Page 68 - Haematologica July

I. Rahal et al.
hypogonadism. Delayed puberty was observed in 21 of 33 patients; most of these cases presented hypergonadotropic hypogonadism (Table 3). The patients who spontaneously started their puberty were significantly younger at trans- plant compared to those who had delayed puberty [median age 2.5 years (range 1.6-5.9) vs. 8.7 years (range 1.7-12), respectively; P<10-3].
Pubertal development in males
Twenty-nine of 45 males were assessed for puberty. Five of 29 males were post-pubertal at HSCT: one patient who had required hormonal replacement therapy before HSCT remained on treatment after HSCT for hypergonadotropic hypogonadism.
The 2 of 29 males with ongoing puberty at transplant completed normal puberty. Among the 22 males who were pre-pubertal at transplant, only 4 (18%) had delayed puber- ty and 3 developed hypogonadism after transplant (hypog- onadotropic in 2 cases). Eighteen of 22 patients (82%) trans- planted at a median age of 5.9 years started puberty spon- taneously.
Fertility and pregnancy
Among the 27 females aged 20 years and over at last eval- uation, 11 (40%) had had at least one successful pregnancy after transplant. Sixteen successful pregnancies were recorded with a median age of 26 years (22-33 years) at delivery. Two patients had benefited from oocyte donation; both had had delayed puberty and post-HSCT hypogo- nadism. Among the 9 remaining patients, 3 experienced normal puberty after HSCT and 6 had delayed puberty. It is worthy of note that 5 of 9 patients were diagnosed with hypergonadotropic hypogonadism.
Among the 21 males aged over 20 years at last visit and evaluable for fatherhood, 4 (19%) fathered at least one child; 3 had experienced normal puberty and one patient had delayed puberty, hypergonadotropic hypogonadism and oligoasthenozoospermia. He and his partner had bene- fited from in vitro fertilization, which had resulted in a full- term pregnancy and delivery.
Other complications
Other relevant long-term late effects were encountered. Eleven patients had acquired hepatitis C virus (HCV) infec- tion before transplant and had a positive HCV-RNA after HSCT. At last evaluation, 3 of 11 patients remained positive (2 of 3 did not require antiviral treatment), 7 of 11 became HCV-RNA negative after an antiviral treatment, and one
recovered spontaneously. Five patients developed liver complications: 3 had liver fibrosis, one nodular regenerative hyperplasia, and one focal nodular hyperplasia; none of them developed hepatocellular carcinoma. At last visit, only 3 patients still had limited chronic GvHD that did not require any treatment, but another patient developed severe bronchiolitis obliterans. Two patients presented psy- chiatric disorders (one schizophrenia, one paranoia). No secondary malignancy was recorded. Creatinine levels (n=99) at a median time of 11 years after transplant were within the normal range for sex and age groups in all patients except for one 14-year old male patient with a chronic kidney disease stage 2 (96 mmoles/L). Another patient with diabetes developed a chronic proteinuria (2 gr/L) without renal insufficiency. Proteinuria was not rou- tinely investigated after transplant in the study population.
Ongoing medication
Half of the patients were on long-term treatment at last evaluation. Hormonal therapy (sex hormone replacement, thyroid hormone or insulin therapy) was prescribed for 34 patients, antibiotic therapy for 17, and cardiac treatment for 2. One patient with mixed chimerism was receiving long- term treatment with erythropoietin. The only patient receiving systemic immunosuppressive therapy at last eval- uation was treated for auto-inflammatory arthritis.
Serum ferritin and hemoglobin levels
Mean serum ferritin level at last evaluation was 405 mg/L±295. Thirty-seven patients were treated with phle- botomy, 7 with chelation therapy, and 11 with both. In multivariate analysis, serum ferritin levels after transplant significantly decreased with time and with the use of phle- botomy/iron chelation therapy. Serum ferritin levels after transplant were higher in older patients and/or in patients with high serum ferritin levels at HSCT (Online Supplementary Table S2).
Median hemoglobin value at last evaluation was 125 g/L (range 86-170 g/L). All patients were free of transfusion, and only one patient received erythropoietin therapy.
Discussion
Nearly all β-TM patients successfully treated in France with allogeneic HSCT were assessed for late effects with a long follow up after transplantation (median duration of fol- low up 12 years). The vast majority of patients were trans-
Table 3. Gonadal dysfunction after hematopoietic stem cell transplantation (HSCT) in female patients.
Ongoing puberty or post-pubertal at HSCT
Delayed puberty and aged ≥ 13 years at HSCT
Number of patients
6
4
Median age at HSCT (years)
19 13.6
Median age at assessment (years)
31 26.5
Spontaneous Secondary Hypogonadism menarche amenorrhea
- 6 4+1* 0 - 2+2*
Pregnancy (≥20 years)
1 /6 1°/2
1146
Pre-pubertal and aged 33 < 13 years at HSCT
Normal puberty
Delayedpuberty 21 8.7 21 5 4 15 5+1°/14
12
2.5
18.5
12 3** 1
3 /5
*Hypogonadotropic hypogonadism. °Oocyte donation. **Transient in 2 cases.
haematologica | 2018; 103(7)