Page 108 - 2020_01-Haematologica-web

F. Bernaudin et al.
Among the 92 patients with mixed chimerism at one year, four rejected the graft (4.3%) at 1.5, 2, 2.3 and 9 years post transplant, but none had been prepared with ATG. Among the other 88 patients, none had rejected the graft at last visit, nine had switched to full donor chimerism, and 69 had high and 10 low mixed chimerism (Table 4). None of those with low mixed chimerism experienced SCA-related vaso-occlusive crisis (VOC) or acute-chest- syndrome (ACS), but five had hemoglobin <100 g/L or reticulocytes >150x109/L, considered as SCA-related symptoms. Thus, despite the absence of rejection and the absence of VOC or ACS occurrence, these patients were deemed as having SCA recurrence, resulting in an overall disease-free survival (DFS) of 95.5% at five years (95%CI: 92.7-98.3%). Three of the patients with low mixed chimerism and hemolytic anemia stigmata received DLI, which did not induce GvHD, but did not offer improve- ment of anemia and hemolysis. Figure 4 reports all biolog- ical data recorded at the same time as chimerism during the entire follow up. It can be seen that as long as donor chimerism remains higher than 50%, Hb and reticulocytes remain normal, resulting in no anemia, no hemolysis and similar HbS% as donor.
Discussion
In this report, we confirm that SCA children and young adults transplanted after year 2000 (n=197) with an MSD and prepared with myeloablative-CR associating busul- fan, cyclophosphamide and ATG have at least a 95% chance of cure. These results compare favorably with other published series using myeloablative19-26 and non- myeloablative27-29 CR.
The TRM < 2% in this series must be interpreted in the context of mortality risk related to the SCA disease itself, which was reported to be 6.1% before the age of 18 years in the Dallas cohort,16 and 1% in the London17 and 2.5% in the Créteil14 newborn cohorts. Thus, MSD-SCT does not expose children to a higher risk of death than SCA itself, but offers improved quality of life. Moreover, it is important to remember that transition to adulthood car- ries a high risk of death,32 and that mortality in adults18 has increased during the last few years, whereas it has signifi- cantly decreased for children.
Except for frequent high fever during ATG infusion, myeloablative conditioning was well tolerated in the 234 young patients, with only one death during aplasia and two mild veno-occlusive diseases. High doses of ATG are known to increase the risk of viral complications. The occurrence of EBV reactivation, however well controlled with anti-CD20 treatment, and the case of fatal adenoviral meningoencephalitis30 are of concern, but the risk benefits between viral infections, which are manageable, and cGvHD, which is more difficult to control, need to be taken into account. Seizures and posterior reversible encephalopathy syndromes (PRES), which were highly
22
frequent (16 of 83; 19%) before year 2005, despite pre-
ventive measures such as anticonvulsant prophylaxis with clonazepam during busulfan administration and cyclosporine therapy, strict control of arterial hyperten- sion, prompt correction of magnesium deficiency, mainte- nance of the Hb concentration above 9 g/dL and platelet count above 50x109/L,33 were significantly (P=0.002) less frequent after 2005 (8 of 151; 5%), following the SFGM-
TC recommendation to promptly replace cyclosporine with mycophenolate mofetil in case of GvHD requiring steroid therapy.22 However, the risk of seizures and PRES remains an adverse effect of cyclosporine and steroid ther- apy,34 and may warrant substituting cyclosporine for
Figure 4. Relationship between % donor cells and hemoglobin S percentage (HbS%), hemoglobin (Hb) level, and reticulocyte count. All biological data (HbS%, Hb and reticulocytes) recorded at the same time as the chimerism dur- ing the overall follow up were used for these box-plots. (A) Box-plot of HbS% according to the donor cell% category. This graph shows that HbS% is similar to that of the donor (AA or AS) as long as donor cell% is higher than 50%. (B) Box plot of Hb level according to donor cell% category. Hb level remains higher than 100g/L as long as donor cell% is higher than 50%. (C) Box plot of reticulocyte count according to % donor cells. Reticulocyte count remains lower than 100x109/L as long as % donor cells is higher than 50%.
98
haematologica | 2020; 105(1)