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.