Neutropenia management

17 (Supplement 10): x85 x89, 2006 doi:10.1093/annonc/mdl243 Neutropenia management H. C. Schouten University Hospital Maastricht, Maastricht, the Netherlands introduction Infectious diseases have been a threat for mankind since its origin. Hygiene measures and improved wealth have decreased the impact of infections. In the western world, nowadays, an important cause of infections is related to medical interventions. The natural resistance against infections is of utmost importance and can be discriminated between defense at the outside barriers of our body (first-line defense) and, subsequently, an internal system (second-line defense). The first line consists of barriers between the outside, hostile world and the inner part of our body. This contains an intact skin, proper acidity in the stomach, intact bronchial lining and cilial function but, probably, most importantly, intact mucosal barriers, like oral mucosa or gut. All types of treatment, which may disrupt these barriers, can cause a port d entrée for microbial agents. So, this is not limited to surgery, but may also apply to intravenous catheters and to treatments like radiotherapy and chemotherapy. Several cytotoxic drugs may cause mucosal barrier damage as a side effect (for a review see [1]). If infectious agents are able to cross the first-line defense the human body starts its second-line defense that, apart from other systems like humoral factors, mainly consists of a cellular defense. Granulocytes, monocytes, macrophages and lymphocytes (T- and B-cell type) play an important role. This chapter will deal with the consequences of neutropenia. neutropenia Neutrophils play an important role in the host defense against bacterial invasion. Primarily they act by prevention and containment of bacterial and fungal infections. In addition they are important mediators of inflammatory responses. Approximately 1 10 9 neutrophils/kg are produced in the bone marrow daily [2]. Major characteristics of these neutrophils are the potential to travel through the body to sites of injury, to phagocytose and destroy the intruders. Neutropenia (generally defined as an absolute granulocyte count of <500/mm 3 ) can be divided into disorders secondary to abnormalities of production, distribution, or secondary to rapid use or turnover of cells in peripheral blood. Of these, production anomalies are the most frequent. A more helpful classification based on production problems classifies neutropenia in forms related to intrinsic hematological disorders and secondary forms caused by extrinsic factors, including drugs, radiation, autoimmune disorders, and infections [3] (see Table 1). Drug-induced neutropenia is probably the most frequent cause of neutropenia [4, 5]. As radiotherapy, cytotoxic drugs predictably cause neutropenia, depending on dose and the individual characteristics of the drug (like class and target cell) by affecting production. neutropenic fever and cytotoxic drugs Neutropenia and fever is major dose-limiting effect of many cytotoxic drugs. The incidence of neutropenic fever is directly related to depth and duration of the neutropenia [6]. This depends on the intensity of regimens used and patient- and disease-related factors [7]. This may be and is currently used to classify patients in risk groups [8 11]. Febrile neutropenia is generally defined as a rise in axillary temperature to above 38.5 C for more than one hour while having an absolute neutrophil count of less than 0.5 10 9 /l. Other definitions are also used like 38 C during one to four hours [7, 12 14]. In the majority of patients with neutropenia, fever may be the only symptom of infection. If treated with corticosteroids, fever may even be absent. Since the early eighties of the previous century it was recognized that, among other explanations, early treatment with broad spectrum antibiotics of neutropenic fever patients greatly reduced the mortality rate [15 17]. This mortality was mainly due to gram-negative sepsis. Nowadays, there is a shift from gram-negative to gram-positive infections [18]. In a recent study the incidence rates of gram-positive microbes seem to increase with an unexpected increase in mortality rates [18]. However, one still has to consider that in the majority of patients blood cultures remain negative [19]. Incidence rates vary enormously, depending on patient groups described, and is generally much higher in patients treated for acute leukemias or stem cell transplantation. In nonleukemic patients leucopenia (World Health Organisation (WHO) grade 4) varies between 2 and 28%, febrile neutropenia up to 10 to 57%, infections (WHO grades 3 or 4) up to 16% but death in febrile neutropenia is less than 7% [20]. In chemo-naïve patients these incidence rates are lower. Neutropenic fever generally results in hospitalization, with its related economic burden. Therefore, there should be a strong urge to prevent these costs. ª 2006 European Society for Medical Oncology

Table 1. Causes of neutropenia (adapted from [3]) Primary hematological diseases Congenital Kostmann s syndrome Cyclic neutropenia Shwachman-Diamond syndrome Diamond-Blackfan syndrome Chediak-Higashi syndrome Bart syndrome Acquired Acute myeloid leukemia Myelodysplastic syndromes Chronic lymphocytic leukemia Malignant lymphoma Aplastic anemia Chronic idiopathic neutropenia Secondary disorders Immune Alloimmune neutropenia Isoimmune neutropenia Autoimmune neutropenia As part of autoimmune diseases Infections Sepsis Viral infections Drugs Idiosyncratic Cytotoxic drugs Irradiation Other Neutropenia with large granular lymphocytes Neutropenia with splenomegaly Table 2. The Multinational Association for Supportive Care in Cancer Scoring System [22] Characteristic Weight Burden of illness: no or mild symptoms 5 No hypotension 5 No chronic obstructive pulmonary disease 4 Solid tumor or no previous fungal infection 4 No dehydration 3 Burden of illness: moderate symptoms 3 Outpatient status 3 Age <60 years 2 Points attributed to the variable burden of illness are not cumulative. The maximum theoretical score is therefore 26. 21: low-risk patients (positive predictive value 91%, specificity 68%, sensitivity 71%). As described before, patients can be discriminated according to their risk of medical complications due to the febrile neutropenia. Low-risk patients are generally younger than 65 years with a good general condition; the underlying disease is known and controlled; there are no signs of pneumonia, sepsis or central nervous system (CNS) there is no central venous catheter and no high levels of C-reactive protein; and short duration of expected neutropenia [21]. The Multinational Association for Supportive Care in Cancer (MASCC) has developed a scoring system to identify low-risk patients with cancer and febrile neutropenia [22]. prevention of neutropenia and febrile neutropenia in cancer treatment Although not all patients with neutropenia develop neutropenic fever, neutropenia is a significant risk factor for infections. Disruption of defense mechanisms may increase the likelihood for infections, as is the duration and depth of the neutropenia. Several factors have been identified, which can be influenced and lower the likelihood of developing infection. Here, we will discuss prevention of neutropenia and, if not possible, decreasing its depth or duration, or other measures which may prevent neutropenic fever. less chemotherapy-dose reduction As cytotoxic drugs, and sometimes radiation or the combination of both are the main causative factors for neutropenia, dose reduction may prevent neutropenia. However, for many drugs there is a significant dose-response relationship. So, decreasing doses may decrease efficacy, which has been demonstrated in several malignancies like breast cancer and Hodgkin s disease. This makes dose reduction in patients with a curative treatment less attractive. In these patients growth factor support should be considered (see next paragraph). In case of palliative treatment indications, one should clearly consider the option of dose reduction and whether the palliative potential can be reached with this dose reduction. growth factors; primary prophylaxis Since the introduction of the hematopoietic growth factors granulocyte macrophage colony stimulating factor (GM-CSF) (Sargramostim), granulocyte colony stimulating factor (G-CSF) (Lenograstim and Filgrastim) and pegylated Filgrastim many trials have been performed to assess the value of these drugs in preventing neutropenia and neutropenic fever and, also, in enabling dose adherence. It is now well established that growth factors can prevent up to 50% of occurrences of neutropenic fever, however, without clear benefits in survival or response [23 27]. This translates in an overtreatment of at least 50% of patients, without benefit and decreasing costs-benefit. If the likelihood of developing neutropenic fever increases over 40% growth factor support may be considered [20, 28]. This also may apply to situations where dose reduction (necessary for neutropenic fever in previous cycles) is deemed detrimental for treatment outcome [20, 28]. The later procedure is called secondary prophylaxis. Several data suggest that the likelihood of neutropenic fever is highest during the first cycles of chemotherapy [29, 30]. This x86 Schouten Volume 17 Supplement 10 September 2006

may be an argument for primary prophylaxis with or without antibiotics [31]. This issue is not completely settled yet. Primary prophylaxis may also be considered in patients with reduced marrow reserve, human immunodeficiency virus infection, active infections, or reduced performance status [20, 28]. In patients with a high-risk for neutropenic fever like those with bone marrow transplantation growth factor support can be helpful [20, 28]. Although not recommended in the European Society for Medical Oncology (ESMO) guidelines, growth factor support may be used in acute myeloid leukemia (AML) trials not to reduce infections but to increase efficacy of chemotherapy [32]. growth factors; secondary prophylaxis Patients with neutropenic fever have an increased risk to develop the same problem during subsequent therapy. If dose reduction is detrimental for the patient and other etiological factors for neutropenia have been excluded or not improved (e.g. bone marrow infiltration) secondary prophylaxis may be considered [20, 28]. In these patients the cost-benefit balance is in favor for growth factor support. antibiotics Prophylactic antibiotic therapy to prevent infections in potentially neutropenic patients has a broad application, especially in the high-dose regimens in hematological malignancies. This approach shows a debatable benefit [23, 24]. Arguments against prophylactic antibiotic use include but are not limited to the potential emergence of resistance against antibiotics. However, in two recently published randomized trials, levofloxacin had not only a significant impact on the reduction of fever, probable infection and hospitalization in low-risk patients with lymphoma and solid tumors [12, 33] but also in high-risk patients with profound and prolonged neutropenia [12]. treatment of febrile neutropenia Although mortality has significantly been reduced, neutropenic fever still is a significant burden for the patient but also for the society, due to the high economic costs of hospitalization. Although many very effective antibiotics are available for the treatment of neutropenic fever many trials have been performed to improve results and to assess cost-efficacy of available treatment options. It is clearly necessary to divide the patients with neutropenic fever into risk groups. Generally these have been defined based on depth and duration of neutropenia or other clinical risk factors [21] or systems like the MASCC Scoring System [22]. antibiotics in febrile neutropenia The rapid initiation of antibiotics in neutropenic fever has lead to a significant improvement of the prognosis over the past decades [15 17]. Nowadays, it is increasingly clear that this observation is correct for high-risk patients, but may be less correct for low-risk neutropenic patients. Several trials have been published presenting data in low-risk patients, including a meta-analysis [13, 14, 34 36]. Oral antibiotics consisting of quinolones (plus in many trials amoxicillin-clavulanate) is safe and at least as effective as standard intravenous therapy [14, 35, 36]. In high-risk neutropenic patients, especially in relation to stem cell transplantation or anti-leukemia therapy, patients are generally hospitalized and treatment is still consisting of broad spectrum intravenous antibiotics [37]. Best approach for these patients is based on local protocols, which take local microbial resistance data into account. These protocols are beyond the scope of this overview. growth factors plus antibiotics in febrile neutropenia Growth factors are able to speed up recovery of neutrophils in patients with neutropenia. This characteristic has been exploited in several trials in patients with neutropenic fever, where growth factors have been added to antibiotic therapy. Recently, a meta-analysis of 13 trials was published [38]. Conclusions from this analysis are that overall mortality was not influenced significantly by the use of growth factors. A marginally significant result was obtained in reducing infection-related mortality (odds ratio = 0.51; 95% CI, 0.26 to 1.00; P = 0.05). In addition they had shorter length of hospitalization and (of course) a shorter time to neutrophil recovery. Table 3. Indications for growth factor use in relation to neutropenic fever (recommendations) Primary prophylaxis If likelihood for neutropenic fever >40% (e.g.) Marrow infiltration Human immunodeficiency virus Reduced performance status Secondary prophylaxis If dose reduction is considered detrimental for outcome History of chemotherapy-induced neutropenic fever Other Increasing sensitivity for chemotherapy (acute myeloid leukemia) Table 4. Indications for antibiotic use in relation to neutropenic fever (recommendations) Primary prophylaxis Prevention of neutropenic fever in case dose-adherence is important (Quinolones are first choice) Secondary prophylaxis History of neutropenic fever (Quinolones are first choice) Treatment of neutropenic fever Low-risk patients: amoxicillin 6 clavulanic acid High-risk patients: regimen effective against gram-negative rods incl. Pseudomonas aeruginosa Volume 17 Supplement 10 September 2006 doi:10.1093/annonc/mdl243 x87

In trials designed to assess costs in relation to efficacy the outcome was not favorable due to the high costs of the growth factors in some [39] but cost-effective in other [40]. application of growth factors Originally two growth factors have been developed: G-CSF and GM-CSF. Currently almost all treatments are with G-CSF, largely because of a relatively lack of side effects compared to GM-CSF. Apart from G-CSF (Lenograstim or Filgrastim) which both have to be administered daily, currently also a once per cycle growth factor is available (peg-filgrastim). Generally the use of 5 lg/kg/day of G-CSF subcutaneously 24 72 h after the last day of chemotherapy until sufficient/stable absolute neutrophil count (ANC) recovery is recommended. It is not necessary to treat patients till they achieve a target ANC of >10 10 9 /l. Peg-filgrastim, injected subcutaneously as a single dose of either 100 lg/kg (individualized) or of a total dose of 6 mg (general approach), is considered equally effective as the other G-CSF s [41, 42]. There is some evidence that G-CSF is better not be used during radiotherapy to the chest due to increased rate of complications and death. Also, some data suggest that severe thrombocytopenia may occur when growth factors are given immediately prior to, or simultaneously with, chemotherapy [43]. conclusions and recommendations (Tables 3 and 4) Neutropenia, and especially neutropenic fever, is a medical emergency. Certainly also in cancer patients alternative diagnoses other than treatment-induced neutropenia should be considered. Prevention of neutropenia by decreasing treatment doses may be an option in a small subset of patients. In patients where optimal dosing is the goal, prophylaxis with either antibiotics or the combination of antibiotics plus growth factor support may be a good alternative. Patients who present with neutropenic fever should be treated with antibiotics. The choice (oral or intravenous) may depend on their individual risk profile. The use of growth factors in the prevention or treatment of neutropenic fever is still debated. further reading ESMO guidelines on growth factor use [20]. ASCO guidelines on growth factor use [28]. references 1. O Brien SN, Blijlevens NMA, Mahfouz TH, Anaissie EJ. Infections in Patients with Hematological Cancer: Recent Developments. Hematology 2003; 2003: 438. 2. Boggs DR. The kinetics of neutrophilic leukocytes in health and in disease. Seminars of Hematology 1967; 4: 359 386. 3. Dale DC, Liles WC. Neutrophils and Monocytes: normal physiology and disorders of neutrophil and monocyte production. In Handin RI, Lux SE, Stossel TP (eds): Blood; Principles and Practise of Hematology, Edition second. Philadelphia: Lippincot Williams & Wilkins 2003; 455 482. 4. Palmblad J, van der Klauw MM, Stricker BHC. Drug-Induced Neutropenias: Now and Then. Arch Intern Med 1999; 159: 2745. 5. van der Klauw MM, Goudsmit R, Halie MR et al. A Population-Based Case-Cohort Study of Drug-Associated Agranulocytosis. Arch Intern Med 1999; 159: 369 374. 6. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64: 328 340. 7. Lalami Y, Paesmans M, Muanza F et al. Can we predict the duration of chemotherapy-induced neutropenia in febrile neutropenic patients, focusing on regimen-specific risk factors? A retrospective analysis. Ann Oncol 2006; 17 (3): 507 514. 8. Rubin M, Hathorn JW, Pizzo PA. Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 1988; 6: 167 184. 9. Talcott JA, Finberg R, Mayer RJ, Goldman L. The medical course of cancer patients with fever and neutropenia. Clinical identification of a low-risk subgroup at presentation. Arch Intern Med 1988; 148: 2561 2568. 10. Talcott JA, Siegel RD, Finberg R, Goldman L. Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J Clin Oncol 1992; 10: 316 322. 11. Pizzo PA, Robichaud KJ, Wesley R, Commers JR. Fever in the pediatric and young adult patient with cancer. A prospective study of 1001 episodes. Medicine (Baltimore) 1982; 61: 153 165. 12. Bucaneve G, Micozzi A, Menichetti F et al. Levofloxacin to Prevent Bacterial Infection in Patients with Cancer and Neutropenia. N Engl J Med 2005; 353: 977 987. 13. Oude Nijhuis C, Kamps WA, Daenen SMG et al. Feasibility of Withholding Antibiotics in Selected Febrile Neutropenic Cancer Patients. J Clin Oncol 2005; 23: 7437 7444. 14. Innes HE, Smith DB, O Reilly SM et al. Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: a prospective randomised controlled single centre study. Br J Cancer 2003; 89: 43 49. 15. Love LJ, Schimpff SC, Schiffer CA, Wiernik PH. Improved prognosis for granulocytopenic patients with gram-negative bacteremia. Am J Med 1980; 68: 643 648. 16. Viscoli C, Varnier O, Machetti M. Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification. Clin Infect Dis 2005; 40 Suppl 4: S240 245. 17. Viscoli, Castagnola. Planned progressive antimicrobial therapy in neutropenic patients. British Journal of Haematology 1998; 102: 879 888. 18. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003; 36: 1103 1110. 19. Yadegarynia D, Tarrand J, Raad I, Rolston K. Current spectrum of bacterial infections in patients with cancer. Clin Infect Dis 2003; 37: 1144 1145. 20. Greil R, Jost LM. ESMO recommendations for the application of hematopoietic growth factors. Ann Oncol 2005; 16: i80 82. 21. Castagnola E, Paola D, Giacchino R, Viscoli C. Clinical and laboratory features predicting a favorable outcome and allowing early discharge in cancer patients with low-risk febrile neutropenia: a literature review. J Hematother Stem Cell Res 2000; 9: 645 649. 22. Klastersky J, Paesmans M, Rubenstein EB et al. The Multinational Association for Supportive Care in Cancer Risk Index: A Multinational Scoring System for Identifying Low-Risk Febrile Neutropenic Cancer Patients. J Clin Oncol 2000; 18: 3038 3051. 23. Donnelly JP. Selective decontamination of the digestive tract and its role in antimicrobial prophylaxis. J Antimicrob Chemother 1993; 31: 813 829. 24. Lew MA, Kehoe K, Ritz J et al. Prophylaxis of bacterial infections with ciprofloxacin in patients undergoing bone marrow transplantation. Transplantation 1991; 51: 630 636. 25. Phillips KA, Tannock IF. Design and interpretation of clinical trials that evaluate agents that may offer protection from the toxic effects of cancer chemotherapy. J Clin Oncol 1998; 16: 3179 3190. 26. Bokemeyer C, Kuczyk MA, Kohne H et al. Hematopoietic growth factors and treatment of testicular cancer: biological interactions, routine use and doseintensive chemotherapy. Ann Hematol 1996; 72: 1 9. x88 Schouten Volume 17 Supplement 10 September 2006

27. Fossa SD, Kaye SB, Mead GM et al. Filgrastim during combination chemotherapy of patients with poor- prognosis metastatic germ cell malignancy. European Organization for Research and Treatment of Cancer, Genito-Urinary Group, and the Medical Research Council Testicular Cancer Working Party, Cambridge, United Kingdom. J Clin Oncol 1998; 16: 716 724. 28. Ozer H, Armitage JO, Bennett CL et al. Update of Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-Based, Clinical Practice Guidelines. J Clin Oncol 2000; 18: 3558 3585. 29. Gomez H, Hidalgo M, Casanova L et al. Risk factors for treatment-related death in elderly patients with aggressive non-hodgkin s lymphoma: results of a multivariate analysis. Journal of Clinical Oncology 1998; 16: 2065. 30. Tjan-Heijnen VC, Postmus PE, Ardizzoni A et al. Reduction of chemotherapyinduced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study. Ann Oncol 2001; 12: 1359 1368. 31. Timmer-Bonte JN, de Boo TM, Smit HJ et al. Prevention of Chemotherapy- Induced Febrile Neutropenia by Prophylactic Antibiotics Plus or Minus Granulocyte Colony-Stimulating Factor in Small-Cell Lung Cancer: A Dutch Randomized Phase III Study. J Clin Oncol 2005; 23: 7974 7984. 32. Lowenberg B, Boogaerts MA, Daenen SM et al. Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 1997; 15: 3496. 33. Cullen M, Steven N, Billingham L et al. Antibacterial Prophylaxis after Chemotherapy for Solid Tumors and Lymphomas. N Engl J Med 2005; 353: 988 998. 34. Escalante CP, Weiser MA, Manzullo E et al. Outcomes of treatment pathways in outpatient treatment of low risk febrile neutropenic cancer patients. Supportive Care in Cancer 2004; 12: 657 662. 35. Vidal L, Paul M, Ben dor I et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients: a systematic review and meta-analysis of randomized trials. J. Antimicrob. Chemother. 2004; 54: 29 37. 36. Freifeld A, Marchigiani D, Walsh T et al. A Double-Blind Comparison of Empirical Oral and Intravenous Antibiotic Therapy for Low-Risk Febrile Patients with Neutropenia during Cancer Chemotherapy. N Engl J Med 1999; 341: 305 311. 37. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993; 328: 1323 1332. 38. Clark OAC, Lyman GH, Castro AA et al. Colony-Stimulating Factors for Chemotherapy-Induced Febrile Neutropenia: A Meta-Analysis of Randomized Controlled Trials. J Clin Oncol 2005; 23: 4198 4214. 39. Vellenga E, Uyl-de Groot CA, de Wit R et al. Randomized placebo-controlled trial of granulocyte-macrophage colony- stimulating factor in patients with chemotherapy-related febrile neutropenia. J Clin Oncol 1996; 14: 619 627. 40. Garcia-Carbonero R, Mayordomo JI, Tornamira MV et al. Granulocyte Colony- Stimulating Factor in the Treatment of High-Risk Febrile Neutropenia: a Multicenter Randomized Trial. J Natl Cancer Inst 2001; 93: 31 38. 41. Green MD, Koelbl H, Baselga J et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003; 14: 29 35. 42. Holmes FA, O Shaughnessy JA, Vukelja S et al. Blinded, Randomized, Multicenter Study to Evaluate Single Administration Pegfilgrastim Once per Cycle Versus Daily Filgrastim as an Adjunct to Chemotherapy in Patients With High-Risk Stage II or Stage III/IV Breast Cancer. J Clin Oncol 2002; 20: 727 731. 43. Timmer-Bonte JNH, Mulder PHM, Peer PGM et al. Timely Withdrawal of G-CSF Reduces the Occurrence of Thrombocytopenia During Dose-dense Chemotherapy. Breast Cancer ResTreat 2005; 93: 117 123. Volume 17 Supplement 10 September 2006 doi:10.1093/annonc/mdl243 x89