-CSF, and 2 of these showed a marked leukemic regrowth that was completely reversible in one patient and appeared to be unrelated to the GM-CSF in the other patient. The GM-CSF appeared to have no effect on remission duration, but, very significantly, the period of neutropenia was reduced by 6 to 9 days in these patients, and this was clinically associated with major improvement in infections in most of the patients. The study concluded that GM-CSF was of clear therapeutic benefit for this group of patients. It must be noted, however, that this was not a randomized study and the data was compared with historical controls. Several other clinical trials in acute leukemia have been published. In one such small trial,50 1 2 patients with newly diagnosed acute leukemia received GM-CSF, at a dose of 120 pg/m2/day by continuous infusion, starting 3 days after completion of induction chemotherapy. There was no significant difference between the group treated with GM-CSF and historical controls in the time to neutrophil recovery or in the rates of infection. Whether the lower dose of GM-CSF given in this trial contributed to the discrepancy with the previously reported trial is unclear. As in the other published trials, stimulation of leukemia after GM-CSF did not appear to be a major clinical problem, if administered close to the nadir blood counts after induction chemotherapy. A large randomized study, conducted in Japan, was reported in 1990.51In this study, 108 patients with relapsed or refractory acute leukemia - 67 with acute myelogenous leukemia, 30 with acute lymphocytic leukemia, 9 in blast crisis of chronic myelogenous leukemia, and 2 with acute leukemia after myelodysplastic syndromes - were treated with GCSF at a dose of 200 pg/m2/day administered over 30 minutes. Therapy was instituted 2 days after the end of chemotherapy and continued until the neutrophi1 count rose above 1500/pL. The results of this major trial showed that G-CSF accelerated the neutrophil recovery significantly, shortening the period of aplasia by approximately 1 week, but had no effect on platelet recovery. There was also a marked reduction in documented infections, although it was not clear whether the actual incidence of febrile episodes was reduced. Once again, there was no evidence of regrowth of leukemia cells in this study. The authors of this study concluded that G-CSF was safe in acute leukemia, clearly accelerated neutrophilic recovery, and reduced the incidence of documented infections. Although randomized, this study was not placebo controlled or blinded in any way.

THERAPEUTIC REVIEW

Major prospective cooperative group clinical trials are being conducted by the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B to try to confirm in double-blind placebo-controlled trials the effects of GM-CSF when administered after induction chemotherapy for acute leukemia, and the results of these major trials are anxiously awaited. Trials in acute leukemia have only recently been initiated in an attempt to actually use the cytokines as priming agents capable of stimulating acute myeloid leukemia blast cells to become more sensitive to cell-cycle-specific drugs. In one such recently published GM-CSF at a dose of 200 pg/m’/ day by continuous infusion was administered to 18 patients with de novo acute myelogenous leukemia. The GM-CSF was started 24 to 48 hours before induction chemotherapy in 14 of the patients, and in 4 patients who had an initially high white blood cell count the GM-CSF was started after induction chemotherapy had reduced the white count to 500/pL after the first or second course of GM-CSF, and 6 are alive and disease free at least 240 to 434 days after transplantation. In all responders, fevers dissipated, and two patients with fungemia cleared their infections. Of the six nonresponders five died, mainly from infections. Of 22 patients undergoing autologous or syngeneic transplant, 12 responded to GM-CSF and 8 are alive 230 to 608 days after transplant. Of 10 nonresponders, 6 have died. All responders defervesced and cleared active bacterial and fungal infections. Toxicity was minimal at doses less than 250 pg/m2, and no increase in relapse rate or graft-versus-host disease (in allogeneic transplant patients) was observed. Overall survival in the GM-CSF-treated group was significantly higher than in a historical group of patients with graft failure treated with supportive care or second transplants. Patients who are in need of bone marrow transplants but cannot be harvested because of marrow involvement by tumor or marrow injury from pelvic radiation may undergo transplants using stem cells collected from the peripheral blood. Indeed peripheral stem cell transplants have been successfully performed in patients with Hodgkin’s disease, non-

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no stomatitis was observed, and all patients noted a Hodgkin’s lymphoma, myeloma, breast cancer, leukemia, and in children with n e u r o b l a s t ~ m a . Al~ ~ - ~ ~significant reduction in the incidence of infections. Apart from mild, transient bone pain in 3 patients, though peripheral stem cells collected without any marrow stimulation can produce rapid and susthe G-CSF was well tolerated in this group of patained engraftmenkgOGM-CSF given alone or in comtients, despite continuation of therapy for as long as 40 months. bination with myeloablative chemotherapy results, Congenital neutropenia or Kostmann’s syndrome respectively, in an 8.5-fold and 60-fold increase in is another disorder of hematopoiesis characterized peripheral blood hematopoietic progenitor cells by severe neutropenia leading to recurrent life(such as CFU-GM).91*92Such increases in the fraction threatening infections during early childhood. In a of progenitor cells present in the peripheral blood, study of 5 patients, 3 to 60 pg/kg/day G-CSF was may hasten engraftment following peripheral stem administered intravenously (as bolus or continuous cell transplants and reduce the number of apheresis procedures needed to obtain a satisfactory stem cell infusion) for 1 or more courses of 14 days followed by a subcutaneous maintenance dose using one third of The use of GM-CSF in this setting may the “effective” intravenous dose.g5 Each patient even permit successful peripheral stem cell transachieved a neutrophil count of at least l O O O / p L , plants in patients with baseline cytopenias due to which has been maintained with subcutaneous inprior courses of myelosuppressive therapy.g1 jections of 3 to 18 pg/kg/day (median, 18 pg/kg/d). In summary, GM-CSF and G-CSF appear to accelerClinical efficacy was indicated by a marked reducate myeloid recovery after marrow transplants and tion in the average, annual, broad-spectrum antibimay thereby reduce the morbidity and mortality otic requirement from about 90 days to 9 days. Derates associated with prolonged aplasia. In addition, spite the high doses of G-CSF required for treatment GM-CSF may enhance the quality of peripheral stem of this disorder, side effects were limited to bone cell collections by increasing the proportion of propain (1 patient), mild splenomegaly (2 patients). and genitor cells. Granulocyte-macrophage colony-stimincreased alkaline phosphatase levels. ulating factor also may improve survival in patients One of the earliest clinical uses of the hematopoiwho experience graft failure or engraftment delay etic growth factors involved their application to the after marrow transplants. treatment of HIV-induced cytopenias. Granulocytemacrophage colony-stimulating factor, given by OTHER SELECTED USES OF COLONYbolus injection followed by continuous infusion for STIMULATING FACTORS 14 days in 16 patients with HIV-associated leukopenia, resulted in a dose-dependent increase in the The foregoing discussion has focused on the uses of leukocyte count (composed mainly of neutrophils GM-CSF and G-CSF in acquired and therapy-inand eosinophils) to as high as 48,000/pL.96 As in duced marrow failure. These CSFs also show promother studies using GM-CSF for marrow failure, ise in the treatment of the rare disorders, cyclic neutropenia, and congenital neutropenia (Kostmann’s counts returned to baseline shortly after discontinuation of the infusion. However, long-term subcutasyndrome), and in offsetting the disturbance of neuneous administration of GM-CSF to leukopenic HIV trophil production and function encountered in hupatients achieved and maintained a dose-dependent man immunodeficiency virus (HIV) infection and seincrease in granulocyte^.^^ vere burns. Concern about the use of GM-CSF in HIV patients Cyclic neutropenia is an uncommon congenital or has been raised because of in vitro studies showing acquired disorder of hematopoiesis characterized by that certain strains of HIV virus may be stimulated to profound fluctuations in the levels of granulocytes, replicate in macrophages exposed to macrophage colmonocytes, platelets, and reticulocytes occurring ony-stimulating factor (M-CSF), GM-CSF, and IL-3, with a periodicity of 2 1 days. During the trough but not in those exposed to G-CSF.98However, one phase, patients experience painful stomatitis, malstudy using a strain of HIV that replicates poorly in aise, and infections. In a study of six patients, G-CSF macrophages failed to show any enhancement of repwas administered daily at a dose of 3 to 10 pg/kg by lication in the presence of GM-CSF.” Indeed, studies either intravenous or subcutaneous injection.” In 5 using a third strain of HIV-1 suggested that GM-CSF patients, cycling continued with a periodicity of 14 could inhibit infection in the presence of zidovudine rather than 2 1 days, but nadir neutrophil counts rose (AZT) to a greater degree than if the cells were exsignificantly from a mean of 17/pL (before treatposed to AZT a1one.’O0 Although no consistent effect ment) to 1393/pL (after treatment). In one patient, of hematopoietic growth factors on in vivo viral replicycling appeared to cease altogether. On treatment,

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cation has emerged, these in vitro data suggest that it may be prudent to use AZT in HIV patients who receive them. Conversely, patients who take AZT to slow progression of HIV-related disease and improve their survival often develop neutropenia and anemia. Although reductions in the dose of AZT may not reduce its antiviral effects significantly, cytopenias usually persist despite dose reductions. One approach has been the administration of G-CSF and erythropoietin together to patients with AZT-induced cytopenias. This approach led to the safe administration of moderate- to high-dose AZT therapy (1000-1500 mg/d) in 22 HIV-patients with AZT-induced cytopenias.'" Although 8 of 20 evaluable patients needed red cell transfusions after restarting AZT, all 20 patients maintained neutrophil counts between 1500 and 15,OOO/pL. Another myelosuppressive agent commonly used to treat cytomegalovirus infections in HIV (and bone marrow transplant) patients is ganciclovir. Preliminary data from a randomized, controlled trial comparing ganciclovir with G-CSF to ganciclovir alone in the treatment of CMV retinitis showed that significantly fewer episodes of severe neutropenia requiring cessation of therapy occurred in the patients receiving G-CSF."' In addition to the defective neutropoiesis frequently encountered in patients with HIV infection, neutrophil dysfunction also is seen. Defects in neutrophil chemotaxis, phagocytosis, and bactericidal activity have been described, and appear to be corrected in part by the administration of GMCSF.103.104 The demonstration that at least some of the neutrophil defects may be corrected in vivo'03 suggests that GM-CSF may have a role in enhancing host defenses in some HIV-infected patients. Yet another area in which GM-CSF and G-CSF have been applied is in the treatment of patients with severe burns. Patients with serious burns demonstrate a variety of defects of host defense, including neutropenia and impaired neutrophil function.'05 These defects may reflect the presence of CSF inhibitors in the serum of thermally injured patients'O6 and may contribute to the high mortality rate from sepsis seen in these patients. One study suggested that the use of G-CSF in animals with serious burns could repair defects in neutrophil chemotaxis.'" Furthermore, the administration of GM-CSF to patients with serious burns did stimulate a rise in neutrophil counts, but induced variable effects on neutrophil function."' Additional work will be needed to refine the role of hemopoietic growth factors in this area. In summary, GM-CSF and G-CSF have established

THERAPEUTIC REVIEW

roles in ameliorating the neutropenic states associated with certain congenital and acquired disorders of hematopoiesis. In addition, these growth factors appear to stimulate neutropoiesis and augment neutrophil functions in patients infected with HIV or receiving myelosuppressive antiviral agents. Additional work in the area of burn therapy and other conditions that contribute to marrow or effector cell dysfunction may reveal other important roles for these agents.

ERYTHROPOIETIN-RESPONSIVE ANEMIA Without any doubt, the most significant advance in the hemopoietic growth factors has been the development of erythropoietin for use in chronic renal failure. Its use in this condition has been unequivocally established and followed several milestone in basic research and clinical application. In 1985, two groups published for the first time the successful isolation, cloning, and expression of the human erythropoie t in gene.109*110 Further work in 1986 confirmed these findings,"' and subsequently large amounts of recombinant human erythropoietin (rhEpo) became widely available for clinical trials. After these publications, initial clinical trials were and were soon followed by multicenter trials in the United States, Japan, and E u r ~ p e . " ~ - " ~ Although it has always been believed that anemia of chronic renal failure was primarily the result of inadequate erythropoietin production, several other factors were thought to contribute, including a shortened red cell survival, blood loss from the gastrointestinal tract and also due to platelet dysfunction, as well as several inhibitors of erythropoiesis. All of the published clinical trials strongly supported the concept that erythropoietin deficiency was indeed the major mechanism for the anemia of chronic renal failure. Initial trials were conducted on patients undergoing hemodialysis, and it quickly became apparent that transfusion requirements ceased when erythropoietin was given at a dose of 50 to 150 U/kg three times per week. Lower doses are also effective, and there is, as would be expected, a great variation in the dose required for any particular individual. Subsequent to the above trials, patients with anemia of renal failure who did not require dialysis also were given erythr~poietin,"~ and these patients also responded to rhEpo in a similar manner to those patients who were on hemodialysis. Most trials have used intravenous erythropoietin, although it is clear that if administered by the subcutaneous route this is also very effecti~e.~''~"~ Other conditions for which erythropoietin may be

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used have not been as clearly defined, but definitely include several important clinical scenarios. Much work is being done in these areas, and a great deal of information ought to be forthcoming over the next few years. A summary of these indications is briefly discussed below. In recent years, anemia that is associated with acquired immune deficiency virus (AIDS) has been commonly observed and occurs more frequently and more severely in those individuals receiving AZT therapy. In one prospective controlled study, rhEpo was shown to decrease by more than 50% the number of red cell transfusions in a group of such patients.'" Although the relationship with serum erythropoietin level is not perfect, in the above study those patients whose plasma erythropoietin level was less than 500 mU/mL had a better response than those patients with higher endogenous erythropoietin levels. In another trial,'" the response of this group of patients, with AIDS and on AZT, to a combination of rhEpo and GM-CSF also led to a significant reduction in the red cell transfusion requirements (as well as a significant amelioration of the neutropenia). Several clinical trials are at present evaluating the use of rhEpo in AIDS patients, and the significance of this in improving the quality of life as well as cost containment cannot be overstated. Recombinant erythropoietin has been used also to enhance the ability of individuals to donate blood for autologous transfusions. With the attendant risks of red cell transfusions associated with transmissible disease, the interest in the use of autologous transfu-

sions at elective surgery has increased significantly in previous years. In a multicenter clinical trial,"' rhEpo allowed for the collection of approximately 40% more red cells than was otherwise possible. Additionally, the hematocrit at the end of the autologous collections was significantly higher (38.6 mL/ dL versus 35.2 mL/dL) for the two groups. The dose of rhEpo used was 600 U/kg twice weekly, and this was a well-conducted double-blinded placebo study. Because of the way this trial was conducted, the results of this have been widely accepted, and in many centers rhEpo is used routinely, with a great potential for increasing the number of procedures that can be used with transfusion of autologous blood alone. Erythropoietin also has been studied in anemias of chronic inflammation,'22but results in this condition are limited, and further information from clinical trials is awaited. Other trials are evaluating the use of rhEpo in a variety of other clinical conditions, including myelodysplastic syndrome and chronic anemia associated with malignancy as well as some anemias associated with hemoglobinopathies, for example, sickle cell disease. In summary, recombinant human erythropoietin has made an enormous difference to the management of patients with chronic renal failure, resulting in dramatic reduction in transfusion requirements, a marked improvement in the quality of life, and a significant cost containment. Although rhEpo has also been successfully used in promoting blood donations for autologous use and for reducing transfusion

TABLE 111 Indications for Use of HernoPoietic Growth Factors Definite

Probable

Possible

Anemia of chronic renal failure (Epo) Neutropenia after autologous BMT conditioning (G-CSF; GM-CSF)

Anemia due to chemotherapy (Epo) Anemia due to malignancy (Epo)

Graft failure after BMT (G-CSF; GM-CSF) Neutropenia due to HIV-infection/ ganciclovir (G-CSF; GM-CSF) Congenital or cyclic neutropenia (G-CSF)

In preparation for autologous red cell transfusions (Epo) Neutropenia in myelodysplasia (G-CSF; GM-CSF) Neutropenia following chemotherapy (G-CSF; GM-CSF) (leukemia, lymphoma) Infections in aplastic anemia (GM-CSF; G-CSF) Augment peripheral stem cell collections (GM-CSF; G-CSF)

Aplastic anemia (GM-CSF, G-CSF, IL-3) Inducing cells into phase-specific parts of cycle-leukemia and myelodysplasia (GM-CSF; IL-3) Anemia of myelodysplasia (Epo)

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Neutropenia, neutrophil dysfunction in severe burns (GM-CSF; G-CSF)

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requirements in patients with AIDS on AZT, the potential for amelioration of anemia in many other chronic conditions is being studied, and it is likely that more uses will be defined for rhEpo in the coming years.

FUTURE DIRECTIONS The past decade has seen a remarkable and dramatic development in the clinical application of the various cytokines. The most widely accepted cytokines in clinical practice at this time are erythropoietin, GM-CSF, and G-CSF. The summary of the present definite, probable, and possible indications for these cytokines is included in Table 111. The next decade will see the consolidation of clinical data and definition of many of the less certain uses of these cytokines. In a sense, a certain retrenchment may occur, limiting their use, once all of the products are freely available, to certain well-defined clinical situations. Cost containment is likely to be an important factor. During this same period, studies are expected to clarify the role many of the other cytokines, in particular IL-1, IL-2, IL-4, and IL-6, all of which have enormous potential and await the results of clinical trials. If progress during the next decade continues at the same pace as it has in the past decade, we can expect, 10 years from now, to have made major further leaps in the amelioration of cytopenias and the possible priming of cells for better responsiveness to conventional cytotoxic therapy.

REFERENCES 1. (:arnot P. Deflandre C: Sur I’activitk hemopo’iktique des differents organes au cours de la rkgeneration du sang. Cr Hebd Acod Sci 1906:143:432-435. 2. Pluznik DH. Sachs I,: The cloning of “massed” cells in tissue culture. j Cell Comp Physiol 1965:66:319-324. 3. Bradley TR. Metcalf D: The growth of mouse bone marrow cells in vitro. Aust j Exp Biol Med Sci 1966:44:287-299. 4. Golde DW. Gasson jC: Hormones that stimulate the growth of blood cells. Sci Am 1988:(July):62-70. 5. Groopman IE. Molina IM. Scadden DT: Hernatopoietic growth factors: Biology and clinical applications. IN Engl j Med 1989;321 : 1449-1459. 6. Stanley ER. Chen DM. Linn HS: Induction of macrophage pro-

duction and proliferation by purified colony-stimulating factor. Nu1 ure 1978:274:168-169.

7. Metcalf D: The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature 1989;339:27-30. 8. Wong GG. Witek JS.Temple PA, Wilkens KM. Leary AC. Luxenburg DP. Jones SS. Brown EL, Kay RM. Orr EC. Schumaker C. Golde DW. Kaufman RJ. Hewick RM, Wang EA, Clark SC: Human GM-CSF: Molecular cloning of the complementary DNA and puri-

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