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females.28-30 In our study, females who spontaneously start- ed their puberty after transplant were significantly younger at transplant than those who experienced delayed puberty.
In this report, the frequency of hypogonadism in male patients (low testosterone levels or long-term hormone replacement therapy) was 14%, less than that usually reported in transplanted thalassemia patients (Table 4). This could be underestimated since more sensitive criteria such as inhibin levels, gonadotrophin-releasing hormone tests or semen analysis were not available.
We found a 5% rate of diabetes mellitus after transplant compared to 0-9% in previous studies on transplanted β- TM patients.19,21,25 Potential risk factors for diabetes mellitus are: IO (because patients developing diabetes tended to be older at HSCT), conditioning therapy administration, use of corticosteroids for GvHD management.
Cardiac complications have rarely been reported after a standard BuCy conditioning and are usually related to resid- ual IO in β-TM patients.21,37 The presence of cardiac IO could not be ruled out in the 2 patients who developed car- diac dysfunction as cardiac MRI T2* was not then routinely used in France. Nonetheless, one patient transplanted at just four years of age with low serum ferritin values at and after HSCT developed cardiac failure.
Three studies have reported several cases of cancer 10-25 years after HSCT for thalassemia, mostly cancer of the oral cavity and thyroid carcinoma.12,38,39 Recently, 8 cases of sec- ondary solid cancer (SSC) have been reported among 112 patients, mostly children transplanted from an MSD.39 SSC occurred at a median time of 18 years after HSCT, stressing the need for a very long-term monitoring of TM survivors after HSCT. The length of follow up after HSCT may be too short in our study to record such cases. In addition, chronic GvHD, reported as an independent risk factor for secondary solid tumor,39 in our study affected only 3 patients with untreated limited disease at last evaluation. Monitoring of thyroid through regular ultrasound, treat- ment of HCV infection, and of residual IO may also con- tribute to the lack of secondary malignancy.
Hepatic, psychiatric, or pulmonary complications were also observed in few patients. It is worth noting that HCV was successfully treated after transplant in nearly all patients with active infection.
In summary, long-term complications were mainly relat- ed to the conditioning regimen in our study population where most patients were transplanted in the early phase of their disease. Pre-transplant ferritin levels were not elevat- ed, and only few patients had IO-related clinical complica- tions. Moreover residual IO was treated in 44% of cases by phlebotomy and/or iron chelation, these 2 modalities of treatment being efficient after HSCT.40-42 Reduced intensity or reduced toxicity conditioning based on treosulfan,43 flu- darabine, and/or use of low doses of busulfan were investi- gated in β-TM patients.23,44 Long-term toxicity results of these studies are not yet available. In our report, Bu-based conditioning was myeloablative in all cases. Indeed, in our national experience, MAC was required in order to limit graft failure.8 In current gene therapy trials, conditioning with high doses of Bu also appeared necessary to allow cor- rected autologous cells to graft.
Although not usually severe or life threatening, long-term effects after HSCT are frequent and diverse in TM patients, half of them undergoing long-term treatment, especially hormonal replacement. National and international guide- lines describing comprehensive long-term monitoring should be established for thalassemia patients treated with HSCT.
Acknowledgments
This research was supported by AORC APHM 2011 (Appel d’Offre de Recherche Clinique).
A few pregnancies after HSCT for thalassemia have been reported but recently Santarone et al.31 described in a mono- centric study 15 women who became pregnant after HSCT. We also observed that fertility was preserved in at least one-third of female patients aged 20 years and over. The proportions of females requiring ovarian stimulation or who tried to conceive without success are not known. Surprisingly, in our study, several females with delayed puberty and hypogonadism became pregnant. All women who became pregnant received oral busulfan (median dose 14-16 mg/kg), which is known to have a wide intra- and inter-patient pharmacokinetic variability. Consequently, fertility should be re-assessed according to the more recent procedure of use, i.e. intravenous busulfan. Fertility in male patients (n=4) was also partially preserved.
We found that the rate of growth of β-TM patients was impaired after HSCT; height was influenced both by age and by serum ferritin levels at the time of transplant. These 2 variables reflect the impact of IO. This result is in agree- ment with most studies (Table 4),14,32 although others report- ed patients catching up in the first years following HSCT.5,19 Time elapsed after transplant also negatively influences the rate of growth, suggesting that a long-term follow up is nec- essary to assess the impact on height growth. We report a median loss from transplant of approximately one SD for patients reaching their full-grown height. Conditioning may contribute to growth delay in β-TM transplanted patients since a moderate decrease in height growth has also been observed in patients with hematologic malignan- cies receiving busulfan-based conditioning.33
Few data are available about weight development after HSCT in β-TM patients. In our study, weight SDS increased with time after transplant, especially in women. Being overweight appeared to be more frequent in thalassemia adult patients treated with HSCT (36% of patients at last evaluation) compared to those receiving conventional therapy (14.6% of adult patients; data from the French β-thalassemia registry, personal communication, 2017) or those receiving Bu-based conditioning for child- hood leukemia.34 This result leads us to propose accurate investigation of the metabolic syndrome after HSCT in thalassemia patients.
The frequency of hypothyroidism after HSCT ranged from 0% to 11% in thalassemia patients (Table 4). In this study, thyroid complications affected 11% of patients. It appeared to be mainly related to the cytotoxic effect of conditioning as half of these patients had received irradi- ation or a second transplant. Their age and serum ferritin levels at transplant were similar to those in the whole study population. It should be noted that hypothyroidism has been reported after treatment with BuCy.35,36
haematologica | 2018; 103(7)