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F. Bernaudin et al.
AB
Figure 1. Matched-sibling donor hematopoietic stem cell transplantation (MSD-SCT) performed in France (1988-2012) after myeloablative conditioning regimen (n=234). Only 2% of patients were not prepared with anti-thymocyte globulin (ATG) in the second cohort versus 20.5% in the first cohort. The transplantation proce- dure and prophylaxis for graft-versus-host disease (GvHD) were as previously reported,22 except that busulfan has been administered intravenously since year 2001 (Busilvex® Pierre Fabre Médicaments, Boulogne-Billancourt, France) from day –10 to day –7 at the total dose of 12.8 mg/kg for patients weighing >34 kg, 15.2 mg/kg for patients weighing 23-34 kg, 17.6 mg/kg for patients weighing 16-23 kg, or 19.2 mg/kg for patients weighing 9-16 kg. Busulfan pharmacokinetics were not performed for the majority of patients (n=202). In addition, cyclosporine was replaced by mycophenolate mofetil after 2002 in case of GvHD requiring steroid therapy. (A) Proportion of patients younger or older than 15 years. (B) ATG doses. NP: not precise; these patients received ATG, but the exact dose was not recorded.
There was no significant difference in TRM (P=0.490) between those prepared with 5-15 mg/kg ATG (5.5%; 95%CI: 0-13.1%) and those prepared with 20 mg/kg ATG (3.0%; 95%CI: 0.4-5.6%).
Event-free survival
Considering deaths (n=7), non-engraftments (n=2), and rejections (n=5) as events, the overall 5-year EFS was 93.9% (95%CI: 90.7-97.1%), but EFS strongly improved with time since it was 97.9% (95%CI: 95.5-100%) in the 151 patients of the second cohort versus 86.9% (79.5- 94.3%) in the 83 patients of the first series (Figure 2B). Among the 190 patients transplanted after year 2000 and prepared with ATG, 5-year EFS was 97.8% (95%CI: 95.6- 100%). EFS was similar in patients prepared with 5-15 mg/kg or with 20 mg/kg ATG (Figure 2C), in patients younger or older than 15 years (Figure 2D), and in patients transplanted from CB alone versus BM (Table 3). Cox regression analysis showed that EFS was not associated with the recipient’s or donor’s age or with the cell source, but was significantly associated (P<0.001) with the period of transplant (i.e. before or after year 2000) (HR=11.3; 95%CI: 3.9-33.4).
Graft-versus-host disease
Acute GvHD was assessable in the 232 successfully
engrafted patients. The overall cumulative incidence of aGvHD ≥II at day 100 was 20.1% (95%CI: 14.9-25.3%). The multivariate Cox regression analysis retained sex mis- match (HR=2.12, 95%CI: 1.15-3.90; P=0.016) and donor’s cytomegalovirus (CMV) positive status (HR=5.10, 95%CI: 2.15-12.05; P<0.001) as significant and independent risk factors for aGvHD ≥II (Figure 3A).
Chronic GvHD was assessable in 228 patients, and occurred in 24 patients. It was mostly mild in 18 patients, but extensive in six. Organ involvement included resolu- tive cutaneo-digestive (n=2), and obliterans bronchiolitis (n=4) which was responsible for death in two patients.
The cumulative incidence of cGVHD at five years was 10.5% (95%CI: 6.5-14.5%), and was significantly lower (5.4%, 95%CI: 1.8-9.0%) in patients who received the highest ATG dose (20 mg/kg) than in those prepared with- out ATG (25%, 95%CI: 5.6-44.4%) and receiving lower doses (5-15 mg/kg) (27.0%, 95%CI: 12.4-41.6%) (Log Rank P<0.001). Moreover, 5-year chronic GvHD in chil- dren under 15 years of age was 7.6% (95%CI: 3.8-11.4%) versus 29.7% (95%CI: 13.1-46.3%) in those over 15 years of age. Multivariate Cox regression analysis retained only the recipient's age (HR=1.098 per 1 year increase, 95%CI: 1.033-1.168; P=0.003) and the ATG dose (HR=0.91 per mg/kg increase, 95%CI: 0.86-0.96; P=0.001) as independ- ent risk factors.
Other post-transplant complications
The number of seizures, hemorrhagic cystitis, and veno- occlusive disease are shown in Table 2. The proportion of patients experiencing seizures and/or posterior reversible leukoencephalopathy was significantly reduced in the sec- ond cohort (5.3% vs. 18.1%; P=0.002). CMV replication occurred in 23.9% of patients. No CMV-related disease occurred with pre-emptive therapy. Epstein-Barr virus (EBV) asymptomatic viral replications had not been sys- tematically assessed in the first cohort, and were observed in 15 patients (6%) in the second cohort. Six of them required anti-CD20 treatment, but none developed post- transplant lymphoproliferative disease. Among the 234 patients, B-lymphoma occurred six years post transplant in one patient who had received long-term immunosup- pressive therapy, but no other secondary malignancies were observed.
Gonadal function
All females who were post-pubertal at the time of trans- plantation (n=14) developed amenorrhea with low serum estradiol and elevated LH and FSH levels during the year following transplant, necessitating hormone replacement
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haematologica | 2020; 105(1)