Pekka Riikonen. Introduction

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1 Recombinant Human Granulocyte-Macrophage Colony-S timulating Factor in Combination with Antibiotics in the Treatment of Febrile Neutropenia in Children Pekka Riikonen Kuopio University Hospital, Division of Pediatric Hematology-Oncology, Kuopio, Finland Key Words: rhugm-csf G-CSF Fever and neutropenia Hematopoietic growth factors Imipenem Cancer Children Abstract. Fever and neutropenia are life-threatening complications of chemotherapy in children with cancer. Prompt initiation of empiric broad-coverage antimicrobial therapy at the first signs of fever has reduced the mortality rates to about 24%. However, myelosuppression with febrile neutropenia is the major dose-limiting side effect of anticancer chemotherapy, results in prolonged hospitalization, and frequently delays the scheduled cycles of chemotherapy. Prophylactic use of hematopoietic growth factors has been shown to reduce the incidence of fever and infectious complications in children with cancer and neutropenia. Therapeutic use of recombinant human granulocyte-macrophage colony-stimulating factor (rhugm-csf) in combination with antibiotics in children with febrile neutropenia has also shown a clear beneficial effect. The number of hospital days due to treatment of febrile neutropenia, the number of days on broad-spectrum antibiotics and the duration of neutropenia were significantly reduced with the use of rhugm-csf. Importantly, rhugm-csf did not prolong the days with fever in children admitted with febrile neutropenia. In the treatment of documented fungal superinfection, it may be beneficial if rhugm-csf and an antifungal drug are used as combination therapy. rhugm-csf is nontoxic and well tolerated in children with cancer. Introduction During the last decade, many of the treatment regimens used in children with cancer have Correspondence: Dr. Pekka Riikonen, Kuopio University Hospital, Department of Pediatrics, FIN Kuopio, Finland. Received September 14, 1994; accepted for publication September 14, OAlphaMed Press /95/$5.00/0 become more intensive and are hallmarked by prolonged periods of profound neutropenia. Children with leukemias and solid tumors are now at comparable risk for neutropenia and its attendant infectious complications [ 11. Infection is the leading cause of death in neutropenic patients with cancer [2, 31. The neutropenic patient who becomes febrile has a 6040% likelihood of being infected with bacterial pathogens [I-41. If the neutrophil count is c100 x 106/1, 20% or more of febrile episodes will have an associated bacteremia [4, 51. In the immunocompromised host, virtually any microorganism can cause serious infection. In recent years, the most frequent infectious agents in the neutropenic host have changed from gram-negative to gram-positive bacteria [3-61. The spectrum of organisms causing infection has changed in response to factors such as the widespread use of indwelling vascular catheters, antimicrobial prophylaxis, and effective antibiotic therapy for some types of infection. Severe neutropenia and oral mucositis due to intensive chemotherapeutic regimens have been proposed as predisposing factors of the entry of the viridans streptococci organisms via damaged mucosa [3, 7, 81. The initiation of antimicrobial therapy soon after the onset of fever accounts for the low incidence of definable infection, so it has become more common for the initial fever in a neutropenic patient to elude a specific clinical or microbiological diagnosis, and most (60-80%) of the febrile episodes in neutropenic patients are fevers of unknown origin (FUO). The infectious etiology is probably masked by the rapid initiation of antibiotics [3-61. A substantial number of these febrile episodes are due to treatable infections. If STEM CELLS 1995;13:

2 202 Therapeutic Use of rhugm-csf in Children untreated, these infections are often rapidly fatal in the neutropenic patient [3, 41. When a child with neutropenia acquires fever, the patient should be promptly examined and an empiric broad-spectrum antibacterial regimen started without delay. The rationale for this approach arose from observations that when antibiotic therapy was delayed in severely neutropenic patients with Pseudomonas bacteremia, 15% of patients died on the day of onset of the infection, and 57% died one day after collection of the first positive blood culture; thus mortality was 70% within 48 h unless patients received antibiotics at the onset of fever [9]. So the most important advance in the management of the immunocompromised host has been prompt initiation of empiric broad-spectrum antibiotics in a neutropenic patient who becomes febrile. This policy has decreased the mortality rate from febrile neutropenia to 2-10% [2-61. There is some variation in the incidence of bloodstream infection from center to center (about 20% of febrile episodes are associated with bacteremia), probably related to the intensity of the chemotherapy being administered and the consequent degree and duration of granulocytopenia. The impaired inflammatory response that accompanies neutropenia tends to prevent or diminish the development of the usual four symptoms and signs of infection: dolor, tumor, rubor and color. Thus, serious infections may occur in these patients with minimal or nonexistent symptoms and signs. The endogenous pyrogen (interleukin 1) is produced by mononuclear cells, not by granulocytes, and these mononuclear cells include not only circulating monocytes but also fixed-tissue macrophages that persist after chemotherapy. This explains the presence of fever despite the otherwise poor inflammatory response in the neutropenic patient [3-41. The relationship between the response to antibiotics and a change in the neutrophil count during therapy was first demonstrated by Bodey et al. [lo]. Recovery of the neutrophil count still remains an important consideration in evaluating the response to antibiotic therapy, a point that has been emphasized in many studies [3-5,7, 111. Current data do not support the use of granulocyte transfusions for febrile neutropenic children. However, there may be a beneficial role for granulocyte transfusions in neutropenic patients with documented bacteremia (particularly due to gram-negative aerobes) who are not expected to recover marrow function within a several-day period. An alternative and preferable approach is to use recombinant human myeloid growth factors to accelerate neutrophil recovery [3, 121. Hematopoietic Growth Factors in the Treatment of Infectious Diseases in Neutropenic Patients The availability of hematopoietic growth factors has made it possible to stimulate production of neutrophils in patients with compromised bone marrow. The administration of colony-stimulating factors (CSFs) after standard-dose chemotherapy may be either prophylactic (i.e., given to prevent infectious complications) or therapeutic (i.e., given to patients in whom fever develops while they have neutropenia) [13, 141. In the use of CSFs to prevent or treat infections, it is of critical clinical importance to know whether neutrophils produced in response to these factors have a normal capacity to circulate, migrate to other sites of inflammation, and kill bacteria and other microbes. Studies in vitro have demonstrated that recombinant human granulocyte-macrophage colony-stimulating factor (rhugm-csf) stimulates phagocytosis and increases the cytotoxicity of neutrophils and eosinophils for antibody-coated targets. These effects are mediated through GM-CSF receptors on mature neutrophils. Monocyteslmacrophages also respond to cytokines such as GM-CSF and macrophage CSF (M-CSF) with increased oxidative burst and bactericidal activity against a number of intracellular pathogens and enhanced fungicidal activity against Candida and Histoplasma yeast cells as well as against Aspergillus. In vivo administration of rhugm-csf causes changes that are similar [ The timing of CSF administration has a major impact on the results obtained. The production of neutrophils and monocytes from early bone marrow precursors requires several days. The immediate increase in neutrophil counts seen after CSF administration is due to an accelerated release of these cells from the bone marrow and requires a supply of preformed neutrophils in the bone marrow. A sustained elevation in levels of these leukocytes requires the production of new cells [ Both rhugm-csf and granulocyte CSF (G-CSF) offer

3 Riikonen 203 a definite benefit for the prevention of infections during neutropenia by restoring phagocytic cells sooner after chemotherapy. The prophylactic use of these agents is most appropriate for patients at risk for prolonged neutropenia, i.e., more than 10 days. They are not appropriate for patients with shorter durations of neutropenia since the outcome in such patients is generally excellent with conventional antibiotic therapy [ Phagocytes work synergistically with antibiotics to clear infection in vivo. Although CSFs may prove useful as single agents for the prevention of infections, the effect of their use in combination with antibiotics should be studied in established infections. The selective activity and low toxicity of these agents should permit their wide use once clinical efficacy has been demonstrated. rhugm-csf in Combination with Antibiotics in the Treatment of Febrile Neutropenia in Children There is only one prospective trial of the use of rhugm-csf in the treatment of febrile neutropenia in children [21]. In a double-blind study of 58 episodes of fever and profound (absolute neutrophil count <200 x 106/1) neutropenia in 40 children with various malignant diseases received either rhugm-csf or placebo, combined with identical antimicrobial therapy, i.e., imipenem, on admission. The dosage of rhugm-csf was 5.0 pgkg daily given i.v. as a 4-hour infusion. Despite the fact that various malignancies were included, the total duration (6.7 months in the rhugm-csf group and 6.5 months in the placebo group) and intensity of the prior chemotherapy exposure was not different between the study groups. The time from the end of the preceding chemotherapy course until admission and entry of the study was not different between the groups. A statistically significant difference could be demonstrated between the study groups in the number of hospital days (totaling 252 days in the rhugm-csf group versus 354 in the placebo group), in the number of days on antibiotics (220 versus 322) and in the resolution of neutropenia (8.7 days versus 11.9 days). The mean number of hospital days was 9.0 in the rhugm-csf group, as compared with 11.8 days in the placebo group (p <.05>[21]. Hospitalization lasted more than 10 days in only 5/28 episodes (18%) in the rhugm-csf group, as compared with 15/30 (50%) in the placebo group (p =.02). A particularly beneficial effect of rhugm-csf was the elimination of the longest episodes of neutropenia due to slow neutrophil recovery in marrow exhausted by strong multiagent chemotherapy. Seven of the episodes (12%) were bacteremias, 15 (26%) were clinically defined focal infections, and 36 (62%) episodes were categorized as FUO. The outcome of all episodes was excellent, with no mortality and no recurrences. A change of the initial antibiotic therapy was needed in 6/58 (10%) episodes (three times in both treatment groups). rhugm-csf was well tolerated in children with cancer. Importantly, there were no adverse events in 16/28 (57%) episodes in the rhugm-csf group or in 20/30 (67%) episodes in the placebo group. None of the adverse effects possibly related to rhugm-csf administration were severe. The adverse effects most commonly detected were bone and muscle pain, skin rashes and vomiting. Some of them were seen in both treatment groups. In no patient was it necessary to discontinue rhugm-csf because of adverse events. The number of days with fever (L38.O"C) was not different between the treatment groups, so the administration of rhugm-csf did not prolong the duration of fever. The propensity of rhugm-csf itself to induce fever and the urgency of empirical antibiotic therapy in patients with febrile neutropenia after chemotherapy have made it difficult to see the precise role of rhugm-csf in the treatment of febrile neutropenia. This was the first study to evaluate rhugm-csf as an adjunct to antimicrobial therapy in sepsis, and it showed a clearly beneficial effect and was cost effective [21]. One of the purposes of the use of CSFs is preventive therapy, i.e., the maintenance of at least minimal neutrophil counts, since apparently many more cells are required to respond to infections than to prevent them. Another alternative is to wait until the patient develops febrile neutropenia; many patients pass through profound neutropenias without sepsis and do perfectly well without growth factors [13, 14, 16, 17-23].

4 204 Therapeutic Use of rhugm-csf in Children rhugm-csf and Deep Fungal Infections A major problem in the management of infection in neutropenic patients is the occurrence of superinfection. These infections are most likely to occur in patients with prolonged neutropenia and are caused by resistant bacteria or fungi. Fungal infections are most likely to occur at sites of previous tissue damage caused by bacterial infection. Fungal infection is an increasingly frequent cause of morbidity and mortality among neutropenic patients, probably because of the higher rate of survival during early bone marrow aplasia that has resulted from improved control of overwhelming bacterial infections. Many studies have identified the use of multiple antibiotics for therapy as a factor predisposing to fungal superinfections. However, this becomes a less important variable in neutropenic patients, a finding suggesting that the use of multiple antibiotics is simply an indicator of patients who are sicker and more susceptible for other reasons. Antibiotics probably have little if any effect on host defenses but suppress the growth of normal gastrointestinal flora, permitting fungal overgrowth. The increase in yeast colonization is related to broad-spectrum antimicrobial activity and penetration into gastrointestinal lumen in animals and humans [ 1, 3,4, 11,24,25]. Macrophages have an important function in the defense against intracellular parasites and fungi. They are known to be the primary cell type to defend against the spores of Aspergillus, whereas neutrophils are the primary defense against the mycelia. Since rhugm-csf stimulates both neutrophils and macrophages, it is expected to be effective in treating neutropenic patients with fungal infections [13-16, 261. This was evaluated in a pilot study by Bodey et al. [27] in adults. Eleven neutropenic patients (absolute neutrophil count c100 x 10%) with various fungal infections due to Aspergillus, Candida and Trichophyton were treated with amphotericin B and rhugm-csf. Six of eight evaluable patients demonstrated a neutrophil response to rhugm-csf; four of these were completely cured of the fungal infection, and two had a partial response. Two patients did not respond to this combination therapy and subsequently died of their infection. The preliminary results of the use of rhugm-csf in the treatment of fungal infections when combined with antifungal therapy are promising, and trials of rhugm-csf treatment in this setting are underway. Further investigations are needed to evaluate the role of rhugm-csf as adjuvant therapy for fungal infections in children with cancer. Conclusion The outcome of most infectious diseases depends on the function and supply of the phagocytic cells of the host. Before the discovery of CSFs, the occurrence and clinical significance of leukopenia and neutropenia were clearly recognized, but mediators or regulators of these events were not known. rhugm-csf can be used as a pharmacological agent to accelerate the production of neutrophils and monocyteshacrophages and to enhance the mechanisms of host defense. Rapidly accumulating evidence justifies the use of CSFs for the prevention of fever and infections in several clinical settings, such as chemotherapyassociated neutropenia, bone marrow transplantation and severe chronic neutropenia in children. The role of cytokines for the treatment of defined infections (e.g., bacterial infections and invasive mycoses) is under investigation. The early results of the use of rhugm-csf in the treatment of infections in combination with antimicrobial or antifungal therapy are promising. References Pizzo PA. Consideration for the prevention of infectious complications in patients with cancer. Rev Infect Dis 1989;11(7): Sanders JW, Powe NR, Moore RD. Ceftazidime monotherapy for empiric treatment of febrile neutropenic patient: a metaanalysis. J Infect Dis 1991 ; 164: Pizzo PA. Management of fever in patients with cancer and treatment induced neutropenia. N Engl J Med 1993;328(18): Hughes WT, Armstrong D, Bodey GP et al. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 1990; 16 1 : Schimpff SC. Empiric antibiotic therapy for granulocytopenic cancer patients. Am J Med 1986;8O(~~ppl5C): Riikonen P. Imipenem compared with ceftazidime plus vancomycin as initial therapy for

5 Riikonen 205 fever in neutropenic children with cancer. Pediatr Infect Dis J 1991;10: Bodey GP. Evolution of antibiotic therapy for infection in neutropenic patients: studies at M.D. Anderson Hospital. Rev Infect Dis 1989;l l(supp1 7): Burden AD, Oppenheim BA, Crowther D et al. Viridans streptococcal bacteremia in patients with haematological and solid malignancies. Eur J Cancer 1991;27(4): Bodey GP, Jadeja L, Eking L. Pseudomonas bacteremia: retrospective analysis of 410 episodes. Arch Intern Med 1985;145: Bodey GP, Buckley M, Sathe YS et a]. Quantitative relationship between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64: Rolston KVI, Berkey P, Bodey GP et al. A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients. Arch Intern Med 1992;152: DiNubile MJ. Therapeutic role of granulocyte transfusions. Rev Infect Dis 1985;7: Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocytemacrophage colony-stimulating factor (first of two parts). N Engl J Med 1992;327(1): Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocytemacrophage colony-stimulating factor (second of two parts). N Engl J Med 1992;372(2): Ruef C, Coleman DL. Granulocyte-macrophage colony-stimulating factor: pleiotropic cytokine with potential clinical usefulness. Rev Infect Dis 1990; Dale DC. Potential role of colony-stimulating factors in the prevention and treatment of infectious diseases. Clin Infect Dis 1994;18(suppl2): Furman WL, Fairclough DL, Huhn RD et al. Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy. J Clin Oncol 1991;9(6): Furman WL, Crist WM. Potential uses of recombinant human granulocyte-macrophage colonystimulating factor in children. Am J Ped Hem Onc 1991; 13(4): Gerhartz HH, Engelhard M, Meusers P et al. Randomized, double-blind, placebo-controlled, phase I11 study of recombinant human granulocyte-macrophage colony-stimulating factor as adjunct to induction treatment for high-grade malignant non-hodgkin s lymphoma. Blood 1993;82(8): Crawford J, Ozer H, Stoller R et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991 ;325(3): Riikonen P, Saarinen UM, Makipernaa A et al. Recombinant human granulocyte-macrophage colony stimulating factor in the treatment of febrile neutropenia: a double-blind placebo controlled study in children. Pediatr Infect Dis J 1994; 13: Saarinen UM, Hovi L, Riikonen P et al. Recombinant human granulocyte-macrophage colony-stimulating factor in children with chemotherapy-induced neutropenia. Med Ped Onc 1992;20: Dale DC, Guerry D, Werweke JR et al. Chronic neutropenia. Medicine 1979;58: Bodey GB. Empirical antibiotic therapy for fever in neutropenic patients. Clin Infect Dis 1993; 17 (Suppl2): Sara1 R. Candida and aspergillus infections in immunocompromised patients: an overview. Rev Infect Dis 1991;13: Roilides E, Pizzo PA. Perspectives on the use of cytokines in the management of infectious complications of cancer. Clin Infect Dis 1993;17(suppl 2): Bodey GB, Anaissie E, Gutterman J et al. Role of granulocyte-macrophage colony-stimulating factor as adjuvant therapy for fungal infection in patients with cancer. Clin Infect Dis 1993;17(4):