Lymphocyte Crossmatch Testing or Donor HLA-DP and -DQ Allele Typing Effectiveness in Single Cord Blood Transplantation for Patients With Anti-HLA Antibodies Other Than Against HLA-A, -B, -C, and -DRB1.

Anti-human leukocyte antigen (HLA) antibodies other than those against HLA-A, -B, -C, and DRB1 are a risk factor for engraftment delay and failure, especially in cord blood transplantation (CBT). The primary objective of this study was to assess the impact of the presence of anti-HLA antibodies on CBT and to evaluate the utility of lymphocyte crossmatch testing or additional HLA-DP and -DQ typing of CB units in improving transplant outcomes. We retrospectively assessed the engraftment rates and transplant outcomes of 772 patients who underwent their first CBT at our hospital between 2012 and 2021. Donors were routinely typed for HLA-A, -B, -C, and-DRB1 alleles, and the anti-HLA antibodies of recipients were screened before donor selection in all cases. Among patients who had antibodies against other than HLA-A, -B, -C, and DRB1 (n = 58), lymphocyte crossmatch testing (n = 32) or additional HLA-DP/-DQ alleles typing of CB (n = 15) was performed to avoid the use of units with corresponding alleles. The median patient age was 57 years (16 to 77). Overall, 75.7% had a high-risk disease status at transplantation, 83.5% received myeloablative conditioning regimens, and >80% were heavily transfused. Two hundred twenty-nine of the 772 recipients (29.6%) were positive for anti-HLA antibodies. There were no statistical differences in the number of infused CD34-positive cells between the anti-HLA antibody-positive and the anti-HLA antibody-negative patients. Of the 229 patients with anti-HLA antibodies, 168 (73.3%) had antibodies against HLA-A, -B, -C, and-DRB1 (Group A), whereas 58 (25.3%) had antibodies against HLA-DP, HLA-DQ, or -DRB3/4/5 with or without antibodies against HLA-A, -B, -C, and -DRB1 (Group B). No patients in both Groups A and B exhibited donor-specific anti-HLA antibodies against HLA-A, -B, -C, and -DRB1. The neutrophil engraftment rate was lower in patients with anti-HLA antibodies than in those without antibodies (89.9% versus 94.1%), whereas nonrelapse mortality (NRM) before engraftment was higher in antibody-positive patients (9.6% versus 4.9%). In patients who received 2 or more HLA allele-mismatched CB in the host-versus-graft (HVG) direction (n = 685), the neutrophil engraftment rate was lower in the anti-HLA antibody-positive recipients than in the antibody-negative recipients with significant differences (88.8% versus 93.8%) (P = .049). Similarly, transplant outcomes were worse in the antibody-positive patients with respect to 2-year overall survival (OS) (43.1% versus 52.3%) and NRM (44.0% versus 30.7%) than in the antibody-negative patients. In contrast, the results of Group B were comparable to those of the antibody-negative patients, while those of Group A were statistically worse than the antibody-negative patients in terms of all engraftment rate (88.6%), OS (34.2%), and NRM (49.0%). The presence of anti-HLA antibodies negatively impacts engraftment, NRM, and OS in CBT. However, HLA-DP/-DQ allele typing of CB units or lymphocyte crossmatch testing could be a useful strategy to overcome poor engraftment rates and transplant outcomes, especially in patients with anti-HLA antibodies against HLA-DP, HLA-DQ, or -DRB3/4/5.

Long-term lymphocyte subset number reconstitution is unique but comparable between umbilical cord blood and unrelated bone marrow transplantation.

The number of umbilical cord blood transplantation (U-CBT) procedures has been growing annually, but little research has been done on long-term immune recovery after U-CBT. Infection risk is high in U-CBT recipients, and this can be partially attributed to immature immunocompetent cells in umbilical cord blood. In this study, we analyzed lymphocyte subset (LST) number to determine the long-term recovery timeline. We included 36 U-CBT and 10 unrelated bone marrow transplantation (U-BMT) recipients who survived more than 2 years after transplantation, and followed them for up to 10 years post-transplant. Recovery kinetics in the early phase post-transplant was different for each LST. Recovery of CD19+ B cells was faster after U-CBT than after U-BMT in the first 5 years after transplantation. Although CD4+ T cells increased in the first several months after U-CBT, long-term cell count recovery was impaired in approximately 20% of patients. Thus, although the LST recovery pattern after U-CBT was unique, LST number recovery was statistically comparable between U-CBT and U-BMT past 5 years post-transplantation.

A case report of a truncated ABL1 mutation in 2 cases with Philadelphia chromosome-positive B cell precursor acute lymphoblastic leukemia.

Acquired point mutations in the ABL1 gene are widely recognized as a cause of Philadelphia chromosome-positive B cell precursor acute lymphoblastic leukemia (Ph+ B-ALL) that is resistant to tyrosine kinase inhibitors, whereas there are few reports about other types of the ABL1 mutation. Here, we report 2 cases of Ph+ B-ALL gaining a partial deletion type mutation of the ABL1 gene (Δ184-274 mutation), which resulted in truncation of the ABL1 molecule and loss of kinase activity. In both cases, the disease was refractory to multiple agents in the recurrent phase after allogeneic hematopoietic cell transplantation. This is a case report of a truncated ABL1 mutation in 2 patients with Ph+ B-ALL.

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.

The clinical impact of the ratio of C-reactive protein to albumin (CAR) in patients with acute- and lymphoma-type adult T-cell leukemia-lymphoma (ATL).

Recently, the ratio of C-reactive protein to albumin (CAR) is used as an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in solid tumors and hematological malignancy. However, no studies of the CAR have been performed in patients with adult T-cell leukemia-lymphoma (ATL). We retrospectively analyzed the clinical features and outcomes in 68 newly diagnosed acute- and lymphoma-type ATL [(acute-(n=42) or lymphoma-type (n=26)] patients in Miyazaki Prefecture from 2013 to 2017. Furthermore, we investigated correlations between pretreatment CAR levels and clinical features. The median age was 67 years (range, 44 - 87). Patients were initially treated by either palliative therapy (n=14) or chemotherapy [n=54; CHOP therapy (n=37)/ VCAP-AMP-VECP therapy (n=17)], and showed median survival durations of 0.5 months and 7.4 months, respectively. The factors affecting OS by multivariate analysis were age, BUN, and CAR. Importantly, we revealed that the high CAR group (optimal cut-off point; 0.553) was a significant indicator of worse OS by multivariate analysis (p< 0.001, HR; 5.46). The median survival of patients with a CAR< 0.553 was 8.37 months, while patients with a CAR>0.553 had a median survival of 3.94 months. The different clinical features between high CAR and low CAR groups were hypoproteinemia and the implementation of chemotherapy. Furthermore, in the chemotherapy group, but not the palliative therapy group, CAR was a significant prognostic marker. Our study indicated that CAR may be a new simple and significant independent prognostic marker in acute- and lymphoma-type ATL patients.

Clinical and microbiological characteristics of bacterial meningitis in umbilical cord blood transplantation recipients.

Bacterial meningitis is a rare but severe infectious complication after hematopoietic stem cell transplantation. However, its clinical features were previously not clear. We reviewed the cases of 7 patients diagnosed with bacterial meningitis with a positive cerebrospinal fluid culture among 1147 patients who underwent cord blood transplantation (CBT) at our institution between September 2007 and September 2020. The diagnosis was made on day + 5- + 45, and 5 patients developed bacterial meningitis before neutrophil engraftment. The causative organisms were all Gram-positive cocci: Enterococcus faecium and Enterococcus gallinarum (2 patients each), and Staphylococcus haemolyticus, Streptococcus mitis/oralis, and Rothia mucilaginosa (1 patient each). Six patients developed bacterial meningitis secondary to prior or concomitant bacteremia caused by the same bacterium. Five patients had received anti-MRSA agents at onset: vancomycin in 3, teicoplanin in 1, and daptomycin in 1. After diagnosis of bacterial meningitis, linezolid was eventually used for 6 patients. Two patients with E. gallinarum were alive at day + 1380 and + 157 after CBT, respectively, whereas 5 patients died 17-53 (median 43) days after the onset of bacterial meningitis. Breakthrough meningitis in CBT can occur even during the use of anti-MRSA drugs, and intensive antibiotic treatment is necessary.

Cord blood index predicts engraftment and early non-relapse mortality in adult patients with single-unit cord blood transplantation.

How to select optimal cord blood (CB) remains an important clinical question. We developed and validated an index of CB engraftment, the cord blood index (CBI), which uses three weighted variables representing cell doses and HLA mismatches. We modeled the neutrophil engraftment time with competing events by random survival forests for competing risks as a function of the predictors: total nucleated cells, CD34, colony-forming units for granulocytes/macrophages, and the number of HLA mismatches at the antigen and allele levels. The CBI defined three groups that had different neutrophil engraftment rates at day 30 (High, 83.7% [95% CI, 79.2-88.1%]; Intermediate, 77.0% [95% CI, 73.7-80.2%]; Low, 68.4% [95% CI, 63.6-73.2%]), platelet engraftment rates at day 60 (High, 70.4% [95% CI, 64.9-75.9%]; Intermediate, 62.3% [95% CI, 58.5-66.0%]; Low, 49.3% [95% CI, 44.2-54.5%]), and non-relapse mortality at day 100 (High, 14.1% [95% CI, 9.9-18.3%]; Intermediate, 16.4% [95% CI, 13.5-19.3%]; Low, 21.3% [95% CI, 17.1-25.5%]). This novel approach is clinically beneficial and can be adopted immediately because it uses easily obtained pre-freeze data of CB.

Transfusion-associated circulatory overload and high blood pressure: A multicentre retrospective study in Japan.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is an adverse reaction associated with a high risk of mortality. The actual incidence of TACO and hypertension associated with transfusion in Japan is unknown. METHODS: A multicentre retrospective observational study was conducted across 23 institutions during the 1-year period of 2016. Patients were included if they developed TACO or their blood pressure (either systolic or diastolic) increased by at least 30 mmHg during the transfusion. TACO was confirmed by the primary physicians and transfusion medicine teams and recorded in the data on passive surveillance, and additional data were extracted from electronic medical records. RESULTS: In our patient cohort of 31 384 patients who underwent transfusion, the incidence of TACO and hypertension was 0·03% and 0·2%, respectively. However, 43% of the participating institutions didn't report any cases. When comparing risk factors between the TACO and hypertension groups, there were significant differences in comorbidities, such as abnormal findings on chest x-ray. Significant differences between the two groups were observed post-transfusion pulse rate, body temperature and oxygen saturation (P < 0·01). In the group of patients with hypertension, the level of BNP increased significantly after transfusion in 45% (5/11) of the patients. We identified 4 patients in the hypertension group who met the new ISBT's TACO criteria. CONCLUSION: Our study suggests that more attention should be given to TACO in Japan, particularly in terms of improving surveillance systems. For the early diagnosis of TACO, it is crucial to carefully monitor vital signs including blood pressure.

The impact of graft cell source on bloodstream infection in the first 100 days after allogeneic hematopoietic cell transplantation.

Bloodstream infection (BSI) is a major infectious complication after allogeneic hematopoietic cell transplantation (HCT). To clarify the impact of graft cell source on the incidence of BSI after transplantation, we retrospectively examined 782 adult patients receiving their first allogeneic HCT: 122 recipients of related peripheral blood stem cells or bone marrow, 215 recipients of unrelated bone marrow, and 445 recipients of unrelated umbilical cord blood (U-CB). The cumulative incidence of BSI was 42.5% at 100 days after transplantation (95% confidence interval, 39.0-46.0). Gram-positive cocci were present in 64.2% of detected isolates. Among the pre-transplant factors including age, performance status, primary disease, disease status, graft cell source, sex and ABO blood type matching, and the intensity of conditioning regimen, U-CB use was identified as the most significant risk factor for BSI by multivariate analysis (hazard ratio, 1.76; 95% confidence interval, 1.40-2.22; p < 0.00001). Among the U-CB recipients, those who are not in remission at the time of transplantation were at the greatest risk of BSI (hazard ratio, 1.69; 95% confidence interval, 1.14-2.50; p < 0.01). The study makes it clear that graft cell source has an impact on BSI development after allogeneic HCT.

Prognostic Impact of Cytogenetic Evolution on the Outcome of Allogeneic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in Nonremission: A Single-Institute Analysis of 212 Recipients.

Recent progress in genetic analysis technology has helped researchers understand the pathogenesis of acute myeloid leukemia (AML). Considering this progress, AML karyotype is still one of the most significant prognostic factors that provides risk-adapted treatment approaches. Karyotype changes during treatment have been observed at times, but their prognostic impact is sparse, especially on allogeneic stem cell transplantation (allo-SCT). Here, we retrospectively investigated the effect of chromosomal changes between diagnosis and pretransplantation on the prognosis of allo-SCT by analyzing the outcomes of 212 consecutive patients who underwent allo-SCT for the first time at Toranomon Hospital, Tokyo, Japan, between 2008 and 2018. Cytogenetic abnormalities at diagnosis and pretransplantation were categorized based on the 2017 European Leukemia Net risk stratification. Genetic abnormalities such as FLT3-ITD and NPM1 were not considered in this study due to lack of genetic information in most patients. We defined cytogenetic evolution as chromosomal changes classified from lower category to higher category. Seventeen patients (8%) had cytogenetic evolution between diagnosis and pretransplantation, and they showed a significantly worse relapse rate than those who were categorized in the intermediate group based on the karyotype at diagnosis (3-year confidence interval [CI] of relapse, 57.4% versus 24.9%; P < .01). In multivariate analysis, cytogenetic evolution before allo-SCT had a significant impact on the CI of relapse (hazard ratio [HR], 3.89; CI, 1.75 to 8.67; P < .01), as well as the high score of the hematopoietic cell transplantation-specific comorbidity index (HR, 0.54; CI, 0.31 to 0.94; P = .03), but had no significant impact on overall survival or nonrelapse mortality. These results indicate that cytogenetic evolution has a significant impact after allo-SCT and should be considered during AML treatment.

Differences among hemoglobin thresholds for red blood cell transfusions in patients with hematological diseases in teaching hospitals: a real world data in Japan.

A hemoglobin (Hb) threshold level of 7 g/dL has been proposed for red blood cell (RBC) transfusion in patients with chronic anemia in the Japanese guideline since 2005. However, Hb thresholds for hematological diseases in clinical practice and factors responsible for higher Hb thresholds remain unclear. Hb thresholds were collected for patients with hematological diseases from 32 Japanese teaching hospitals. Uni- and multivariate analyses were used to analyze relationships between Hb threshold level and various patient and hospital factors. In total, 4996 units of RBC were transfused to 1054 patients with hematological diseases in 2421 transfusions. Median age was 68 years. Myelodysplastic syndrome was the most frequent diagnosis. Overall median Hb threshold level was 6.9 g/dL. Multivariate linear regression analysis detected the following variables associated with Hb threshold level: hospital; cardiovascular disease; symptomatic anemia; and hematopoietic stem cell transplantation. Hospital was the most significant factor. Collectively, median Hb threshold level in clinical practice in Japan was similar to the guidelines. Higher Hb threshold level depended on the hospitals at which the transfusions were performed as well as patient condition. Educational approaches directed toward hospitals may be useful to promote transfusion guidelines.

Splenomegaly Negatively Impacts Neutrophil Engraftment in Cord Blood Transplantation.

Delayed neutrophil engraftment (NE) has been reported in cord blood transplantation (CBT) compared with other stem cell transplantation methods. The numbers of total nucleated cells (TNCs), CD34+ cells (generally ≥ 1 × 105/kg), and granulocyte/macrophage colony-forming units (CFU-GM) significantly impact NE. Splenomegaly exerts negative effects on NE, but the appropriate cell dose for the patients with splenomegaly has not yet been determined, especially in CBT. We retrospectively investigated the effect of splenomegaly and number of CD34+ cells infused on NE through the analysis of outcomes of 502 consecutive patients who underwent single CBT for the first time at Toranomon Hospital between 2011 and 2018. Spleen index, Lmax × Hvert (SI Lmax × Hvert), was defined as maximal length at any transverse section, (Lmax) × vertical height (Hvert), and splenomegaly was defined as SI Lmax × Hvert ≥ 115 cm2. Our results show that splenomegaly (hazard ratio [HR], .60; P < .01) and low dose of infused CD34+ cells (HR, .58; P < .01) had significant negative impact on NE, whereas neither CFU-GM dose nor TNC dose had any impact on NE in multivariate analysis. Other factors with a significant negative impact on NE in multivariate analysis were myeloid disease (HR, .62; P < .01), nonremission status at CBT (HR, .71; P < .01), low Eastern Cooperative Oncology Group Performance Status (HR, .68; P < .01), and graft-versus-host disease prophylaxis (other than tacrolimus alone) (HR, .76; P < .01). Without splenomegaly, even patients infused with < .8 × 105/kg CD34+ cells achieved up to 94.3% NE, with the median value observed at 21 days post-CBT. This study shows that splenomegaly has a significant negative impact on NE after CBT. Cord blood units with < .8 × 105/kg CD34+ cells may still be a suitable choice for patients without splenomegaly.

Feasibility of autologous fibrin glue in general thoracic surgery.

BACKGROUND: Fibrin glue effectively controls air leakage in lung surgery; however, allogenic fibrin glue cannot eliminate the risks of infection and allergy despite current sterilization methods. Autologous fibrin glue (AFG) could be a good alternative, but is not commonly used worldwide because of its limited availability and lack of evidence. Herein, we report clinical outcomes of AFG in thoracic surgery. METHODS: We retrospectively analyzed patients who underwent lobectomies or segmentectomies between November 2016 and September 2017 in our institution. We used two types of AFGs. One was a partially-autologous fibrin glue (PAFG), the components of which are largely autologous but which contains allogenic thrombin. The other was a completely-autologous fibrin glue (CAFG) which has no allogenic components. PAFG was used in the first half of the study period, after which CAFG was used from March 2017 onward. Patients who did not undergo AFG generation were categorized as the non-AFG group. The perioperative outcomes of the three groups were evaluated. RESULTS: A total of 207 patients underwent lung surgery, including 118 lobectomies and 89 segmentectomies. Among them, 83 patients received PAFG, 94 received CAFG, and 30 received non-AFG. The mean postoperative drainage period was within a few days in each group (PAFG vs. CAFG vs. non-AFG: 3.23±3.91 vs. 3.16±4.04 vs. 3.17±4.16 days, respectively; P=0.405), and the incidence of postoperative prolonged air leakage was within an acceptable range (PAFG vs. CAFG vs. non-AFG: 13.3% vs. 12.8% vs. 16.7%, respectively; P=0.821). CONCLUSIONS: The use of AFG is clinically feasible for patients who undergo lobectomies or segmentectomies. AFGs could be a viable alternative to conventional allogenic fibrin glues.

Clinical significance of autologous blood transfusions in bone marrow harvest from unrelated donors.

In the Japan Marrow Donor Program (JMDP), autologous blood is collected from most unrelated bone marrow (BM) donors. We retrospectively evaluated 5772 donors who underwent BM harvest between 2010 and 2015 through the JMDP. Autologous blood was collected in 96.8% of the donors; the wastage rate was 0.6%. Allogeneic blood transfusion was not required. The mean hemoglobin (Hb) levels were 12.1 g/dL after the BM harvest (mean 891 mL) together with autologous blood transfusion (mean 596 mL). Propensity-score matching was used to adjust the backgrounds. Among donors with harvested BM of 100-400 mL, autologous blood transfusion had no impact on Hb levels or complications after BM harvest. Among donors with harvested BM of > 400 mL, more autologous blood transfusion followed by a bleeding volume of ≤ 100 mL did not confer clinical benefit to donors compared with less autologous blood transfusion followed by a bleeding volume of > 300 mL. The findings of the present study suggest that autologous blood transfusion to BM donors is excessive in terms of Hb changes and post-harvest outcomes.

Utility of autologous fibrin glue and polyglycolic acid sheet for preventing delayed bleeding associated with antithrombotic therapy after gastric ESD.

Background and study aims Delayed bleeding is one of the most serious adverse events of gastric endoscopic submucosal dissection (ESD), especially in patients taking antithrombotic therapy. This study aimed to evaluate the utility and safety of a shielding method with autologous fibrin glue and polyglycolic acid (PGA) sheets for patients undergoing gastric ESD who are receiving antithrombotic therapy. Patients and methods One hundred twenty-three patients who were treated with gastric ESD while receiving antithrombotic therapy between December 2014 and September 2017 were enrolled in this study. Patients who received the shielding method were classified into the shielding group. Others were classified into the conventional group. Various clinico-pathological factors were retrospectively compared between the two groups. Results The shielding group consisted of 38 patients, and the conventional group consisted of the remaining 85 patients. In the shielding group, the rate of continuation of antithrombotic therapy was significantly higher (68.4 % vs 41.2 %). Incidence of delayed bleeding was lower in the shielding group (2.6 %, 1/38) than in the conventional group (14.1 %, 12/85). In the propensity score-adjusted logistic regression analysis, the delayed bleeding rate in the shielding group tended to be lower than in the conventional group ( P  = 0.070). Allogeneic transfusion was performed in eight patients (8/85, 9.4 %) in the conventional group and none in the shielding group ( P  = 0.047). No adverse event associated with endoscopic shielding were observed in the shielding group. Conclusions This study suggests that a shielding method with autologous fibrin glue and PGA sheet effectively prevents delayed bleeding after gastric ESD in patients receiving antithrombotic therapy.