Discussion
In this study, the safety and efficacy of low dose thalidomide in
transfusion-dependent thalassemia children is presented by the
retrospective analysis. The most important result of this study is that,
the dose of thalidomide between 2.5 mg·kg-1·d-1 to 3.6 mg·kg-1·d-1 is
effective in children with TDT. This is the first available protocol for
thalidomide treatment for children with TDT in a large scale. The HbF
concentration of 47.298 g·L-1 at the third month of treatment may be the
predictor for further treatment response.
The effective dose of thalidomide in β-thalassemia children was not
reported in previous studies. In this study, we found that, with the
start dose of 2.5 mg·kg-1·d-1, the major response rate and the minor
response rate at the third month could be as high as 67.5% (52/77).
When the mean dose of thalidomide was increased to 3.6mg·kg-1·d-1 at the
third month to the sixth month, the major response rate and the minor
response rate could elevated to 80.5% (62/77) at the sixth month.
However, when the proportion for improvement in response with higher
dose (32/45) was compared with the proportion for no response
improvement with higher dose (20/32), the different was not significant.
For this result, the reason for increased response rate cannotbe
attributed simply to the increased dose.
In previous study, cases were reported that patient with TDT responding
to thalidomide effectively increased hemoglobin level for long term with
high dose of thalidomide 75 mg·kg-1·d-1 or
100mg·d-1[9, 10], while β thalassemia intermedia
was reported responding to low dose of thalidomide
(1-2mg·kg-1·d-1)[11]. Children cases of β
thalassemia major were presented no response to
thalidomide[12]. The response to thalidomide
seemed to be controversial. Phase Ⅱ clinical trial for thalidomide in
adult patients with thalassemia intermedia at the dose of 50 mg orally
per night presented little data for safety[13]. In
Iraqi Kurdistan[8], a cohort of 37 patients with
symptomatic β-thalassemia on the dose of 2-10 mg·kg-1·d-1 achieved
response rate of 75.7%, while minimal side effects were documented. The
overall response rates of thalidomide(50 mg·d-1 for <30 kg ,
100 mg once daily for >30 kg) and hydroxyurea (500 mg·d-1)
combination treatmentas 68.2% at 3 months, while thalassaemia
intermedia(78.6%) presented higher response rate than thalassaemia
major (50%)[4], indicating the low response rate
in thalassemia major. In a multicenter study in southern China
population, the initial dose of thalidomide was 50 mg·d-1, and the dose
of 100 mg·d-1 was given to patients needing blood transfusions at least
twice a month. The overall response rate was
93.5%[15]. In the Indian report for 20 patients
with transfusion-dependent E-Beta thalassemia[14],
the starting dose of thalidomide was 50 mg·d-1 in patients less than 12
years age and 100 mg·d-1 in patients more than 12 years age, 15 (71.4%)
attained transfusion independence and 1 (4.7%) attained partial
response while 5 (23.9%) were non-responders. The major adverse effect
documented was constipation(47%).
In this current study, we attained a different approach to dose of
thalidomide. It is proposed that the start dose of 2.5 mg·kg-1·d-1 may
be suitable and the observation for 3 months for side effects and
efficacy would be recommended. For the unclear benefit, the increased
dose over 3.6 mg·kg-1·d-1 was not recommended.
In the analysis parameters related to thalidomide efficacy, HbF
concentration in peripheral blood before transfusion was the only found
parameter that related to the treatment response. According to the ROC
analysis results, the HbF concentration prior to response evaluation
predicted the response probability. The HbF concentration at the third
month may be a dependable predictor for the response at the sixth month.
The HbF concentration of 47.298 g·L-1 at the third month could be
regarded as the threshold for major responders at the sixth month. Long
term observation for more than 6 months is not recommended if there is
no evidence for elevated HbF concentration over threshold. However, the
HbF concentration is not a good predictor for identification between
minor responders and non-responders according to the result that the HbF
concentration differences between minor response group and no response
group were not significant. In a multicenter adults
study[15], the ratio of HbF at baseline was an
independent risk factor for response to thalidomide in southern China
population. The primary response to thalidomide was significantly
correlated with the HbF ratio before treatment and splenic status, but
not related to age, sex, phenotype (TDT or NTDT), duration of treatment,
thalidomide dose or baseline Hb level[15]. It has
been announced that elevated Hb was mainly attributable to increased HbF
levels[15]. For the observation in HbF
concentration changes were common in major responders in previous
studies, researchers performed gene polymorphisms study. Single
nucleotide polymorphisms (SNPs) in HBG2 and HBS1L-MYB were reported to
be related to thalidomide response in Chinese patients, while the
cumulative number of minor SNP alleles may be good predictors of
treatment response[16]. These results might
support good indicators for targeted prescription of thalidomide in
Chinese patients, but not necessary good indicators for global
promotion, considering genomic diversity between races. HbF
concentration may be a general predictor for thalidomide treatment
response, which needs further validation. Moreover, the underlying
mechanism was yet clarified. Further study of genetic and metabolism
reasons for differences in response would be necessary for targeted
treatment.
High incidence of toxicity and fatal adverse events were highly
concerned by physicians. Dizziness and/or lethargy, constipation,
abdominal pain and/or vomiting and/or nausea are most commonly seen at
the beginning of treatment. Most of the symptoms relieved spontaneously
without withdraw. However, there were cases that presented severe
adverse events, including central venous thrombosis and seizure, which
led to hospitalization and withdraw of thalidomide. Thalidomide-induced
stroke in a child with thalassemia major was also reported
before[17]. This study still lacked of long term
observation for persistent application. Neither did other previous
studies. Long term adverse effects, such as pulmonary hypertension,
growth retardation, fetal malformation, were not included in this
report. So, long term application of low dose thalidomide for more than
1 year in β-thalassemia children should not be prescribed for the known
adverse effects of thalidomide.