Chemotherapy- induced neutropenia (CIN) is the most common haematological toxicity associated with cancer chemotherapy [1]. During neutropenia, the presence of abnormally few neutrophils or an Absolute Neutrophil Count (ANC) of≤1500/mm³ renders children and adolescents extremely vulnerable to various infections and complications. A major clinical feature associated with CIN is Febrile Neutropenia which is defined according to CTCAE criteria 5.0, a disorder characterized by an ANC <1000/mm³ and a single body temperature of > 38.5 degree Celsius [2]. The risk of CIN and its complications increases when one or more several co-morbidities are present in the patient such as advanced disease stage, history of prior neutropenia, or no antibiotic prophylaxis [3]. Neutropenia has been recognized for many decades as a major risk factor for the development of infections in patients with haematological malignancies. Effective strategies to anticipate, prevent, and manage infectious complications in neutropenic patients with cancer have led to improved outcomes [4]. However, susceptibility towards infection remains the most common complication of myelosuppressive antineoplastic therapy, and is associated with substantial morbidity and mortality despite major advances in supportive care. The severity of neutropenia differ in different cycles, as it is more common during the earliest phases i.e., the induction and consolidation phases, depending upon the therapy being given, and the child’s immunity to cope up with the therapy. The common sites of infection include bloodstream infections, respiratory tract infections (both upper and lower respiratory tract), urinary tract infections, and sites along the gastro-intestinal tract [5]. Depending on the degree of neutropenia, chemotherapeutic agents may be withheld until the neutrophil count recovery and an addition of granulocyte- colony stimulating factor (G-CSF) as a supportive measure might help in dosing schedules. The adverse event with CIN often constitutes a dose-limiting toxicity which leads to treatment delays or reduction and prolonged hospitalization which may compromise treatment outcomes. Mortality rates up to 12.8% and 17.4% were seen in children with FN, aged 1 to 9 years and 10 to 19 years respectively and morbidity rates up to 20-30% [6]. Many studies from developed countries have reported the significance of prompt management and pattern of CIN. However, reports from the developing countries are lacking and no published reports for outcomes of CIN in pediatrics are available in India. Thus this study was carried out to identify the outcomes of CIN in pediatric cancer patients at tertiary health care center.

A prospective observational study was carried out among fifty pediatric cancer patients in Pune. The study duration was for a period from August 2017 to March 2019. The study protocol was approved by the Institutional Research Committee and objectives were explained to the healthcare professionals involved in the study. The patient caretaker informed consent and informed patient assent form for children above twelve years were taken before initiating the study. Patients enrolled in the study were ensured confidentiality. Children and adolescents (less than 18 years) with haematological cancer treated with systemic chemotherapeutic agents and presenting with an absolute neutrophils count <1000/mm³ were included in the study. Patients having neutropenia other than chemotherapy and those not willing to participate were excluded from the study. Relevant data were collected including demographic features, clinical feature at presentation, types of hematological malignancy, phase of chemotherapy, number of previous neutropenia attacks, duration of neutropenia, initial laboratory findings including white blood cell (WBC), ANC and platelet count; microbiological data and antibiotic used, recovery with or without G-CSF, outcomes data were noted in patient proforma. The mean of neutrophils count was calculated and grades of ANC were analyzed using the Common Technical Criteria for Adverse Events (CTCAE) Version 5.0 2017 (Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0 2017). A correlation of ANC and duration of neutropenia with different dose-limiting toxicity were calculated for the outcomes of CIN. Statistical analysis used continuous variables which were expressed as mean ± SD. The difference between the means of groups were compared by a student‘t’ test. The p-value of <0.05 was considered significant.

A total of 50 patients, presented with 584 episodes of CIN and 188/584 episodes of FN during this study period, were enrolled in this study. Their mean age was 5.9 ± 4.1 years (range, <1year-18 years), with highest reported CIN seen in the age group of 1-6 years (66%), where 37/50 (74%) of the patients were male as shown in (Table 1). The primary leading diagnosis among our cases was acute lymphoblastic leukemia (ALL) of different subtypes, whereas other hematological malignancies exhibited significantly lower prevalence rates. The ANC was significantly lowered in Burkitt’s lymphoma and acute myeloblasticleukemia (AML). Among the phases of chemotherapy, the number of neutropenia was highest in Consolidation phase (n=165) followed by Induction phase (n=141) as shown in (Figure 1).

Figure 1:  Episodes of Neutropenia in phases of chemotherapy.

Figure 2: Complications related to outcomes of neutropenic episodes.

Figure 3:  Correlation between granulocyte colony-stimulating factor (G-CSF) and duration of Neutropenia.

Figure 4: Outcomes of neutropenic episodes.

A description of neutropenic episodes is presented in (Table 2). Among our patients, 49.7% presented the significant neutropenia for the first time, while (50.3%) had recurrent episodes of neutropenia throughout the treatment protocol. The mean ANC during neutropenia was 768.1 ± 269.3/mm3, (range, 10-1000/mm³) starting at 16.3± 15.7 days after onset of chemotherapy and resolving within 17.9 ± 13.8 days either with (34.9%) or without (65.1%) implementation of granulocyte colony stimulating factor (G-CSF). There was a significant inverse correlation between the duration of neutropenia and G-CSF, with faster recovery with G-CSF implementation (Figure 2).

The CIN related outcome included respiratory tract infection (35.1%) and febrile neutropenia (32.2%) which were the leading complications in our cases; mucositis, gastrointestinal (GIT) and skin infections were also documented.

Table 1: Baseline characteristics of the study subjects.

Table 2:  Description of Neutropenia episodes.

Table 3: Association between complications of CIN and Neutrophil count.

Prolonged neutropenia necessitating delay in chemotherapy 23 patients (46 %) and dose reduction 18 patients (36.0%) were also reported. The outcomes associated with CIN are shown in (Figure 3). An analysis of correlation between ANC and duration of neutropenia with different complications emphasized the following: ANC was significantly lowered with an increase in duration among CIN patients who presented with complications such as FN, mucositis, GIT infection, skin infection, treatment delay and mortality; however, prolonged neutropenia with less duration in complications such as respiratory tract infection and dose reduction as shown in (Table 3).

Studies on pattern of CIN at pediatric oncology institutes in developing countries are lacking, but CIN remains a major cause of hospitalization apart from admissions for chemotherapy administration. The chemotherapeutic drugs and its therapeutic strategies for cancer proceed to evolve important roles in different malignancies. The current study used a single institution experience from a developing country to assess and identify the pattern and outcomes for development of prolonged CIN in pediatric cancer patients. In the present study, patient characteristics (age, or gender) and the risk of CIN was identified. Age group has emerged as an important risk factor for both longer length of stay and death in many studies. In the current study, the pattern of CIN was higher in children between one to six years. It is possible that there are contrasts in the malignancy type, pharmacokinetics of chemotherapy received and its resilience among the distinctive age groups. A total of 76% of neutropenic episodes in the present study occurred in ALL, 4% in acute myeloblasticleukemia (AML), 10% in lymphomas;these percentage rates are in concordance with a study conducted by Asthana S 2018 [7], concluded that a higher incidence of CIN is related with hematological malignancies. Among the phases of chemotherapy, the number of neutropenia was highest in Consolidation phase (n=165) followed by Induction phase (n=141). A study conducted in New Delhi reported highest number of neutropenia in consolidation phase (n=175) followed by induction phase (n=172). The ANC is the measure of the count of neutrophils and the total blood leucocyte. One of the criteria established in FN management is the presentation of ANC, with an increased risk of infection and complications associated with ANC < 1000 / mm³. However, it was found that ANC was not associated with cancer or patient risk levels. The bone marrow usually produces platelets, including neutrophils. The life-saving malignancy treatments including chemotherapy and radiation targets rapidly growing cells and has an antagonistic effect on the neutrophils production. This effect may lead to a drop in ANC and therefore sometimes considered as an expected side-effect. The CTCAE criteria 5.0 were utilized in the present study for classification of grades of neutropenia. Our study indicates that patients of grade III severity, having an ANC <1000/mm³ had 567 episodes of neutropenia, which was the highest reported. This is in concordance to an adult study conducted by Li Y et al., where infection risk increases dramatically with each additional day of grade 3 or 4 CIN [8]. The relationship with the total WBC and other clinical parameters helps in investigating the duration and outcome of neutropenia. The pattern of severe neutropenia in the study was associated with an outcome in extension of febrile neutropenic episodes. This is in accordance with studies carried out by Basu SK and Timothy [9,10]. The duration and number of days of G-SCF implementation is associated with the improvement in neutrophil count. In this present study, there was a significant inverse correlation between the duration of neutropenia and G-CSF days, with faster recovery due to G-CSF implementation. Likewise, these merits were accounted for by different researchers like Badr M et al, Vathana, N. et al and Marshall E et al In concurrence with our results, an analysis led in India by D Doshi reported that high risk of FN and various adverse events were seen in patients with severe neutropenia [11-14]. This relationship emerges as an important consideration in the management of episodes of FN. The treatment-related morbidity and the duration of neutropenia may be reduced by implementation with G-CSF therapy. It is indicated in patients depending on the intensity of chemotherapy and clinical presentation of the patient. The dosing schedule of chemotherapy and the type of underlying malignancy is also considered as a key point in considering G-CSF that routine utilization of G-CSFs in adult patients with solid tumour can lessen the occurrence of FN by half.14 Most of our patients with CIN had various complicated outcomes of which, (32.2%) had FN, with a significant association between the length of neutropenia and ANC. Similarly, FN was the recorded factor for extreme complications associated with CIN. A pediatric report led Ozdemir N et al in Turkey revealed that although significant improvement has happened in supportive treatment measures, the principal reason for death in leukemia was FN [15]. Our frequency of FN might be clarified by the higher predominance of underlying hematological malignancies that increase the risk, as 10-16% of patients with solid tumours may have FN, compared to 84% of those with hematological malignancies. The prolongation of neutropenia in patient receiving chemotherapy was significantly associated with various complications. Lower ANC, prolonged hospitalization and aggressive chemotherapy led patients more prone to infection and associated complication. The most common infections seen in our neutropenia episodes were respiratory tract (35.1%), gastrointestinal tract (29.8%), skin (17.1%) and mucositis (3.6%). Few studies conducted in the USA and Turkey on pediatric cancer reported respiratory tract infection as the most common occurrence among 25-35% and 40% respectively [16,5]. Among the major complications, FN (32.19%) was considered to be the harbinger of infections. These results were in contrast to an adult cancer study conducted by Lindsey R that revealed gastrointestinal tract infection to be the primary complication in CIN. Delay in chemotherapy (34.76%) and dose modification (20.71%) were frequently observed in the present study among CIN patients due to low ANC. Similar factors were reported in adult cancer patients, suggestive of dose delay by (20-30%) and dose reduction by (5-15%) in their respective studies [17,18]. The emphasis of the statistical analysis in this study suggests that the neutrophil count was significantly lowered with an increase in duration among CIN patients who presented with complications such as febrile neutropenia, mucositis, GIT infection, skin infection, treatment delay and mortality. However, the neutrophil counts were high with less duration in complications such as respiratory tract infection and dose reduction. The major cause of the outcomes in various complications was considered due intensity in chemotherapeutic drugs. A total of 8% of our patients succumbed to severe neutropenia, with similar rates reported by previous studies in pediatric oncology by Salstrom J et al and Bakhshi S et al. These study report features on the definite risk responsible for vulnerable infections in childhood cancer, and to opt immediate management [19,20]. For pediatric oncology centers in developing countries, assessment of the pattern of chemotherapy- induced neutropenic episodes has favorable outcomes by reducing the associated complications. In spite of the fact that this study has a moderate patient sample, our findings are important to the clinical consideration of pediatric cancer patients in Indian population.

Our study indicates that, most of the study subjects with chemotherapy- induced neutropenic episodes were ALL patients. The outcome pattern analyzed development of prolonged febrile neutropenia with (ANC < 1000/mm³) as a major dose- limiting toxicity resulting in treatment delay and dose reduction during the early treatment cycles. Severe and prolonged neutropenia is life threatening and requires aggressive treatment.

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