Page 257 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Pubertal development of transfusion-dependent thalassemia patients in the era of oral chelation with deferasirox: results from the French registry
Over the last decades, advances in transfusion regimen, chelation therapy and iron overload monitoring have allowed a steady increase in life expectancy of patients with trans- fusion-dependent thalassemia (TDT), mainly related to a decrease in cardiac mortality.1,2 However, endocrinopathies remain the most frequent and early complications of iron overload in TDT patients, the first being hypogonadism with a prevalence ranging from 30 to 60% in numerous registries and cohorts.3-5 Early diagnosis and treatment are essential to achieve normal puberty, target height, and reduce the risk of long-term infertility and sexual dysfunction. It has been established that well-managed chelation therapy and its early initiation, allowing good control of iron overload, reduce the risk of hypogonadism.6,7 However, definitions of pubertal disorders and hypogonadism vary according to studies, and data from the literature regarding pubertal development are often incomplete.
The French National Thalassemia Registry (NaThalY) has recently initiated a study on the health status of TDT chil- dren aged <15 years, mostly (80%) under deferasirox (DFX) therapy, reporting an excellent probability of survival (98.3%) and a very low rate of iron-related complications.8 In the context of the global improvement in endocrinopathies al- ready described under DFX,9 here we report the remaining pubertal disorders and hypogonadism in TDT adolescents and young adults included in the French Thalassemia Reg- istry who received oral chelation with DFX before puberty onset. This study respects the French ethical rules. The French registry was approved by the Comission Nationale de l’Informatique et des Libertés (CNIL) (declaration N. 903064V1, authorization N. 04-1396).
A total of 50 patients, treated in 24 registry-participating centers, accumulated at least three years of DFX therapy before puberty in their history of chelation therapy and met the inclusion criteria of this study (Figure 1). Their median age at last visit was 20 years for girls (N=25, range 14-24) and 18 years for boys (N=25, range 14-24). Regular transfusions and chelation therapy were initiated early, at 1.3 years old (range 0.3-4) and 3 years old (range 1-6), respectively. The median duration of DFX chelation before 13 years in girls and 14 years in boys was seven years (range 3-12).
All 50 patients were evaluable for pubertal delay, defined as lack of pubertal onset by 13 years in girls and 14 years in boys. All had spontaneous puberty onset, at a median age of 12.5 years in girls (range 10.5-14) and 13.5 years in boys (range 12.5-15). Eight patients (16%) experienced delayed puberty, mostly (7/8) simple pubertal delay, with a delay
ranging from 6 to 12 months (Table 2). Among the 7 patients with simple pubertal delay, 5 were boys.
Only one patient, suffering from a pubertal delay, presented with primary amenorrhea out of the 24 girls who had either menstruated or who were >15 years old (4.2%). Median age at first menstruation was 13.5 years (range 12-17). Two girls had their first menstruation delayed, at 16 and 17 years old, both after a simple pubertal delay.
Twenty-three patients were assessable for secondary amen- orrhea (menstruated girls). Three developed secondary amenorrhea (13%) 2, 3, and 7 years after their menarche. Mean follow-up duration after menarche for the 20 other girls without secondary amenorrhea was 6.3 years.
The 4 patients with primary or secondary amenorrhea had hypogonadism with low sexual hormone levels (estradiol <25 pg/mL). Three showed hypogonadotropic hypogonadism (HH) (Online Supplementary Table S1). Despite existing HH,
Figure 1. Study population. DFX: deferasirox; HSCT: hemato- poietic stem cell transplantation; TDT: transfusion-dependent thalassemia.
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