Discussion
A global CSVT rate of 2.9% was reported in a meta-analysis of 17
prospective studies that included 1752 pediatric patients with childhood
ALL [7]. Two recent studies have reported incidences of 1.4% and
1.9% from the United Kingdom and the Nordic Society of Pediatric
Hematology and Oncology (NOPHO) [2, 8]. However, we report an
incidence of 10.5% for CSVT during treatment of our ALL patients which
is much higher than that of the literature. This may be related to the
treatment protocol that we use, in addition to our patients’
characteristics [9]. Carouso et al. found that a combination of ASP
and steroids in the presence of other prothrombotic factors like
inherited thrombophilia were significantly associated with thrombosis
(OR: 34.5; 95% CI: 4.39–271.42; P = 0.0008) [7]. These
studies have reported the incidence of thrombosis during ALL treatment
to be highest during the induction phase, whereas in our studies, most
CSVT events occurred during early continuation and reinductions I and
II. This might be explained by the lower prednisone dose that we use
during the induction phase compared to the BFM protocols reported by
Nowak-Gottl et al. [10] (40 mg/m2/day vs. 60 mg/m2/day). However, we
use higher doses of dexamethasone during early continuation and
reinduction (12 mg/m2/day vs. 10 mg/m2/day). Moreover, the duration of
the combined treatment (steroids + ASP) given was longer in the
post-induction phase compared to the induction phase.
In Lebanon the carrier rate of factor V Leiden is 14.4% compared to
3–8% in Europe and the United States [11]. Similarly, the carrier
rate of Prothrombin G20210A in Lebanon is 3% similar to that in Europe
but higher than what is reported in the United States [9]. There is
no solid evidence for screening all ALL children during treatment for
heritable thrombophilia [12, 13]. Since such screening is of a high
financial burden in a middle-income country like Lebanon, we screened
only patients who developed CSVT. The lack of thrombophilia status in
patients who did not develop CSVT prevented us from investigating
thrombophilia as a risk factor and integrating it into our analysis.
Nonetheless, due to the higher incidence of CSVT in our study combined
with the high thrombophilia rate in our country, we suggest revisiting
the role of thrombophilia screening in regions with high prevalence of
thrombophilia, using well-designed studies, especially if their
treatment protocol relies on intensive combined ASP and steroids therapy
[4].
The strong association between CSVT during childhood ALL treatment and
older age at diagnosis, T-cell immunophenotype, and an
intermediate/higher risk disease that is observed in our univariate
analysis has been well described previously [2, 10]. In our study, T
cell phenotype was only significant in the univariate analysis, whereas
intermediate/high risk disease and mediastinal mass retained
significance in multivariate analysis.
Studies have linked asparaginase and corticosteroids treatment to the
increased TG level in ALL patients [14, 15]. Hypertriglyceridemia
induced by asparaginase was recently reported to be significantly
associated with increased thrombosis in childhood ALL [16]. We
describe a maximum TG level of more than 615mg/dL (3x the upper normal
limit) to be a statistically significant risk factor for the development
of CSVT during treatment for childhood ALL. Our study was the first to
report a TG level of more than 615 mg/dL to be a significant cutoff for
the development of CSVT. Further studies with larger sample sizes are
recommended to confirm this cutoff.
Our study was the first to describe a significant association between
BSA and CSVT. BMI is a measure used to determine a person’s degree of
overweight. BSA measures the total surface area of the body and
is used to calculate drug dosages and medical indicators or assessments.
When height value is fixed, a strong correlation exists between BSA and
BMI as only weight values vary. However, when the two parameters change,
no correlation exists between BSA and BMI [17] which explains why
BSA and not BMI was significant in our study. Larger BSA requires higher
doses of therapeutic drugs and hence possibility of more frequent side
effects. Similar findings were observed in a previous study where
moderate dose methotrexate caused toxicity in patients with larger body
size upon treating non-Hodgkin’s lymphoma [18]. Further studies on
larger patient samples are recommended to find an appropriate cutoff for
BSA. This may help in considering prophylactic anticoagulation and/or
capping of chemotherapy doses.
A previous study described the link between the presence of mediastinal
mass in Nordic children with ALL and overall thrombotic events in
general but not CSVT specifically [10]. To the best of our knowledge
we are the first to describe the presence of mediastinal mass as a
significant risk factor for the development of CSVT in children treated
for ALL.
Initial blast count and BMI were not significant as risk factors for
CSVT in our study. These results are supported by the Nordic study while
exploring their relation to any thrombotic event [10].
Non-O blood group has been reported to be an important genetic risk
factor for venous thromboembolism [19]. In our previous report, we
reported lack of significance of non-O blood group for the development
of CSVT in our patient population [4]. This factor was
reinvestigated in our population and found to be not significant.
Given the significant delay that CSVT has on treatment, and the higher
chances of disease relapse from early discontinuation of ASP as reported
from Dana–Farber Institution [3], we believe that this issue is of
significant importance and needs further investigation and future
guideline modifications in areas where thrombotic/CSVT incidence is
high. The incidence of CSVT is protocol specific such as use of
prednisone or dexamethasone and their respective doses, the intensity
and duration of ASP therapy and concomitant (Asparaginase plus steroid)
therapy, as well as ethnic specificities. In a patient population
similar to ours that is being treated with a protocol similar to St.
Jude Total XV, we encourage considering the use of prophylactic
anticoagulation in the presence of the risk factors that we highlighted.
Studies with larger sample sizes are needed to confirm our
recommendation. Furthermore, we recommend additional studies in
different patient populations to tailor recommendations based on the
population characteristics.