To the Editor:
Unrelated cord blood transplantation (UCBT) has become a widely accepted treatment for hematological malignancies, but it has less been used in cases of severe aplastic anemia (SAA) . High-graft failure (GF) rates have been observed in early retrospective studies [2, 3]. Recently, several studies reported improvements in engraftment and overall survival (OS) using conditioning regimens containing low-dose total-body irradiation (TBI) [4,5,6,7,8]. To overcome graft rejection, we investigated the outcomes of patients who underwent UCBT for SAA using a new TBI-free intensified immunoablative regimen based on the standard conditioning regimen of cyclophosphamide (CY) 200 mg/kg .
Fifteen consecutive acquired SAA patients who underwent UCBT between October 2013 and November 2018 were analyzed in this retrospective study. Data collected as of 28 February 2019. This study was approved by the Ethics Committee of our institute. No patients had a response to previous therapy; nine patients had received immunosuppressive treatment (IST), including cyclosporin A (CsA) and rabbit antithymocyte globulin (ATG), prior to UCBT, whereas the other six patients were treated with CsA only for economic reasons.
All patients received the conditioning regimen of fludarabine (FLU) 180 mg/m2, days −7 to −2 + CY 200 mg/kg days −5 to −2 (FC), and a combination of CsA and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Five patients received an FBC regimen (busulfan (BU) 6.4 mg/kg, days −7 to −6, added to the FC regimen).
The patients’ characteristics and outcomes are summarized in Table 1. Neutrophil engraftment (>0.5 × 109/L) was achieved in 13 out of 15 (86.7%) patients, and the median time to engraftment was 17 days (range, 8–54 days). Platelet engraftment (>20 × 109/L) was observed in 13 patients (86.7%), and the median time to recovery was 23 days (range, 10–80 days). Primary GF was observed in two patients, no patients experienced secondary GF, and sustained engraftment was observed in 13 patients (Table 1). Chimerism analysis showed complete donor chimerism in all 13 patients. Five patients (33.3%) developed grade II-III aGVHD, and three patients (27.3%) developed limited chronic GVHD (cGVHD). To date, twelve of 15 patients are alive. The median follow-up period was 33.8 (range, 3.0–64.5 months) months after UCBT. The causes of death were GF (n = 2) and bacterial/fungal infections (n = 1). The 2-year OS of all patients was 80% (95% CI, 50.0–93.1%) (Fig. 1). To confirm the impact of these favorable factors, we discuss patients into two situations according to the previous treatment and conditioning regimen.
All eight patients (case nos. 1–6, 8, and 9) who were refractory to IST and underwent CBT with the FC regimen achieved engraftment (100%), and seven of eight patients (87.5%) have survived for a median of 46 months (28–64 months); the hematopoiesis returned to completely normal. CY 200 mg/kg is still the standard conditioning regimen for young patients undergoing bone marrow transplantation (BMT) from an HLA-matched sibling. Because the risk of GF is greater with UCBT than BMT, we added FLU 180 mg/m2 to CY 200 mg/kg to form an intensified immunoablative regimen to achieve the engraftment of cord blood in patients with SAA. Our results show that the FC regimen is tolerable. For young patients with IST treatment failure, the regimen can overcome rejection and achieve effective engraftment. In addition, this non-TBI and non-BU regimen prevented possible late adverse effects of irradiation and BU, especially in the more susceptible pediatric and adolescent age groups. Considering that this particular high-risk population achieved such high efficacy, this regimen is promising. There are few reports on the effects of the conditioning regimen on the engraftment rate of UCBT as salvage treatment after IST failure. Early studies showed that the favorable outcome factors were conditioning with FLU, CY and low-dose TBI and the absence of ATG [2, 10]. Peffault de Latour et al.  reported that excellent outcomes, including an 88% engraftment rate and an 84% OS at 2 years, were achieved in 26 SAA patients who were conditioned with FLU, CY, ATG, and TBI 2 Gy; however, GF was still observed in three patients, and rejection is still a problem. Because Tolar et al.  found that high doses of CY (150 mg/kg) and low doses of TBI produced excessive organ toxicity, it is impossible to improve engraftment by increasing the CY dose in this combination. Ochi et al.  increased the TBI dose to 4 Gy in the FLU/CY/TBI combination, and all six patients achieved engraftment. Improvements in these TBI-based regimens have improved the engraftment and survival of UCBT as a salvage therapy.
Of the six patients (case nos. 10–15) who received CsA only before UCBT, two (6/6 matched) children who used the FC regimen developed GF, although the total nucleated cell (TNC) dose was >3.9 × 107/kg. The conditioning regimen, which consisted of BU 6.4 mg/kg + CY 200 mg/kg, was successfully used in haploidentical transplantation for acquired SAA . Based on this study and experience with our FC regimen, we added BU to FC to form the FBC regimen to further overcome the rejection reaction. The remaining four patients plus the one aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome patient (case no. 7), for a total of five patients, used the FBC regimen successfully, achieved engraftment, and have survived for a median of 8 months (3–14 months). The FBC regimen was efficient in terms of UCBT engraftment.
In summary, the immunoablative intensity of the conditioning regimen is positively correlated with successful engraftment in UCBT for SAA.
ATG is widely used for peripheral blood transplantation and BMT in SAA to promote engraftment and in vivo T-cell depletion to prevent GVHD [9, 13]. However, in several studies on CBT, for both malignant  and nonmalignant diseases , both the engraftment and survival rates of conditioning regimens containing ATG were lower than those of regimens not containing ATG. T cells in cord blood are more susceptible to ATG damage and difficult recovery but are critical for engraftment . Without ATG, our infection mortality rate was low: only one patient died of infection, and while 12 patients developed CMV infection, no cases of CMV-related disease occurred, and no posttransplant lymphoproliferative disorders were observed.
The cell dose is an important factor related to engraftment . Although two patients in this study and four of the six patients recently reported  had a TNC dose <3.9 × 107/kg, they still achieved engraftment and survived.
This study has several limitations. Patients were not tested for the presence or absence of cross-reactive antibodies with donor cells before transplantation. Moreover, the cohort was small, the study was retrospective in nature, and the follow-up duration was short. Although this study investigated only 15 patients, the successful outcomes might be helpful when considering the regimen for UCBT; in particular, the addition of FLU 180 mg/kg to the traditional regimen of CY 200 mg/kg significantly improved the engraftment and survival of UCBT as a salvage therapy after IST treatment failure in children and young adults with SAA, and no serious conditioning-related toxicity was observed. Similar to the CY 200 mg/kg regimen, the FC regimen is also TBI-free and easy to carry out; thus, it merits a prospective study to validate the results presented here.
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The authors would like to thank all the patients and their families for participating in this study. The authors would like to thank the physicians, nurses, and support personnel for their care of patients in this study.
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The authors declare that they have no conflict of interest.
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Du, S., He, W., Yang, Y. et al. Unrelated cord blood transplantation for severe aplastic anemia using intensified immunoablative conditioning regimen leading to high engraftment and survival. Bone Marrow Transplant 55, 1677–1680 (2020). https://doi.org/10.1038/s41409-019-0736-5