Our results show a 10-year OS of 74% for patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, which is comparable to that from multicenter studies in other countries (Europe, 69% over 10 years ; Australia and New Zealand, 72% over 5 years ; Brazil, 72% over 5 years ; Colombia, 62% over 5 years ).
We demonstrated the effect of URBM and URCB on the outcome of HCT for non-SCID IEI in Japan. The HCT from URBM was the most frequently performed, showing comparable 10-year OS to that for HCT from MSD (79% vs 81%, respectively). The equivalent outcome for HCT from URBM and MSD has also been reported from other countries [12,13]. Although the incidence of aGVHD was high with HCT from URBM, the excellent survival was partly due to robust hematologic recovery, low retransplantation incidence, and sufficient donor chimerism. The preparation for HCT from URBM takes several months in Japan and is not suitable for urgent transplantation, but our analysis reconfirms that URBM can be considered as a useful alternative donor source for stable patients who have enough time to prepare for HCT.
The OS for URCBT over 10 years was 69%. Although the OS was inferior to that for HCT from MSD, this might be acceptable for patients who require urgent transplantation and do not have MSD. A similar incidence of GVHD in URCBT and HCT from MSD also suggested its utility in Japan. However, the engraftment after URCBT was not robust, as evident from a slow hematologic recovery, high retransplantation incidence, and low donor chimerism. Furthermore, multivariate analyses demonstrated that URCB was an independent risk for poor EFS and retransplantation. Although URCBT for SCID patients in Japan showed excellent outcome, including OS, hematologic recovery, and stable engraftment [submitted], the disadvantage for engraftment is well known in the HCT for hematologic disorders other than SCID [16-20]. Despite the ready availability and feasibility of URCBT, we recognize the risk for poor engraftment for non-SCID IEI as a whole.
For patients who received HCT from ORD, we observed a poor OS/EFS, as well as poor engraftment and a high incidence of cGVHD. In our cohort, post-transplant cyclophosphamide or TCRαβ+/CD19+ depletion, which are beginning to be adopted in haploidentical HCTs for IEIs worldwide [21-26] as well as in Japan , was not used in most of the cases. The introduction of these novel techniques can expectedly help exploit more available donors and also improve the outcome of HCT from ORD in the coming decades. Furthermore, gene therapy (GT) for numerous IEIs, including SCID, WAS, CGD, and leukocyte adhesion deficiency, is being developed . Promising results for these novel approaches should improve the prognosis of IEI patients without suitable donors.
We analyzed the association of conditioning regimens and the outcomes of HCT. In the recent decade, RIC regimens have been commonly chosen. The OS, retransplantation incidence, and donor chimerism for RIC regimens were not significantly different from those for MAC regimens, indicating sufficient efficacy of RIC regimens. This was also true in the analysis for each disease category. Although we did not observe a difference in HCT-related complications between the two regimens, MAC regimens were more commonly associated with death from infection; and we speculate that strong tissue injury associated with MAC, such as mucosal damage, probably contributed to it. RIC regimens potentially reduce short- and/or long-term conditioning-related toxicities and are considered suitable in HCT for IEI.
We also demonstrate that respiratory impairment at HCT was an independent risk for OS. The strong association between respiratory impairment and infection implied that the infection was responsible for dyspnea in most of the patients. Unlike for SCID patients in western countries [10,12] and Japan [submitted], the presence of infection alone was not associated with poor survival, but infection and subsequent pulmonary damage could be a risk. The management of non-infectious manifestations is equally important as the control of infectious events before HCT. For instance, it is well known that the remission status of hemophagocytic syndrome is associated with good survival after HCT [29,30]. Several targeted therapies have been developed for IEI in recent years, such as anti-interferon-γ antibody for hemophagocytic lymphohistiocytosis , JAK inhibitor for hemophagocytic lymphohistiocytosis , or STAT1 or STAT3 gain-of-function , CTLA4-Fc fusion protein for CTLA4 haploinsufficiency  or LRBA deficiency , and PI3K inhibitor for activated PI3Kδ syndrome . Those novel pharmacological treatments are expected to control the disease activity as bridging therapies before HCT.
Besides the results for non-SCID IEI as a whole, IEI comprises heterogeneous diseases and each disorder is associated with a different background of the patients (Fig. S1 and Table S1) or outcome of HCT (Fig. S3). In patients with WAS, the similar outcomes for URBM and MSD confirmed that URBM was preferable as an alternative donor. We also show that OS or incidence of retransplantation after URCBT for WAS patients was not different from that for HCT from MSD, suggesting the potential of URCB as a candidate donor as well. The availability of URCB for WAS patients was consistent with the finding from studies from western countries [37,38]. Busulfan-based RIC regimen is effective for WAS patients in terms of survival and donor engraftment , and our results are consistent with this finding.
The interval between diagnosis and HCT was the shortest for patients with hemophagocytic syndrome compared with that for patients with other diseases, indicating the urgency for HCT. URCB was the most commonly chosen for these diseases probably owing to rapid availability. The 10-year OS for URCBT was 58%, which was similar to that reported from Europe  and Japan ; however, it was not satisfactorily compared to the 10-year OS for HCT from MSD (79%), and the incidence of retransplantation was higher in URCBT than for HCT from MSD. Further approaches, including optimal conditioning regimen, exploring indication of haplo-HCT with post-transplant cyclophosphamide , or better pre-HCT disease control using molecular-targeted therapies [31,32], would be necessary for improving the management of HCT in the coming decades.
In patients with phagocytic disorder, the outcome for HCT from URBM and MSD was equivalent. Moreover, this disease category showed a risk for retransplantation as well as poor EFS, and URCBT for these diseases showed a significant risk for retransplantation. The patients were more commonly complicated with infection or respiratory impairment at HCT (Table S1), which may also pose a risk for infection, concerning poor engraftment in URCBT. URCBT for CGD patients is reported to have poor engraftment in studies from Japan  and European countries , which is consistent with our results. Because the time between diagnosis and HCT was relatively long and urgent HCT is considered rare, URCB may be used for these diseases only on limited occasions. We also observed the non-inferiority of the RIC regimen to MAC regimen for phagocytic disorders. Recently, the prospective clinical trials have shown that a fludarabine/busulfan-based RIC regimen is effective in CGD patients [44,45]. To reduce regimen-related toxicity, especially in recipients with concomitant infection, RIC is recommended for these diseases.
We provided some insights for preferred management of HCT for some disease categories. To establish a better disease-specific management, it is important to conduct a precise evaluation for each disease through retrospective analyses, or possibly through prospective studies. Moreover, novel therapeutic modalities including GVHD prophylaxis, GT, or molecular targeted approaches are being established with a sufficient number of patients, requiring revision of the current strategies for each IEI.
Our study has several limitations. First, some important information, such as precise genotype of the diseases was not available in the TRUMP registry for the patients who received HCT in the earlier period, which might have reduced the sample size and affected the analyses. Second, the TRUMP registry was not oriented for the HCT for IEI; some disease-specific complications that might affect the outcome of HCT were missing (e.g., colitis for WAS, CGD, or XIAP deficiency, and autoimmunity for WAS or CTLA4 haploinsufficiency). The data of immunologic reconstitution after HCT, such as lineage specific chimerism or discontinuation of immunoglobulin were also unavailable. Third, a precise analysis of each disease was not performed. For further detailed analysis, we have already published retrospective studies for each IEI from Japan [42,46,47] and will also perform such studies for other diseases in the future on behalf of the Hereditary Disorder Working Group of the JSTCT, collaborating with the Primary Immunodeficiency Database in Japan  and the TRUMP.
In conclusion, we present an overview of the backgrounds and outcome of HCT for non-SCID IEIs in Japan with a large number of patients for sufficient statistical power. We demonstrate that the OS for HCT from URBM and MSD was almost equivalent in Japan, confirming URBM as an alternative donor source in HCT for non-SCID IEI. URCBT, which was also commonly performed in Japan, showed substantial applicability for some diseases but has a high risk for poor engraftment. We also demonstrate the efficacy of RIC regimens and highlight the importance of disease control before HCT. These results should contribute to the development of future management strategies for IEIs in Japan. Furthermore, detailed evaluation for individual IEI, along with recent advances in novel therapeutic approaches, needs to be addressed for establishing an optimal HCT strategy for each disease.