Factors Associated With Chemotherapy-Induced Neutropenia
In Patients With Haematological Malignancies At Dr
George Mukhari Academic Hospital, Pretoria, South
Africa
Japhet Manda1, Olakunle Adewunmi Towobola1, Mampinane
Florence Moshesh1, Nguvuyabo Mutidja1
1Department of Internal Medicine, School
of Medicine, Sefako Makgatho
Health Sciences University, Pretoria, South Africa
Corresponding author: Professor O.A. Towobola,
Department of Internal Medicine, School of Medicine, Sefako
Makgatho Health Sciences University, Pretoria, South
Africa. Tel.: +27 12 521 4566, Cell: +27 0723377340, Fax: +27 12 521 3815. E-mail:
olakunle.towobola@smu.ac.za
Afr J Haematol
Oncol 2017;6:20-27
ABSTRACT
AIM Chemotherapy for haematological
malignancies is often associated with occurrence of neutropenia
and often times such an association is influenced by a number of factors. This
study investigated various factors that could have been responsible for neutropenia among patients treated with chemotherapy for
haematological malignancies.
METHODS A retrospective,
cross-sectional, descriptive study of 245 patients, diagnosed with neutropenia while being treated with chemotherapy for
haematological malignancies was conducted at Dr George Mukhari
Academic Hospital, Pretoria, South Africa. Descriptive statistics was performed
and Pearson’s correlation coefficient analysis was used to evaluate the
association of physical characteristics and laboratory variables of patients
with chemotherapy-induced neutropenia (CIN). All
statistical analyses were performed using the Statistical Package for Social
Sciences (SPSS) version 21.0.
RERSULTS Patients’ ages
ranged between 18 and 87 years (median = 45 years), most of the patients (150;
61%) were older than 40 years and only 13 patients (5.3%) were ≤ 20
years. The cohort was made up of 52.7% males (n = 129) and 47.3% females (n =
116). Haematological malignancies treated at the time of the study were:
Non-Hodgkin lymphoma (46.9%), Multiple-myeloma (15.9%), Hodgkin lymphoma
(15.5%), Chronic lymphocytic leukaemia (6.9%), Chronic
myeloid leukaemia (6.1%), Acute lymphoblastic leukaemia (3.7%), Acute myeloid
leukaemia (2.0%) and Myelodysplastic syndrome (2.0%).
The most significant co-morbid condition in association with CIN was HIV (n =
70; 28.6%). Advanced age (> 60 years) and BMI (> 20 kg/m2)
were significantly correlated (p < 0.05) with CIN. However, gender of the
patients, serum albumin, haemoglobin and body surface
area were not directly related to CIN.
CONCLUSION The study
emphasizes the need for healthcare professionals to adopt more stringent
monitoring of patients with haematological malignancies while on chemotherapy,
with particular emphasis for patients in their advanced age and those with
co-morbidities (such as HIV infection and obesity).
Keywords: Chemotherapy;
Neutropenia; Haematological malignancy; South Africa;
Africa.
INTRODUCTION
Neutropenia is a condition of low absolute neutrophil count (ANC)
below 1.5x109/L, and it is categorized based on the severity
of ANC reduction [1]. When it occurs, chemotherapy induced neutropenia (CIN) is
a condition that warrants special medical attention and if not appropriately
managed could result in hospitalization and further compromise quality of life
of the patient.
A previous report did
indicate that CIN as well as febrile neutropenia (FN) occur frequently as
complications in patients with cancer, undergoing chemotherapy [2]. FN refers to an ANC below 0.5x109/L
accompanied with 38°C or more by oral temperature for over one hour [3]. The
blood neutrophil concentration itself is influenced by age, physical activity,
genetic as well as environmental factors, and drugs. For instance, CIN is the
most common side-effect associated with the administration of cancer drugs [4].
The severity of neutropenia does determine the prognosis and course of
treatment outcomes, hence a grade 4 neutropenia
characterized with ANC below 0.5x109/L, moderate neutropenia with
ANC in the range of 0.5x109/L to 1.0x109/L and mild
neutropenia of 1.0x109/L to 1.5x109/L will present
different medical challenges.
CIN incidence and prevalence
vary widely. Studies have shown that the CIN prevalence among hospitalised
patients ranges from 12% to 23% [5, 6]. These previous studies estimated that
the condition accounts for overall mortality rates of about 5% among cases with
solid tumours, 1% among low-risk patients and up to 11% in some cases with
haematological malignancies. Individuals with neutropenia are more vulnerable
to infectious organisms found on the skin, in the nasopharynx and those
occurring in the intestinal flora. It was previously reported that the risk of
infections varies inversely with the severity of neutropenia [5]. In a
retrospective study involving 11,980 cancer patients on chemotherapy, CIN
patients had a relatively high mortality risk of 15%. More especially,
non-Hodgkin lymphoma (NHL) patients with CIN were reported to have
significantly higher overall mortality rate than individuals who did not have
CIN [6].
Complications and/or side
effects of chemotherapy treatment for haematological malignancies may have a
negative bearing on clinical outcomes and quality of life (QOL) of a patient.
According to Lyman and Kuderer [7], chemotherapy may
adversely affect patient's QOL socially, physically and global functionality.
For instance, patients with febrile neutropenia are frequently hospitalized and
treated with antibiotics in order to prevent the threat to life posed by sepsis
[8, 9]. CIN according to Caggiano et al [10] is
associated with neutropenia hospitalization incidence of about 7.83 cases in
every 1000 cancer patients. The effect of hospitalization and isolation alone
may adversely affect the quality of life, apart from the possibility of clinical
consequences of febrile neutropenia.
Patients with bacteraemia are characterised with the
worst prognosis of which those with gram-negative and gram-positive bacteraemia
have mortality rates of 18% and 5% respectively. The prognostic index showed mortality rates in
the range of 3% for Multinational Association for Supportive Care in Cancer
(MASCC) score of > 21 to high 36% for the MASCC score of < 15
[11].
Therefore, this study was
guided by the following objectives: to establish the association between CIN
with age, gender, BMI, serum albumin levels as well as blood haemoglobin among patients
undergoing chemotherapy for haematological malignancies. The study also
provided an opportunity to evaluate any possible association between co-morbidities with prevalence of CIN among these patients.
METHODS
Study
design and sample size
The study used a retrospective, cross-sectional,
descriptive design to describe CIN associated factors among 245 patients with haematological
malignancies who were undergoing chemotherapy treatment at Dr
George Mukhari Academic Hospital (DGMAH). The health facility responsible for the
treatment of these patients is a “quaternary” level
institution located at approximately 30 km to the north of the city of Pretoria,
South Africa. All participants were confirmed cases of haematological malignancy using relevant laboratory methods: biopsy, cytogenetics and other laboratory parameters as determined
by the malignant type. Medical records of patients treated between 1st
January 2010 and 31st December 2012 were included in the study. The
sample size of 278 patients was calculated based on previous reported CIN
prevalence range of 12% and 23% among hospitalized patients [6, 10], 90% power
of the study and an alpha error limit of 0.05. The number was later scaled down
to 245, corresponding to 88.1% retrieval of records because 26 (11.9%)
attrition cases were excluded as a result of illegible entries and/or
insufficient information as well as inappropriate diagnosis.
Eligibility
criteria For this
study, medical records of all patients who received treatment at the haematology
clinic, based on the eligibility criteria including: those who started new
chemotherapies, those with proven cancers using recommended laboratory methods
and parameters, those above 18 years of age and cases with no previous
chemotherapy and/or radiotherapy for any other malignancy. Patients would have
had absolute neutrophil count below 2.0 x 109/l; patients had been
treated with appropriate as well as standard chemotherapy regimen. Cases
excluded were records of patients with non-haematological cancers, cases with
past chemotherapy or radiotherapy treatment or absolute neutrophil count
greater than 2.0 x 109/l and records of patients on non-standardized
treatment including salvage regimens.
Data collection methods and research instrument Data collection was done using pre-determined patient
data collection form containing variables relevant for the study objectives. Cases
with neutropenia and its severity were graded based on European Society for
Medical Oncology (ESMO) as well as Common Toxicity Criteria of the National
Cancer Institute [12]. Notably, those parameters that were missing in the
patients records were considered as an omission rather than a negative finding.
The data collection form was pre-tested for completeness
of the desired information and to ensure that there was no ambiguity in the
research variables using five patients’ files which were selected based on
study criteria. The pilot was followed with correction of the data collection
form to ensure necessary wording and contents.
The files that were used in the pilot study to clarify any potential
data collection errors were excluded from the final study analysis. The data
collected were age, gender, weight, height, body surface area (BSA), body mass
index (BMI), types of haematological malignancy, FBC and serum albumin
concentration and patients’ co-morbidities. The study was approved by the
institutional ethics committee of Sefako Makgatho Health Sciences University (Cert. No: SMUREC/M/251/2013: PG).
Data
management The data
collected was assessed, reviewed for completeness and accuracy and entered into
a Statistical Programme for Social Sciences programme (SPSS; Version 21.0) for
analysis. Descriptive statistics was used for analysis of means (± standard
deviation), proportions, standard deviation as well as significant differences
across the grade levels of neutropenia. Percentages were used to describe risk
factors associated with CIN in patients with haematological malignancies.
Comparisons were done between patient groups with their chemotherapy
regimens. Pearson’s correlation coefficient was calculated to evaluate
association of variables to the occurrence of CIN. The study was tested at 95%
confidence level and at significant level ≤ 0.05.
RESULTS
Demographic
and physical characteristics of the patients The
study evaluated 245 medical records for patients with CIN (i.e. ANC < 2 x 109/l).
The patients’ age ranged from 18 to 87 years with a median of 45 years. The
majority (n = 150; 61%) of the patients were above 40 years compared to the
least group of 13 (5.1%) patients below the age of 20 years. Out of a total of
245 CIN patients, 52.7% (n= 129) were males and 47.3% (n= 116) were females.
The patients’
body surface area (BSA) and body mass index (BMI) as derived from their weights
and heights show that the patients’ weight distribution ranged from 27.0 to
95.0 kg with a mean (±
standard deviation; SD) of 61.0 kg (±
13.1) and the heights ranged from 1.2 to 1.9 metres (m) with an average of 1.62
m (± 0.11 SD). The
mean BMI (± SD) and BSA (± SD) for the group were 23.5 kg/m2 (± 6.0) and 1.65m2 (± 0.22) respectively (Table 1).
|
Table 1. Demographic and physical characteristics of the patients |
Patients’ baseline haematological indices White blood cells (WBC) ranged from 0.2 - 11.2 (x 109/l)
with a mean of 3.75 ± SD (1.67), haemoglobin was 5.1-19.7 g/l ± SD (2.33), haematocrit was 0.02 - 0.72, a mean of 0.33 ± SD (0.08), platelets; 3 – 1061 (x 109/l), mean of
250 ± SD (139), neutrophils; 0.02 - 7.22 x 109/l,
mean of 1.59 ± SD (0.94), lymphocytes, 0.03 - 5.94 x 109/l;
mean (1.44) ± SD (1.01) and eosinophils were 0.01-3.39 (x 109/l),
mean of 0.15 44 ± SD (0.07), (Table 2).
Types of haematological malignancies treated About half of the patients, 115 (46.9%) had
Non-Hodgkin Lymphoma (NHL), 39 (15.9%) had Multiple-Myeloma (MM), 38 (15.5%)
Hodgkin Lymphoma, 17 (6.9%) Chronic Lymphocytic Leukaemia (CLL), 15 (6.1%)
Chronic Myeloid Leukaemia (CML), 9 (3.7%) Acute Lymphoblastic
Leukaemia (ALL). Acute Myeloid
Leukaemia (AML) and Myelodysplastic Syndrome (MDS)
had 5 (2%) each; and 2 (0.8%) had Myeloproliferative
Neoplasm (MPN)/Polycythemia Rubra
Vera (PRV), (Figure 1).
|
|
Types of chemotherapy regimens used
The study patients
received systemic anti-cancer therapy with either palliative or curative
intent. Chemotherapeutic regimens administered were (Table 3): CHOP (82;
33.5%), Hyper-CVAD (36; 14.7%), ABVD-P (35; 14.3%), CVAD (19; 7.8%), MP (14;
5.7%), CODOX/IVAC (7; 2.9%), Glivec (6; 4.1%), Chlorambucil
and Allopurinol 4 (1.6%), CALGB 8811 regimen 3
(1.2%), 7 + 3 regimen (2; 0.8%) and
others (33; 13.5%). For all patients who received conventional cytotoxic
chemotherapy, the dose was based on their weight, height and body surface area
(Table 3).
|
Table 3. Chemotherapy regimens
and number of patients treated in the study |
Types of co-morbidities among patients There were 32.2% (n = 79) of cancer patients with
co-morbidities. The most common co-morbidity was human immunodeficiency virus
infection (HIV) found in 28.6% (n=70) as against 3 patients (1.2%) with sepsis,
3 patients (1.2%) diagnosed with tuberculosis, 2 patients (0.8%) had
hypertension and only one patient (0.4%) with diabetes mellitus (Table 4).
Association of gender with CIN Patients on CHOP (being the most used chemotherapy
regimen) were evaluated for association of CIN with gender. The result showed
male to female ratio of between 1.5:1.0 for severe neutropenia; 1.8:1.0 for
moderate neutropenia and 1.01:1.0 for mild neutropenia. There were 34.1% (n = 28)
male patients with severe neutropenia versus 29.2% (n = 19) females. Male and
female patients who had moderate neutropenia were 24.4% (n = 20) and 16.9% (n =
11) respectively. There was virtually no difference in the number of males (34,
41.5%) versus females (35, 53.8%) who had mild neutropenia. Gender differences
in the occurrence of neutropenia were not statistically significant across all
three severity levels of neutropenia (Table 5).
Association of CIN with patients’ physical and
laboratory variables The table shows
that BMI < 20 kg/m2 is significantly associated (p
<0.05) with CIN and this is closely related to the weight (<70 kg, p =
0.0003) and height (<1.65 metres, p < 0.0001) of the patients. Similarly, age of patients older than 60
years was significantly associated with CIN with p < 0.05. However, serum
albumin, haemoglobin as well as body surface area were not significantly
associated with CIN (Table 6).
|
Table 6. Association of CIN with patients’ physical and laboratory
variables |
Hospital admission patterns among the patients revealed that 109
patients (44.5%) did not require hospital admission for neutropenia,
93 (38.0%) had 1 - 2 admissions, 13 (5.3%) required 3 - 4 admissions and 4
patients (1.6%) in the series were admitted for more than five times.
DISCUSSION
This study investigated the various factors associated
with occurrence of neutropenia in patients on chemotherapy for treatment of
haematological malignancies at DGMAH. The results found that although the
patients’ age ranged from 18 to 87 years, majority of the patients were over
the age of 40 years. This is consistent with the findings by Hasan et al [13]
who had reported that the incidence of neutropenia was higher among patients
who were 50 – 59 years. The present study also found that there were more male
patients (52.7%; n = 128) as compared with females (47.3%; n = 117). The gender
differences in incidence of CIN were also reflected in the pattern of severity,
in which male patients were more prone to have severe neutropenia. However,
this finding is inconsistent with a previous report by Lyman and Delgado [14]
which had shown that female gender was at higher risk of hospitalization for
CIN than the male gender. The gender effect was again emphasized in the study by
Lyman
and Wilmot [15] who reported that female gender is a risk factor that plays a
role in the development or occurrence of neutropenia and febrile neutropenia (FN).
However, their study did not show significant association between female gender
and severity of neutropenia an observation which was attributed to the small sample
size of that particular study.
In a different study by Nakagawa et al [16], the investigators reported that the risk
of febrile neutropenia remained significantly associated with a number of risk
factors: age ≥ 65 years, (Hazard Ratio = 1.65; 95% CI:
1.18 – 2.32), renal disease (HR = 1.91; 95% CI: 1.10 – 3.30), cardiovascular
disease (HR = 1.54, 95% CI: 1.02 – 2.33) and baseline haemoglobin < 12 g/dl.
(HR = 1.44, 95% CI: 1.04 – 2.0) [15]. It is in the face of such evidence that
the authors advocated the need for frequent monitoring of patients with
haematological malignancies and co-morbidities when undergoing chemotherapy.
The most common haematological malignancy found in the
present study was non-Hodgkin lymphoma which was reported in 115 patients
(46.9%), followed by Multiple-Myeloma (39 patients; 15.9%), Hodgkin lymphoma
(38 patients; 15.5%), chronic lymphocytic leukaemia (17 patients; 6.9%) and
chronic myeloid leukaemia (6.1%). In addition, the finding in this study of
human immunodeficiency virus (HIV) being the most common co-morbid infection is
not surprising, considering the state of the HIV pandemic in Southern Africa.
Nevertheless, the predominant nature of HIV co-morbidity is at variance with
the work of Lyman and Delgado [14] who in their study found a strong
association between hepatic disease and increased risk of hospitalization for
febrile neutropenia.
The patients’ weight distribution ranged between 27.0 to 95.0 kg while
the height ranged from 1.2 – 1.9 metres. The mean body mass index (BMI) and
body surface area (BSA) for the group were 23.5 kg/m2 and 1.65 m2
respectively. All the chemotherapy regimens used (CHOP, Hyper-CVAD and ABVD-P),
except one (CVAD) were significantly associated with BMI in terms of comparison
between > 20 kg/m2 and
< 20 kg/m2 (p <
0.001). This suggests that BMI < 20 kg/m2
is significantly associated with occurrence of neutropenia when patients were
on chemotherapy for haematological malignancy. This finding is in agreement
with previous reports that low BMI or low BSA increases the risk of CIN or CIN-related
hospitalization [15, 16]. Although Pettengell et al
[17] reported that bigger weight was protective against developing CIN in the
first cycle of chemotherapy. This phenomenon is most likely reflected as
reductions in the delivered dose intensity associated with dose capping or the
use of idealized body weight in dose calculations.
CONCLUSION
The occurrence of neutropenia among patients treated with chemotherapy for
haematological malignancies is influenced by various factors, including age,
weight, co-morbid conditions such as HIV and TB as well as the level of haemoglobin.
Although haematological malignancies can be managed by the use of chemotherapy,
this study found that some agents are associated with higher incidence of
neutropenia, as in the case of CHOP and Hyper-CVAD. This highlights the need
for close monitoring of patients with haematological malignancies and
co-morbidities while on treatment with chemotherapy. However, this study was
limited by inadequate number of patients who were treated with a variety of
other chemotherapy regimens and the degree of their effects in association with
CIN.
FOOTNOTES
Conflict of
interest: The authors declare no competing conflicts of
interest.
Acknowledgment: The authors herewith express their gratitude
to the management of Dr George Mukhari Academic
Hospital, Pretoria, South Africa, for the permission to utilise the medical
records of patients. We are thankful to the nursing staff of the oncology unit
for their help in retrieving the medical records. The sponsorship of the World
Health Organisation and the Zambian government towards the postgraduate
training of the first author of this report is highly appreciated.
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