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Journal of Clinical Oncology, Vol 18, Issue 2 (January), 2000: 325
© 2000 American Society for Clinical Oncology

Factors That Predict Chemotherapy-Induced Myelosuppression in Lymphoma Patients: Role of the Tumor Necrosis Factor Ligand-Receptor System

By Eric Voog, Jacques Bienvenu, Krzysztof Warzocha, Isabelle Moullet, Charles Dumontet, Catherine Thieblemont, Guillaume Monneret, Marie-Claude Gutowski, Bertrand Coiffier, Gilles Salles

From the Service d’Hématologie and Laboratoire d’Immunologie, Centre Hospitalier Lyon-Sud, Pierre-Bénite; and Jeune Equipe (Pathologie des Cellules Lymphoïdes), Université Claude Bernard, Lyon, France.

Address reprint requests to G. Salles, Service d’Hématologie, Centre Hospitalier Lyon-Sud, 69495 Pierre-Benite Cedex, France; email gilles.salles{at}chu-lyon.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To analyze factors that predict the occurrence of chemotherapy-induced myelosuppression and, in particular, the role of the tumor necrosis factor (TNF) ligand-receptor system in lymphoma patients at the beginning of their treatment.

PATIENTS AND METHODS: We investigated the predictive factors for myelosuppression after the first course of chemotherapy in a cohort of 101 consecutive, previously untreated lymphoma patients receiving regimens that include doxorubicin and cyclophosphamide. Plasma samples were tested at baseline by enzyme-linked immunosorbent assay for TNF and its soluble receptors. Univariate and multivariate analyses were performed with a forward regression procedure that included all of the parameters that were found to be significant in the univariate analysis. The dose of chemotherapy and the prophylactic treatment with granulocyte colony-stimulating factor were deliberately included in this model.

RESULTS: Sixty-seven patients experienced World Health Organization (WHO) grade 4 neutropenia, and 37 patients experienced febrile neutropenia, which was responsible for WHO grade 2 through 4 infections in 23 patients. In multiparametric regression analysis, the occurrence of grade 4 neutropenia was associated with high doses of cyclophosphamide (odds ratio [OR], 19.8; P = .008) and high levels of soluble p75-R-TNF (OR, 8.52; P = .001). The duration of grade 4 neutropenia for more than 5 days was associated with the lack of hematopoietic growth factor administration (OR, 6.76; P = .004) and high levels of soluble p75-R-TNF (OR, 5.84; P = .0023). The occurrence of febrile neutropenia was associated with high doses of cyclophosphamide (OR, 4.7; P = .007), altered performance status (OR, 18.8; P < .0001) and high levels of soluble p75-R-TNF (OR, 3.49; P = .029).

CONCLUSION: This study indicates that in addition to the dose of chemotherapy and the administration of hematopoietic growth factors, poor performance status and high p75-R-TNF levels can predict the occurrence of chemotherapy-induced myelosuppression in lymphoma patients. This model may help in selecting patients for prophylactic growth factor administration.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
MYELOSUPPRESSION is the most common adverse effect of cytotoxic chemotherapy. It is frequently complicated by febrile neutropenia, a life-threatening complication that can cause death in a small proportion of lymphoma patients.1,2 Although less frequent, thrombocytopenia is another serious complication, and anemia, which may also be linked to the host-tumor relationship, worsens a patient’s quality of life. The major determinant of myelosuppression occurrence is the intensity of the cytotoxic drugs given to the patient, but other variables may influence the probability of such an event.3 However, there is no simple and accurate method at present to identify patients who are at risk for myelosuppression at the beginning of their first chemotherapy regimen.

Tumor necrosis factor (TNF) was originally detected in the serum of mice as cachectin, a soluble factor that induces fever, wasting, and anemia. TNF has now been shown to be a key cytokine that plays a central role in inflammatory processes.4,5 Two different TNF receptors with molecular weights of 55 kd (p55-R-TNF) and 75 kd (p75-R-TNF) have been identified and are present on the surface of different cells. Shedding from the cell membrane of these two receptors results in soluble proteins that are constitutively found in the circulation and are elevated in a variety of inflammatory and noninflammatory diseases.6,7 Preliminary reports suggest that TNF may impair neutrophil recovery in the transplantation setting or after chemotherapy in leukemic patients.8

Circulating TNF and its two soluble receptors were prospectively found in the plasma of cancer patients, and we previously demonstrated that they constitute valuable prognostic markers in lymphoma patients.9 We also observed a strong correlation between TNF circulating levels and anemia in such patients.10 In this report, we analyzed the influence of baseline levels of TNF and its soluble receptors as tested before treatment in lymphoma patients, with the aim to identify their role, among others factors, in predicting myelosuppression and its complications after the first course of chemotherapy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
This study was performed in 101 newly diagnosed lymphoma patients who provided pretreatment samples for our previous studies.9,10 Patients were to be at least 18 years of age, negative for human immunodeficiency virus, and previously untreated (including corticosteroid therapy). All histologic subtypes and stages were included, but only patients who received a chemotherapy regimen that included anthracycline and cyclophosphamide were analyzed.

Description of Chemotherapy Regimens
The doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) regimen2 included the following and was delivered every 14 or 21 days in 56 patients: doxorubicin 75 mg/m2 on day 1, cyclophosphamide 1,200 mg/m2 on day 1, vindesine 2 mg/m2 on days 1 and 5, bleomycin 10 mg on days 1 and 5, prednisone 60 mg/m2 on days 1 through 5, and intrathecal methotrexate 15 mg on day 2. The ECVBP regimen (seven patients) was similar to the former except that doxorubicin was replaced with epirubicin (120 mg/m2) and that cyclophosphamide was administered at higher doses (2,000 mg/m2). The original cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen1 was administered in 16 patients every 3 weeks and included cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and prednisone 40 mg/m2 on days 1 through 5; doxorubicin was replaced with pirarubicin (50 mg/m2) in five patients, epirubicin (50 mg/m2) in four patients, and mitoxantrone (10 to 12 mg/m2) in 13 patients. Concomitant treatment with cytokines was not allowed, with the exception of prophylactic treatment with granulocyte colony-stimulating factor (G-CSF), which was administered to 53 patients.

Evaluation of Cytokine Levels
All samples were collected before any treatment initiation using sterile tubes that contained edathamil (EDTA) to prevent further release of cytokines from circulating mononuclear cells before analysis. Plasma samples were tested using enzyme-linked immunosorbent assay (ELISA) kits for TNF (Medgenix Diagnostics, Fleurus, Belgium) and its soluble receptors p55 (p55-R-TNF) and p75 (p75-R-TNF) (Roche, Basel, Switzerland). The detection limits of the ELISA tests were 3 pg/mL for TNF, 0.1 ng/mL for p55, and 1 ng/mL for p75, and the thresholds retained for the analysis of these parameters were the median values of their distribution in the original cohort.9

Analysis of the Toxicity
After the completion of chemotherapy, patients were advised to check their axillary temperature once daily and in case of clinical suspicion of fever. Complete blood counts were performed at least twice weekly. Febrile neutropenia was defined as World Health Organization (WHO) grade 4 neutropenia and an axillary temperature of 38°C twice consecutively at a 3 hour-interval or an axillary temperature greater than 38.5°C. In case of febrile neutropenia, patients were readmitted to the hospital for systemic empirical antimicrobial chemotherapy, which usually consisted of the combination of a third-generation cephalosporin and an aminoside; this was eventually adapted on clinical and microbiologic documentation. RBC transfusions were given when hemoglobin was less than 8 g/dL or for the occurrence of clinical symptoms related to anemia. Platelet transfusions were administered prophylactically when platelet counts were less than 20 x 109/L or when clinically indicated. All other toxicities were coded according to the WHO classification.11

Statistical Analysis
The association between clinical or biologic parameters and the incidence of myelosuppression was tested using the Pearson {chi}2 test. A logistic regression analysis that included all of the parameters that were found to be significant in the univariate analysis was performed to identify independent risk factors for myelosuppression, with a forward regression procedure and a P value <= .05 for entry. All statistics were performed using the BMDP package (Statistical Software, Los Angeles, CA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Medical data of 101 consecutive lymphoma patients, obtained before their first treatment, were retrospectively analyzed (Table 1). More than one half (56%) of the patients had advanced disease stage according to the Ann Arbor Conference classification of disease stages, and 28% had an altered Eastern Cooperative Oncology Group performance status (PS). Other adverse prognostic factors were each found in approximately one third of the patients: elevated serum lactate dehydrogenase level in 35%, elevated serum beta 2-microglobulin in 35%, and low serum albumin in 31%. According to the International Lymphoma Study Group classification,12 nine patients had lymphocytic/lymphoplasmacytoid lymphoma, one had mantle-cell lymphoma, 13 had follicular lymphoma, 16 had peripheral T-cell lymphoma, 57 had diffuse large-cell lymphoma, three had Burkitt’s lymphoma, and two had lymphoblastic lymphoma.


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  		Table 1. Patient Characteristics Before Treatment
 
Toxicity of Chemotherapy
To assess the myelotoxicity of chemotherapy regimens, those regimens were first categorized as (1) anthracycline-low if the patient received 50 mg/m2 of doxorubicin (or epirubicin or pirarubicin) or 10 to 12 mg/m2 of mitoxantrone, or (2) anthracycline-high if the patient received a dose of doxorubicin or epirubicin >= 75 mg/m2. Using these criteria, 63 patients were considered to be in the anthracycline-high group, and 38 patients were considered to be in the anthracycline-low group. Similarly, regimens were considered to be cyclophosphamide-low (62 patients) if less than 1,000 mg/m2 of cyclophosphamide was administered versus cyclophosphamide-high if the cyclophosphamide dose was >= 1,000 mg/m2 (39 patients).

Only the first course of chemotherapy was analyzed for drug-related toxicity (Table 2). The nadir of neutropenia consisted of an absolute neutrophil count (ANC) of less than 0.5 x 109/L in 67 patients; 47 of those patients had ANCs of less than 0.1 x 109/L. Twenty-two patients experienced neutropenia of less than 0.5 x 109/L that lasted for more than 5 days. Thirty-seven courses (37%) were followed by febrile neutropenia, which was responsible for 23 infections (23%) of grade 2 or higher. One patient died as a result of an infection. The nadir of hemoglobin was less than 8 g/dL in 22 patients; 18 patients needed at least one RBC transfusion. Platelet counts were less than 50 x 109/L in 11 patients, but only two needed platelet transfusion support.


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  		Table 2. Toxicity of Chemotherapy
 
Factors That Influenced Myelosuppression and Its Complications
The association between the incidence of myelotoxicity and clinical or biologic parameters was tested in univariate analysis (Table 3). All parameters were available for the majority of patients. The occurrence of grade 4 neutropenia was significantly associated with high doses of anthracycline or cyclophosphamide (P < .0005 for both), advanced Ann Arbor stage (P < .05), low serum albumin (P < .05), and high levels of p55-R-TNF and p75-R-TNF (P < .05 and < .05, respectively). The duration of grade 4 neutropenia for more than 5 days was significantly associated with the lack of administration of G-CSF (P < .05), Ann Arbor stages III/IV disease (P < .05), presence of "B" symptoms (P < .05), poor PS (P < .05), high serum beta2-microglobulin levels (P < .05), and high TNF, p55-R-TNF, and p75-R-TNF levels (P < .005, < .005, and < .005, respectively). The occurrence of febrile neutropenia was also significantly associated with high doses of anthracycline and cyclophosphamide (P < .005 and < .0005, respectively), stage III/IV disease and poor PS (P < .005 and < .0005, respectively), high serum beta2-microglobulin and low serum albumin levels (P < .05 and < .005, respectively), and high TNF and p75-R-TNF levels (P < .05 and < .05, respectively). In addition, the same parameters were also found to be significantly associated with the need of hospitalization between the first two chemotherapy cycles, with grade 2 or higher infections, and with intravenous antimicrobial chemotherapy administration for 5 days or more (data not shown).


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  		Table 3. Clinical and Biologic Factors Predicting Hematologic Toxicity in 101 Lymphoma Patients Before Their First Course of Therapy
 
Finally, the need for packed RBC transfusion was significantly associated with poor PS and presence of B symptoms (P < .0005 and < .0005, respectively), anemia at time of diagnosis (P < .0005), low serum albumin and high serum beta2-microglobulin levels (P < .0005 for both), and high TNF, p55-R-TNF, and p75-R-TNF levels (P < .005, < .0005, and < .0005, respectively).

Multiparametric Analysis
To determine the factors that were independently associated with the occurrence of chemotherapy-induced myelosuppression and its complications, a logistic regression analysis was performed with all of the significant variables (P < .05) that were associated with these events in the univariate analysis. However, because the dose of chemotherapy (high-anthracycline and high-cyclophosphamide) and the prophylactic treatment with G-CSF were thought to be important factors for myelosuppression and related to physician choice, eventually on the basis of the likelihood to present adverse events, these three parameters were deliberately included in the model (Table 4).


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  		Table 4. Multiparametric Logistic Regression Analysis for the Occurrence of Hematologic Toxicity
 
The occurrence of a grade 4 neutropenia was significantly associated only with high doses of cyclophosphamide (odds ratio [OR], 19.8; 95% confidence interval [CI], 1.65 to 237; P = .008) and high levels of soluble p75-R-TNF (OR, 8.52; 95% CI, 1.95 to 37.3; P = .001). Similarly, only two parameters were significantly predictive for grade 4 neutropenia with a duration of more than 5 days: the lack of hematopoietic growth factor administration (OR, 6.76; 95% CI, 1.71 to 26.7; P = .004) and a high level of soluble p75-R-TNF (OR, 5.84; 95% CI, 1.74 to 19.7; P = .0023). Finally, the occurrence of febrile neutropenia was associated with high doses of cyclophosphamide (OR, 14.7; 95% CI, 1.65 to 132; P = .007), altered PS (OR, 18.8; 95% CI, 3.71 to 95; P < .0001), and high levels of soluble p75-R-TNF (OR, 3.49; 95% CI, 1.10 to 11.2; P = .029). Therefore, these data indicate that elevated levels of p75-R-TNF constitute an independent parameter that predicts the occurrence and duration of grade 4 neutropenia as well as the occurrence of febrile neutropenia.

The need for RBC transfusion was significantly associated with high doses of chemotherapy, low serum albumin levels, and high serum beta2-microglobulin levels but was not associated with other clinical or biologic factors (data not shown). Low platelet counts were significantly associated with altered PS and high TNF levels (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Myelosuppression is a frequent and potentially serious complication of chemotherapy. A correlation between occurrence of neutropenia and doses of chemotherapy agents is well known, but seldom reports do indicate the factors that predict myelosuppression in a given patient population. Older age, bone marrow involvement, and altered PS were reported to be risk factors for neutropenia and fever in some reports without conclusive results, and most of these studies included variable numbers of patients treated heterogeneously.13,14 A recent prospective study emphasized the predictive value of low lymphocyte counts as assessed 5 days after chemotherapy for the occurrence of febrile neutropenia in several cohorts of patients receiving chemotherapy, including lymphoma patients.15 Another study recently demonstrated that neutropenia after the first chemotherapy course was a good predictor of subsequent neutropenic events in breast cancer patients.16 Of note, these two studies identified parameters that are assessed after the delivery of chemotherapy, although it may be helpful to characterize factors that predict myelosuppression before a choice is made regarding a given chemotherapy regimen. In the present study, in which parameters collected before treatment initiation in newly diagnosed patients were analyzed, several factors were associated with the presence of chemotherapy-related cytopenia. Those factor may have been related to the disease itself (Ann Arbor stage), to the host status (PS and B symptoms), and to the treatment (drug dosages and prophylactic administration of growth factors). Of note, lymphoma bone marrow involvement was not found to be associated with increased myelosuppression after chemotherapy, as had been previously reported.15 Alterations of usual biologic parameters, such as hemoglobin, lactate dehydrogenase, beta2-microglobulin, and serum albumin, were also associated with chemotherapy-induced myelosuppression. This study finally indicates that baseline plasma levels of circulating TNF ligands-receptors are good indicators of chemotherapy-associated marrow toxicity. Moreover, p75-R-TNF appears in the logistic regression analysis as an independent factor predicting the occurrence of neutropenia and its duration. In fact, in this study, baseline p75-R-TNF and PS were the only two pretreatment variables retained in multiparametric analysis. Soluble p75-TNF receptor was the best parameter unrelated to treatment for predicting both occurrence and duration of neutropenia, whereas PS seemed more potent for predicting febrile neutropenia.

Both TNF and its soluble receptors were implicated at different levels of hematopoiesis. Earlier studies demonstrated that TNF was a potent inhibitor of erythropoiesis, and the cytokine has been shown in vitro to inhibit the growth of erythroid and myeloid progenitors.17-20 In cancer patients, the administration of recombinant TNF-{alpha} led to transient decreases in granulocytes, RBCs, and platelets.21 The circulation of soluble TNF receptors is considered to be a good correlate of the production of TNF itself, and because the receptors are more stable than the cytokine, their dosage may be a better reflection of endogenous TNF production.22,23 The functions of soluble TNF receptors are not fully understood, because they can either inhibit TNF activity or prolong its biologic effects.24,25 In addition, other cytokines may also increase the production of soluble TNF receptors.7 Some reports already pointed out the role of TNF in chemotherapy-induced myelosuppression. One study indicated that TNF may influence the number of RBC transfusions that are required in acute myeloid leukemia patients.8 Others found an association between elevated TNF levels and a delayed hematologic recovery in cancer patients who receive G-CSF.26 Finally, some reports have documented that elevated endogenous TNF concentrations precede major treatment-related complications in bone marrow transplant recipients.27,28 Of note, increased TNF production may also impair albumin production by the liver, and the present study indicates that low albumin levels were also associated with myelosuppression. Altogether, these data and those presented in the present study indicate that production of TNF and its soluble receptors may be involved in the pathogenesis of drug-induced myelosuppression.

The ability to predict myelosuppression after cytotoxic chemotherapy is important in making treatment choices for cancer patients; eventually, cytotoxic regimens will be adapted to the expected tolerance of the patient. In addition, factors that predict neutropenia may turn out to be quite useful in making the decision of whether to administer prophylactic G-CSF, which has been shown to reduce the occurrence of febrile neutropenia in randomized trials.29 The usual recommendation of prophylactic G-CSF administration advocates its use in patients when the expected incidence of febrile neutropenia is 40%.30 If biologic parameters that are simple and inexpensive to measure are available to help predict such complications, then the use of such parameters should be advised for the selection of patients at risk who will most likely benefit from a prophylactic approach. This is particularly important in terms of cost savings and may also prove to be of value for the future use of other growth factors that are currently used as prophylactic or curative treatment of anemia and thrombocytopenia.


   ACKNOWLEDGMENTS
 
Supported by Hospices Civils de Lyon-Programme Hospitalier de Recherche Clinique (96.044) and by L’Institut National de la Santé et de la Recherche Médicale, Paris, France.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993[Abstract/Free Full Text]

2. Coiffier B, Gisselbrecht C, Herbrecht R, et al: LNH-84 regimen: A multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma. J Clin Oncol 7:1018-1026, 1989[Abstract]

3. Chabner B: Anticancer drugs, in De Vita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA,Lippincott, 1993, pp 325-417

4. Warzocha K, Bienvenu J, Coiffier B, et al: Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system. Eur Cytokine Netw 6:83-96, 1995[Medline]

5. Bazzoni F, Beutler B: The tumor necrosis factor ligand and receptor families. N Engl J Med 334:1717-1725, 1996[Free Full Text]

6. Aderka D, Englemann H, Hornik V, et al: Increased serum levels of soluble receptors for tumor necrosis factor in cancer patients. Cancer Res 51:5602-5607, 1991[Abstract/Free Full Text]

7. Van Zee KJ, Kohno T, Fischer E, et al: Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A 89:4845-4849, 1992[Abstract/Free Full Text]

8. Hall PD, Benko H, Hogan KR, et al: The influence of serum tumor necrosis factor-alpha and interleukin-6 concentrations on nonhematologic toxicity and hematologic recovery in patients with acute myelogenous leukemia. Exp Hematol 23:1256-1260, 1995[Medline]

9. Warzocha K, Salles G, Bienvenu J, et al: Tumor necrosis factor ligand-receptor system can predict treatment outcome in lymphoma patients. J Clin Oncol 15:499-508, 1997[Abstract/Free Full Text]

10. Salles G, Bienvenu J, Bastion Y, et al: Elevated circulating levels of TNF alpha and its p55 soluble receptor are associated with an adverse prognosis in lymphoma patients. Br J Haematol 93:352-359, 1996[Medline]

11. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[Medline]

12. Harris N, Jaffe E, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994[Free Full Text]

13. Watkins SM: Predicting neutropenia after chemotherapy for lymphoma. Leuk Lymphoma 9:107-109, 1993[Medline]

14. Kitay-Cohen Y, Lishner M, Shelef A, et al: Bone marrow involvement, in intensively treated patients with intermediate grade non-Hodgkin’s lymphoma, is a risk factor for granulocytopenia and fever. Leuk Lymphoma 20:333-336, 1996[Medline]

15. Blay JY, Chauvin F, Le Cesne A, et al: Early lymphopenia after cytotoxic chemotherapy as a risk factor for febrile neutropenia. J Clin Oncol 14:636-643, 1996[Abstract/Free Full Text]

16. Silber JH, Fridman M, DiPaola RS, et al: First-cycle blood counts and subsequent neutropenia, dose reduction, or delay in early-stage breast cancer therapy. J Clin Oncol 16:2392-2400, 1998[Abstract]

17. Ulich TR, del Castillo J, Yin S: Tumor necrosis factor exerts dose-dependent effects on erythropoiesis and myelopoiesis in vivo. Exp Hematol 18:311-315, 1990[Medline]

18. Warzocha K, Robak T, Korycka A, et al: The influence of recombinant human tumor necrosis factor-alpha, alone and in combination with cyclophosphamide or methotrexate, on leukemia L1210 and normal hematopoiesis in mice. Arch Immunol Ther Exp 39:587-595, 1991

19. Ulich TR, Shin SS, del Castillo J: Haematologic effects of TNF. Res Immunol 144:347-354, 1993[Medline]

20. Zhang Y, Harada A, Bluethmann H, et al: Tumor necrosis factor (TNF) is a physiologic regulator of hematopoietic progenitor cells: Increase of early hematopoietic progenitor cells in TNF receptor p55-deficient mice in vivo and potent inhibition of progenitor cell proliferation by TNF alpha in vitro. Blood 86:2930-2937, 1995[Abstract/Free Full Text]

21. Blick M, Sherwin SA, Rosenblum M, et al: Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res 47:2986-2989, 1987[Abstract/Free Full Text]

22. Joyce DA, Steer JH: Tumor necrosis factor alpha and interleukin-1 alpha stimulate late shedding of p75 TNF receptors but not p55 TNF receptors from human monocytes. Interferon Cytokine Res 15:947-954, 1995

23. Cope AP, Aderka D, Wallach D, et al: Soluble TNF receptor production by activated T lymphocytes: Differential effects of acute and chronic exposure to TNF. Immunology 84:21-30, 1995[Medline]

24. Aderka D, Engelmann H, Maor Y, et al: Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. Med 175:323-329, 1992

25. Olsson I, Gatanaga T, Gullberg U, et al: Tumour necrosis factor (TNF) binding proteins (soluble TNF receptor forms) with possible roles in inflammation and malignancy. Eur Cytokine Netw 4:169-180, 1993[Medline]

26. Petros WP, Rabinowitz J, Gibbs JP, et al: Effect of plasma TNF-alpha on filgrastim-stimulated hematopoiesis in mice and humans. Pharmacotherapy 18:816-823, 1998[Medline]

27. Holler E, Kolb HJ, Moller A, et al: Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. Blood 75:1011-1016, 1990[Abstract/Free Full Text]

28. Rabinowitz J, Petros WP, Stuart AR, et al: Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support. Blood 81:2452-2459, 1993[Abstract/Free Full Text]

29. Vose JM, Armitage JO: Clinical applications of hematopoietic growth factors. J Clin Oncol 13:1023-1035, 1995[Abstract]

30. American Society of Clinical Oncology: Update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based clinical practice guidelines. J Clin Oncol 14:1957-1960, 1996 [Free Full Text]

Submitted April 21, 1999; accepted August 16, 1999.




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