Recombinant Hemopoietic Growth Factors: Comparative Hemoboietic Response in Younger and Older Subjects Walter A. Shank, Jr., M D and Lodovico Balducci, M D Objective: To study the effectiveness of hemopoietic growth factors in older patients. Design: Literature review. All articles published in English language between 1987 and 1990 were reviewed. Those reporting studies without age limits as entry criteria and describing the effects of growth factors in individual patients were suitable for analysis. Bone marrow transplantation related articles were excluded. Main Outcome Measures: The meanfold increase of granulocytes for Granulocyte-Colony Stimulating Factor, Granulocyte Macrophage-Colony Stimulating Factor, and Interleukin 3 and of hemoglobin for erythropoietin were compared in subjects younger and older than 65, by Mann-Whitney U test. Results: Of 68 studies, 23 were suitable for analysis. These
included patients with myelodysplastic syndromes, aplastic anemia, chemotherapy-induced myelosuppression, chronic granulocytopenia, anemia, and myelosuppression of malignancies and of chronic disease. Of 204 patients, 67 were 65 years of age or older and 42 were over 70. No difference was seen in meanfold increase of granulocyte and hemoglobin in time of response to growth factors or in response in presence of an absolute neutrophil count lower than lOOO/pL between younger and older patients. Conclusion: Early response to hemopoietic growth factors appears well maintained with advanced age. Prospective studies of the prolonged effects of these factors in older and younger patients are needed. J Am Geriatr SOC40151154,1992
ging is associated with inadequate response to hemopoietic stresses such as bleeding, infection, or cytotoxic chemotherapy.' Hence, morbidity and mortality of these conditions are heightened.2-9The risk of treatment-related life-threatening myelotoxicity is a major obstacle to cancer control in By utilizing recombinant DNA techniques, the hemopoietic growth factors (HGFs) have become available for clinical use and have ameliorated hemopoietic dysfunctions from chronic diseases and myelosuppressive drugs." These compounds hold the promise to restore the hemopoietic response of older-aged persons. Hemopoiesis is a highly organized, serial process by which the circulating blood elements are generated from pluripotent hemopoietic stem cells entering the subsequent stages of commitment, differentiation, and m a t ~ r a t i o n Hemopoiesis .~ is supported by the hemopoietic stroma and is modulated by specific HGFs (Table 1).The causes of age-related hemopoietic insufficiency are poorly understood and may involve different hemopoietic phases, including depletion of hemopoietic stem cell reserves, reduced growth factor secretion, metabolic changes of hemopoietic progenitors, and microenvironmental disruption. The aim of this study is to establish whether the hemopoietic response to HGFs is maintained in subjects of advanced age. For this purpose, we performed an analysis of previously
published data and compared response to HGFs in patients of different ages.
A
From the James A. Haley Veterans Hospital, University of South Florida College of Medicine, Tampa, Florida. Presented in part at the National Meeting of the American Geriatrics Society, Chicago, Illinois, May 11, 1991. Address reprints requests to Lodovico Balducci, MD, Chief, Oncology Section (111N), James A. Haley Veterans Hospital, 13000 Bruce B. Downs Boulevard, Tampa, FL 33612.
JAGS 40:151-154, 1992 01992 by the American Geriatrics Society
MATERIALS AND METHODS A National Library of Medicine literature search was performed to identify published clinical trials in which geriatric patients were treated with G-CSF, GM-CSF, IL-3, or epoietin. The time period searched was 1987 to 1991 using Index Medicus and the Medline database. In addition, the reference list of each retrieved article was reviewed to identify other relevant publications. No literature prior to 1987 was included since HGFs produced by recombinant DNA techniques were unavailable until that year. Studies were selected for analysis if they included subjects 2 65 years of age and detailed the hematologic response of individual patients treated with a particular HGF. Studies involving pediatric malignancies or pediatric illnesses, studies which failed to report subject age or individual patient data, and bone marrow transplantation studies were excluded from analysis. Bone marrow transplantation studies were excluded because patients over 50 are not considered candidates for this procedure in most institutions. The literature was reviewed by one author (W.A.S.) and the findings were discussed with the other author (L.B.). Controversial interpretations of data were resolved by consensus. The response of individual patients to HGFs was calculated as the average of the proportionate increase ("meanfold" increase, MFI) in hemoglobin for subjects receiving epoietin and MFI in granulocyte count for subjects treated with G-CSF, GM-CSF or IL-3. If no change occurs in an outcome measure, the MFI would be 0.0; if the outcome measure doubles, the MFI would be 1.0, and so forth. The Mann-Whitney U test was utilized to compare the magnitude of hemopoietic re-
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SHANK AND BALDUCCI
IAGS-FEBRUARY 1992-VOL. 40, NO. 2
TABLE 1. HEMOPOIETIC GROWTH FACTORS (HGFs) FOR CLINICAL USE OR CLINICAL TRIALS Growth Factor Source Best Defined Actions Ervt hropoietin (Epoietin)
Kidney
Granulocyte-MacrophageColony Stimulating Factor (GM-CSF)
Lymphocytes (T) Monocytes Stromal Cells (endothelial,fibroblasts) Monocytes and Stromal cells
65 Years >70 Years GM-CSF G-CSF Epoietin IL-3
Total
12 7 2 2 23
(11-22) (23-29) (30-31) (32-33)
sponse to each HGF in populations of different age groups. The number of patients older or younger than 65 who experienced resolution of neutropenia, ie, absolute neutrophil count (ANC) ?1000/pL, from administration of G-CSF, GM-CSF or IL-3 were compared by chi-square test for contingency tables.
RESULTS A total of 68 reports were identified in the English language which reported the hematologic effects of GCSF, GM-CSF, IL-3,or epoietin administered to a total of 1,392 subjects. Of these, 23 studies did not specify patient age or did not include patients older than 65. Of the remaining clinical trials, 23 studies met the inclusion criteria and were suitable for analysis (Table 2). These 23 studies reported pre- and post-HGF data on 204 persons, of whom 74 were 65 years of age or older and 42 were over 70. All studies were performed in university medical centers or research institutes in the USA,"-'3f '5-26*29r31 Western Europe,'6,28'30t32-33 and J a ~ a n . ' ~ ,Treatment ~' duration, baseline CBC, dose of HGFs, highest blood count obtained during treatment, and therapeutic complications were reported in all studies. The research plan was detailed and involved blood count monitoring at close intervals (daily or weekly) as appropriate for different conditions. All studies were combined Phase 1/11 trials. The clinical trials used in the analysis investigated the utility of HGFs in various hematologic disorders including aplastic anemia (3), myelodysplastic syndromes (6), chemotherapy-induced myelosuppression (3), chronic granulocytopenia (3), and anemia or myelosuppression associated with malignancy (7) or chronic disease (1).
115 42 30 17 204
36 18 13 7 74
22 10 7 3 42
Advanced Age and Response to GM-CSF GM-CSF was the most extensively studied HGF. Twelve trials involving 115 patients described the effects of GM-CSF in patients with myelodysplastic syndromes, chemotherapy-induced myelosuppression, aplastic anemia, and various malignancies."-22 Thirtysix of the 115 patients were over the age of 65 years with 22 of these patients being 70 years of age or older. The overall MFI in ANC was 6.6 for patients under 65 and 6.9 for those aged 65 and older (two-tailed P = 0.5). A further analysis of the data investigated the possibility of a different dose-response effect between younger and older patients at different dose-intensities. As illustrated in Table 3, however, no difference in response was observed at any of the three dosing levels of GM-CSF therapy. Increasing doses of GM-CSF produced, on average, an increased hematopoietic response that was of similar magnitude in both populations. Side effects including bone pain, rash, and flulike symptoms were evenly distributed among patients of all ages. In general GM-CSF was well tolerated, with more serious adverse reactions occurring at the higher dosages and following intravenous administration. Advanced Age and Response to G-CSF Seven studies described the effects of G-CSF in
42 patients, 18 of whom were over 65 and 10 over 70.23-29 The effects of G-CSF were evaluated in patients with cyclic neutropenia, myelodysplastic syndromes, and neutropenia associated with chemotherapy or hairy cell leukemia. Dosages of G-CSF ranged from 0.3 &kg to 1,600 &M2 which produced 1.4 to 232fold increase in ANC. The MFI was 12.2 in patients over 65 years and 10.1 for younger patients (two-tailed
JAGS-FEBRUARY 1992-VOL. 40, NO. 2
P = 0.3).Side-effects were mild and infrequent in both age groups studied.
RECOMBINANT HGF's
153
TABLE 3. RESPONSE TO GM-CSF BY DOSE AND AGE Meanfold Increase in Granulocyte Count-
Advanced Age and Response to Epoietin Age (yrs) 0.3-1 &Kg* 60-150 p g / M 2 >240 &M2 Two studies detailed the effects of epoietin in 30 2.3 (19)** 4.9 (28) 17.6 (30) patients, 13 of whom were L 65 years of age.30-31 0.2). Side-effects were not observed in these stud- * Dose. of patients. ies, and most patients without active infection reported **Number *** Mann-Whitney U test statistic. a heightened sense of well being and improved exercise tolerance. TABLE 4. NEUTROPENIA AND THE USE OF
G-CSF, GM-CSF, IL-3 Advanced Age and Response to Interleukin-3 Age (Years) AGC* > l O O O / J AGC 1,000/~1.Neu- polypharmacy, the incidence of this condition increases tropenia was reversed in 46 of 62 (74%) patients < 65 with age. At present, HGFs represent the most viable years of age as compared to 26 of 35 (74%) of older option to restore adequate response to hemopoietic patients (Table 4). stress and to reduce morbidity and mortality of hemopoietic insufficiency. DISCUSSION By performing a systematic literature search, we The HGFs are glycoprotein hormone-like substances discovered that 48 of 68 clinical trials involving HGFs that support growth and differentiation of blood-form- did not exclude patients on the basis of age. As shown ing cells'o,34-35and include colony stimulating factors in Table 2, we identified 23 studies which detailed the (CSFs), epoietin, and interleukins. CSFs modulate pro- effects of HGFs in 204 individual patients, 74 of whom liferation and differentiation of granulocytes and mon- were aged 65-87. Based upon a comparison of meanocyte-macrophage precursors, while epoietin stimu- fold increase in granulocyte count or hemoglobin, we lates proliferation of late committed erythroid progen- were unable to detect age-related difference in rei t o r ~ . ' , ~Interleukins ,'~ exert various effects including sponse to HGFs (Table 5). The time to response to HGF induction of CSF production by accessory cells and was similar in younger and older patients, and the enhancement of responsiveness of progenitor cells to percentage of neutropenic patients responding to Gother HGFs. Recombinant DNA technology has al- CSF, GM-CSF, or IL-3with a granulocyte count higher lowed the production and clinical testing of many of than l,OOO/pl was identical (74%) in both age groups. these agents, and their potential utility in the area of A further analysis of data involving GM-CSF therapy hematology-oncology appears great. There are ongoing revealed no age-related difference in dose-response efforts to discover new HGFs, and clinical trials are relationship. HGFs are generally well tolerated, and underway to investigate the utility of growth factors the toxicity of these compounds does not appear to be used sequentially or in combination to achieve desired age-related. On the basis of this review, we conclude that early effects on hematopoiesis. The focus of this study was the responsiveness to G- response to HGFs is well preserved in some older CSF, GM-CSF, IL-3 and epoietin in the aged. This is subjects. These are preliminary findings based upon an an issue of high clinical relevance, as abundant circum- analysis of published studies, and several important stantial evidence supports age-related hemopoietic in- questions remain unanswered. The first is whether sufficiency. In experimental models of aging, hemo- response to HGFs in older persons may be sustained
154
JAGS-FEBRUARY 1992-VOL. 40, NO. 2
SHANK AND BALDUCCI
TABLE 5. EFFECT OF AGE ON RESPONSE TO HGFs No.of Mean-Fold Age P Value Increase HGF (Years) Patients G-CSF
GM-CSF IL-3
Epoietin
265
included patients with myelodysplastic syndromes, aplastic anemia, chemotherapy-induced myelosuppression, chronic granulocytopenia, anemia, and myelosuppression of malignancies and of chronic disease. Of 204 patients, 67 were 65 years of age or older and 42 were over 70. No difference was seen in meanfold increase of granulocyte and hemoglobin in time of response to growth factors or in response in presence of an absolute neutrophil count lower than lOOO/pL between younger and older patients. Conclusion: Early response to hemopoietic growth factors appears well maintained with advanced age. Prospective studies of the prolonged effects of these factors in older and younger patients are needed. J Am Geriatr SOC40151154,1992
ging is associated with inadequate response to hemopoietic stresses such as bleeding, infection, or cytotoxic chemotherapy.' Hence, morbidity and mortality of these conditions are heightened.2-9The risk of treatment-related life-threatening myelotoxicity is a major obstacle to cancer control in By utilizing recombinant DNA techniques, the hemopoietic growth factors (HGFs) have become available for clinical use and have ameliorated hemopoietic dysfunctions from chronic diseases and myelosuppressive drugs." These compounds hold the promise to restore the hemopoietic response of older-aged persons. Hemopoiesis is a highly organized, serial process by which the circulating blood elements are generated from pluripotent hemopoietic stem cells entering the subsequent stages of commitment, differentiation, and m a t ~ r a t i o n Hemopoiesis .~ is supported by the hemopoietic stroma and is modulated by specific HGFs (Table 1).The causes of age-related hemopoietic insufficiency are poorly understood and may involve different hemopoietic phases, including depletion of hemopoietic stem cell reserves, reduced growth factor secretion, metabolic changes of hemopoietic progenitors, and microenvironmental disruption. The aim of this study is to establish whether the hemopoietic response to HGFs is maintained in subjects of advanced age. For this purpose, we performed an analysis of previously
published data and compared response to HGFs in patients of different ages.
A
From the James A. Haley Veterans Hospital, University of South Florida College of Medicine, Tampa, Florida. Presented in part at the National Meeting of the American Geriatrics Society, Chicago, Illinois, May 11, 1991. Address reprints requests to Lodovico Balducci, MD, Chief, Oncology Section (111N), James A. Haley Veterans Hospital, 13000 Bruce B. Downs Boulevard, Tampa, FL 33612.
JAGS 40:151-154, 1992 01992 by the American Geriatrics Society
MATERIALS AND METHODS A National Library of Medicine literature search was performed to identify published clinical trials in which geriatric patients were treated with G-CSF, GM-CSF, IL-3, or epoietin. The time period searched was 1987 to 1991 using Index Medicus and the Medline database. In addition, the reference list of each retrieved article was reviewed to identify other relevant publications. No literature prior to 1987 was included since HGFs produced by recombinant DNA techniques were unavailable until that year. Studies were selected for analysis if they included subjects 2 65 years of age and detailed the hematologic response of individual patients treated with a particular HGF. Studies involving pediatric malignancies or pediatric illnesses, studies which failed to report subject age or individual patient data, and bone marrow transplantation studies were excluded from analysis. Bone marrow transplantation studies were excluded because patients over 50 are not considered candidates for this procedure in most institutions. The literature was reviewed by one author (W.A.S.) and the findings were discussed with the other author (L.B.). Controversial interpretations of data were resolved by consensus. The response of individual patients to HGFs was calculated as the average of the proportionate increase ("meanfold" increase, MFI) in hemoglobin for subjects receiving epoietin and MFI in granulocyte count for subjects treated with G-CSF, GM-CSF or IL-3. If no change occurs in an outcome measure, the MFI would be 0.0; if the outcome measure doubles, the MFI would be 1.0, and so forth. The Mann-Whitney U test was utilized to compare the magnitude of hemopoietic re-
0002-8614/92/$3.50
152
SHANK AND BALDUCCI
IAGS-FEBRUARY 1992-VOL. 40, NO. 2
TABLE 1. HEMOPOIETIC GROWTH FACTORS (HGFs) FOR CLINICAL USE OR CLINICAL TRIALS Growth Factor Source Best Defined Actions Ervt hropoietin (Epoietin)
Kidney
Granulocyte-MacrophageColony Stimulating Factor (GM-CSF)
Lymphocytes (T) Monocytes Stromal Cells (endothelial,fibroblasts) Monocytes and Stromal cells
65 Years >70 Years GM-CSF G-CSF Epoietin IL-3
Total
12 7 2 2 23
(11-22) (23-29) (30-31) (32-33)
sponse to each HGF in populations of different age groups. The number of patients older or younger than 65 who experienced resolution of neutropenia, ie, absolute neutrophil count (ANC) ?1000/pL, from administration of G-CSF, GM-CSF or IL-3 were compared by chi-square test for contingency tables.
RESULTS A total of 68 reports were identified in the English language which reported the hematologic effects of GCSF, GM-CSF, IL-3,or epoietin administered to a total of 1,392 subjects. Of these, 23 studies did not specify patient age or did not include patients older than 65. Of the remaining clinical trials, 23 studies met the inclusion criteria and were suitable for analysis (Table 2). These 23 studies reported pre- and post-HGF data on 204 persons, of whom 74 were 65 years of age or older and 42 were over 70. All studies were performed in university medical centers or research institutes in the USA,"-'3f '5-26*29r31 Western Europe,'6,28'30t32-33 and J a ~ a n . ' ~ ,Treatment ~' duration, baseline CBC, dose of HGFs, highest blood count obtained during treatment, and therapeutic complications were reported in all studies. The research plan was detailed and involved blood count monitoring at close intervals (daily or weekly) as appropriate for different conditions. All studies were combined Phase 1/11 trials. The clinical trials used in the analysis investigated the utility of HGFs in various hematologic disorders including aplastic anemia (3), myelodysplastic syndromes (6), chemotherapy-induced myelosuppression (3), chronic granulocytopenia (3), and anemia or myelosuppression associated with malignancy (7) or chronic disease (1).
115 42 30 17 204
36 18 13 7 74
22 10 7 3 42
Advanced Age and Response to GM-CSF GM-CSF was the most extensively studied HGF. Twelve trials involving 115 patients described the effects of GM-CSF in patients with myelodysplastic syndromes, chemotherapy-induced myelosuppression, aplastic anemia, and various malignancies."-22 Thirtysix of the 115 patients were over the age of 65 years with 22 of these patients being 70 years of age or older. The overall MFI in ANC was 6.6 for patients under 65 and 6.9 for those aged 65 and older (two-tailed P = 0.5). A further analysis of the data investigated the possibility of a different dose-response effect between younger and older patients at different dose-intensities. As illustrated in Table 3, however, no difference in response was observed at any of the three dosing levels of GM-CSF therapy. Increasing doses of GM-CSF produced, on average, an increased hematopoietic response that was of similar magnitude in both populations. Side effects including bone pain, rash, and flulike symptoms were evenly distributed among patients of all ages. In general GM-CSF was well tolerated, with more serious adverse reactions occurring at the higher dosages and following intravenous administration. Advanced Age and Response to G-CSF Seven studies described the effects of G-CSF in
42 patients, 18 of whom were over 65 and 10 over 70.23-29 The effects of G-CSF were evaluated in patients with cyclic neutropenia, myelodysplastic syndromes, and neutropenia associated with chemotherapy or hairy cell leukemia. Dosages of G-CSF ranged from 0.3 &kg to 1,600 &M2 which produced 1.4 to 232fold increase in ANC. The MFI was 12.2 in patients over 65 years and 10.1 for younger patients (two-tailed
JAGS-FEBRUARY 1992-VOL. 40, NO. 2
P = 0.3).Side-effects were mild and infrequent in both age groups studied.
RECOMBINANT HGF's
153
TABLE 3. RESPONSE TO GM-CSF BY DOSE AND AGE Meanfold Increase in Granulocyte Count-
Advanced Age and Response to Epoietin Age (yrs) 0.3-1 &Kg* 60-150 p g / M 2 >240 &M2 Two studies detailed the effects of epoietin in 30 2.3 (19)** 4.9 (28) 17.6 (30) patients, 13 of whom were L 65 years of age.30-31 0.2). Side-effects were not observed in these stud- * Dose. of patients. ies, and most patients without active infection reported **Number *** Mann-Whitney U test statistic. a heightened sense of well being and improved exercise tolerance. TABLE 4. NEUTROPENIA AND THE USE OF
G-CSF, GM-CSF, IL-3 Advanced Age and Response to Interleukin-3 Age (Years) AGC* > l O O O / J AGC 1,000/~1.Neu- polypharmacy, the incidence of this condition increases tropenia was reversed in 46 of 62 (74%) patients < 65 with age. At present, HGFs represent the most viable years of age as compared to 26 of 35 (74%) of older option to restore adequate response to hemopoietic patients (Table 4). stress and to reduce morbidity and mortality of hemopoietic insufficiency. DISCUSSION By performing a systematic literature search, we The HGFs are glycoprotein hormone-like substances discovered that 48 of 68 clinical trials involving HGFs that support growth and differentiation of blood-form- did not exclude patients on the basis of age. As shown ing cells'o,34-35and include colony stimulating factors in Table 2, we identified 23 studies which detailed the (CSFs), epoietin, and interleukins. CSFs modulate pro- effects of HGFs in 204 individual patients, 74 of whom liferation and differentiation of granulocytes and mon- were aged 65-87. Based upon a comparison of meanocyte-macrophage precursors, while epoietin stimu- fold increase in granulocyte count or hemoglobin, we lates proliferation of late committed erythroid progen- were unable to detect age-related difference in rei t o r ~ . ' , ~Interleukins ,'~ exert various effects including sponse to HGFs (Table 5). The time to response to HGF induction of CSF production by accessory cells and was similar in younger and older patients, and the enhancement of responsiveness of progenitor cells to percentage of neutropenic patients responding to Gother HGFs. Recombinant DNA technology has al- CSF, GM-CSF, or IL-3with a granulocyte count higher lowed the production and clinical testing of many of than l,OOO/pl was identical (74%) in both age groups. these agents, and their potential utility in the area of A further analysis of data involving GM-CSF therapy hematology-oncology appears great. There are ongoing revealed no age-related difference in dose-response efforts to discover new HGFs, and clinical trials are relationship. HGFs are generally well tolerated, and underway to investigate the utility of growth factors the toxicity of these compounds does not appear to be used sequentially or in combination to achieve desired age-related. On the basis of this review, we conclude that early effects on hematopoiesis. The focus of this study was the responsiveness to G- response to HGFs is well preserved in some older CSF, GM-CSF, IL-3 and epoietin in the aged. This is subjects. These are preliminary findings based upon an an issue of high clinical relevance, as abundant circum- analysis of published studies, and several important stantial evidence supports age-related hemopoietic in- questions remain unanswered. The first is whether sufficiency. In experimental models of aging, hemo- response to HGFs in older persons may be sustained
154
JAGS-FEBRUARY 1992-VOL. 40, NO. 2
SHANK AND BALDUCCI
TABLE 5. EFFECT OF AGE ON RESPONSE TO HGFs No.of Mean-Fold Age P Value Increase HGF (Years) Patients G-CSF
GM-CSF IL-3
Epoietin
265
