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© 1999 American Society for Clinical Oncology Comparative Effects of Three Cytokine Regimens After High-Dose Cyclophosphamide: Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), and Sequential Interleukin-3 and GM-CSFFrom the Department of Internal Medicine, University of Genoa, Genoa, Italy. Address reprint requests to Professor Franco Patrone, Dipartimento di Medicina Interna Università, Viale Benedetto XV no 6, 16132 Genova, Italy.
PURPOSE: To compare the toxicity and effects on hematologic recovery and circulating progenitor cell mobilization of three cytokine regimens administered after high-dose cyclophosphamide (HD-CTX; 6 g/m2), given as the first step of a high-dose sequential chemotherapy. PATIENTS AND METHODS: Forty-eight patients with breast cancer or non-Hodgkin's lymphoma were randomized to receive granulocyte colony-stimulating factor (G-CSF) alone (arm 1), granulocyte-macrophage colony-stimulating factor (GM-CSF) alone (arm 2), or sequential interleukin-3 (IL-3) and GM-CSF (arm 3). Cytokines were administered as a single daily subcutaneous injection at a dose of 5 to 6 µg/kg/d. Progenitor cells were evaluated in peripheral blood as well as in apheretic product as both CD34+ cells and granulocyte-macrophage colony-forming units (CFU-GM). RESULTS: Neutrophil recovery was faster in arm 1 as compared with arms 2 and 3 (P < .0001); no significant differences were observed between arms 2 and 3. In arm 3, a moderate acceleration of platelet recovery was observed, but it was statistically significant only as compared with arm 1 (P = .028). The peak of CD34+ cells was hastened in a median of 2 days in arm 1 compared with arms 2 and 3 (P = .0002), whereas the median peak value of CD34+ cells and CFU-GM was similar in the three patient groups. Administration of IL-3 and GM-CSF resulted in more significant toxicity requiring pharmacologic treatment in 90% of patients. CONCLUSION: The three cytokine regimens administered after HD-CTX are comparably effective in reducing hematologic toxicity and mobilizing the hematopoietic progenitor cells. G-CSF accelerates leukocyte recovery and progenitor mobilization. Although G-CSF–treated patients have somewhat slower platelet recovery, they definitely have fewer side effects.
CYCLOPHOSPHAMIDE (CTX), even when given at extremely high doses, ie, up to 7 g/m2, spares the totipotent hematopoietic stem cells and early multipotential progenitors, so that hematologic recovery can take place spontaneously. High-dose (HD)-CTX can be therapeutically useful in lymphoma, breast cancer, multiple myeloma, ovarian cancer, and small-cell lung cancer. Administration of myeloid human growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), after HD-CTX reduces hematologic toxicity and induces a striking increase of peripheral-blood progenitor cells (PBPCs) at the beginning of hematopoietic recovery. Thus, progenitors can be collected by leukapheresis, cryopreserved, and then reinfused after myeloablative therapy to reconstitute the normal marrow function. Therefore, HD-CTX has been incorporated into several schedules of HD sequential chemotherapy.1-5 Recombinant human interleukin-3 (IL-3) stimulates the proliferative capacity of multipotent and committed myeloid progenitors and produces a dose-dependent increase of circulating neutrophils, platelets, and reticulocytes after approximately 2 weeks.6 When given for shorter periods, up to 7 days, IL-3 seems to behave mainly as a primer for growth factors that act on intermediate and late phases of myelopoiesis.7 Actually, a synergistic effect of sequential administration of IL-3 and G-CSF or GM-CSF on both the progenitor cell compartment and the differentiating cell populations has been suggested by the results of laboratory and animal studies as well as by clinical investigations.8-14 In particular, several authors have suggested that pretreatment with IL-3 may increase the G-CSF– or GM-CSF–induced mobilization of circulating progenitors both when administered as unique mobilizing agents or after chemotherapy.11-14 However, other studies have not been able to confirm these results.15,16 When IL-3 was administered alone after HD-CTX, it hastened hematologic recovery but had no effect on the mobilization of hematopoietic progenitor cells in the peripheral blood.17 On the other hand, both G-CSF and GM-CSF consistently lowered the hematologic toxicity of HD-CTX and were equally capable of mobilizing PBPCs.18 PBPC mobilization by means of chemotherapy and growth factors is an important step in HD sequential treatments. As such treatments become more and more widespread, a great deal of emphasis is being placed on the search for new mobilizing agents as well as on the definition of optimal regimens in terms of feasibility, low toxicity, efficacy, and costs. In this article, we report the results of a randomized study designed to evaluate the effects of three different cytokine regimens after HD-CTX administered as part of multi-step, HD chemotherapy in patients with breast cancer or non-Hodgkin's lymphoma (NHL). The cytokine regimens studied were G-CSF alone, GM-CSF alone, and sequential IL-3 and GM-CSF. The aim of the study was to compare the toxicity of these cytokine regimens and their efficacy in hastening hematologic recovery and increasing circulating progenitor cell mobilization and collection.
Study Design Forty-eight patients were enrolled onto the study. They received HD-CTX as the first step of an HD sequential chemotherapy program administered either as adjuvant therapy for breast cancer or as treatment for metastatic breast cancer and diffuse large-cell NHL. Patients were randomized to receive one of three different cytokine regimens after HD-CTX: G-CSF alone (arm 1), GM-CSF alone (arm 2), or sequential IL-3 and GM-CSF (arm 3). Hematologic toxicity was evaluated by daily blood sampling, and toxic effects were registered and graded according to World Health Organization criteria. To evaluate the mobilization of circulating progenitor cells, flow cytometry and colony-forming assays were performed daily from day 9 onward after HD-CTX (day 0) until 2 days after the last leukapheresis. Furthermore, the bone marrow–repopulating capability of PBPCs mobilized with the three cytokine schedules was evaluated by comparing homogeneously treated patients in each subgroup.
Patient Characteristics and Eligibility
Eligibility criteria included age below 65 years, performance status (Karnofsky)
HD Sequential Treatment
HD-CTX Treatment
Growth Factors
Patient Monitoring and Supportive Care
After PBPC reinfusion, all patients were supported in single or double rooms equipped with a high-efficiency particulate air filtration unit until they achieved a neutrophil count of
PBPC Collection Yields were suspended in autologous plasma and 10% dimethylsulfoxide, frozen using a controlled-rate freezer (Cryo 10; Planer Biomed, Sunbury Middlesex, United Kingdom), and stored in liquid nitrogen. At the time of reinfusion, the cells were rapidly thawed at 37°C at bedside and reinfused through the central line.
PBPC Evaluation
Statistical Analysis
Hematologic Toxicity Hematologic recovery after HD-CTX was rapid and complete in all 48 patients. The administration of G-CSF was associated with faster neutrophil recovery (Fig 1A). In fact, the duration of severe neutropenia (neutrophil count < 500/µL) and the time needed to reach a neutrophil count of greater than 500/µL were significantly reduced (median, 2 days) in the patient group supported with G-CSF (Table 2). No significant differences in neutrophil recovery were observed in patients who received GM-CSF or IL-3 and GM-CSF. A similar pattern of recovery was observed for total leukocytes.
Patients pretreated with IL-3 experienced a moderate acceleration of platelet recovery (Fig 1B), which proved to be statistically significant only as compared with the G-CSF–supported group (Table 2). However, the platelet transfusion requirement was negligible in all three groups of patients; only one patient in arm 2 who had a platelet nadir below 10,000/µL from day 12 received one unit of single-donor prophylactic platelet transfusion. Similarly, no statistically significant differences were observed in the packed RBC requirement.
The duration of neutropenic fever
PBPCs
Growth Factors No significant side effects were related to G-CSF administration. Only one patient experienced moderate bone pain requiring treatment with nonsteroidal anti-inflammatory drugs. No patient required dose reductions or discontinuation. Fever was the most frequent side effect in the GM-CSF group (6 [37.5%] of 16 patients). In five patients, it was less than 38.5°C and was controlled by acetaminophen, whereas only one patient required a 25% dose reduction. Mild myalgia and bone pain were observed in two patients (12.5%) and cutaneous rash requiring antihistaminic premedication was seen in one patient (6%). A different toxicity pattern was registered in patients of arm 3. During IL-3 administration, 12 patients (75%) had fever, and in five cases (31%), fever was above 38.5°C. In all cases, fever required antipyretic administration, and in three cases it required corticosteroids as well. One patient required a 50% dose reduction of IL-3. Two patients experienced myalgia and bone pain and were treated with anti-inflammatory drugs, and five patients with cutaneous rash required antihistaminic treatment. Headache was observed in six patients. As a rule, these side effects rapidly subsided after the week of IL-3 administration; however, on the day of the start of GM-CSF, a transient worsening of fever and headache was observed in three patients.
Effects of Mobilized PBPCs
The present study was designed to compare the toxicity as well as the capacity to stimulate both hematologic recovery and circulating progenitor cell compartment expansion of three different cytokine regimens administered after HD-CTX. The bone marrow–repopulating capacity of harvested progenitors was also evaluated. In two groups of patients, HD-CTX was supported either by G-CSF or by GM-CSF, which are the most commonly used growth factors in clinical practice. In the third group, a sequential combination of IL-3 and GM-CSF was assayed to verify the possible priming effect of IL-3. This had been previously suggested both in primate as well as human studies.8-14 G-CSF and GM-CSF were administered at standard dosages, ie, 5 to 6 µg/kg. IL-3 was given at the dosage of 6 µg/kg, which is considered to be the most suitable in terms of both safety and cost, according to several authors,11-17 as well as in terms of our preliminary experience. The cytokines were all administered subcutaneously. The three cytokine regimens displayed no significant differences in their capacity to lessen the hematologic toxicity of HD-CTX. Actually, in the three patient groups, the period of severe cytopenia induced by HD-CTX was short, neutropenic fever was moderate, and no serious infections or hemorrhagic complications were registered. All patients underwent subsequent chemotherapy at the scheduled time. According to its lineage-specific action, G-CSF significantly accelerated neutrophil recovery, which took place 2 days earlier (median) with respect both to GM-CSF alone and to sequential IL-3 and GM-CSF. The shortening of the leukocytopenia period allowed an earlier discharge (approximately 3 or 4 days) but had no effect on the duration of neutropenic fever or on the time to subsequent chemotherapy. No differences in neutrophil recovery were observed between patients treated with GM-CSF alone or sequential IL-3 and GM-CSF. Platelet recovery was similar in the G-CSF– and GM-CSF–treated groups. In a previous study that used continuous intravenous infusion of G-CSF, slower platelet recovery and an increased requirement for platelet transfusion were noted.18 In our series, pretreatment with IL-3 induced a slight acceleration of platelet recovery, which reached statistical significance only as compared with the patient group supported by G-CSF. This finding, however, had only marginal clinical relevance because thrombocytopenia after HD-CTX was, on the average, mild, and only one patient in the GM-CSF group required a single-donor platelet transfusion. Despite the in vitro and in vivo primate studies indicating a synergistic effect of IL-3 and GM-CSF in enhancing the proliferation and differentiation of hematopoietic progenitors, a clinical effect on hematologic recovery after HD-CTX was not found in the present study. Actually, the major parameters defining neutrophil and platelet aplasia were not significantly different in patients treated with sequential IL-3 and GM-CSF as compared with patients treated with GM-CSF alone. Similar results were reported in prior nonrandomized studies in which IL-3 and GM-CSF were administered alone or after conventional-dose chemotherapy.24,25 Thus, the priming with IL-3 provides only minor benefit, if any, in short-term hematologic recovery after HD chemotherapy with respect to the use of lineage-specific factors alone. This is in accordance with previous findings with conventional doses. A clinically relevant priming effect might possibly be obtained by combining IL-3 with other cytokines which are still awaiting validation in clinical trials. HD-CTX mobilizes circulating hematopoietic progenitor cells in a dose-dependent manner,26 and this phenomenon is remarkably enhanced by the addition of G-CSF or GM-CSF.18 When administered alone or after chemotherapy (eg, HD-CTX), IL-3 was not able to consistently increase the circulating-progenitor compartment.17,27,28 However, several observations in vitro, as well as in primate and human models, suggest that IL-3 pretreatment markedly potentiates the ability of GM-CSF and G-CSF to increase circulating progenitors.8-14 Brugger et al11 reported that IL-3 and GM-CSF administered sequentially after polychemotherapy with etoposide, ifosfamide, and cisplatin significantly increase, with respect to GM-CSF alone, the number of peripheral progenitors, as evaluated by clonogenic assay for CFU-GM, burst-forming unit, erythroid, and colony-forming unit, granulocyte-erythroid-macrophage-megakaryocyte. However, in contrast with this finding, the number of mobilized CD34+ cells was not different between the two groups. When administered without previous chemotherapy, IL-3 displayed a synergistic effect with GM-CSF and G-CSF in others studies where the mobilization of peripheral progenitors was evaluated by clonogenic assay but not by CD34+ cell count.12-14 However, in the majority of these studies, no apheretic collection was performed. By contrast, in a small randomized study, Engel et al16 reported that G-CSF or IL-3 followed by G-CSF generates a comparable expansion of circulating progenitor cells with no differences in the apheretic collection. In the present study, both the peak of circulating progenitors and the yield of apheretic collection were comparable in the three patient groups. In fact, no significant differences were observed in the peak peripheral-blood concentration of both CFU-GM and CD34+ cells (Table 3 and Fig 2) and in the number of CD34+ cells collected by apheresis (Table 3). The only significant difference was observed in the kinetic of the mobilization. Consistently with the accelerated leukocyte recovery, in the G-CSF patient group, the progenitor peak occurred 2 days earlier with respect to the other patients and the day of first apheresis was anticipated accordingly. The bone marrow–repopulating capacity of collected progenitor cells was comparable irrespective of the mobilizing regimen used. In fact, no significant differences in hematopoietic reconstitution parameters were registered among the three patient groups after myeloablative treatment. In the present study, toxicity related to both G-CSF and GM-CSF was low and, on the average, milder than previously reported with continuous intravenous administration.18 In particular, with G-CSF, side effects were negligible and only one patient experienced bone pain, which was easily manageable with nonsteroidal anti-inflammatory drugs. With GM-CSF administration, 35% of patients experienced fever, which responded to antipyretics and in only one case required a cytokine dose reduction. As compared with G-CSF or GM-CSF, the sequential combination of IL-3 and GM-CSF resulted in more significant toxicity. During IL-3 administration, fever, which was frequently above 38°C, was registered in 75% of patients, headache in 37%, cutaneous rash in 30%, and osteomyalgias in 12%. These patients required pharmacologic treatment with antipyretics, nonsteroidal anti-inflammatory drugs, and in some cases, corticosteroids. In a few patients, a transient worsening of symptoms was also observed the day GM-CSF was started. In conclusion, the present study demonstrates that the three cytokine regimens evaluated are comparably effective in reducing the hematologic toxicity of HD-CTX and in mobilizing the hematopoietic progenitor cells. In contradiction with preclinical studies and with several observations in humans, a priming effect of IL-3 was not evident. IL-3 administration induced significant toxicity that required pharmacologic treatment in 90% of patients, whereas G-CSF and GM-CSF were well tolerated; in particular, G-CSF proved to be suitable for outpatient administration. G-CSF also induced accelerated kinetics of leukocyte recovery and progenitor mobilization, which may represent an advantage in terms of cost-effectiveness as compared with both GM-CSF and sequential IL-3 and GM-CSF.
Supported by a grant from the Associazione Italiana per la Ricerca sul Cancro, Milan, Italy, grant no. 96.03507.CT04 from Consiglio Nazionale delle Ricerche, and a grant from the University of Genoa. We thank Sandoz SpA, Milan, Italy, for the IL-3 supply and the nursing staff of the intensive chemotherapy unit for their dedicated patient care.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
80%, and normal heart, lung, liver, and kidney function. Patients with bone marrow involvement, as determined by bilateral iliac biopsy, as well as patients with previous or concomitant neoplasia, diabetes mellitus, or brain metastases were excluded. All patients provided written, informed consent in keeping with institutional ethical committee guidelines. 
2 test was performed. The significance threshold was set at .05. 
