Cancer Investigation
ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20
The Use of Hematopoietic Growth Factors in HIV Infection and AIDS-Related Malignancies Steven A. Miles To cite this article: Steven A. Miles (1991) The Use of Hematopoietic Growth Factors in HIV Infection and AIDS-Related Malignancies, Cancer Investigation, 9:2, 229-238, DOI: 10.3109/07357909109044233 To link to this article: http://dx.doi.org/10.3109/07357909109044233
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Cancer Investigation, 9(2) 229-238 (1991)
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The Use of Hematopoietic Growth Factors in HIV Infection and AIDS-Related Malignancies Steven A. Miles, M.D. Division of Hematology-Oncology UCLA AIDS Clinical Research Center UCLA School of Medicine Room 60-051 Center for the Health Sciences Los Angeles, California 90024-1 793
ABSTRACT
Human immwtodeJciencyvirus (HW) infection is associated with multiple ddeets in immune regulation and hematopoiesis. nese Meets include decreased proliferation of hemutop*eticprogenitor cells and increased &stmaion of -re cells. %re are also disturbances of regulatory cytokines. As a result, hematopoietic cytopenias are common and the tolerance a f myelosuppressive therapy ispoor. One successfir1 approach to the munugement of these clinical problems is the use of hematopoietic growth factors. To dute, three agents have been d i e d in patients with HIV infection. In a Phase I trial, granulocyte mucrophuge-colony stimulating factor (GMCSF) corrected leukopenia and pre-existing neutrophil defects in patients with HIV infection. In uncontrolled trials, GM-CSFalso appears to reduce toxicity from zidovudine, ganciclovir, alpha-interferon,and antineoplastic therapy. In a placebocontrolled trial, erythropoietin @PO) decreased tmnsfirsin requirements and corrected anemia in the majority ofpan'ents receiving zidovudine. In a Phase I/II trial, granulocyte colony-stimulating factor (GCSfl also corrected leukopenia and neutrophil defects in patients withAIDS without altering HNexpression. Combined GCSF and EPO treatment corrected both anemia and lehpenia and reduced zidovudine toxicity. New combinations of hematopoietic stimulants are being used to decrease the taxicityfrom cytotoxic chemotherapy in the treatment of AIDS-related malignancies. Future treatments with other recombimt cytokines may result in both reduction in myelosuppression @om drug therapy and, possibly, reconstitution of the immune and hematopoietic systems of HIV-infected patients.
229 Copyright 0 1991 by Marcel Dekker, Inc.
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INTRODUCTION The advent of recombinant cytokine therapy has led to improvements in therapy for patients infected with the human immunodeficiency virus (HIV). Although these agents can be used for a variety of clinical conditions, in HIV infection, hematopoietic growth factors have been used primarily to decrease the toxicity of myelosupprasive therapy. To date, three kmatopoietic growth factors have been used in clinical trials. As additional cytokines become available, future uses may include the improvement in host defense against opportunistic infections and immunohematopoietic reconstitution. The magnitude of the problem of hematopoietic suppression is substantiall.?his is the result of two processes. Infection with the HIV results in multiple disturbances of immuneregulation and hematopoiesisand the treatment of HN infection or its consequences frequently involves the use of myelosuppmsivedrugs. While the pathogenesis of some of the abnormalities in blood cell production and function is not clear, potential mechanisms include HIV infection of hematopoietic progenitor cells (l),helper lymphocytes (2), monocytes (3), or bone marrow stromal elements (4) with subsequent alterations in cell function (5), proliferation and,in some instances, cell number (6). These alterations may include an increase or decrease in cytokine production (5) and the possible loss of important accessory cell functions. Additional abnormalities may result from immunologic destructionof HTV-infected or uninfected hematopoietic elements by the patients' residual immune system with a resultant decline in progenitor pools or alterations in mature cell function (6-8). Although there are multiple disturbances in immunohematopoiesis in HIV infection, the principal defect is infection of the CD4 helper cell with the resultant loss of cell number and function (6). This results in decreased effectiveness of immune recognition and surveillance. Thus patients with HN infection are at increased risk for the developmentof clonal and nonclonal neoplasms. For example, Kaposi's sarcoma occurs in nearly 50% of patients with AIDS at some time in their course of disease. This rate is approximately 20,000 times the risk for the general population. Also, there is an increased incidence of high-grade non-Hodgkin's lymphomas (9) and, perhaps, an increase in Hodgkin's disease. Many of these neoplasms, as well as the opportunistic infections characteristic of AIDS, are treated with myelosuppressive agents. Given the marginal hematopoietic reserve of these patients, bone marrow suppression frequently limits both the intensity and duration of chemotherapy. Reductions in dose intensity may result
Table 1 Selected Biologic Activities of Growth Factors: GrMulocyte-Macrophage Colony-StimulatingFactor (GM-CSF) and Granulocyte Colony-Stimulatingfactor (GCSF) Biologic activity Increases ADCC in: Macrophages Neutrophils Increases neutrophils Mitogen for macrophages Increases eosinophils Increases phagocytosis and intraeuular killing in: Macrophages Neutrophils Increases red blood cell production Alters 2 3 'dideoxynucleoside analogue uptake or metabolism Increases HIV expression in macrophages I,
GM-CSF
G-CSF
Yes YeS Yes Yes Yes
No Yes Yes No No
Yes Yes Unknown
No Yes Yes
Yes
Unknown
Yes
No
in decreases in clinical activity. The use of hematopoietic growth factors to ameliorate the myelosuppressive complications of chemotherapy is a major goal in the successful treatment of patients with severe HIV infection. To date, granulocyte macrophage-colonystimulating factor (GM-CSF), granulocytecolony stimulating factor (GCSF), and erythropoietin@PO) have been used with good effect in patients with a variety of complications related to HIV infection and chemotherapy (Table 1).
TREATMENT OF AIDS PATIENTS WITH GM-CSF The first trial of bematopoietic growth factor in humans was the use of GM-CSF in patients with AIDS (10). This pioneering study utilized glycosylated GM-CSF produced by recombinant DNA techniques in Chinese hamster ovary (CHO) cells. Sixteen patients received GM-CSF by continuous intravenous infusion at doses ranging between 0.5 and 8 pg/kg/day . Rapid, dose-related increases in granulocytes, monocytes, and eosinophils were seen. No significant increases in other circulating blood elements were observed during the 2-week period of treatment. Toxicities included fevers, facial flushing, transient
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Use of Hematopietic Growth Factors in AIDS
23 1
skin rash, and local vein irritation. This latter toxicity may have been due to local leukostasis when the drug was administered by peripheral vein. Phlebitis was not seen when GM-CSF was administered by a central venous catheter. Increases in total marrow cellularity were observed in 11 of 14 patients. Despite these increases, a prompt drop in leukocyte counts was seen at the end of drug infusion (see Fig. 1). Neutrophil function was assessed in 6 patients in this Phase I trial (1 1). Two of these six patients had selectivedefects in either neutrophilbacterial phagocytosis or intracellular killing. The administration of GM-CSF transiently corrected these defects. HIV recovery from peripheral blood mononuclear cells and HIV p24 antigen expression was not altered in a consistent direction during the 14-day period of drug administration. The next stage in development of this agent was the demonstration that these hematopoietic effects could be sustained. Long-term subcutaneous administrationof GMCSF in patients with HIV infection and neutropenia for up to eight months resulted in continued leukocyte response with no evidence of stem cell depletion or marrow exhaustion (12). At doses of 0.25-4.0 pglkglday of GM-CSF, persistent improvements in leukocyte counts were observed without accompanying changes in hemoglobin or platelet counts. Bacterial and opportunistic infections were observed in this patient population which was not given AZT or prophylactic antimicrobial treatment. No consistent increases in viral replication as measured by HIV p24 antigenemiaor virus recovery from cocultured lymphocytes were seen.
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Figure 1. Total leukocytecount and differentialin a patient with AIDS treated with recombinant human GM-CSF.
THE USE OF GM-CSF TO REDUCE MYELOSUPPRESSIVE TOXICITY Because of the ability of GM-CSF to correct neutropenia in patients with AIDS, attempts were made to combine GM-CSF with a variety of myelosuppressiveanti-infective agents. Since the most common cause of drug-related hematopoietic defects in patients with AIDS is the use of zidovudine, initial attempts were aimed at ameliorating zidovudine-related myelosuppression. Zidovudine-related bone marrow suppression is a significant clinical problem. In patients with AIDS who receive more than 600 mg of zidovudineper day, approximately 50% of patients will require dose reduction as a result of hematopoietic toxicity and an additional25 % will have drug therapy discontinued within the first year. In this population, only 25 % of patients are able to tolerate fulldoses of zidovudine after 1 year (13). Despite the use of lower doses of zidovudine and treatment of patients in earlier stages of HIV infection, zidovudine still causes significant neutropenia (neutrophils 4OO/pL appear to tolerate induction therapy with interferon better than patients with CD4 helper cell number 50% suppression of p24 antigen with this regimen. This is a very
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high response rate for patients with this advanced stage of HIV infection.Whether this response rate is reflective of a synergistic activity of the three drug regimen or related to the sample size is not known. These have been no opportunistic infections although, interestingly, two patients have developedHemophilus injluenza pneumonia while receiving GM-CSF therapy. Twenty-four percent of patients had a dose reduction as a result of drug-related toxicity and 28 of 29 individuals developed a flu-like syndrome ascribed to the alphainterferon. According to the investigators, this side effect may have been exacerbated by GM-CSF treatment. Three patieats have had their dose modified because of transfusion requirements; 2 for thrombocytopenia, 1 for myositis, and 2 for CNS toxicity from zidovudine. Overall, the regimen appe4lrs to be tolerable with an increase in response rates in patients who are at risk for progressive disease while receiving alpha interferon monotherapy. Because dmg-rekd hematopoetic toxicity can be easily corrected by the use of colony-stimulating factors, future trials in AIDS-related Kaposi sarcoma will involve the use of not only combined GM-CSF, zidovudine, and alpha-interferon, but also GM-CSF along with chemotherapeutic regimens using adriamycin, bleomycin, and vincristine (ABV)(26).Phase I clinical trials of these agents have been initiated by the AIDS Clinical Trials Group. GM-CSF IN NON-HOffiIUN’SLYMPHOMA Two Wase I clinical trials have investigated the use of GM-CSF to decrease the myelosuppressive effects of cancer chemotherapy in AIDS-related non-Hodgkin’s lymphoma. Previous studies have demonstrated that patients with AIDSrelated n~n-Hodgkin’~ lymphoma do not tolerate conventional chemotherapy but are able to tolerate a modifiedregimen of m-BACOD. Overall response rates of approximately 5496 can be achieved with this dosemodified regimen (32). In an attempt to increase the overall response rate by increasing the dose of chemotherapy while protecting patients from drug-related leukopenia, patients were treated with modified doses of m-BACOD and GM-CSF therapy in a Phase I trial (33). GM-CSF was given on Days 3 through 13 at 20 pglkglday. The first three patients received no GM-CSF and halfdose m-BACOD (25 mg/m2 hydroxydaunorubicin (Adriamycin) , 300 mg/m2 cyclophosphamide (Cytoxan), 500 mg/m2 methotrexate with leukovoxin rescue, and standard doses of vincristine, bleomycin, and dexamethasone). The median nadir
neutrophjl count was 1805/pL(range 893-2700/pL).Two additional cohorts were enrolled. The second cohort of five patients received GM-CSF on Days 3-13 and increased doses of adriamycin (35 mg/m2) and cytoxan (450 mg/m2). ”he mean neutrophil nadir was 799/pL (range 38-1836/pL).The final cohort of 8 patients received full doses m-BACOD (45 mg/m2adriamycin, 600 mg/m2 cytoxan, plus the same doses of methotrexate, vincristine, bleomycin, and dexamethasone) along with GM-CSF on Days 3-13.The mean neutrophil nadir was 1227/pL(range 100-4400/pL)and this regimen was well tolerated (33). Thus,it is clear that patients with HIV can receive full doses of m-BACOD provided that sufficient granulocyte stimulationis provided. A subsequentclinical trial has been planned to investigate the important question of whether the increase in chemotherapy dose intensity will result in an increase in complete response rate or response duration (AmG 142).In that futuretrial, patients will be randomly assigned to modified dose mBACOD or fulldose m-BACOD with GM-CSF. One other trial of GM-CSF with cancer chemotherapy in non-Hodgkin’s lymphoma has been initiated (34). In this trial, the CHOP chemotherapy regimen (cyclophosphami& 650 mg/m2, hydroxydaunorubicin 35 mg/m2, vincristine 1.4 mg/&, and prednisone 60 mg/day for 5 days) was used with GM-CSF on Days 1-13. After the first three patients showed no amelioration of neutropenia, subsequent groups were given GM-CSF on Days 3-13.This modification in GM-CSF drug administration resulted in a significant improvement in neutrophil counts with partial protection against granulocytopenia (34).This latter observation may illustrate the importance of the schedule of administration of GM-CSF on its effectiveness in ameliorating drug related toxicity. Interestingly, significant reductions in HIV antigens were seen in the serum of patients receiving these cytoablative chemotherapy regimens.
ExYTHRomIETIN IN PATIENTS WITH AIDS Severe anemia (hemoglobin 5OOO/pL was achieved and maintained for two weeks. After correction of the leukopenia, subcutaneous EPO was administeredin increasing doses until an increment of 1.5 g/dl of hemoglobin was observed. Following correction of both cytopenias, successive groups of patients were given 1O00, 1500, or 2000 mg of zidovudine per day. G-CSF and EPO therapy was continued throughout, with dose modificationto maintain an ANC > 1500/pL and hemoglobin > 100 g/L. All 22 patients responded to G-CSF with a mean tenfold increase in neutmphils in less than two weeks. Significant increases in CJM and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in 20 of 20 evaluable patients within 8 weeks. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in 8 of the 20 patients, six of whom were
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discontinued from study. No patient was discontinued because of leukopnia or thrombocytopenia. Toxicities were minimal and did not require dose modifications for any patient. Unlike GM-CSF, patients treated with G-CSF had no fatigue, fevers, myalgias, or inanition. Anaysis of semiquantitative cultures for HIV and p24 antigen levels showed no significant alterations in viral expression after G-CSF or combined G-CSF and EPO therapy confinning earlier in vitro studies (39). H W p24 antigen decreased significantly with zidovudine therapy. The potency of this combination of hematopoietins is best illustrated by the demonstration that multiple myelosuppressiveagents can be simultaneouslyused with zidovudine. In this population of patients with severe hematopoietic defects, not only were patients able to resume fulldose or even higher doses of zidovudine, but 7 patients received simultaneousinduction courses of ganciclovir without modification of zidovudine doses. From these studies, it is clear that combined therapy with GCSF and EPO can ameliorate the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of zidovudine therapy in many patients who were previously intolerant of the hematologic effects of zidovudine
POTENTLAL COMPLICATIONS OF GROWTH FACTOR THERAPY IN HIV INFECTION The major concern in the use of hematopoietic growth factors in patients with HIV infection is the possibility that these agents may cause disease progression. Theoretidy, these agents could increase the number of target cells for HIV replication or may enhance HIV replication within target cells resulting in acceleration of HIV-related disease. This concern results from the muItiple physiologic activities of these compounds and the possible perturbations possible in patients with HIV infection. With each growth factor and within each patient a complex set of interactions may occur between the growth factor, host defense, target cells, and the populations of HlV virus resulting in different clinical outcomes. For example, one patient may have low titers of neutralizing antibodies and lack significant macrophage infection with HN.When given GM-CSF, the growth factor may augment antibodydependent cell cytotoxicity which may decrease viral expression. Since there is no significant macrophage viral infection, the overall result may be a decrease in HIV expression. Obviously, the converse is
also true. Moreover, the effects may vary considerably depending on the stage of disease and other concurrent medications and illnesses. As a result, the effects of GCSF or GM-CSF on HIV replication in individual patients receiving zidovudine may be unpredictable. The only way to adequately address this issue is to carefully measure viral load before and after therapy or compare between treated and untreated arms of controlled trials. To date, the best markers to follow are measurementsof HIV antigens and semiquantitative cultures of lymphocytes and plasma (32). In multiple Phase I and 11trials, no consistent increase has been observed in HIV p24 antigen levels or HIV viral recovery from lymphocytes with the use of either G-CSF or GM-CSF. Thus, while this remains a theoretical concern, evidence to date suggests that treatment with either G-CSF or GM-CSF do not result in acceleration of HN replication.
GROWTH FACTORS AS ADJUNCTIVE THERAPY MIR IMMUNOHEMATOPOIESIS IN PATIENTS WITH HIV INFECTION Until now, the major focus of the use of growth factors has been on their ability to ameliorate drug-related hematopoietic suppression. While laudable, the development of newer less myelosuppressive antiviral and antineoplastic agents will eventually supplant these uses. In the future, greater emphasis will be placed on the ability of cytokines and hematopoieticgrowth factors to enhance host defenses against opportunisticinfections and increase immune function. Both G-CSF and GM-CSF have been shown to increase neutrophil function and correct neutrophil defects. G-CSF has also significantly increased CD4 cell number in patients with advanced stages of HIV infection. With the recent discoveries, cloning and commercial production of IL-4, IL-6, IL-7, and IL-9 new avenues of therapy are possible. Two of these agents have effects on B-cell development (IL-4 and 6) while the other two have some effects on T-cell development (IL-7 and 9). Combined with IL-2 and newer less myelosuppressive antiretroviral agents, it is hoped that some combination of the hematopoietichormones will be able to reverse the steady loss of CD4 cells and reduce mortality.
CONCLUSIONS
Three hematopoietic stimulants have been used in patients with HIV infection and a variety of AIDSrelated complications. Both G-CSF and GM-CSF have
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Use of Hematopietic Growth Factors in AIDS
demonstrated the ability to correct leukapenia related to HIV infection and ameliorate drug-relatedmyelosuppressive effects of zidovudine, cotrimoxazole, ganciclovir, and, in the case of GM-CSF, alpha-interferon, and chemotherapeutic regimens. Erythropoietinhas been successfully used to ameliorate the anemia associated with HN infection and zidovudine therapy. Treatment with these hematopoietic stimulants is very well tolerated with minimal toxicity. Of the granulocyte stimulants, G-CSF appears to have a more favorable side effect profile than GM-CSF in trials conducted to date. Future trials demonstrating that the amelioration of hematopoietic suppression by the colony stimulating factors will result in increased overall clinical response rates and improved survival are necessary to appropriately access the value of this approach to the c m of HIV-infected patients.
ACKNOWLEDGMENTS The author thanks the State of California for funding as directed by the UnivetsitywideTask Force on AIDS (87JA039 and 89C-CC86LA). Additional funding was provided by the National Institute of Allergy and Immunological Diseases (AI27660).
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237 10. Groopman JE, Mitsuyasu RT, D e b MJ et al: Effect of recombinant human granulocyte-macrophage colony-stimulating factor on rnyelopoiesk in the acquired immunodeficiency syndrome. N Engl J Med 317593-5983, 1987. 11. Baldwin CG, Gasson JC, Quan SG et al: GM-CSF enhances neumphil function in AIDS patients. Proc Natl Acad Sci (USA) 85~2763-2766, 1988. 12. Mitsuyasu R, Levbe 3, Miles SA et al: Effects of long term subcutaneous (SC) administration of recombinant granulocytemacrophage colony-stimulating fator (GM-CSF) in patients with HW-related leukopcnia. Blood 72 (suppl 1):357 (abstr), 1988. 13. Richman DD, Fischl MA, Grim MH et al: The toxicity of azidothymidine(AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, pla&xtontrolled trial. N Engl J Med 317:192-197, 1987. 14. Volberding PA, Lagakos SW,Koch MA et al: Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Instituteof Allergy and Infectious Diseases (see comments). N Engl J Med 32291-949, 1990. 15. Fischl MA, Richman D,D Grieco MH et al: The efficacy of azidothymidine(AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. N Engl J Med 317:185-191, 1987. 16. P e m C, Yarchoan R, Cooney DA et al: Replication of human immunodeficiency virus in monocytes. GM-CSF potentiates viral production yet enhances the antiviral effect mediated by AZT and other dideoxynucleoside congeners of thymidine. J Exp Med 169:933-951, 1989. 17. Hammer SM, GiUis JM: Synergistic activity of granulocytemacrophage colony-stimulating factor and 3 '-azido-3 '-deoxythymidine against human immunodeficiency virus in vitro. Antimicrob Agents Chemother 31:1046-1050, 1987. 18. Bhalla K, Bihofer M, Grant S, Graham: The effect of recornbinant human GM-CSF on AZT-mediated biochemical and cytotoxic effects on n o d human myeloid progenitor cells. Exp Hematol 17~17-20, 1989. 19. Levine JD, Allan JD, TessitoreJH et al: Granulocyte-macrophase colony stimulating factor amelioratesthat neutropenia induced by azidothymidine in AIDS/ARC patients. Proc Am Soc Clin Onc 8:l (abstr), 1989. 20. Grossberg HS, Bonnem EM, Buhles WC: GM-CSF with ganciclovir for the treament of CMV retinitis in AIDS (Letter). N Engl J Med 320:1560, 1989. 21. Hardy D, Spector S, Polsky B et al: Safety and efficacy of combined ganciclover (GCV)and granulocytemacrophagestimulating factor (GM-CSF) vs. gancicloviralone for C M V retinitis in AIDS (ACTG 073): a prelunhary qmt. In Proceedings VI Inrenmtiod Conference on AIDS: AIDS in the Nineties: From Science to Policy (San Francisco, June 19-24, 1990). California: Moscone Center: F.B.92 (abstr), 1990. 22. Berman E, Duigou-Oskmdorf R, Gown SE et al: Synergistic cytotoxic effect of azidoU~ymidineand recombinant interferon alpha on normal human bone marrow progenitor cells. Blood 74: 1281-1286, 1989. 23. Krown SE, Gold JWM, Niedzwiecki D et al: Interferon-a with zidovudine: Safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the aquired immunodeficiency syndrome (AIDS).An Int Med 112:812-821, 1990.
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238 24. Davey Jr RT, Davey V, Zurlo J et al: A phase I/II trial of zidodine, interferon aIpha, and granulocyte-mamphage colony stimulating factor in treatment of HIV infection. In Proceedings VI International Conference on AIDS: AIDS in the Nineties: from Science to Policy (SanFrancisco, June 19-24.1990). California, USA: Moecone Center: S.B. 420 (abstr), 1990. 25. Mitsuyasu R T AIDS-related K a p i ’ s sarcoma: a review of its pathogenesis and treatment. Blood Rev 2:222-231, 1988. 26. Gill PS, Akil B, Colletti P et al: Pulmonary Kaposi’s sarcoma: c h i a d 6ndings aad results of therapy.Am J Med 87:57-61,1989 27. Miles SA, Wang HJ, Cortes E et aI: Beta-interferon therapy in r#rrieats withpaa-progmeis Kaposi sarwmarelatedtotheaquued immunodeficiency syndrome (AIDS). A phase Ii trial with preliminary evidence of antiviral activity and low incidence of opportunistic infections. Ann Inter Med 112582489. 1990. 28. Krown SE Approaches to interferon combination therapy in the treatment of AIDS. Sem Oncol 17(1 Suppl 1):ll-15; discussion 38-41, 1990. 29. Pihl M, Reme J, Dearmas1 et al: Phase I study of interferonalpha and AZT in patients with AIDS-related Kaposi’s sarcoma. IV International Confexence AIDS, 253 (abstr), 1988. 30. Fischl MA, UUanchandani R, Gagnon S et al: Phase I study of intmfmn alpha-2b(lntron), zidovudine and rGM-CSF in patients with AIDS-associated Kaposi’s sarcoma. In Proceedings V Intem’onal Cbnference on AIDS: lhe Scientific and Social Challenge (Montteal, Quebec, Canada, June 69,1989) International Developlnent Research Center, Ottawa, 1989, p 342 (abstr). 31. scadden D, Bering H, Levine J et al: Combined AZTAnterferonaIpha/GMCSF for A.DS-asso&ed Kaposi’s sarcoma 0. Blood 74:127 (abstr), 1989. 32. Gill PS, k i n e AM, Krailo M et al: AIDS-related malignant lymphoma: results of prospective treatment trials J Clin Oncol 5:1322-1328, 1987.
Miles 33. Walsh C, W e m J, Laubenstein L et al: Phase I study of mBACOD and GMCSF n AIDS-associatednorkHodgkin’slympma (MIL): preliminary results. Blood 74:126a (abstr), 1989. 34. KaplanLD, Kahu JO, GrossbergH,Vokedmg PA chemotherapy with or without rGM-CSF in patients with AIDS-associated nonHodgkin’s lymphoma (NHL). In Proceedings V IntelnaiioMl Conference on AIDS: lhe Scientijlc and Social Challenge (Montreal, Quebec, Canada, June 4-9, 1989). International Development Research Center, Ottawa, 1989, p 334 (abstr). 35. Spivakn, Barnes DC,Fuchs E, Quinn TC:S e r u m i m m m‘ve erythropoietin in HIV-infected patients. JAMA 261:3104-3117, 1989. 36. Fisch M, Galpin JE, Levine JD et al: Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med 322:1488-1493, 1990. 37. Rarick M, Wilson E, Bernstein-Singer M et al: Double-blind placebo controlled study of recombinant human erythropoietin in AIDSpatientswithanemiacausedbyHIVinfectionandzidovudjne. In Proceedings V International G m f m e on AIDS: Ihe Sciemjlc andsocial chaaenge ( M o d , Quebec, cansda,June 4-9,1989), International DevelopmentResearch Center, Ottawa, 1989, p 195 (abstr). 38. Abels R, personal communication. 39. Koyanagi Y, O’Brien WA, Zhao JQ et al: Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science 241:1673-1675, 1988. 40. Miles SA, Mitsuyasu R, Fink N et al: Recombinant G-CSF and recombinant erythropoietin may abrogate the neutropenia and anemiaof AIDS and may allow resumpb‘on of AZT. In Proceedings V International Conference on AIDS: Ihe Scienrific and Social Chalfenge (Montreal,Quebec, Canada, June 4-9, 1989), International Development Research Center, Ottawa, 1989, p 550 (abstr).
ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20
The Use of Hematopoietic Growth Factors in HIV Infection and AIDS-Related Malignancies Steven A. Miles To cite this article: Steven A. Miles (1991) The Use of Hematopoietic Growth Factors in HIV Infection and AIDS-Related Malignancies, Cancer Investigation, 9:2, 229-238, DOI: 10.3109/07357909109044233 To link to this article: http://dx.doi.org/10.3109/07357909109044233
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The Use of Hematopoietic Growth Factors in HIV Infection and AIDS-Related Malignancies Steven A. Miles, M.D. Division of Hematology-Oncology UCLA AIDS Clinical Research Center UCLA School of Medicine Room 60-051 Center for the Health Sciences Los Angeles, California 90024-1 793
ABSTRACT
Human immwtodeJciencyvirus (HW) infection is associated with multiple ddeets in immune regulation and hematopoiesis. nese Meets include decreased proliferation of hemutop*eticprogenitor cells and increased &stmaion of -re cells. %re are also disturbances of regulatory cytokines. As a result, hematopoietic cytopenias are common and the tolerance a f myelosuppressive therapy ispoor. One successfir1 approach to the munugement of these clinical problems is the use of hematopoietic growth factors. To dute, three agents have been d i e d in patients with HIV infection. In a Phase I trial, granulocyte mucrophuge-colony stimulating factor (GMCSF) corrected leukopenia and pre-existing neutrophil defects in patients with HIV infection. In uncontrolled trials, GM-CSFalso appears to reduce toxicity from zidovudine, ganciclovir, alpha-interferon,and antineoplastic therapy. In a placebocontrolled trial, erythropoietin @PO) decreased tmnsfirsin requirements and corrected anemia in the majority ofpan'ents receiving zidovudine. In a Phase I/II trial, granulocyte colony-stimulating factor (GCSfl also corrected leukopenia and neutrophil defects in patients withAIDS without altering HNexpression. Combined GCSF and EPO treatment corrected both anemia and lehpenia and reduced zidovudine toxicity. New combinations of hematopoietic stimulants are being used to decrease the taxicityfrom cytotoxic chemotherapy in the treatment of AIDS-related malignancies. Future treatments with other recombimt cytokines may result in both reduction in myelosuppression @om drug therapy and, possibly, reconstitution of the immune and hematopoietic systems of HIV-infected patients.
229 Copyright 0 1991 by Marcel Dekker, Inc.
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INTRODUCTION The advent of recombinant cytokine therapy has led to improvements in therapy for patients infected with the human immunodeficiency virus (HIV). Although these agents can be used for a variety of clinical conditions, in HIV infection, hematopoietic growth factors have been used primarily to decrease the toxicity of myelosupprasive therapy. To date, three kmatopoietic growth factors have been used in clinical trials. As additional cytokines become available, future uses may include the improvement in host defense against opportunistic infections and immunohematopoietic reconstitution. The magnitude of the problem of hematopoietic suppression is substantiall.?his is the result of two processes. Infection with the HIV results in multiple disturbances of immuneregulation and hematopoiesisand the treatment of HN infection or its consequences frequently involves the use of myelosuppmsivedrugs. While the pathogenesis of some of the abnormalities in blood cell production and function is not clear, potential mechanisms include HIV infection of hematopoietic progenitor cells (l),helper lymphocytes (2), monocytes (3), or bone marrow stromal elements (4) with subsequent alterations in cell function (5), proliferation and,in some instances, cell number (6). These alterations may include an increase or decrease in cytokine production (5) and the possible loss of important accessory cell functions. Additional abnormalities may result from immunologic destructionof HTV-infected or uninfected hematopoietic elements by the patients' residual immune system with a resultant decline in progenitor pools or alterations in mature cell function (6-8). Although there are multiple disturbances in immunohematopoiesis in HIV infection, the principal defect is infection of the CD4 helper cell with the resultant loss of cell number and function (6). This results in decreased effectiveness of immune recognition and surveillance. Thus patients with HN infection are at increased risk for the developmentof clonal and nonclonal neoplasms. For example, Kaposi's sarcoma occurs in nearly 50% of patients with AIDS at some time in their course of disease. This rate is approximately 20,000 times the risk for the general population. Also, there is an increased incidence of high-grade non-Hodgkin's lymphomas (9) and, perhaps, an increase in Hodgkin's disease. Many of these neoplasms, as well as the opportunistic infections characteristic of AIDS, are treated with myelosuppressive agents. Given the marginal hematopoietic reserve of these patients, bone marrow suppression frequently limits both the intensity and duration of chemotherapy. Reductions in dose intensity may result
Table 1 Selected Biologic Activities of Growth Factors: GrMulocyte-Macrophage Colony-StimulatingFactor (GM-CSF) and Granulocyte Colony-Stimulatingfactor (GCSF) Biologic activity Increases ADCC in: Macrophages Neutrophils Increases neutrophils Mitogen for macrophages Increases eosinophils Increases phagocytosis and intraeuular killing in: Macrophages Neutrophils Increases red blood cell production Alters 2 3 'dideoxynucleoside analogue uptake or metabolism Increases HIV expression in macrophages I,
GM-CSF
G-CSF
Yes YeS Yes Yes Yes
No Yes Yes No No
Yes Yes Unknown
No Yes Yes
Yes
Unknown
Yes
No
in decreases in clinical activity. The use of hematopoietic growth factors to ameliorate the myelosuppressive complications of chemotherapy is a major goal in the successful treatment of patients with severe HIV infection. To date, granulocyte macrophage-colonystimulating factor (GM-CSF), granulocytecolony stimulating factor (GCSF), and erythropoietin@PO) have been used with good effect in patients with a variety of complications related to HIV infection and chemotherapy (Table 1).
TREATMENT OF AIDS PATIENTS WITH GM-CSF The first trial of bematopoietic growth factor in humans was the use of GM-CSF in patients with AIDS (10). This pioneering study utilized glycosylated GM-CSF produced by recombinant DNA techniques in Chinese hamster ovary (CHO) cells. Sixteen patients received GM-CSF by continuous intravenous infusion at doses ranging between 0.5 and 8 pg/kg/day . Rapid, dose-related increases in granulocytes, monocytes, and eosinophils were seen. No significant increases in other circulating blood elements were observed during the 2-week period of treatment. Toxicities included fevers, facial flushing, transient
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23 1
skin rash, and local vein irritation. This latter toxicity may have been due to local leukostasis when the drug was administered by peripheral vein. Phlebitis was not seen when GM-CSF was administered by a central venous catheter. Increases in total marrow cellularity were observed in 11 of 14 patients. Despite these increases, a prompt drop in leukocyte counts was seen at the end of drug infusion (see Fig. 1). Neutrophil function was assessed in 6 patients in this Phase I trial (1 1). Two of these six patients had selectivedefects in either neutrophilbacterial phagocytosis or intracellular killing. The administration of GM-CSF transiently corrected these defects. HIV recovery from peripheral blood mononuclear cells and HIV p24 antigen expression was not altered in a consistent direction during the 14-day period of drug administration. The next stage in development of this agent was the demonstration that these hematopoietic effects could be sustained. Long-term subcutaneous administrationof GMCSF in patients with HIV infection and neutropenia for up to eight months resulted in continued leukocyte response with no evidence of stem cell depletion or marrow exhaustion (12). At doses of 0.25-4.0 pglkglday of GM-CSF, persistent improvements in leukocyte counts were observed without accompanying changes in hemoglobin or platelet counts. Bacterial and opportunistic infections were observed in this patient population which was not given AZT or prophylactic antimicrobial treatment. No consistent increases in viral replication as measured by HIV p24 antigenemiaor virus recovery from cocultured lymphocytes were seen.
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Figure 1. Total leukocytecount and differentialin a patient with AIDS treated with recombinant human GM-CSF.
THE USE OF GM-CSF TO REDUCE MYELOSUPPRESSIVE TOXICITY Because of the ability of GM-CSF to correct neutropenia in patients with AIDS, attempts were made to combine GM-CSF with a variety of myelosuppressiveanti-infective agents. Since the most common cause of drug-related hematopoietic defects in patients with AIDS is the use of zidovudine, initial attempts were aimed at ameliorating zidovudine-related myelosuppression. Zidovudine-related bone marrow suppression is a significant clinical problem. In patients with AIDS who receive more than 600 mg of zidovudineper day, approximately 50% of patients will require dose reduction as a result of hematopoietic toxicity and an additional25 % will have drug therapy discontinued within the first year. In this population, only 25 % of patients are able to tolerate fulldoses of zidovudine after 1 year (13). Despite the use of lower doses of zidovudine and treatment of patients in earlier stages of HIV infection, zidovudine still causes significant neutropenia (neutrophils 4OO/pL appear to tolerate induction therapy with interferon better than patients with CD4 helper cell number 50% suppression of p24 antigen with this regimen. This is a very
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high response rate for patients with this advanced stage of HIV infection.Whether this response rate is reflective of a synergistic activity of the three drug regimen or related to the sample size is not known. These have been no opportunistic infections although, interestingly, two patients have developedHemophilus injluenza pneumonia while receiving GM-CSF therapy. Twenty-four percent of patients had a dose reduction as a result of drug-related toxicity and 28 of 29 individuals developed a flu-like syndrome ascribed to the alphainterferon. According to the investigators, this side effect may have been exacerbated by GM-CSF treatment. Three patieats have had their dose modified because of transfusion requirements; 2 for thrombocytopenia, 1 for myositis, and 2 for CNS toxicity from zidovudine. Overall, the regimen appe4lrs to be tolerable with an increase in response rates in patients who are at risk for progressive disease while receiving alpha interferon monotherapy. Because dmg-rekd hematopoetic toxicity can be easily corrected by the use of colony-stimulating factors, future trials in AIDS-related Kaposi sarcoma will involve the use of not only combined GM-CSF, zidovudine, and alpha-interferon, but also GM-CSF along with chemotherapeutic regimens using adriamycin, bleomycin, and vincristine (ABV)(26).Phase I clinical trials of these agents have been initiated by the AIDS Clinical Trials Group. GM-CSF IN NON-HOffiIUN’SLYMPHOMA Two Wase I clinical trials have investigated the use of GM-CSF to decrease the myelosuppressive effects of cancer chemotherapy in AIDS-related non-Hodgkin’s lymphoma. Previous studies have demonstrated that patients with AIDSrelated n~n-Hodgkin’~ lymphoma do not tolerate conventional chemotherapy but are able to tolerate a modifiedregimen of m-BACOD. Overall response rates of approximately 5496 can be achieved with this dosemodified regimen (32). In an attempt to increase the overall response rate by increasing the dose of chemotherapy while protecting patients from drug-related leukopenia, patients were treated with modified doses of m-BACOD and GM-CSF therapy in a Phase I trial (33). GM-CSF was given on Days 3 through 13 at 20 pglkglday. The first three patients received no GM-CSF and halfdose m-BACOD (25 mg/m2 hydroxydaunorubicin (Adriamycin) , 300 mg/m2 cyclophosphamide (Cytoxan), 500 mg/m2 methotrexate with leukovoxin rescue, and standard doses of vincristine, bleomycin, and dexamethasone). The median nadir
neutrophjl count was 1805/pL(range 893-2700/pL).Two additional cohorts were enrolled. The second cohort of five patients received GM-CSF on Days 3-13 and increased doses of adriamycin (35 mg/m2) and cytoxan (450 mg/m2). ”he mean neutrophil nadir was 799/pL (range 38-1836/pL).The final cohort of 8 patients received full doses m-BACOD (45 mg/m2adriamycin, 600 mg/m2 cytoxan, plus the same doses of methotrexate, vincristine, bleomycin, and dexamethasone) along with GM-CSF on Days 3-13.The mean neutrophil nadir was 1227/pL(range 100-4400/pL)and this regimen was well tolerated (33). Thus,it is clear that patients with HIV can receive full doses of m-BACOD provided that sufficient granulocyte stimulationis provided. A subsequentclinical trial has been planned to investigate the important question of whether the increase in chemotherapy dose intensity will result in an increase in complete response rate or response duration (AmG 142).In that futuretrial, patients will be randomly assigned to modified dose mBACOD or fulldose m-BACOD with GM-CSF. One other trial of GM-CSF with cancer chemotherapy in non-Hodgkin’s lymphoma has been initiated (34). In this trial, the CHOP chemotherapy regimen (cyclophosphami& 650 mg/m2, hydroxydaunorubicin 35 mg/m2, vincristine 1.4 mg/&, and prednisone 60 mg/day for 5 days) was used with GM-CSF on Days 1-13. After the first three patients showed no amelioration of neutropenia, subsequent groups were given GM-CSF on Days 3-13.This modification in GM-CSF drug administration resulted in a significant improvement in neutrophil counts with partial protection against granulocytopenia (34).This latter observation may illustrate the importance of the schedule of administration of GM-CSF on its effectiveness in ameliorating drug related toxicity. Interestingly, significant reductions in HIV antigens were seen in the serum of patients receiving these cytoablative chemotherapy regimens.
ExYTHRomIETIN IN PATIENTS WITH AIDS Severe anemia (hemoglobin 5OOO/pL was achieved and maintained for two weeks. After correction of the leukopenia, subcutaneous EPO was administeredin increasing doses until an increment of 1.5 g/dl of hemoglobin was observed. Following correction of both cytopenias, successive groups of patients were given 1O00, 1500, or 2000 mg of zidovudine per day. G-CSF and EPO therapy was continued throughout, with dose modificationto maintain an ANC > 1500/pL and hemoglobin > 100 g/L. All 22 patients responded to G-CSF with a mean tenfold increase in neutmphils in less than two weeks. Significant increases in CJM and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in 20 of 20 evaluable patients within 8 weeks. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in 8 of the 20 patients, six of whom were
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discontinued from study. No patient was discontinued because of leukopnia or thrombocytopenia. Toxicities were minimal and did not require dose modifications for any patient. Unlike GM-CSF, patients treated with G-CSF had no fatigue, fevers, myalgias, or inanition. Anaysis of semiquantitative cultures for HIV and p24 antigen levels showed no significant alterations in viral expression after G-CSF or combined G-CSF and EPO therapy confinning earlier in vitro studies (39). H W p24 antigen decreased significantly with zidovudine therapy. The potency of this combination of hematopoietins is best illustrated by the demonstration that multiple myelosuppressiveagents can be simultaneouslyused with zidovudine. In this population of patients with severe hematopoietic defects, not only were patients able to resume fulldose or even higher doses of zidovudine, but 7 patients received simultaneousinduction courses of ganciclovir without modification of zidovudine doses. From these studies, it is clear that combined therapy with GCSF and EPO can ameliorate the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of zidovudine therapy in many patients who were previously intolerant of the hematologic effects of zidovudine
POTENTLAL COMPLICATIONS OF GROWTH FACTOR THERAPY IN HIV INFECTION The major concern in the use of hematopoietic growth factors in patients with HIV infection is the possibility that these agents may cause disease progression. Theoretidy, these agents could increase the number of target cells for HIV replication or may enhance HIV replication within target cells resulting in acceleration of HIV-related disease. This concern results from the muItiple physiologic activities of these compounds and the possible perturbations possible in patients with HIV infection. With each growth factor and within each patient a complex set of interactions may occur between the growth factor, host defense, target cells, and the populations of HlV virus resulting in different clinical outcomes. For example, one patient may have low titers of neutralizing antibodies and lack significant macrophage infection with HN.When given GM-CSF, the growth factor may augment antibodydependent cell cytotoxicity which may decrease viral expression. Since there is no significant macrophage viral infection, the overall result may be a decrease in HIV expression. Obviously, the converse is
also true. Moreover, the effects may vary considerably depending on the stage of disease and other concurrent medications and illnesses. As a result, the effects of GCSF or GM-CSF on HIV replication in individual patients receiving zidovudine may be unpredictable. The only way to adequately address this issue is to carefully measure viral load before and after therapy or compare between treated and untreated arms of controlled trials. To date, the best markers to follow are measurementsof HIV antigens and semiquantitative cultures of lymphocytes and plasma (32). In multiple Phase I and 11trials, no consistent increase has been observed in HIV p24 antigen levels or HIV viral recovery from lymphocytes with the use of either G-CSF or GM-CSF. Thus, while this remains a theoretical concern, evidence to date suggests that treatment with either G-CSF or GM-CSF do not result in acceleration of HN replication.
GROWTH FACTORS AS ADJUNCTIVE THERAPY MIR IMMUNOHEMATOPOIESIS IN PATIENTS WITH HIV INFECTION Until now, the major focus of the use of growth factors has been on their ability to ameliorate drug-related hematopoietic suppression. While laudable, the development of newer less myelosuppressive antiviral and antineoplastic agents will eventually supplant these uses. In the future, greater emphasis will be placed on the ability of cytokines and hematopoieticgrowth factors to enhance host defenses against opportunisticinfections and increase immune function. Both G-CSF and GM-CSF have been shown to increase neutrophil function and correct neutrophil defects. G-CSF has also significantly increased CD4 cell number in patients with advanced stages of HIV infection. With the recent discoveries, cloning and commercial production of IL-4, IL-6, IL-7, and IL-9 new avenues of therapy are possible. Two of these agents have effects on B-cell development (IL-4 and 6) while the other two have some effects on T-cell development (IL-7 and 9). Combined with IL-2 and newer less myelosuppressive antiretroviral agents, it is hoped that some combination of the hematopoietichormones will be able to reverse the steady loss of CD4 cells and reduce mortality.
CONCLUSIONS
Three hematopoietic stimulants have been used in patients with HIV infection and a variety of AIDSrelated complications. Both G-CSF and GM-CSF have
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demonstrated the ability to correct leukapenia related to HIV infection and ameliorate drug-relatedmyelosuppressive effects of zidovudine, cotrimoxazole, ganciclovir, and, in the case of GM-CSF, alpha-interferon, and chemotherapeutic regimens. Erythropoietinhas been successfully used to ameliorate the anemia associated with HN infection and zidovudine therapy. Treatment with these hematopoietic stimulants is very well tolerated with minimal toxicity. Of the granulocyte stimulants, G-CSF appears to have a more favorable side effect profile than GM-CSF in trials conducted to date. Future trials demonstrating that the amelioration of hematopoietic suppression by the colony stimulating factors will result in increased overall clinical response rates and improved survival are necessary to appropriately access the value of this approach to the c m of HIV-infected patients.
ACKNOWLEDGMENTS The author thanks the State of California for funding as directed by the UnivetsitywideTask Force on AIDS (87JA039 and 89C-CC86LA). Additional funding was provided by the National Institute of Allergy and Immunological Diseases (AI27660).
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