232

ORIGINALRISK FACTORS OF VINCRISTINE-INDUCED PERIPHERALNEUROPATHY IN ACUTE LYMPHOBLASTIC LEUKAEMIA
CHILDREN
Dinda Anes Tunjungsari, Prastiya Indra Gunawan, and I Dewa Gede Ugrasena
Department of Pediatrics, Faculty of Medicine Universitas Airlangga / Dr Soetomo General Academic Hospital, Surabaya - Indonesia

Abstract : Objective : This study analysed Vincristine-induced peripheral neuropathy (VIPN) risk factors in
Acute Lymphoblastic Leukaemia (ALL) children. Method : This cross-sectional study design was performed at
Dr. Soetomo Hospital, Surabaya, Indonesia, from August to October 2019. It included ALL children, aged 4–18
years, undergoing the 2013 or 2018 ALL Indonesian Protocol of Chemotherapy, with a cumulative vincristine
dose ≥ 12 mg / m2. VIPN diagnosis is based on complaints, the Total Neuropathy Score Pediatric Vincristine (TNSPV), and nerve conduction studies (NCS). The examined risk factors were sex, age, ALL classification, nutritional
status, impaired liver function, and cumulative vincristine dose. Results : There were 52 ALL children : medianage 7 years, 59.6% boys, 59.6% ALL standard risk, 44.2% experienced impaired liver function at initial ALL diagnosis. Based on a single parameter for diagnosis, 26.9% had VIPN based on complaints, 76.9% had it based on
the TNS-PV, and 100% had it based on NCS. VIPN was diagnosed in 25% of children, with predominantly motor
impairment and located in lower extremities. Impaired liver function is a risk factor for VIPN in ALL children(p = 0.046, prevalence ratio (PR) 2.84). Conclusion : Impaired liver function is a significant risk factor for VIPN in
ALL children. J. Med. Invest. 68 : 232-237, August, 2021
Keywords : risk factor, children, acute lymphoblastic leukaemia, vincristine, neuropathy

INTRODUCTION
Vincristine-induced peripheral neuropathy (VIPN) is a sensory, motoric, or autonomic nerve disorder following vincristine
therapy (1). Vincristine is a chemotherapy agent that is used totreat acute lymphoblastic leukaemia (ALL) patients in the induction, intensification, and maintenance phases (2). Vincristine
affects small and large nerve fibres and thus causes impaired
sensory, motor, and autonomic function (1). For ALL patients
who received vincristine, 13.8% experienced clinical peripheral
neuropathy and 33.75% received a diagnosis based on electrophysiologic tests (3). Another study revealed 78% were diagnosed
using the Total Neuropathy Score Pediatric Vincristine (TNSPV) (1). Factors thought to contribute to the emergence of VIPN
in children include age, sex, race, genetics, pharmacokinetics,
vitamin B12 deficiency, drugs, and cumulative doses. However,until now there has been no report on a definite risk factor (4).
ALL is the most common lymphoid cell progenitor malignancy
in children (1, 5-7). Each year, at least 3,000 children in the
United States and 5,000 children in Europe are diagnosed with
ALL (8). At the Dr. Soetomo Hospital (Surabaya, Indonesia),
there were 143 children with ALL in 2017 and 114 children in2018 (9). The survival rate has increased gradually from 10% in
1960 to 90% (7).
Long-term sequelae of VIPN leads to a quality of life reduction(1, 4, 10, 11). Recognising risk factors for VIPN will alert healthcare workers and families to detect early VIPN symptoms andthus ensure early treatment and, ideally, prevent a decrease inquality of life (1, 3). There have been limited studies of VIPN in
Received for publication September 29, 2020 ; accepted February 15,
2021.
Address correspondence and reprint requests to Prastiya Indra
Gunawan, MD, PhD, Department of Pediatrics, Faculty of Medicine,
Universitas Airlangga / Dr Soetomo General Academic Hospital,
Surabaya, Indonesia, Jl. Prof Dr Moestopo 6-8 Surabaya, Indonesia.

Indonesia. The aim of this study was to analyse the VIPN risk
factors in ALL children.

MATERIALS AND METHODSPatients

The study was carried out on 4–18-years-old ALL children
who underwent chemotherapy according to the ALL Indonesia
2013 or 2018 protocol, with a cumulative vincristine dose > 12
mg / m2 . Comprehensive informed consent and was obtained
from a legal representative of each patient. Patients were excluded if they were uncooperative during nerve conduction studies(NCS) ; had a history of intracranial disorder, neuropathy,
myopathy ; were septic ; had diabetes mellitus ; there was anincomplete medical record ; or refused to follow the procedure.
All patients were undergoing the 2013 or 2018 ALL IndonesianProtocol of Chemotherapy maintenance phase treatment using
intravenous Vincristine, intrathecal Methotrexate, and oral
Dexamethasone.

Methods
This cross-sectional study was conducted from August to
October 2019, using consecutive sampling. The Ethical Committee in Health Research Dr. Soetomo Hospital Surabaya approved this study with internal review board number
1363 / KEPK / VIII / 2019. In every patient, anamnesis and physical examination were carried out at Pediatric Hematology Oncology Outpatient Clinic. TNS-PV and NCS were performed at the
Medical Rehabilitation Outpatient Clinic. TNS-PV assessment
includes subjective symptom, temperature, vibration, muscle
tone, tendon reflex, and presence of autonomic and laryngeal
neuropathy. NCS was performed using the Cadwell Sierra Wave
EMG system (version 11.0.116). The examined risk factors were
gender, age, ALL classification, nutritional status, impaired
liver function, and cumulative vincristine dose ; these data were

The Journal of Medical Investigation Vol. 68 2021

The Journal of Medical Investigation Vol. 68 August 2021
obtained from medical records. Age was divided into ≤ 10 and >10 years old. ALL classification was based on prognostic factor,
categorised into standard and high risk (12). Nutritional status
were considered from the time children were diagnosed with
ALL, using the World Health Organization (WHO) and Centers
for Disease Control and Prevention (CDC) chart, categorised
into obesity and overweight, healthy weight, and moderate andsevere malnutrition (13). Liver function was considered from thetime children were diagnosed ALL, assessed using aspartatetransaminase (AST) and alanine transaminase (ALT). Statedas impaired liver function if AST and or ALT were above normal
ranges based on gender and age (14). Diagnosis of axonal, demyelinating, and axonal demyelinating neuropathy were based on
NCS result, by comparing patients’ distal latency, action potential amplitude, and nerve conduction velocity with their normal
range according to child’s age and nerve type (15). Axonal
neuropathy was established if NCS showed lower motor and sensory action potential amplitude. Demyelinating neuropathy wasestablished if NCS showed slower distal latency and / or slower
nerve conduction velocity. Axonal demyelinating neuropathy wasestablished if NCS showed slower distal latency, lower motor andsensory action potential amplitude, slower motor and sensory
nerve conduction velocity.

VIPN diagnosis
VIPN was diagnosed if the patients met all the following
criteria :1. Complaint of neuropathy (pain, paraesthesia, weakness,
constipation, urinary retention, orthostatic hypotension) ;2. TPN-VS score ≥ 4 ; and3. NCS assessed by a medical rehabilitation specialist to indicate peripheral neuropathy.

Statistical analysis
SPSS version 21.0 was used for statistical analysis. Multivariate logistic regression was applied to evaluate data comparison
between groups. Statistical significance was considered at amean difference with p < 0.05.

RESULTS
The study included 54 patients. Two patients were excluded
because they refused the NCS examination. The subject characteristics are shown in Table 1.
This study was used three parameters in assessing peripheral
neuropathy : neuropathy complaints, TNS-PV, and NCS ; Figure
1 presents the distribution for each parameter. Table 2 presents
NCS parameters value which consist of distal latency, amplitude, nerve conduction velocity on each nerve. A VIPN diagnosis
required all three criteria to be met. Based on single parameter,
26.9% had VIPN clinically (i.e. based on complaints), 76.9%
based on TNS-PV, and 100% by NCS. Overall, 25% of the participants had VIPN.
VIPN was more frequent in females (33.3% vs 19.4%) andage > 10 years old (41.7% vs 20%). There was no significant relation between VIPN and sex (p = 0.185) or age (p = 0.375).
VIPN was more frequent in the ALL high risk group (33.3%
vs 19.4%). Based on nutritional status, ALL children with ahealthy weight had the highest incidence of VIPN (31.8%),
followed by overweight and obesity (25%), then moderate andsevere malnutrition (19.2%). There was no significant relation
between VIPN and ALL classification (p = 0.739) or nutritional
status (p = 0.643).
There was no significant relationship between VIPN and cumulative vincristine dose (p = 0.581). VIPN was more frequent inTable 1.

233

Characteristic data

Characteristic
Gender, n (%)• Male31 (59.6)• Female21 (40.4)
Age groups, n (%)• < 10 years old
40 (76.9)• > 10 years old
12 (23.1)
Age (years), median (min-max)
7 (4 – 17)Race, n (%)• Javanese
44 (84.6)• Maduranese
8 (15.4)
Bone marrow aspiration result, n (%)• ALL-L1
49 (94.2)• ALL-L2
3 (5.8)ALL classification, n (%)• ALL standard risk
31 (59.6)• ALL high risk
21 (40.4)
Nutritional status, n (%)• Obesity and overweight
4 (7.7)• Healthy weight
22 (42.3)• Moderate and severe malnutrition
26 (50.0)
Concurrent medication, n (%)• Vincristine
52 (100.0)• Dexamethasone
52 (100.0)• Methotrexate
9 (17.3)
Laboratory, median (min-max)• Hemoglobin (mg / dl)
9.1 (1.3 – 14.5)• Leukocyte (cell / mm3)
6,953.5 (640 – 279,940)• Thrombocyte (cell / mm3)
33,520 (5,000 – 424,000)• AST (U / L)
34.5 (14 – 350)
• ALT (U / L)
29.5 (6 – 233)
Impaired liver function, n (%)• Yes
23 (44.2)• No
29 (55.8)
Peripheral neuropathy complain, n (%)• Yes
14 (26.9)• Pain4• Weakness
9• Paresthesia
1• No
38 (73.1)
Cumulative dose of Vincristin (mg / m2),
36 (13.5 – 52.0)
median (min-max)
Peripheral neuropathy based on NCS, mean %• Motoric vs sensory• Motoric100• Sensory
76.5• Upper vs lower extremities• Upper
88.6• Lower
91.7• Type• Axonal
9.6• Demyelinating
20.7• Axonal demyelinating
59.6
Peripheral neuropathy, n (%)• Complain
14 (26.9)• TNS-PV
40 (76.9)• NCS
52 (100.0)• NCS and complain
14 (26.9)• NCS and TNS-PV
40 (76.9)• NCS, TNS-PV, and complain
13 (25.0)
Vincristine Induced Peripheral Neuropathy, n (%)• Yes
13 (25.0)• No
39 (75.0)
ALL, acute lymphoblastic leukemia ; ALT, alanine transaminase ; AST,
aspartate transaminase ; NCS, nerve conduction studies ; SD, standard
deviation ; TNS-PV, total neuropathy score pediatric vincristineD. A. Tunjungsari, et al. VIPN in ALL Children

234

Figure 1. Frequency distribution of peripheral neuropathy based on NCS, TNS-PV, and complaint

Table 2. NCS characteristics of nerves
MedianMotoric

Sensory

Latency (ms)

Amplitude (mV)

NCV (m / s)Latency (ms)

Amplitude (µV)

Mean ( ± SD)

3.4 ( ± 0.8)

6.2 ( ± 2.3)

53.2 ( ± 7.3)

2.7 ( ± 0.7)

26.8 ( ± 14.5)

40.6 ( ± 7.4)

(Min – Max)

(1.9 – 7.5)

(1.5 – 12.7)(38.0 – 72.0)(1.7 – 6.3)

(2.3 – 61.3)(17.0 – 61.0)

Latency (ms)

Amplitude (mV)

NCV (m / s)Latency (ms)

Amplitude (µV)

NCV (m / s)

Mean ( ± SD)

3.0 ( ± 1.3)

4.7 ( ± 1.9)

58.9 ( ± 7.6)

2.5 ( ± 1.0)

21.0 ( ± 11.7)

38.7 ( ± 12.1)(Min – Max)

(1.3 – 7.8)

(1.3 – 8.4)

(40.0 – 75.0)(0.6 – 6.9)

(0.0 – 64.0)(0.0 – 74.0)

Ulnar

Motoric

Peroneal

NCV (m / s)SensoryMotoric
Latency (ms)

Amplitude (mV)

NCV (m / s)

Mean ( ± SD)

4.3 ( ± 1.6)

1.5 ( ± 1.1)

43.8 ( ± 13.6)(Min – Max)

(0.8 – 10.6)(0.0 – 4.6)

(0.0 – 80.0)

Latency (ms)

Amplitude (mV)

NCV (m / s)

Mean ( ± SD)

3.9 ( ± 1.2)

6.2 ( ± 3.6)

45.2 ( ± 6.9)

(Min – Max)

(0.5 – 8.1)

(0.1 – 14.7)(32.0 – 56.0)

TibialMotoric

Sural

Sensory
Latency (ms)

Amplitude (µV)

NCV (m / s)

Mean ( ± SD)

2.6 ( ± 0.5)

17.1 ( ± 9.0)

46.5 ( ± 12.3)(Min – Max)

(1.3 – 4.8)

(1.5 – 41.2)(29.0 – 92.0)

NCV, nerve conduction velocity

ALL children with impaired liver function (39.1% vs 13.8%) ; thisrelationship was significant (p = 0.046 ; prevalence ration (PR)2.837). Table 3 presents risk factors of VIPN in ALL children.

DISCUSSION
There is no consensus on the best method to diagnose VIPN
based on the child’s age (16). There are nine diagnostic methodsof peripheral neuropathy used in children. One instrument issubjective pain reports based on perceptions that are assessedusing facial expressions : the Wong–Baker FACES pain scale.
Five objective assessments of peripheral neuropathy use physicalexamination : neurological examination, NCS, current perception threshold (CPT), tactile perception threshold (TPT),and vibration perception threshold (VPT). Three methods use
subjective and objective assessment to evaluate the presence of
peripheral neuropathy : Common Terminology Criteria for Adverse Events (CTCAE v3.0 or 4.0), the paediatric-modified Total
Neuropathy Scale (ped-m TNS), and the TNS-PV (17).
In a study that involved 101 4–18-year-old ALL survivors,
clinical peripheral neuropathy was found in 26.7% of individuals ; 68.3% would be diagnosed based on NCS. However, VIPN
diagnosed based on both criteria was 15.8% (18). Another study
diagnosed VIPN in 78% of patients using TNS-PV and only
44% of those who complained of pain (1). Jain studied VIPN

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The Journal of Medical Investigation Vol. 68 August 2021
Table 3. Risk factors of VIPN in ALL children
Risk factors

VIPN

p valueYes (%)

No (%)• Male6 (19.4)

25 (80.6)• Female

7 (33.3)

14 (66.7)• Standard risk

6 (19.4)

25 (80.6)• High risk

7 (33.3)

14 (66.7)• Yes

9 (39.1)

14 (60.9)• No

4 (13.8)

25 (86.2)• < 10 years old

8 (20.0)32 (80.0)• > 10 years old

5 (41.7)

7 (58.3)

Gender0.185

ALL classification
0.739

Impaired liver function
0.046*

Age
0.375

Nutritional status• Obesity and overweight

1 (25.0)

3 (75.0)• Healthy weight

7 (31.8)

15 (68.2)• Moderate and severe malnutrition

5 (19.2)

21 (80.8)• Mean ( ± SD)

30.8 ( ± 9.9)

32.6 ( ± 12.2)(Min – Max)

(13.5 – 48)(13.5 – 52)

0.643

Cumulative dose of Vincristin (mg / m2)
0.581*Significant for Multivariate logistic regression. ALL, acute lymphoblastic leukemia ; SD, standard deviation

using three parameters : clinical, TNS-PV, and electrophysiology. Based on a single parameter, 13.8% had VIPN clinically,
33.8% by TNS-PV, and 33.8% by electrophysiology. Only 6.3%
had VIPN based on all three parameters (3). In Indonesia, a
study in ALL children showed 0.3% had VIPN clinically (19).
In this study, VIPN was diagnosed in 25% patients, based oncomplaints of neuropathy, TNS-PV, and NCS.
In agreement with previous studies, VIPN in this study was
more frequent in females (20, 21). Another study stated that
VIPN was more frequent in males (22). Seven studies showedno significant relationship between sex and VIPN (1, 11). Anghelescu studied 498 ALL children and divided their age into
four groups (1–5, 6–10, 11–15, and 16–20 years). The highest
incidence of VIPN was in the 16–20-year-old group (40%), andthe lowest was in the 1–5-year-old group (30.6%). This phenomenon may be due to age-related factors, but it was not statisticallysignificant (11).
In previous study, the VIPN incidence was significantly higher in the ALL high risk group (75.4% vs 24.6%, p = 0.019). The
authors hypothesised that the higher cumulative vincristine
dose in the ALL high risk group (48 vs 33.36 mg / m2) explained
this increased VIPN incidence (18).
Adequate and constant nutrition supports optimal peripheral
nerve function. ALL children often suffer from malnutrition andnutrient deficiency, while symptoms occur at the terminal stageof malnutrition. Nutrients that are thought to play an important role in optimal nerve function are vitamin E, vitamin B12,
thiamine, niacin, pyridoxine, copper, and folic acid (23, 24). Jain
(25) found that there was no significant difference in the level ofalpha tocopherol, vitamin B12, and folic acid serum (p ≥ 0.15) in
ALL children with or without neuropathy (n = 80) (25). Althoughvitamin B12 and other micronutrient deficiencies were associat-

ed with the incidence of neurotoxicity in the general population,
vitamin levels were not significantly different in patient with orwithout VIPN (26).
Liver transaminases are considered to be the most sensitive
tests for hepatocellular necrosis (hepatitis). ALT is a more specific marker than AST for liver injury because it is mostly foundin liver tissue, localised to the hepatocyte cytosol. Although ALT
isoenzymes are expressed in many tissues, elevated serum ALT
activity is considered the ‘gold standard’ clinical marker for liver
injury in humans. AST is more broadly distributed in other extrahepatic sites, including heart, skeletal muscle, kidney, brain,
and red blood cells (27). Hepatic infiltration usually occurs withsubsequent hepatomegaly and often in conjunction with splenic
involvement. ALL in paediatric patients presents with hepatomegaly and liver involvement in 68% of the cases and is one of
the most frequent presenting symptoms (28). Liver involvement
mostly appears to be mild and asymptomatic, but a post-mortem
study found liver infiltration in more than 95% of ALL patients(29). Liver involvement in ALL at diagnosis is due to direct
portal and sinusoidal infiltration by leukaemic cells, with anelevation in hepatic transaminases a consequence of the hepatocellular necrosis. Perhaps further injury is mediated by acetaminophen, which is often used to treat underlying fever that ispresent at the time of a leukaemia diagnosis (27). Vincristine is
distributed through passive diffusion into organs and metabolised in the liver ; it has efficacy against tumour cells and toxicity
against neurons (26). Vincristine is mainly excreted through bileand faeces ; only a small amount is excreted by the kidneys (30).
Cytochrome P450 3A (CYP3A), found in the liver, is a subfamily of important enzymes in drug metabolism. CYP3A-mediatedvincristine metabolism leads to neurotoxicity. Vincristine ismainly metabolised by CYP3A4 – the main metabolic enzyme

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D. A. Tunjungsari, et al. VIPN in ALL Childrenof the CYP3A family – and CYP3A5. Genetic polymorphism
of CYP3A5 expression affects individual clinical variabilities
related to vincristine efficacy. More than 70% of African Americans have at least one CYP3A5*1 allele that facilitates active
CYP3A5 expression. The CYP3A5*1 allele is only found in
10%–20% of Caucasians. In people with the CYP3A5*1 allele,
CYP3A5 represent more than 50% of CYP3A in liver microsomes (26). In another study, CYP3A5 was more frequently expressed in livers of African Americans (60%) compared with
Caucasians (33%) (31). Several studies in specific genotypes
related to race revealed that African Americans are more effective in vincristine metabolism, and hence they exhibit lower
vincristine toxicity (16). Vincristine toxicity increases along with
impaired liver function (32), which negatively affects vincristine
metabolism and excretion (33).
A previous study found a significant relationship between
the cumulative vincristine dose and VIPN. The authors divided
ALL children into two groups and gave them a different chemotherapy protocol. The first group used vincristine 2 mg / m2 / dose,
while the second group used vincristine 1.5 mg / m2 / dose. The
occurrence of VIPN in this study was thought to be due to higher
dose per time administration, so it was indirectly related to cumulative doses (20). The amplitude of peroneal nerve potential
action, ulnar, and median sensory decreased during vincristine
therapy, but there was neither a significant relationship to thevincristine cumulative dose nor an effect from vincristine therapy on the nerve conduction velocity (22).
There are a few limitations of this study. First, genetic factors
were neither checked nor included as a cofounding factor. Second, NCS was not performed before the chemotherapy began.
In conclusion, impaired liver function was a risk factor of VIPN
in ALL children, while sex, age, ALL classification, nutritional
status, and cumulative vincristine dose were not.

CONFLICTS OF INTEREST
The authors declare no potential conflicts of interest in thisstudy.

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