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Myeloablative MSD-SCT for SCA: long-term outcome
sirolimus27,28 that is less neurotoxic and induces good toler- ance.35 Hemorrhagic cystitis occurred in 21 of 234 patients (9%) and was particularly severe in two patients. Cyclophosphamide is generally considered to be the most important predisposing factor for occurrence of hemor- rhagic cystitis.36,37 Despite the absence of prospective ran- domized trials comparing busulfan-fludarabine to busul- fan-cyclophosphamide, several reports mention a lower risk of hemorrhagic cystitis with fludarabine.38,39 This complication may suggest replacing cyclophosphamide with fludarabine, as only a 2% risk of hemorrhagic cystitis was reported in children transplanted for non-malignant disease following busulfan-fludarabine versus 9% with busulfan-cyclophosphamide CR.39
The major long-term concern with busulfan is the ovar- ian failure observed in post-pubertal females and infertili- ty risk in both genders.40,41 Despite the occurrence of spon- taneous puberty in girls transplanted at a younger age and the birth without treatment of several babies from females transplanted 20-25 years ago during infancy, demonstrat- ing some reversibility of ovarian dysfunction, it remains crucial to maximize the chances of fertility and to recom- mend pre-transplant cryopreservation of ovarian42-44 and testis45 tissues before SCT with myeloablative CR. In France, systematic ovarian and testicular tissue cryopreser- vation has been established since 1998 and 2010, respec- tively, and is free of charge. However, CR preserving fer- tility such as the one proposed by the National Institutes of Health (NIH) protocol using 3Gy total body irradiation with testis shielding in males and alemtuzumab27-29 should be preferred when gonadal cryopreservation is not easily accessible and for adults. It is also important to keep in mind that fertility is also compromised by SCA itself,46 and that this risk is lower when SCT is performed at a younger age.
Event-free survival in this series was similar for patients younger and older than 15 years, but the risk of cGvHD, not acceptable in this non-malignant disease, was much more frequent in older patients. We show that the high dose of ATG (20 mg/kg) significantly reduced the risk of cGvHD independently of the age at transplant by favoring mixed chimerism occurrence. In the 20 of 234 patients not prepared with ATG, mixed chimerism was unstable, and secondary graft failed in 5 of 20. In contrast, only one sec- ondary rejection was observed before year-1 among the
214 patients prepared with ATG.
Mixed chimerism was present in 44% of patients at one
year in this series. None of the patients prepared with ATG rejected the graft and none experienced VOC or acute chest syndrome. The absence of SCA-related symp- toms in patients with mixed chimerism has been reported in other series.22,47-50 Low levels of donor erythroid engraft- ment were shown to result in donor cell predominance among erythroblasts and erythrocytes.48 This stimulated the development of non-myeloablative CR in order to reduce TRM and preserve fertility, and resulted in the rec- ommendation of HSCT to older adult patients with organ dysfunction. While the first results after non-myeloabla- tive SCT have been disappointing, very encouraging results were obtained by the NIH team in adults (17-64 years of age)27,28 using as stem cell source granulocyte- colony stimulating factor (G-CSF)-stimulated peripheral blood progenitors from HLA-matched sibling donors and sirolimus for GvHD prophylaxis, which was stopped after one year in those with >50% donor T-cell chimerism. The mean duration of immunosuppression was 2.1 years (range: 1.0-8.4). Among 30 patients transplanted, four experienced rejection (13%), which was responsible for one death in a patient with Moya Moya, but no TRM and no GvHD were observed. Mean donor T cell was 48%, mean myeloid chimerism was 86%, and 15 patients had stable chimerism despite sirolimus withdrawal. These results were reproduced in 13 adult patients by another team in Chicago.29 Thus, among the 43 patients reported in both series, 88% were alive, free of SCA and without GvHD. However, the limitations of the protocol are the long-term immunosuppression and the 300 cGy TBI that could favor a secondary malignancy. Other non-myeloab- lative or reduced intensity CR have been reported by sev- eral teams and fully described in a review,50 but the most successful results were obtained with the NIH protocol described above.
It is to be noted that the excellent results reported here mostly concern young patients and are less applicable to older patients with higher morbidities. Moreover, out- comes of cognitive performances, quality of life, costs and organ functioning are not reported here. This is an impor- tant limitation of our study but only prospective trials comparing MSD-SCT to standard-care would be able to define the true risk benefit balance for each procedure.
Table 4. Biological data in patients with low mixed chimerism (5-49% donor cells) at last visit.
Donor genotype
AS
AS AS AS AS AA AA AA AA
AA
Years Donor cells % HbS % Hb g/L Retic x109/L post-HSCT at 1 year at last visit at last visit
15.5 24 19 51 103 226
5.1 60 20 60 83 230 7.1 35 21 70 69 422 14.1 46 22 63 87 360
15.4 73 42 44 151 79 12.1 20 12 36 73 138 9.5 30 20 30 130 nd 10.23222511883 6.2 61 30 10 100 101
5.9 57 38 8 103 75
HSCT: hematopoietic stem cell transplantation; HbS: sickle hemoglobin; Retic: reticulocytes.
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