Repeated apheresis donations cause important iron deficiency in male Japanese donors.

BACKGROUND AND OBJECTIVES: In Japan, apheresis donation of plasma is allowed to a maximum of 24 times a year, and plateletpheresis are counted as two plasmapheresis donations. Diversion of the initial blood flow is conducted for all donations, and additionally, blood remaining in apheresis machine circuit is lost. Here, we aimed to investigate on the health impact of frequent apheresis donations, as measured by the serum ferritin (sFer). MATERIALS AND METHODS: A total of 538 male apheresis donors and 538 age-matched whole blood (WB) donors, who gave informed consent to join the study, were enrolled. sFer were compared, according to age. Another group of 19 apheresis donors were followed during four consecutive donations. RESULTS: About half (48%) of repeat male apheresis donors had iron deficiency (sFer < 26 ng/mL), compared with lower rates (13.9%) among male WB donors. It was evident in all age groups, except for teenagers, possibly because of the lower number of donations. Follow-up of the 19 donors for 4 months revealed a progressive decrease in sFer. CONCLUSION: Blood remaining in the apheresis machine circuit and diversion of the initial blood flow have been implicated in iron deficiency for many years. Taking the present results, the manufacturer of apheresis equipment was requested to improve it to allow rinseback of the remaining blood, which was achieved only for plateletpheresis. Until further improvement, plasmapheresis frequency was reduced to 12 times a year. Additional measures, such as oral supplementation of iron, need to be considered.

Associations between acute and chronic graft-versus-host disease.

ABSTRACT: Chronic graft-versus-host disease (GVHD) is 1 of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Although various risk factors for chronic GVHD have been reported, limited data are available regarding the impact of acute GVHD on chronic GVHD. We examined the association between acute and chronic GVHD using a Japanese registry data set. The landmark point was set at day 100 after allo-HCT, and patients who died or relapsed before the landmark point were excluded. In total, 14 618 and 6135 patients who underwent allo-HCT with bone marrow or peripheral blood (BM/PB) and with umbilical cord blood (UCB), respectively, were analyzed. In the BM/PB cohort, the risk for chronic GVHD that requires systemic steroids increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [hazard ratio (HR), 1.32; 95% confidence interval (CI), 1.19-1.46; P < .001]; grade 1 vs 2 [HR, 1.41; 95% CI, 1.28-1.56; P < .001]), but the risk was similar between acute GVHD grade 2 and grade 3 to 4 (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0). These findings were confirmed in the UCB cohort. We further observed that the risk for severe chronic GVHD increased with each increment in the grade of acute GVHD, even between acute GVHD grade 2 and grade 3 to (grade 2 vs 3-4: HR, 1.70; 95% CI, 1.12-2.58; P = .025). In conclusion, the preceding profiles of acute GVHD should help to stratify the risk for chronic GVHD and its severity, which might be useful for the development of risk-adopted preemptive strategies for chronic GVHD.

Superiority of BM over PBSC for recipients with pre-transplant lung dysfunction in HLA-matched allogeneic HCT.

BACKGROUND AIMS: Pre-transplant lung dysfunction is known to be a risk factor for non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT). It is unclear which cell source gives better outcomes for patients with pulmonary dysfunction. METHODS: We analyzed 3289 adult patients with standard-risk disease who had received HLA-matched allo-HCT, and compared outcomes between those who received peripheral blood stem cell (PBSC) vs. bone marrow (BM) in two cohorts based on the presence of a lung score by the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI): the Lung-scored (LS) and non-LS cohorts. RESULTS: In the LS cohort, the 2-year overall survival (OS) in the BM group tended to be higher than that in the PBSC group (72.4% vs. 61.4%; P = 0.044). In the non-LS cohort, there was no significant difference between the two groups (71.7% vs. 73.2%; P = 0.13). Multivariate analyses confirmed that PBSC was significantly associated with inferior OS in the LS cohort (hazard ratio [HR], 1.66; 95% CI, 1.09-2.54; P = 0.019). On the other hand, the cell source did not affect OS in the non-LS cohort (HR, 0.92; 95% CI, 0.76-1.12; P = 0.41). We found that PBSC was associated with an increased risk of NRM in the LS cohort (HR, 2.17; 95% CI, 1.16-4.05; P = 0.016), while the cell source did not significantly affect NRM in the non-LS cohort. PBSC was not identified as a risk factor for relapse in either cohort. CONCLUSIONS: Our results suggest that BM might be beneficial for recipients with lung dysfunction in HLA-matched allo-HCT.

Iron deficiency among Japanese whole-blood donors measured by serum ferritin.

BACKGROUND AND OBJECTIVES: A more restrictive blood donation criterion has been applied in Japan, with a maximum volume of whole blood (WB) donation of 400 mL, allowing twice a year for female donors and thrice a year for male donors. However, iron deficiency was as high as 20.5% among female donors prior to donation, increasing to 37.7% after blood donation. More than 20 years have passed since then, so we set out to investigate the present situation. MATERIALS AND METHODS: A total of 2659 (male/female: 1496/1163) donors of 400 mL WB who gave informed consent to join the study were enrolled. Serum ferritin (sFer) of first-time/reactivated (FT/RA) donors were compared with those of repeat donors, according to gender and age; those who returned for subsequent donations during the study period were also followed up. RESULTS: About one-third of FT/RA female donors had iron deficiency, possibly reflecting its high incidence among the general population. Interestingly, although sFer levels were low among pre-menopausal FT/RA female donors, these values were not much different in repeat donors, whereas significant differences were observed between FT/RA and repeat donors among post-menopausal females and in most age groups among males. As expected, donors with a normal initial sFer (≥26 ng/mL) recovered faster than those with a low initial sFer. CONCLUSION: Female donors, especially, have iron deficiency even before donation, and the rate increased compared to what was found previously. Measures to prevent iron deficiency of blood donors is required, and studies are going on in Japan.

Criteria for storage of cord blood units at Japan's largest cord blood bank.

BACKGROUND AND OBJECTIVES: In Japan, cord blood transplantations exceed those done with adult-sourced unrelated stem cells. This study analyses cord blood (CB) storage criteria to maintain high-quality CB units. MATERIALS AND METHODS: The Kanto-Koshinetsu Cord Blood Bank received 29,795 units from 2014 to 2021, mostly >60 mL, and 5486 (18.4%) were stored as transplantable units. We investigated the mother's gestational period, CB volume, total nucleated cells (TNCs), CD34+ cells, total colony-forming units (CFUs), time from collection to reception and cryopreservation, cell viability, and the reasons for not storing a unit. RESULTS: The average time from collection to reception of 29,795 units was 18.0 h. The most common reason for not storing a CB unit was low cell numbers (pre-processing TNC count <1.2 billion), accounting for 67.9% of the units received. There was no correlation between the CB volume and the CD34+ cell count. The shorter the gestational period, the lower the TNC count, but the higher the CD34+ cell count. There was no correlation between the time from collection to cryopreservation, within a 36-h time limit, and the CD34+ cell recovery rate. CONCLUSION: We could accept units with a TNC count <1.2 billion and a CB volume <60 mL from a gestational period of 38 weeks or less if we did a pre-processing CD34+ cell count. This would secure more units rich in CD34+ cells.

Association between human herpesvirus-6 encephalitis and antiviral prophylaxis after allogeneic hematopoietic stem cell transplantation in the letermovir era.

The impact of letermovir (LTV)-an anti-cytomegalovirus (CMV) drug-on human herpesvirus-6 (HHV-6) encephalitis is unclear. We hypothesized that LTV prophylaxis may increase the incidence of HHV-6 encephalitis by reducing anti-CMV therapies after allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the association between HHV-6 encephalitis and antiviral prophylaxis, 7985 adult patients from a nationwide registry who underwent their first HSCT between January 2019 and December 2021 were analyzed. The incidence of HHV-6 encephalitis on day 100 after HSCT was 3.6%; 11.5% for the broad-spectrum antiviral group (foscarnet, ganciclovir, or valganciclovir); 2.8% for the LTV group, and 3.8% for the other antiviral group (p < 0.001). These differences persisted when cord blood transplantation (CBT) was analyzed separately (14.1%, 5.9%, and 7.4%, p < 0.001). In the multivariate analysis, CBT (hazard ratio [HR]: 2.90), broad-spectrum antiviral prophylaxis (HR: 1.91), and grade II-IV acute graft-versus-host disease requiring systemic corticosteroids (HR: 2.42) were independent risk factors for encephalitis (all p < 0.001). The findings of this large modern database study indicate that broad-spectrum antiviral prophylaxis, rather than LTV prophylaxis, is paradoxically associated with HHV-6 encephalitis in the LTV era. This paradoxical finding needs to be further explored in future studies.

Center effect on allogeneic hematopoietic stem cell transplantation outcomes for B-cell acute lymphoblastic leukemia.

This nationwide study retrospectively examined the center effect on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia. The cohort analyses were separated into Philadelphia chromosome (Ph)-positive and -negative cases. The patients were divided into low- and high-volume groups according to the number of allo-HSCTs at each facility. The primary endpoint was 5-year overall survival (OS). This study included 1156 low-volume and 1329 high-volume Ph-negative and 855 low-volume and 926 high-volume Ph-positive cases. In Ph-negative cases, 5-year OS was significantly higher in the high-volume centers at 52.7% (95% confidence interval [CI]: 49.9-55.5) versus 46.8% (95% CI: 43.8-49.7) for the low-volume centers (P < 0.01). Multivariate analysis identified high volume as a favorable prognostic factor (hazard ratio [HR]: 0.81 [95% CI: 0.72-0.92], P < 0.01). Subgroup analysis in Ph-negative cases revealed that the center effects were more evident in patients aged ≥40 years (HR: 0.72, 95% CI: 0.61-0.86, P < 0.01) and those receiving cord blood transplantation (HR: 0.62, 95% CI: 0.48-0.79, P < 0.01). In Ph-positive cases, no significant difference was observed between the high and low-volume centers for 5-year OS (59.5% [95% CI: 56.2-62.7] vs. 54.9% [95% CI: 51.3-58.3], P = 0.054). In multivariate analysis, center volume did not emerge as a significant prognostic indicator. This study showed center effects on survival in Ph-negative but not in Ph-positive cases, highlighting the heterogeneity of the center effect in allo-HSCT for B-cell acute lymphoblastic leukemia. Collaborative efforts among transplant centers and further validation are essential to improve outcomes.

RhD mismatch does not affect haematopoietic recovery, graft-versus-host disease and survival in allogeneic haematopoietic cell transplantation: A Japanese registry-based study.

BACKGROUND AND OBJECTIVES: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated. MATERIALS AND METHODS: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database. RESULTS: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis. CONCLUSION: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT.

Machine Learning Prediction Model for Neutrophil Recovery after Unrelated Cord Blood Transplantation.

Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. A predictive model for neutrophil recovery after single-unit CBT was developed by using a machine learning method, which can handle large and complex datasets, allowing for the analysis of massive amounts of information to uncover patterns and make accurate predictions. Japanese registry data, the largest real-world dataset of CBT, was selected as the data source. Ninety-eight variables with observed values for >80% of the subjects known at the time of CBT were selected. Model building was performed with a competing risk regression model with lasso penalty. Prediction accuracy of the models was evaluated by calculating the area under the receiver operating characteristic curve (AUC) using a test dataset. The primary outcome was neutrophil recovery at day (D) 28, with recovery at D14 and D42 analyzed as secondary outcomes. The final cord blood engraftment prediction (CBEP) models included 2991 single-unit CBT recipients with acute leukemia. The median AUC of a D28-CBEP lasso regression model run 100 times was .74, and those for D14 and D42 were .88 and .68, respectively. The predictivity of the D28-CBEP model was higher than that of 4 different legacy models constructed separately. A highly predictive model for neutrophil recovery by 28 days after CBT was constructed using machine learning techniques; however, identification of significant risk factors was insufficient for outcome prediction for an individual patient, which is necessary for improving therapeutic outcomes. Notably, the prediction accuracy for post-transplantation D14, D28, and D42 decreased, and the model became more complex with more associated factors with increased time after transplantation.

Updated comparable efficacy of cord blood transplantation for chronic myelomonocytic leukaemia: a nationwide study.

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.

The effect of center experience on allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia.

This study aimed to address the prognostic impact of center experience based on the data of 7821 adults with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2019 in Japan, where medical care was provided within a uniform healthcare system. Center experience was defined based on the number of allogeneic HCTs performed for any indication during the study period, by which centers were divided into low-, intermediate-, and high-volume centers. After adjusting for known confounding factors, the risk of overall mortality was lowest for the high-volume centers and highest for the low-volume centers, with the difference between the center categories attributed primarily to the risk of relapse. Patients transplanted at high-volume centers had higher risks of acute and chronic graft-versus-host diseases but without an increased risk of non-relapse mortality (NRM). These findings reveal the presence of a center effect in allogeneic HCT conducted during the past decade in Japan, highlighting the difference in relapse based on center experience. The weaker effect on NRM compared with that on relapse suggests that the transplantation care quality is becoming equalized across the country.

Development of an umbilical cord blood transplantation-specific nonrelapse mortality risk assessment score.

ABSTRACT: Higher rate of nonrelapse mortality (NRM) remains yet to be resolved in umbilical cord blood transplantation (UCBT). Considering that UCBT has some unique features compared with allogeneic hematopoietic cell transplantation from other graft sources, a UCBT-specific NRM risk assessment system is required. Thus, in this study, we sought to develop a UCBT-specific NRM Risk Assessment (CoBRA) score. Using a nationwide registry database, we retrospectively analyzed 4437 recipients who had received their first single-unit UCBT. Using the backward elimination method, we constructed the CoBRA score in a training cohort (n = 2687), which consisted of recipients age ≥55 years (score 2), hematopoietic cell transplantation-specific comorbidity index ≥3 (score 2), male recipient, graft-versus-host disease prophylaxis other than tacrolimus in combination with methotrexate, performance status (PS) 2 to 4, HLA allele mismatch ≥ 2, refined Disease Risk Index high risk, myeloablative conditioning, and CD34+ cell doses < 0.82 × 105/kg (score 1 in each). The recipients were categorized into 3 groups: low (0-4 points), intermediate (5-7 points), and high (8-11 points) groups according to the CoBRA score. In the validation cohort (n = 1750), the cumulative incidence of NRM at 2 years was 14.9%, 25.5%, and 47.1% (P < .001), and 2-year overall survival (OS) was 74.2%, 52.7%, and 26.3% (P < .001) in the low, intermediate, and high groups, respectively. In summary, the CoBRA score could predict the NRM risk as well as OS after UCBT. Further external validation will be needed to confirm the significance of the CoBRA score.

Impact of Center Volume on Chronic Graft Versus Host Disease in Patients With Allogeneic Stem Cell Transplantation.

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT), negatively impacting quality of life (QoL) and increasing the risk of death. Complexity in cGVHD diagnosis and treatment causes significant variations in cGVHD management strategies across medical centers and physicians despite the existence of published guidelines. Thus, we hypothesized that center volume is associated with cGVHD incidence and outcomes after cGVHD develops. This study aimed to evaluate the effect of center volume on the incidence of cGVHD in patients who underwent HSCT and outcomes in patients with cGVHD. Our retrospective study included 28,786 patients who underwent their first HSCT (overall cohort) and 7664 who developed cGVHD (cGVHD cohort). We categorized institutions into quartiles (very low, low, high, and very high) using the number of HSCTs performed during the study period. We assessed cGVHD incidence in overall cohort and overall survival (OS) in cGVHD cohort. The very high-volume group showed significantly higher cGVHD incidence (adjusted hazard ratio [HR], 1.38; 95% confidence interval [CI]: 1.30 to 1.46) compared to the very low-volume group. However, the cGVHD incidence was similar among very low-, low- and high-volume groups. Low, high, and very high-volume groups showed significantly higher OS with adjusted HRs of 0.83 (95% CI: 0.73 to 0.94), 0.69 (95% CI: 0.61 to 0.79), and 0.68 (95% CI: 0.60 to 0.76), respectively, compared with the very low-volume group. In conclusion, we revealed a higher incidence of cGVHD in the very high-volume group and a poor survival outcome in the very low-volume group in patients with cGVHD.

Development and validation of a scoring system to predict vasovagal reaction upon whole-blood donation.

BACKGROUND AND OBJECTIVES: Risk factors for vasovagal reaction (VVR) have been extensively studied. With knowledge of the relative importance of these risk factors for VVR, collection staff could take care of blood donors from the same standpoint, leading to improved donor safety. We therefore developed a scoring system to predict VVR, which incorporates registration information. MATERIALS AND METHODS: Pre-syncopal and syncopal symptoms, as well as on- and off-site reactions, are included in this analysis as VVR. We defined the donor status as follows: first-time donors, repeat donors with no history of reaction and repeat donors with a history of reaction. We prepared two datasets: whole-blood donations at a blood donation site in Tokyo between January 2019 and December 2019 were included in training data (n = 361,114), and whole-blood donations between January 2020 and August 2020 were included in testing data (n = 216,211). RESULTS: The most important variable was the donor status, followed by age, estimated blood volume and height. We integrated them into a scoring system. Training and testing datasets were combined (n = 577,325), and VVR rates in groups with scores of 0, 1, 2, 3, 4 and 5 or more were 0.09% (95% CI: 0.081%-0.10%), 0.33% (95% CI: 0.31%-0.36%), 0.87% (95% CI: 0.78%-0.96%), 1.17% (95% CI: 1.05%-1.30%), 2.15% (95% CI: 1.98%-2.32%) and 3.11% (95% CI: 2.90%-3.34%), respectively. CONCLUSION: The scoring system enables staff to significantly predict VVR and may help them to identify donors at increased risk of experiencing syncope, thereby mitigating the negative impact of VVR on donor safety and return by paying close attention to high-risk donors.

Scoring system for optimal cord blood unit selection for single cord blood transplantation.

BACKGROUND: We conducted a retrospective study to categorize the cord blood unit (CBU)s to identify the optimal units. METHODS: A total of 8503 adults (female, n = 3592; male, n = 4911) receiving their first single cord blood transplantation (CBT) in 2000-2019 were analyzed. Factors associated with CBUs affecting overall survival (OS) and neutrophil engraftment were selected to create ranked categorization for each outcome, followed by comparison with transplantation using HLA-matched bone marrow (BMT)/peripheral blood stem cell (PBSCT) from unrelated (n = 6052) and related donors (n = 4546). RESULTS: Sex-mismatch, CD34+ cell and CFU-GM counts were selected in the OS analysis. Considering the strong interaction between sex mismatch and CD34+ cell counts, we analyzed females and males separately. For females, female CBU with CD34+ cell counts {greater than or equal to} 0.5 × 10e5/kg and CFU-GM counts {greater than or equal to} 15 × 10e3/kg offered the best OS (Group I), followed by other groups with any (Groups II-IV) or all (Group V) of the risk factors. Group I consistently showed favorable OS (Group IV: HR1.22, P = 0.027; Group V: HR1.31, P = 0.047), comparable to those of rBMT/PBSCT (OS: HR1.02, P = 0.654) and uBM/PBSCT in patients with higher rDRI (HR1.07, P = 0.353). Male patients lacked significant factors affecting OS. Categorization for neutrophil engraftment consisting of CD34+ cell and CFU-GM counts, sex-mismatch, presence of donor-specific antibodies, and the number of HLA-mismatches was effective but not predicted OS. CONCLUSION: Our ranked categorizations sufficiently predicted female OS and engraftment. The best-ranked CBUs offered preferable outcomes comparable to conventional BM/PB donors in female but not in male patients.