Outcomes of Stem Cell Transplantation with Fludarabine and Melphalan Conditioning for Children with Acquired Bone Marrow Failure: A Nationwide Retrospective Study

Survival after stem cell transplantation (SCT) in children with acquired bone marrow failure (aBMF) has improved over decades. However, we have experienced a certain number of patients who presented with bone marrow aplasia with full donor chimerism after SCT, especially in the last decade. We named the complication “donor-type aplasia”, and now, this is one of the main causes of treatment failure after SCT in children with aBMF. Because fludarabine (FLU)-based conditioning regimen has been often used for Japanese children with aBMF since the 2000s, use of FLU was suspected to associate with donor-type aplasia. On the other hand, when FLU was introduced in the regimen for children with aBMF, the dose of cyclophosphamide (CY) was reduced by half, to reduce the toxicity. Given these, we previously investigated the risk factors for donor-type aplasia, and reported that the dose reduction of CY rather than the use of FLU in itself was relevant to the recent increase of donor-type aplasia (Yoshida N, et al. ASH 2012). To reduce the risk for donor-type aplasia, the conditioning regimen for children with aBMF needs to be reconsidered. The purpose of the present study is to evaluate the outcomes of SCT using FLU/melphalan (MEL)-based conditioning instead of the standard FLU/CY-based regimen in children with aBMF.

We retrospectively reviewed the clinical data of 488 patients (<16 years) with aBMF (aplastic anemia and refractory cytopenia of childhood) who received the first SCT from 2000 to 2012 and whose records were available in the Japan Society for Hematopoietic Cell Transplantation Registry. Totally, 28 patients received the FLU/MEL-based regimen, while 233 received the FLU/CY-based regimen. Of the 28 patients, 11 received SCT from a related donor, whereas 17 received it from an unrelated donor. The stem cell source was bone marrow in 19 patients, peripheral blood in 1, or cord blood in 8. The conditioning regimen was based on FLU (100-180 mg/m²) and MEL (70-180 mg/m²), and ATG was included in the regimen in 17 patients, while low dose irradiation was used in 23 patients.

The 5-year overall survival and event free survival of all patients who received the FLU/MEL-based regimen was 88%. Engraftment was achieved in 27 out of 28 patients (96%) and secondary graft failure including donor-type aplasia was not observed. Regarding the MEL dose, the favorable survival in patients who received 120 mg/m² or more was observed (100% vs. 62%; P=0.006). Notably, all patients who received bone marrow transplantation (BMT) were alive without any complication. We then compared the outcomes in the setting of BMT with the FLU/MEL-based regimen (n=19) to those with the FLU/CY-based regimen (n=219). The event free survival was inferior in patients treated with the FLU/CY-based regimen (85% vs. 100%), although this difference was not statistically significant. With the FLU/CY-based regimen, engraftment was achieved in 214 patients (98%), whereas secondary graft failure including donor-type aplasia was seen in 18 patients.

In conclusion, the FLU/MEL-based conditioning regimen provided excellent outcomes especially in the setting of BMT. To validate whether this regimen can reduce the risk of donor-type aplasia, a larger study is necessary. Therefore, a prospective study on SCT with this conditioning for aBMF children with high risk of donor-type aplasia is now planned by the Japan Childhood Aplastic Anemia Study Group.