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Drug-Induced Neutropenia – Pathophysiology, Clinical Features, and Management

Address correspondence to Abdus Saleem MD, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; tel 713 440 2439; fax 713 793 1603; e-mail asaleem{at}bcm.tmc.edu.

	Abstract

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Drug therapy plays a significant role in causing neutropenia. The neutropenia may be immune mediated or due to direct inhibition of the bone marrow precursors. Recently, due to wide use of chemotherapy, febrile neutropenia has become a common and devastating problem. Neutropenia predisposes to many bacterial and fungal infections with organisms including Gram negative bacilli such as E. coli, Klebsiella, and Pseudomonas; Gram positive organisms such as Staphylococcus, Streptococcus viridans, and Enterococcus species; and fungi, like Candida and Aspergillus. In addition to the customary supportive care for neutropenic patients, therapy with recombinant human granulocyte colony-stimulating factor (rG-CSF) (filgrastim) has been shown to be beneficial. Filgrastim was a significant advance in the management of drug induced neutropenia in the past decade, but therapy with pegfilgrastim (a pegylated, long-acting form of filgrastim) ushers in the current decade. Pegfilgrastim (Neulasta) is administered as a single sc injection once per chemotherapy cycle. This results in fewer injections, fewer patient visits to the physician’s office, and better patient compliance with therapy.

(received 24 December 2003; accepted 8 March 2004)

Keywords: neutropenia, filgrastim, pegfilgrastim

	Introduction

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Neutrophils or PMN (polymorphonuclear neutrophils) constitute the majority of the blood leucocytes (60–70% in adults). These cells are derived from bone marrow stem cells. Next to macrophages, they are the most important phagocytic cells of the immune system. In response to chemotactic stimuli, neutrophils marginate (adhere to the endothelial cells) and migrate from the blood into the tissues and to the sites of infection. They engulf micro-organisms within vacuoles termed phagosomes, which fuse with lysosomes to form phagolysosomes that destroy the ingested organisms.

The absolute neutrophil count (ANC) is the product of the total leucocyte count and the percentage of neutrophils and band cells observed in the peripheral blood by a differential leucocyte count. Neutropenia is defined as an ANC of <1500 cells/mm³ for most adults and children. Neutropenia can be graded as mild, moderate, and severe, corresponding respectively to ANC values of 1000–1500 cells/mm³, 500–1000 cells/mm³, and <500 cells/mm³. Neutropenia results either from failure of production of neutrophils in the bone marrow or from their peripheral destruction. Although there are multiple congenital and acquired causes of neutropenia (eg, bacterial, viral, fungal, and parasitic infections, nutritional deficiencies, copper deficiency, protein malnutrition, and immune reactions), drug therapy plays a significant role in causing neutropenia.

	Incidence

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Drug-induced neutropenia was first reported by Kracke in 1931, attributed to administration of an analgesic (pyramiden) in patients with agranulocytosis [1]. The drug was then eliminated from clinical use [2–4].

In 1979, a 10-yr nation-wide study in Sweden indicated that the incidence of drug-induced neutropenia was 1 case/million population/yr [5]. An international study in 1991 yielded an incidence of 3–4 cases/million population/yr [6]. Recently, owing primarily to chemotherapeutic agents, the incidence has greatly increased. Drug-induced neutropenia is most common in women and the elderly, probably because of more frequent use of medications. Genetic and physiological traits may also contribute to the higher incidence [7]. The drugs commonly used in practice that cause neutropenia are listed in Table 1.

	Mechanisms of action

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Hapten.  Some drugs act as haptens to induce antibody formation against neutrophils, leading to their destruction. Continuous presence of the drug is required for the destruction of neutrophils. Drugs like aminopyrine, penicillin, and gold compounds appear to act as haptens [9–10].

Apoptosis.  Neutrophils are destined to undergo apoptosis, with a life span in the circulation of 8 to 20 hr. Clozapine accelerates the process of apoptosis, as shown by in vitro studies [11]. Clozapine undergoes bioactivation by P450 and peroxidase enzymes to form the toxic and reactive nitrenium ion. This unstable metabolite covalently binds to cellular proteins, depletes intracellular glutathione (GSH), and leads to polymorphonuclear and mononuclear cell toxicity in vitro. Williams et al [11] studied the ability of nitrenium ion to induce polymorpho-nuclear apoptosis at clozapine concentrations from 0.1 to 3 mM, in vitro, which correspond to therapeutic concentrations. Concentrations of clozapine above 3 mM, in the presence of an enzyme activating system, produced cell death. Apoptosis was assessed morphologically and by flow cytometry. Another simultaneous assessment of apoptosis and cellular binding showed that haptenation was greater in the cells undergoing apoptosis. In patients who receive chronic clozapine therapy, it is possible that haptenation of polymorphonuclear cells occurs and that they may become depleted of glutathione, leading to apoptosis.

Immune complexes.  Circulating immune complexes may be formed, which bind to neutrophils and cause their destruction. These complexes do not require the continuous presence of the drug, which is evident in vitro by the presence of antineutrophilic antibodies even in the absence of the inducing drug [12].

Complement mediated mechanism.  Akamizu et al [13] recently reported a patient with Grave’s disease who developed neutropenia and anti-neutrophil cytoplasmic antibodies (ANCA) after propylthiouracil treatment. ANCA disappeared after withdrawal of the drug. The patient’s serum was negative for ANCA before propylthiouracil and became positive by both perinuclear staining (P-ANCA) and cytoplasmic staining (C-ANCA) (using indirect-staining immunofluorescence) after administration of the drug. Using ELISA, the serum showed anti-proteinase-3 and anti-myeloperoxidase antibodies. Cytotoxicity tests demonstrated that the antineutrophilic antibodies lysed the neutrophils via a complement mediated mechanism and not by antibody-dependent cell-mediated cytoxicity (ADCC). The cessation of propylthioracil therapy resulted in gradual increase of neutrophils and disappearance of the anti-proteinase-3 and anti-myeloperoxidase antibodies.

Dose-dependent inhibition of granulopoiesis.  This is seen by drugs such as beta-lactam antibiotics [14], carbamazepine [15], and valproic acid [16]. At high concentrations, these drugs induce inhibition of colony forming units of granulocytes and macrophages in all bone marrow samples, but produce variable result at low concentrations. Watts et al [16] added valproic acid to normal donor cells at varying concentrations; CFU-GM were quantified and compared to controls in soft agar and plasma clot assays. They found that at 60 Ìg/ml (ie, a low therapeutic level), CFU-GM production decreased by 26±4% whereas, at 120 and 240 Ìg/ml, CFU-GM production was reduced by 67±15% and 84±27%, respectively.

Direct toxicity for myeloid precursors.  Reversible direct cytotoxity of ticlopidine for pluripotent or bipotent hemopoietic progenitor stem cells was noted by Symeonidis et al [17]. Busulfan, factitiously ingested by a 34-yr-old woman, resulted in life threatening bone marrow suppression [18]. Ford et al [19] reported a case of methotrexate-induced bone marrow suppression, which was also factitiously ingested. A case of pancytopenia was reported by Breier et al [20], in which the usual bone marrow hypoplasia due to methimazole was replaced by massive plasmacytosis. Doxorubicin, cyclophosph-amide, and cis-diamminedichloroplatinum caused reductions in the pluripotent and committed hematopoietic stem cells [21]. In vitro studies by Pisciotta et al [22] suggested that excessive levels of chlorpromazine partially inhibited the influx of thymidine and uridine into granulocytes of patients with agranulocytosis due to this drug. Chlor-promazine, even at high levels, did not affect nucleic acid synthesis in patients with normal leucocyte counts.

	Clinical features

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Patients with cancer undergoing chemotherapy, especially if neutropenic, are highly susceptible to almost any type of bacterial or fungal infection. Such infections cause substantial morbidity and mortality. Recurrent infections are commonly seen with neutropenia. The most common site of infection is the oral cavity and mucous membranes, presenting as oral ulcers, pharyngitis, and periodontitis. Skin is another site of infection, with rashes, ulcerations, abscesses, and poor wound healing. Perirectal and genital infections are also common. Systemic infections of the lungs, gastrointestinal tract, and blood stream occur and may prove fatal in patients with persistent severe neutropenia [7].

The pathogens that cause these infections are mainly bacteria and fungi. From the late 1960s to the early 1980s, Gram negative bacilli, such as E.coli, Klebsiella, and Pseudomonas were commonly isolated. In the mid-1980s, there was steady rise in Gram positive organisms (eg, coagulase negative Staphylococcus, Streptococcus viridans, and Staphylococcus aureus). Recently, Gram negative bacilli are again commonly seen due to parsimonious use of fluoroquinolones; Staphylococcus aureus, coagulase negative Staphylococcus, Streptococcus viridans, and Enterococcus species (E. faecium is overtaking E. faecalis) are increasingly being isolated. Of these infected patients, 10% develop a syndrome resembling toxic shock, with fever, hypotension, diffuse rash, desquamation, and adult respiratory distress syndrome, leading to about 30% mortality [23].

Fungal infections have increased in the past 30 years, and are a common cause of morbidity and mortality in patients with leukemia. An international autopsy study by Bodey et al [24] showed that up to 50% of patients with hematological malignant disease had evidence of invasive fungal infections at autopsy [24]. Most of the systemic yeast infections (oral and gastrointestinal tract) are due to Candida albicans; other Candida species such as C. tropicalis, C. glabrata, and C. parapsilosis are increasingly being isolated. In medical centers where flucanazole is used for prophylaxis, C. krusei has emerged as an important pathogen [25]. Aspergillosis in neutropenic patients is usually caused by A. fumigatus or A. flavus. Although the most frequent clinical manifestation of aspergillosis is pneumonia, it may also occur as invasive rhinosinusitis, cerebral infection, or disseminated infection [23]. Rare fungi that cause systemic infections in neutropenic patients include Fusarium, Cryptococcus, Trichosporon, Rhizopus, and Rhizomucor.

	Diagnosis

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During or immediately following drug exposure, the occurrence of febrile neutropenia with decreased classic signs of inflammation, reduced absolute neutrophil count, and bone marrow findings of myeloid hypocellularity, neutrophilic maturation arrest, or hypercellularity with increased myeloid precursors and little maturation, all suggest a diagnosis of drug-induced neutropenia.

	Preventive measures and management

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Measures to prevent drug-induced neutropenia include the following precautions:

Discontinuation of the offending drug or presumed causative agent.

Maintenance of good oral hygiene (cleaning of teeth and correction of dental problems), avoidance or minimizing trauma to perirectal area (using stool softeners for constipated patients and avoiding rectal temperature monitoring), and cleanliness of the skin (prompt cleaning and antibacterial topical therapy for skin abrasions). Such measures limit the number and severity of infections and facilitate efforts to recognize and treat any infections that arise.

Recombinant human granulocyte colony-stimulating factor (rG-CSF). G-CSF is the major cytokine that stimulates the growth and development of neutrophils in the bone marrow. A recombinant form of G-CSF (filgrastim; r-metHuG-CSF) is commercially available. Filgrastim has the same pharmacologic effects as endogenous human G-CSF; it increases the activation, proliferation, and differentiation of neutrophil progenitor cells and enhances the function of mature neutrophils. It results in increased granulopoiesis without reducing the half-life of neutrophils. Consequently, it produces dose-dependent increases in the absolute neutrophil count (ANC) and is associated with decreased incidence, duration, and severity of neutropenia [26].

Filgrastim, which received FDA approval in the United States in 1991, has been used during the past decade to decrease the incidence of neutropenia-associated infection in patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy. It reduces the incidence, severity, and duration of chemotherapy-induced neutropenia and the hospitalization rates and use of antibiotics. It also prevents chemotherapy dose delays and dose reductions and facilitates patient adherence to chemotherapy regimens with curable malignancies, such as early breast cancer and aggressive non-Hodgkins lymphoma. Though rG-CSF is useful in chemotherapy-induced neutropenia, not all patients with myelosuppression require prophylactic rG-CSF [27]. Elderly patients are particularly appropriate for primary prophylaxis with rG-CSF [28].

As a part of a Phase I/II study, a dose from 1 to 60 µg/kg of body weight of rG-CSF was given before chemotherapy to 22 patients with transitional cell carcinoma of the urothelium [29]. Dose-dependent increases were seen in ANC and in bone marrow myeloid-to-erythroid cell ratio. rG-CSF was thus established as a potent stimulus for neutrophilic proliferation and maturation. rG-CSF also proved useful for neutropenia induced by melphalan in patients with ovarian cancer, breast cancer, multiple myeloma, melanoma, and germ cell tumors. It was used at a doses from 1 to 60 µg/kg of body weight as daily infusions over 20–30 min for 5 days before and 9 days after melphalan [30]. An initial transient disappearance of circulating neutrophils was seen within 5 min after every administration of rG-CSF followed by a dose-dependent rise by 4 hr. This rise of neutrophils was attributed to early release of neutrophils from the bone marow granulocyte reserve, demargination of neutrophils, and prolongation of survival of neutrophils in circulation. rG-CSF was well tolerated except for mild bone pain during infusions.

rG-CSF was used in two cases of neutropenia induced by analgesics (mefanamic acid and ketoprofen) [31]. The patients were treated with rG-CSF, 100 µg/m² for 7 days, and 200 µg/m² for 3 days, respectively. The therapy proved to be beneficial, with progressive increases of granulocytes from 400/µl to 15,000 ml on day 7 and 2300/µl to 18,000/µl on day 3, respectively.

Randomly assigned patients with small cell carcinoma of lung were given either placebo or rG-CSF with treatment beginning on day 4 and continuing through day 17 of a 21-day chemotherapy cycle (cyclophosphamide, doxorubicin, etoposide) [32]. It was found that with rG-CSF the number of days of treatment with IV antibiotics and the number of days of hospitalization were decreased by 50%, compared to placebo.

Filgrastim constituted a significant advance in management of chemotherapy-induced neutropenia during the last decade. Recently, pegfilgrastim, which is produced by covalent binding of a 20-kD polyethylene glycol moiety to the N-terminal of filgrastim, has been shown to have a sustained colony-stimulating factor effect. Polyethylene glycol (PEG)-conjugated or pegylated agents have longer half-lifes, greater physical and thermal stability, greater protection against enzymatic degradation, more stable plasma concentrations, and reduced immunogenicity and antigenicity [33]. Pegfilgrastim has been evaluated for preventing chemotherapy-induced neutropenia (CIN) in patients with high-risk breast cancer and in patients with lung cancer and non-Hodgkin’s lymphoma [26].

Preclinical studies with pegfilgrastim in non-neutropenic mice showed increased ANC (both the peak count and the duration of elevated count) [34]. In phase I studies in 32 healthy adult volunteers and in adult patients with cancer, administration of pegfilgrastim as single sc doses ranging from 30 to 300 µg/kg were well tolerated and produced dose-dependent increases of absolute neutrophil count (ANC) [34,35].

In a phase I/II dose-escalation study, the pharmacokinetics, clinical efficacy, and safety of pegfilgrastim (single-injection of 30, 100, or 300 µg/kg) were compared with filgrastim (5 µg/kg/day) given 2 weeks before and again 24 hr after treatment with carboplatin and paclitaxel, in a randomized open-label trial in 13 patients with non-small cell lung cancer [35]. The post-chemotherapy ANC nadirs were similar with pegfilgrastim (30 µg/kg) and filgrastim (5 µg/kg/day), and the ANC nadirs were higher in the two other pegfilgrastim cohorts. A phase II dose-finding study compared single injections of pegfilgrastim (30, 60, or 100 µg/kg) and daily filgrastim (5 µg/kg) in patients with breast cancer treated with four cycles of doxorubicin and docetaxel [36]. Treatment with both the drugs began 24 hr after the chemotherapy. The results showed that pegfilgrastim (100 µg/kg) administered once per chemotherapy cycle provided neutrophil support similar to that with daily filgrastim (5 µg/kg), and was as safe as filgrastim [37]. Two randomized, double-blind, phase III clinical trials in patients with breast cancer treated with myelosuppressive chemotherapy showed that a single dose of pegfilgrastim provided neutrophil support comparable to that obtained with an average of 11 daily injections of filgrastim [38].

Pegfilgrastim is currently administered once, 24 hr after chemotherapy and before CIN [39]. This reduces the incidence and severity of CIN and its complications. Additionally, it permits full doses of chemotherapy and dense-dose chemotherapy (ie, administration of standard dose chemotherapy in shorter cycles), and it increases patient adherence because no doses are missed. It improves the quality of life of cancer patients by decreasing distress, discomfort, hospitalization, and life threatening febrile neutropenia. Pegylated G-CSF provides patients similar benefits as filgrastim, but with a simpler (once/chemotherapy cycle) dosing regimen that is efficient and cost-effective

Other therapeutic measures for drug-induced neutropenia include (a) British anti-lewisite (BAL) or penicillamine therapy, if the neutropenia is associated with gold or arsenic exposure, and (b) iv antibiotics against specific bacterial or fungal pathogens.

Tranfusions of granulocyte concentrates have been used during the past two decades for severe bacterial and fungal infections in patients with neutropenia. Low cost-effectiveness, frequent reinfusions due to short survival of granulocytes, the large number of granulocytes required for clinical efficacy, and the attendent risks (eg, pulmonary toxicity, graft versus host reaction, transmission of viral infections, and febrile reactions) have led to reduced clinical use of granulocyte transfusions for adult patients with neutropenia. This therapeutic option however is useful in neonates with Gram negative septicemia and severe neutropenia [40].

	References

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