Keywords
nusinersen - spinal muscular atrophy - safety - effectiveness - creatinine
Introduction
Spinal muscular atrophy (SMA) is a genetic disease that occurs as a result of a mutation
in the survival motor neuron (SMN) gene and causes clinical findings such as motor
neuron degeneration, progressive muscle atrophy, and weakness by affecting the anterior
horn of the spinal cord. Its incidence is reported as 1 in every 10,000 live births,
and its prevalence as 1 in 100,000.[1] The pathogenesis of this disease, which is frequently an autosomal recessive disease,
is explained by rapidly progressive apoptosis involving the spinal cord anterior horn
cells and brain stem motor nuclei. With the mutation in the SMN1 gene, the expression
of SMN protein, which protects organisms against apoptosis, decreases. In addition,
SMN2, a paralogous gene, provides the production of 10% of the required SMN protein
by alternative splicing by removing exon 7. Therefore, the SMN2 copies are directly
related to the clinical condition of patients.[2]
Nusinersen is an antisense oligonucleotide (ASO) that acts by increasing the production
of the SMN protein by binding to mRNA on the SMN2 gene.[3]
[4] It is known that this drug, which is administered intrathecally with four loading
doses in the first 2 months, followed by maintenance doses every 4 months, significantly
contributes to the quality of life and motor functions of patients.[5] In addition to the efficacy of nusinersen, the reliability of the treatment is the
determining factor for the success of the treatment. Elevated liver transaminase enzyme
levels, renal failure, coagulation abnormalities, or thrombocytopenia are the adverse
effects reported with the use of ASOs.[6]
[7]
[8]
[9] Studies examining the effect of nusinersen on the laboratory results of patients
published in 2021 showed a positive safety profile of the treatment.[10]
[11] However, studies on this subject are limited to a small number of patients and have
short follow-up periods. Nusinersen was approved in our country for use in patients
with SMA type 1 in 2017, and patients with SMA type 2 and 3 in 2019. In this process,
we observed positive effects of nusinersen on the clinical course in SMA, causing
difficulties in phenotypic heterogeneity, prognosis, evaluation of disease activity,
and monitoring of treatment response. We examined the laboratory findings and motor
functions of our patients with SMA who received nusinersen in our study. Thus, by
evaluating the effects of nusinersen on patients' motor functions and laboratory parameters,
we aimed to evaluate its efficacy, safety, and whether there was a certain parameter
that it affected.
Methods
Electronic records obtained from the data analysis unit and files of patients with
SMA who were followed up in the Department of Pediatric Neurology of Dokuz Eylul University
Faculty of Medicine between September 2017 and June 2021 were retrospectively analyzed.
Age, sex, age of onset of clinical findings, age of genetic diagnosis, SMN2 copy number,
type of SMA disease, nusinersen treatment status, age of onset of nusinersen treatment
and the number of doses, and laboratory parameters obtained from patient files, and
system data were recorded.
Patients who received nusinersen were divided into two groups consisting of patients
with SMA type 1 (group 1) and SMA type 2 and 3 (group 2). Glucose, protein, potassium
(K), chloride (Cl), and sodium (Na) levels, and leukocyte (white blood cell [WBC])
and erythrocyte (red blood cell [RBC]) counts in cerebrospinal fluid (CSF) samples;
blood urea nitrogen (BUN), creatinine (Cr), aspartate aminotransferase (AST), alanine
aminotransferase (ALT) and gamma-glutamyltransferase (GGT) levels, hemoglobin (Hgb)
levels, WBC, neutrophil and lymphocyte counts, mean platelet volume (MPV), platelets
(PLT), prothrombin time (PT), international normalized ratio (INR), active partial
thromboplastin time in serum samples; and protein and Cr levels in spot urine samples
were examined before each nusinersen treatment in patients in these two groups. The
interdose status of the above-determined laboratory parameters of the patients in
groups 1 and 2 was compared with each other. In addition, to determine whether laboratory
parameters were affected by nusinersen, glucose, protein, K, Cl, Na, BUN, Cr, Hgb,
WBC, neutrophil, lymphocyte, MPV, PLT in serum, and protein and Cr levels in spot
urine were compared between doses. Motor scale tests were performed on patients by
a physical therapy and rehabilitation specialist before each dose of nusinersen. The
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)
tests were performed for type 1 SMA and Hammersmith Functional Motor Scale-Expand
(HFMS-E) for type 2 and 3 SMA. In addition, the effect of treatment onset time (age)
on the motor scale test scores was investigated.
Based on the treatment national protocol used in our country's Ministry of Health,
four loading doses on day 0 and the 14th, 28th, and 56th days in patients with SMA
type 1, and day 0 and the 28th, 84th, and 273rd days in patients with SMA type 2 and
3 were administered. Following the four loading doses of nusinersen, maintenance doses
were administered every 4 months. Intrathecal injection of 12-mg nusinersen was performed
in each dose. Patients who might have problems during the intrathecal injection procedure
due to the presence of scoliosis were treated by interventional radiology through
fluoroscopic lumbar puncture (LP). CSF and serum samples were collected before each
nusinersen injection and the relevant parameters were studied in the medical biochemistry
and medical microbiology laboratories of Dokuz Eylul University Faculty of Medicine.
Blood samples were collected 5 days[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] before each dose, and CSF samples were taken just before drug administration during
LP for injection. The relevant predose laboratory parameter of all patients was enumerated
with that dose (such as Cr level before the first dose; Cr1).
To determine changes in the laboratory values of patients with SMA under treatment,
the mean level of change from baseline for each parameter was examined. To assess
long-term changes, the most recently measured value available was compared with the
corresponding baseline value in each patient and the value at each dose with each
other. In addition, it was evaluated whether the parameter of each treatment dose
deviated from the lower or upper limit of normal. The necessary permission for the
research was obtained from the Ethics Committee of Dokuz Eylül University Faculty
of Medicine (Date: January 18, 2021, Decision number: 2021/02-02).
Statistical Analysis
The data obtained in the study were entered into a database created in the SPSS 22.0
program, and statistical analyses were performed using the same program. Mean, standard
deviation, median, minimum, and maximum values of continuous variables were calculated.
The conformity of these variables to normal distribution was investigated. Considering
the sample diameters, it was decided that normal distribution fitness conditions could
not be met in all variables, so nonparametric methods were used. Comparisons of repeated
measurements were made using the Friedman test and Wilcoxon test, and comparisons
of independent subgroups were made using Kruskal–Wallis and Mann–Whitney test methods.
p-Values were calculated using Bonferroni correction, adjusted p (adj p). The relationship between independent variables was examined using the nonparametric
correlation Shearman's rho method. In all statistical comparison tests, the margin
of error for type 1 was determined as α = 0.05 and was tested bidirectionally. If
the p-value was less than 0.05, the difference between the groups was considered statistically
significant.
Results
Patient and Treatment Characteristics
Twenty-seven patients with SMA followed in our clinic were included in the study.
In total, 13 (48.1%) patients had SMA type 1 and 14 (51.8%) had SMA type 2 and 3.
In total, 13 (48.1%) of the patients were female and 14 (51.9%) were male. The mean
age (± standard deviation) at the onset of symptoms was 3 ± 1.21 (range, 1.5–6) months
in group 1 and 12 ± 4.27 (range, 8–24) months in group 2. The mean age at the onset
of treatment was found as 9.5 ± 34.55 (range, 4–133) months in group 1 and 72 ± 56.14
(range, 30–218) months (p < 0.001) in group 2. Of the patients receiving nusinersen treatment, 48.1% (n = 13) had SMA type 1, 44.4% (n = 12) had SMA type 2, and 7.4% (n = 2) had SMA type 3. A total of 164 (3–13 doses) intrathecal nusinersen injections
were performed between September 2017 and June 2021. A total of three doses for two
patients with SMA type 1 and a total of 23 doses for five patients with SMA type 2
were administered with fluoroscopy ([Table 1]).
Table 1
Demographic and treatment characteristics of the patients
|
Patients
|
Group 1 (SMA type 1)
|
Group 2 (SMA type 2 and 3)
|
p-Value
|
|
Number of patients (n)
|
13
|
14
|
|
Sex
|
7F/6M
|
6F/8M
|
|
Age (months)
|
9.5 ± 34.55 (range, 6–133)
|
72 ± 56.14S (range, 30–218)
|
p
< 0.05
|
|
Age of onset of symptoms (median) (months)
|
3 ± 1.21 (range, 1.5–6)
|
12 ± 4.27 (range, 8–24)
|
p
< 0.05
|
|
Age of treatment onset (months)
|
5 ± 34.55 (range, 4–133)
|
72 ± 56.14 (range, 30–218)
|
p
< 0.05
|
|
Total number of treatment doses
|
79 (range, 3–13)
|
85 (range, 4–8)
|
|
Treatment duration
|
September 2017–June 2021
|
March 2019–May 2021
|
|
Treatment type
|
Conventional (without fluoroscopy)
|
76 (96.2%)
|
62 (72.9%)
|
p
< 0.05
|
|
Fluoroscopy
|
3 (n = 2) 37.8%
|
23 (n = 5 SMA type 2) 27%
|
p
< 0.05
|
|
Posttreatment adverse event
|
Restlessness (n = 42)
|
Back pain (n = 50)
|
|
Death (n)
|
3
|
0
|
Abbreviation: SMA, spinal muscular atrophy.
Note: The statistically significant values are in bold (p < 0.05)
When the intrathecal treatment methods of the patients in groups 1 and 2 were compared,
the rate of performing fluoroscopic procedures in the patients in group 2 was found
to be significantly higher ([Fig. 1]) (p < 0.05).
Fig. 1 Median values of CHOP-INTEND and HMSFE scores of the patients at relevant doses.
The patients were followed up for an average of 8 (range, 6–24) hours after treatment.
The most common adverse event in the posttreatment follow-up was restlessness in group
1 (n = 42; 26%) and low back pain (n = 50; 58%) in group 2. The demographic characteristics of our patients are shown
in [Table 1], the treatment characteristics are given in [Table 1], and the median values of CHOP-INTEND and HMSF-E scores for each dose are given
in [Fig. 1]. It was observed that CHOP-INTEND and HMSF-E scores increased significantly as our
patients received treatment (p < 0.05). A boxplot graph showing the distribution of the minimum and maximum quartiles
of the median values of the CHOP-INTEND and HMSF-E scores at the relevant dose is
presented in [Fig. 2].
Fig. 2 Boxpilot chart giving the distribution of median values of CHOP-Intend and HMSFE
scores of the patients at each dose.
We also evaluated the effect of the treatment onset time (age) on the increase in
the motor scala scores of our patients. In group 1, a statistically significant negative
correlation was observed between the age of treatment onset and the increase of CHOP-INTEND,
after the first four loading doses. Similarly, we found a statistically significant
negative correlation between the increase in HMSF-E at all nusinersen doses and the
age at onset of treatment in group 2 ([Table 2]). In conclusion, the earlier the treatment was initiated, the greater was the increase
in HMSF-E and CHOP-Intend scores. The change in maximum points on motor scales between
the prefirst and preseventh doses is given in [Fig. 3].
Table 2
The effect of age at first application on increase of motor scale scores
|
Spearman's rho
|
CHOP-INTEND /HMSFE 2–1
|
CHOP-INTEND /HMSFE 3–1
|
CHOP-INTEND /HMSFE 4–1
|
CHOP-INTEND /HMSFE 5–1
|
CHOP-INTEND /HMSFE 6–1
|
CHOP-INTEND/HMSFE 7–1
|
|
.
|
Group 1
|
Correlation coefficient[a]
|
0.152
|
0.003
|
0.001
|
−0.693
|
−0.663
|
−0.817
|
|
Sig. (two tailed)[b]
|
0.620
|
0.993
|
0.996
|
0.018
|
0.073
|
0.025
|
|
Patient number (n)
|
13
|
13
|
13
|
11
|
8
|
7
|
|
Group 2
|
Correlation coefficient
|
−0.400
|
−0.656
|
−0.664
|
−0.740
|
−0.747
|
−0.739
|
|
Sig. (two tailed)
|
0.156
|
0.011
|
0.010
|
0.006
|
0.008
|
0.009
|
|
Patient number (n)
|
14
|
14
|
14
|
12
|
11
|
11
|
Abbreviations: CHOP-INTEND, the Children's Hospital of Philadelphia Infant Test of
Neuromuscular Disorders; HMSF-E, Hammersmith Functional Motor Scale-Expand.
a Correlation is significant at the 0.01 level (two tailed).
b Correlation is significant at the 0.05 level (two tailed).
Fig. 3 Change in maximum points on motor scales (between pre-1st and pre-7th doses). Lines
represent regression lines and suggest that early initiation of treatment corresponds
to a better outcome (statistically significant both of two groups).
The Comparison of Findings of Patients with Spinal Muscular Atrophy Receiving Nusinersen
Treatment According to Clinic Type and Treatment Doses
Cerebrospinal Fluid Examination
It was observed that there was no significant difference between the glucose, Na,
K, Cl, WBC, and RBC levels in the CSF of both groups in comparisons between doses.
It was observed that only the CSF protein levels of group 1 were significantly higher
than those of group 2 before the first three doses and that the elevation continued
in the following doses but not at a significant level ([Table 3]).
Table 3
Statistical evaluation of the laboratory parameters of group 1 and 2
|
Dosage 1
|
Dosage 2
|
Dosage 3
|
Dosage 4
|
Dosage 5
|
Dosage 6
|
|
Mean ± SD Gr1
|
Mean ± SD Gr2
|
p-Value
|
Mean ± SD Gr1
|
Mean ± SD Gr2
|
p-Value
|
Mean ± SD Gr1
|
Mean ± SD Gr2
|
p-Value
|
Mean ± SD Gr1
|
Mean ± SD Gr2
|
p-Value
|
Mean ± SD Gr1
|
Mean ± SD Gr2
|
p-Value
|
Mean ± SD Gr1
|
Mean ± SD Gr2
|
p-Value
|
|
Protein (CSF) mg/dL
|
29.05 ± 12.44 (22–51)
|
21.80 ± 8.08 (15.90–46.70)
|
0.004
|
33.50 ± 46.62
(19–142)
|
22.40 ± 8.21 (15.70–46.10)
|
0.013
|
42.85 ± 57.43 (19–170)
|
22.10 ± 11.00 (14.20–48.30)
|
0.006
|
33.40 18.03 (10.00–57.00)
|
20.00 55.70 (11.70–198.90)
|
0.284
|
32.75 ± 14.68 (17.90–54.00)
|
23.80 ± 22.55 (16.10- 87.00)
|
0.248
|
25.45 ± 7.97 (14.90- 36.50)
|
23.00 ± 6.97 (14.50- 38.70)
|
0.964
|
|
Hgb
(serum) g/dL
|
11,70 ± 1.3 (9.9–13.1)
|
12.3 ± 0.89 (11.3–14.00)
|
0.049
|
11.6 ± 1.29 (10.3–13.80)
|
0.89 ± (11.1–14.00)
|
0.044
|
11.80 ± 1.23 (9.70–13.20)
|
12.20 ± 1.09 (10.70–14.20)
|
0.410
|
11.6 ± 5 (0.99–10.80)
|
12.60 ± 1 (11.00–14.00)
|
0.226
|
11.4 ± 0.56 (11.10- 12.70)
|
13.00 ± 0.91 (11.30–14.60)
|
0.008
|
11.40 ± 1.31 (9.10–12.90)
|
13.30 ± 0.94 (12.00–15.10)
|
0.011
|
|
Cr (serum) mg/dL
|
1.25 ± 0.035 (0.080–0.170)
|
0.170 ± 0.067 (0.080–0.3)
|
0.011
|
0.115 ± 0.04 (0.060–0.17)
|
0.130 ± 0.048 (0.080–0.240)
|
0.125
|
0.105 ± SD (0.032–0.080)
|
0.130 ± 0.034 (0.080–0.190)
|
0.084
|
0.11 ± 0.021 (0.100–0.160)
|
0.120 ± 0.053 (0.070–0.250)
|
0.322
|
0.100 ± 0.018 (0.080–0.130)
|
0.130 ± 0.045 (0.070–0.230)
|
0.034
|
0.110 ± SD (0.041–0.060)
|
0.120 ± 0.051 (0.051–0.070)
|
0.820
|
|
BUN (serum) mg/dL
|
8.45 ± 4.66
(6.70–19.00)
|
11.10 ± 3.11 (8.00–17.30)
|
0.004
|
7.80 ± 4.45 (5.80–16.00)
|
11.20 ± 4.05 (7.60–20.60)
|
0.006
|
8.65 ± 1.84 (6.20–11.40)
|
8.90 ± 2.69 (6.00–14.00)
|
0.006
|
9.95 ± 4.32 (8.00–19.40)
|
10.20 ± 4.09 (6.20–18.00)
|
0.150
|
12.00 ± 4.31 (6.40–19.20)
|
10.90 ± 2.79 (4.90–13.50)
|
0.220
|
12.05 ± 4.01 (6.70–18.00)
|
10.20 ± 2.69 (7.30–15.70)
|
0.342
|
|
WBC (serum) 103/µL
|
9.10 ± 1.57 (7.90–11.90)
|
8.40 ± 2.26 (6.70–14.30)
|
0.438
|
10.85 ± 1.92 (8.40–14.00)
|
7.60 ± 1.69 (5.00–10.50)
|
0.009
|
9.50 ± 1.86 (7.60–12.10)
|
6.90 ± 1.53 (4.50–10.60)
|
0.006
|
9.50 ± 1.86 (7.60–12.10)
|
6.90 ± 1.53 (4.50–10.60)
|
0.015
|
11.95 ± 2.22 (10.70–16.80)
|
7.50 ± 1.39 (5.40–9.30)
|
0.003
|
13.70 ± 4.58 (10.80–22.60)
|
7.50 ± 8.68 (6.20–36.30)
|
0.013
|
|
Lymphocyte (serum) 103/µL
|
6.30 ± 1.27 (4.60–8.20)
|
3.70 ± 0.95 (1.00–4.40)
|
0.002
|
6.90 ± 1.02 (5.20–8.10)
|
3.20 ± 0.68 (2.20–4.20)
|
0.002
|
6.55 ± 1.91 (3.90–9.00)
|
3.30 ± 0.81 (1.20–4.20)
|
0.027
|
6.80 ± 1.48 (5.60–9.30)
|
3.50 ± 0.90 (2.50–5.20)
|
0.057
|
6.45 ± 1.32 (5.80–9.20)
|
3.50 ± 0.68 (2.50–4.90)
|
<0.001
|
5.90 ± 1.69 (4.10–8.30)
|
3.60 ± 0.57 (2.70–4.70)
|
0.001
|
Abbreviations: BUN, blood urea nitrogen; Cr, creatinine; CSF, cerebrospinal fluid;
Gr, group; HGB, hemoglobin; LENF, lymphocyte; NEU, neutrophil; SD, standard deviation;
WBC, leukocyte.
Serum Examination
There was no statistically significant difference between the doses in terms of the
AST, ALT, GGT, lymphocyte, neutrophil, PLT, PT, MPV, PTT, and INR values of groups
1 and 2. Significant differences were found between doses in terms of blood Cr, BUN,
HGB, WBC, and lymphocyte values. These differences are detailed in [Table 3]. Cr1 was higher in group 1 and Cr5 was higher in group 2 (p < 0.05) ([Table 3]). BUN was higher in group 2 in the first four doses and in group 1 in the fifth
and sixth doses (BUN1-2-3; p < 0.05) (BUN4; p > 0.05) (BUN5-6; p < 0.05) ([Table 3]). Serum WBC counts of group 1 before the second, third, fourth, fifth, and sixth
doses and lymphocyte counts of group 1 before the first, second, third, fifth, and
sixth doses were higher than those of group 2 (p < 0.05) ([Table 3]). MPV6 was higher in group 1 (p > 0.05) ([Table 3]).
Urine Examination
There was no statistically significant difference in terms of spot urine protein and
Cr levels.
Comparison of Laboratory Parameters of Patients Between Doses of Nusinersen Treatment
Cerebrospinal Fluid Parameters
There was no significant change in terms of the levels of glucose, protein, K, Cl,
and Na in the cerebrospinal fluid between doses.
Serum Parameters
When the BUN, Cr, Hgb, WBC, neutrophil, lymphocyte, MPV, and PLT values of both groups
were compared between doses, there were significant differences between MPV and Hgb
values in group 2. When the MPV values of both groups were examined, it was observed
that there was a slight increase in MPV values after the first dose of treatment,
a decrease in the continued doses, and then an increase again toward the sixth dose.
In the first group, MPV2 was significantly higher than MPV5 (adj p < 0.05). In group 2, MPV5 was significantly higher than MPV3 and MPV4 (adj p < 0.05); MPV6 was significantly higher than MPV4 (adj p < 0.05). In addition, NEU6 was found to be significantly higher in group 1 than in
the other five doses (adj p < 0.05). When the Hgb levels of group 2 were evaluated between doses, it was seen
that Hgb6 was significantly higher than Hgb1-2-3 (adj p < 0.05).
Urine Examination
There was no significant difference between doses in terms of Cr, protein, and protein/Cr
levels in spot urine.
Discussion
Due to concerns about the safety of nusinersen, a new and promising treatment for
SMA, its effects on laboratory parameters, and its adverse effects are topics of interest
to patients and physicians. As nusinersen applications continue, new results have
started to be reported about this drug. For the follow-up of patients, it is important
to determine whether there is a specific parameter that nusinersen affects. Defects
in liver function tests (transaminases) and coagulation parameters, renal failure,
and thrombocytopenia are reported adverse effects of ASOs.[7]
[12]
[13]
[14] In our study, these adverse effects related to ASOs were not observed.
When we compared the findings of our patients with SMA who received treatment, the
CSF protein levels and the frequency of conventional LP were higher in group 1. Studies
reported that total protein levels in CSF tended to increase with age, were highest
in the neonatal period in childhood, and then decreased with age.[15]
[16]
[17] In a comprehensive study conducted to determine the variability of CSF total protein
levels in childhood according to age, it was stated that the total protein level,
which was highly variable between 0 and 6 months, was at its lowest values between
2 and 6 years of age and gradually increased from 6 years to 18 years of age. The
authors stated that factors such as blood–brain barrier permeability, myelination,
CSF flow rate, and the clearance rate of proteins in CSF might affect this result.[17] Wurster et al found no relationship between age (between 11 and 60 years) and CSF
protein levels in their study in which they examined the CSF findings of patients
with SMA receiving nusinersen treatment, and they added that they found no parameters
affecting CSF protein levels.[18] By contrast, Müschen et al reported that intrathecal (such as conventional, fluoroscopy,
or CT-guided) nusinersen in patients with SMA was effective on CSF protein levels.[19] This study was conducted on adult patients with SMA types 2 to 4, and higher CSF
protein levels were found to be associated with SMA type 3, male sex, conventional
LP, and SMN2 copy numbers ≥3. They attributed this result to the older age of the
patients with type 3 SMA, with SMN2 copy numbers ≥3, and in whom conventional LP was
performed. They also added that the CSF protein levels of most of their patients were
within the reference range specified in the literature according to age (upper limit
500 mg/L for patients aged 18 to 30 years and 600 mg/L for patients aged ≥30 years).
However, it has been reported that CSF total protein levels in childhood are highly
variable under 2 years of age, especially 0 to 6 months, and gradually increase thereafter.
Although the patients in the group with high CSF protein levels in our cohort were
diagnosed as having infantile SMA type 1 and most were aged under 2 years (median
9.5 months), which might have caused high CSF protein levels in this group, we thought
that the main reason was due to conventional LP, as Müschen et al stated that because
conventional LP is open to trauma, it is often performed without anesthesia in wards
and it may cause increased CSF protein levels. This result suggests that the LP method
has a direct effect on CSF protein levels. Therefore, fluoroscopy should be preferred
in patients to prevent traumatic LP if necessary. In addition, Müschen et al stated
that there was a significant increase in CSF protein levels during regular intrathecally
administered nusinersen, and this could be due to nusinersen or repeated LP procedures,
and that intrathecal treatment could increase CSF protein levels.[19] However, in our patients, there was no significant change in CSF protein levels
between doses. Our result suggested that nusinersen or repeated LP applications had
no direct effect on CSF protein levels.
Abnormal liver function tests are a known adverse event with the use of ASOs.[9]
[10] However, regarding nusinersen, it was shown in the NURTURE study that transaminase
levels were stable in presymptomatic children.[20] In the ENDEAR and CHERISH studies on the safety of nusinersen, there were deviations
from normal in the levels of liver transaminases, but it was not found to be statistically
significant when compared with control groups.[21]
[22] In addition, no significant deterioration was observed in liver function tests in
pediatric and adult patient studies published in 2021.[10]
[11] In our study, the liver enzyme levels of our patients were within the normal range.
This result suggested that nusinersen, an ASO, was safe in terms of hepatotoxicity,
unlike other ASOs.
When we examined the renal function tests of our patients, there was no significant
change in the serum Cr levels of patients in both groups receiving nusinersen treatment
between doses. When the Cr levels of the two groups receiving treatment were compared
with each other, it was seen that Cr levels were higher in group 1 before the first
dose and group 2 before the fifth dose. Cr levels decreased in our patients with SMA
type 1 who received treatment and it tended to remain constant or increase in patients
with SMA type 2 to 3 in the follow-up. It is known that serum Cr levels are associated
with skeletal muscle mass, SMA disease type, SMN2 copy number, motor function, and
the severity of denervation.[23] Alves et al emphasized that the natural course of serum Cr levels tended to decrease
in patients with SMA and that Cr levels were lower as the severity of SMA disease
increased and the SMN2 copy number decreased in patients with SMA who did not receive
nusinersen.[24] In addition, in a very recent study, the effect of nusinersen on serum Cr levels
in patients with SMA type 3 aged over 18 years was examined, and it was reported that
there was an increase in serum Cr levels with treatment.[25] Our result was similar to this study for patients in group 2, but the same result
was not obtained in patients with SMA type 1. Decreased serum Cr levels in patients
with SMA type 1 treated with nusinersen and increased serum Cr levels in patients
with SMA type 2 and 3 treated with nusinersen were observed in our cohort.
We explain this positive effect of nusinersen on the Cr levels of our patients with
SMA type 2 and 3 through the direct effect of nusinersen on maximum motor capacities.
In patients with SMA type 1, the effect of nusinersen on Cr levels may not have been
reflected in the laboratory due to the faster course of muscle breakdown. We thought
that there was a decrease in Cr levels in this patient group due to the decrease in
muscle mass secondary to rapid destruction. Given that the loss of muscle mass is
less in SMA types 2 and 3, nusinersen may increase it by affecting Cr levels.
More comprehensive pediatric studies are needed, especially in patients with SMA type
1, regarding the relationship between nusinersen and Cr levels. In addition, it was
observed that other renal function tests remained in the normal range throughout the
treatment period except for one patient with transient proteinuria. In the literature,
no significant difference was found between the patients treated with nusinersen and
the control group in terms of the rate of proteinuria.[21]
[26] In another study, transient proteinuria was reported as the most common laboratory
abnormality.[11] Our results were supportive of the renal safety of nusinersen in this respect.
Among the hematologic parameters, the most intriguing parameter regarding nusinersen
is PLT levels. Thrombocytopenia is one of the main reported adverse events of ASOs,
which reduces LP safety because it increases the risk of hemorrhagic complications.[6]
[7]
[8]
[9]
[27] Accordingly, thrombocytopenia that may develop due to nusinersen is also important
because it will put other doses at risk. In the ENDEAR and CHERISH studies on PLT
counts under nusinersen treatment, no patient had persistent thrombocytopenia or bleeding
and median PLT counts remained stable during treatment.[21]
[22] In the NURTURE study on nusinersen treatment in presymptomatic patients, it was
shown that PLT counts remained stable.[20] Goedeker et al reported that no patients had a thrombocyte count of <100/nL in their
study published in 2021.[11] In another study, mild and transient thrombocytopenia was reported in a single child
treated with nusinersen.[28] These results showed that nusinersen did not cause persistent thrombocytopenia or
thrombocytopenia that required transfusion. Our results were similar to these studies
because we did not see thrombocytopenia in any patients.
When the blood Hgb levels of both groups receiving treatment were examined, the Hgb
levels in the first three doses of group 1 were significantly lower than those of
group 2. There was no difference in Hgb levels in the other three doses (fourth, fifth,
and sixth) between groups 1 and 2. This situation might be iatrogenic, especially
in patients with SMA type 1, due to frequent blood collection due to the shorter intervals
between the first doses. In addition, when the Hgb levels of group 2 were compared
between doses, the Hgb values of the first three doses were significantly lower than
those with the sixth dose. This result suggests that Hgb levels increase as the doses
increase.
These results might also be because our patients with type 1 SMA were in the period
of infant physiologic anemia. However, as the drug doses of patients with type 2 and
3 SMA are increased, the increase in Hgb values supports the possibility of iatrogenicity.
With these results, reducing the frequency of blood collection will reduce the psychosocial
and medication burden on patients and their families and secondary treatment and examination
costs. In addition, anemia may be associated with SMA disease and nusinersen. In an
animal study, Szunyogova et al showed that the SMN protein was required for normal
erythropoiesis.[29] It is known that SMN protein levels increase with treatment in patients with SMA.[3]
[4] We speculate that this result in Hgb levels in our study is due to the effect of
SMN protein on erythropoiesis.
In other hemogram findings of our patients, serum WBC and lymphocyte counts of group
1 were higher than in group 2. We attributed this result to the fact that the patients
in group 1 were younger than in group 2 because it is known that the normal values
of WBC and lymphocyte counts in childhood vary with age and tend to decrease with
increased age.[30]
Coagulopathy, another reported adverse event of ASOs, was not observed in our study.
In the NURTURE study and recently published studies, it was reported that nusinersen
caused no significant abnormalities in coagulation parameters.[10]
[11]
[20] Our findings showed that nusinersen had no negative effect on coagulation parameters.
Our results showed that the CHOP-INTEND and HMSF-E scores of patients with SMA improved
during follow-up with nusinersen treatment. In studies conducted to determine the
natural history of CHOP-INTEND and HMSF-E scores in patients with SMA who did not
receive treatment, a decrease in scores was observed in the follow-up,[31]
[32] which suggests that nusinersen significantly contributes to the quality of life
of patients with its effect on motor functions. In addition, when we evaluated the
effect of the age of treatment onset on the increase in motor scores of our patients.
We found that the earlier the treatment was started, the more positive were the motor
scale results. We observed that this effect appeared especially after the first four
loading doses in patients with SMA type 1. Similar results have been obtained in recent
studies.[33] This result once again demonstrated the importance of early diagnosis and treatment
of SMA patients. However, another important point is that these patients will reach
their maximum CHOP-INTEND and HMSF-E scores as they receive treatment. We think that
these scoring methods will not objectively reflect the clinical conditions of patients
after a certain upper level. Therefore, it is necessary to develop new markers for
the typing, prognosis, and treatment response of patients with SMA who have significant
changes in their clinical presentation with new treatments.
Conclusion
We detected no persistent or significant laboratory abnormalities related to treatment
in our unit, where we have been administering nusinersen for nearly 4 years. The laboratory
abnormalities of our patients who received treatment were mostly mild and caused no
significant change in our treatment plan. Our findings suggest that nusinersen, unlike
other ASOs, does not affect the liver, renal function tests, and coagulation parameters,
suggesting that it is safe. We think that the need for frequent laboratory monitoring
in patients receiving nusinersen should be reevaluated considering the development
of anemia.
It was observed that there was a significant increase in CHOP-INTEND and HMSF-E scores
as the patients received treatment. This situation supports the positive effect of
nusinersen on motor milestones, and we think that these scores will be insufficient
for follow-up in patients who will reach maximum scores with further doses.
Limitations
The most important limitation of our study is the sample size. Therefore, studies
with larger samples are needed to better evaluate the efficacy and safety of nusinersen.
