Upfront HSCT with an Alemtuzumab Based Conditioning Regimen in Children with Acquired Aplastic Anemia: A Retrospective Study from the SFGM-TC

Acquired aplastic anemia (AA) is the most common form of bone marrow failure. While pediatric patients with AA respond better than adults to immunosuppressive therapy (IST), the long-term event free survival (EFS) is poor due to relapse, cyclosporine dependence, and clonal evolution. Because of those and the low treatment related mortality (TRM) in young patients, up-front fully matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) became an attractive first-line option. In 2015, excellent outcomes after HSCT with an alemtuzumab based conditioning regimen (FCC) has been reported by Dufour et al in this population of patients (Br J Haematol. 2015). To evaluate this strategy in an independent cohort, we retrospectively analyzed the outcome of all children receiving 1st-line HSCT with a MUD and this conditioning regimen in France between 2013 and 2023.

Methods: The clinical and biological data of all the children (<18 year at time of HSCT) with an acquired AA transplanted in 1^st line with a MUD and after an FCC conditioning were extracted from the data base of the SFGM TC (Société francaise de greffe de moelle osseuse et Therapie cellulaire) ; an informed consent has been signed before HSCT by their parents.

Results: 20 children (8 female ; median age 10.4 years (IQR: 7.3-12.6)) with severe AA from 9 centers had received the same conditioning with Fludarabine (150 mg/m2), Cyclophosphamide (120 mg/kg) and Alemtuzumab (0.9 mg/kg). Five patients received rituximab 150 mg/m² at day+5 for EBV prophylaxis. The stem cell source was bone marrow for 19 patients, and peripheral blood stem cell in the last. All donors were at least 10/10 MUD.

With a median follow up of 2.5 years, the overall survival at any time is 100%. 60 days incidences of platelets and neutrophils engraftment were 94.1% and 100% respectively with median time to engraftment as 29 days IQR (17;35) and 23 days IQR (19;29) respectively. There was no primary graft failure but 3 patients experienced secondary graft failure at days 40, 43 and 51 respectively corresponding to a 2 years graft failure incidence at 16.4%. Two had autologous reconstitution and are alive with good hematological function 2.7 and 6.4 years later (at last follow up donor blood chimerism were 3% and 25% respectively; none developed PNH or malignancy at last FU). The other one required a 2^nd HSCT, as well another patient with poor graft function despite full donor chimerism. They are both alive at 2 and 6.2 years after the 2^nd HSCT. The 2 years second HSCT incidence was 10%

Event free survival defined by the absence of death and/or graft failure was 83.6% at 2 years.

Cumulative incidence (CInc) of acute and chronic GvHD were very low : 5.6% at Days 100 and 10.5% at 2 years respectively without grade 3-4 acute GvHD and extensive chronic GvHD. Only two patients experienced skin acute GvHD with good evolution (one grade I treated by steroid topic and the second treated with corticosteroid systemic during 3 months). Only one patient required Ruxolitinib treatment for chronic GvHD of the skin (mild stage with eczema at the elbow) with good evolution. At last FU, 18 patients (90%) were free of IST.

Two patients developed immune warm hemolytical anemia at days 33 and 287 post HSCT corresponding of a cumulative incidence of 11.8%. Both were treated with high dose systemic steroid therapy and rituximab as first line therapy. One of them required a 2^nd line of treatment with Bortezomib to achieve response. At the last FU, they are in remission without IST. A third patient developed an inflammatory bowel disease and a fourth an hashimoto thyroiditis 18 and 13 months after the HSCT respectively.

Viral infection requiring therapy occurred in 4 patients: EBV infection without post-transplant lymphoproliferative disorders treated by Rituximab in 3 and a disseminated ADV infection requiring cidofovir therapy and third part T cell in the last. One patient experienced severe hemorrhagic cystic.

In conclusion, overall survival was excellent after upfront MUD HSCT in this pediatric cohort of acquired AA and CInc of acute and chronic GvHD were very low, however incidence of secondary graft failure or dysfunction and immune complications other than GvHD suggest evaluating other conditioning.