三﨑 柚季子

Th17, a subset of helper T cells that produce interleukin-17 (IL-17), is thought to play a pivotal role in the pathogenesis of chronic graft-versus-host disease (GVHD). However, the kinetics of Th17 following allogeneic haematopoietic stem cell transplantation (allo-HSCT) have not been elucidated. In this study, we evaluated the temporal dynamics and diversity of peripherally circulating Th17 after allo-HSCT. The study included 86 patients who survived without disease relapse for 1 year or more, and for whom peripheral blood samples 3 months after allo-HSCT were available. Th17 was detected and sorted by flow cytometry, and T-cell receptor (TCR) repertoire was analysed by a next-generation sequencing (NGS) method. Patients with chronic GVHD showed a higher TCR repertoire diversity, while those with severe chronic GVHD showed a lower TCR diversity and Th17/Cluster of Differentiation (CD) 4 ratio. The amino acid sequence in complementarity determining region 3 of Th17-TCR was not apparently different between patients with and without chronic GVHD. Additionally, a higher Th17/CD4 ratio at 3 months was related to a lower incidence of subsequent chronic GVHD. The current study explored the kinetics of peripherally circulating Th17 after allo-HSCT, which might be associated with the development of chronic GVHD.

BACKGROUND: Cytomegalovirus reactivation (CMVR) after allogeneic hematopoietic cell transplantation (allo-HCT) is a reversible event, and conventional indicators such as the simple cumulative incidence cannot reflect transitional CMVR states. We propose a novel indicator, current CMVR (cCMVR), which visualizes both the occurrence and remission of CMVR over time. METHODS: To evaluate the utility of cCMVR, we analyzed 389 CMV seropositive patients who had received their first allo-HCT. cCMVR was defined as the probability of the state where anti-CMV drugs were administered for CMVR or CMV disease without relapse or death at any time. RESULTS: We compared two groups with or without letermovir prophylaxis (LTV and no-LTV groups). The 1-, 2-, 3-, and 6-month cCMVR values were 0.0%, 0.0%, 2.9%, and 2.9% in the LTV group, and 7.1%, 31.9%, 11.0%, and 0.8% in the no-LTV group. In the LTV group, cCMVR never exceeded 10%, while in the no-LTV group, cCMVR peaked at approximately 2 months after allo-HCT, and fewer than 5% of patients developed CMVR after 4 months post-HCT. Next, in the no-LTV group, we assessed cCMVR stratified according to the presence of risk factors for the simple cumulative incidence of CMVR, and this revealed that patients grafted from HLA-mismatched related donors and those who received alemtuzumab for GVHD prophylaxis appeared to experience repeated episodes of CMVR, whereas the early difference in cCMVR according to pretransplant CMV-IgG titer diminished over time. CONCLUSION: cCMVR could be a valuable indicator for visualizing recurrent CMV infection and illustrating differences in the time course of CMVR.

Thioredoxin (TXN) is a component of a major reductive system in various eukaryotes. Although oxidative stress is considered to contribute to the development of acute graft-versus-host disease (GVHD), the clinical significance of TXN remains to be elucidated. The current study included 118 patients who had undergone their first allogeneic haematopoietic stem cell transplantation (allo-HSCT) between 2022 and 2025, and their serum samples at day 0 were sequentially collected (training cohort). The study also assessed 47 patients who had undergone their first allo-HSCT between 2012 and 2015 and whose serum at around day 0 had previously been cryopreserved and was available (validation cohort). The high-TXN group showed a lower cumulative incidence of grade II-IV acute GVHD (100-day incidence: 47.5% vs. 59.2%), although the difference did not reach statistical significance (p = 0.058). The validation cohort demonstrated similar results (0% vs. 35.8%, p = 0.053). However, multivariate analysis revealed that high-TXN group was significantly associated with a reduced risk of acute GVHD (hazard ratio [HR] 0.48, p = 0.031). In addition, the combination of TXN with clinical factors enhanced the predictive potential for acute GVHD compared with that of clinical factors alone (p = 0.0039). TXN might be useful for predicting acute GVHD and could contribute to the establishment of a prediction model.

A 19-year-old woman with acute myeloid leukemia who had received a subcutaneous implantable cardioverter defibrillator (SICD) was scheduled to undergo allogeneic hematopoietic stem cell transplantation (HSCT). The conditioning regimen included total body irradiation (TBI) at a dose of 12 Gy, under which the SICD was considered at high risk for malfunction. We planned to deactivate and reactivate the SICD before and after each TBI session to mitigate the risk of device malfunction. Additionally, SICD shielding measures were implemented during TBI to minimize the risk of malfunction. Through these procedures, HSCT could be performed without significant adverse events linked to the SICD.

Systemic corticosteroids are the standard initial therapy for gastrointestinal graft-versus-host disease (GI-GVHD), but are associated with increased infectious risk and potential attenuation of graft-versus-leukemia effects. Beclomethasone dipropionate (BDP) has minimal gastrointestinal absorption and may provide localized efficacy, but evidence for monotherapy is limited. We retrospectively analyzed 37 patients who underwent first allogeneic hematopoietic cell transplantation and received oral BDP as initial monotherapy for acute GI-GVHD. Treatment response was assessed at days 28 and 56, and treatment failure was defined as initiation of systemic corticosteroids. All patients had stage 0-1 disease. Upper and lower GI-GVHD were observed in 24 (64.9%) and 13 (35.1%) patients, respectively. Response rates at days 28 and 56 were 62.9% and 65.6%. Treatment failure occurred more frequently in patients with lower GI-GVHD, female-to-male transplantation, and reduced-intensity conditioning. BDP monotherapy may be effective for selected patients with mild GI-GVHD, although careful monitoring is required in high-risk populations.

BACKGROUND: We evaluated the relationship between repertoire diversity of IgG-BCR heavy chain and encapsulated bacterial infections after allogeneic hematopoietic cell transplantation. METHODS: Ten patients with such infections (Infection group) and ten matched controls (Control group) were analyzed. Five patients had repeated infections. High-throughput IgG-BCR heavy chain (IgH) sequencing yielded a median of 147,504 in frame reads (minimum 71,867) and 28,248 unique reads per sample. RESULTS: IGHV3-11 and IGHV4-59 usage was significantly lower in the Infection group and showed a stepwise decrease from Control to patients with one infection to those with repeated infections. In patients with repeated infections, reduced IGHV3-IGHJ4 usage and increased IGHV3-IGHJ3/5 usage were observed. In addition, CDR3 amino acid (AA) length distribution differed, with fewer 16-AA and more 17- and 21-AA sequences, sharing similar motifs. CONCLUSIONS: Selective reduction in IGHV3-11 and IGHV4-59 usage and specific CDR3 features may be associated with susceptibility to encapsulated bacterial infections.

Ibrutinib, a Bruton tyrosine kinase inhibitor, has improved outcomes for patients with relapsed or refractory mantle cell lymphoma, yet prognosis remains inadequate for many. The choice between high-dose therapy with autologous hematopoietic cell transplantation (HCT) and allogeneic HCT remains a topic of debate in this patient population. This Japanese retrospective study (2017–2023) analyzed 155 patients with relapsed or refractory mantle cell lymphoma receiving autologous (n = 105) or allogeneic HCT (n = 50). Autologous and allogeneic HCT showed comparable efficacy, with similar median OS (28 vs. 27 months). However, outcome predictors differed significantly. Autologous HCT: age > 60 years predicted worse OS (hazard ratio [HR] = 2.73) and allogeneic HCT: early progression surrogate based on diagnosis-to-HCT interval ≤ 24 months and relapsed or refractory status at HCT (HR = 4.10) and non-complete remission (HR = 3.53) correlated with poorer outcomes. Ibrutinib integration demonstrated critical benefits: post-autologous relapse patients receiving ibrutinib had superior 2-year OS (57% vs. 25%, P = 0.035), and no transplant-related mortality occurred in allogeneic HCT patients on ibrutinib (n = 10). This study confirms HCT use in the ibrutinib era, highlighting age, disease kinetics, and targeted therapy as key prognostic factors, and supports risk-adapted strategies combining HCT with novel agents like ibrutinib to optimize outcomes for high-risk mantle cell lymphoma.

Second allogeneic stem cell transplantation (SCT2) is a potentially curative treatment for relapsed hematological malignancies; however, its outcomes generally remain poor. In this multicenter retrospective study, we aimed to validate the Geriatric Nutritional Risk Index (GNRI) as a prognostic factor for SCT2 and develop a novel scoring system for predicting SCT2 outcomes. We retrospectively analyzed data from 376 patients who underwent SCT2 between 2004 and 2020. Multivariate analysis identified GNRI, disease status, and C-reactive protein (CRP) levels as independent prognostic factors for overall survival (OS). Patients with a high GNRI (≥92.0) had significantly better 3-year OS (36.0% versus 14.3%, P < .001) and lower non-relapse mortality (27.2% versus 50.9%, P < .001) than those with a low GNRI. A novel scoring system incorporating GNRI, disease status, and CRP levels effectively stratified patients into low-, intermediate-, and high-risk groups, with respective 3-year OS rates of 50.7%, 29.5%, and 11.1%. Our findings highlight the importance of nutritional status in SCT2 outcomes and provide a practical tool for risk classification. The inclusion of patient- and disease-specific factors in this scoring system offers new insights into optimizing treatment strategies and improving outcomes following SCT2. Further studies are needed to evaluate interventions based on this approach.

Choosing an optimal alternative donor is an important clinical concern in allogeneic hematopoietic cell transplantation (HCT). In Japan, single-unit umbilical cord blood transplantation (UCBT) has been widely used in the last two decades, whereas HCT from HLA-haploidentical related donors (haplo-HCT) has been increasingly used following the advent of posttransplant cyclophosphamide (PTCY) for graft-versus-host disease (GVHD) prophylaxis. This registry-based study aimed to compare outcomes between single-unit UCBT (n = 848) and PTCY-based haplo-HCT (n = 241) performed during first complete remission in patients with acute myeloid leukemia. UCBT was associated with a lower likelihood of engraftment (P < 0.001), a higher risk of grade 2-4 and grade 3-4 acute GVHD (P = 0.003 each), and a lower risk of extensive chronic GVHD (P = 0.048). The UCBT and haplo-HCT groups did not significantly differ in 3-year probabilities of overall survival (68% versus 69%, P = 0.686), GVHD/relapse-free survival (55% versus 54%, P = 0.866), relapse (14% versus 16%, P = 0.463), and non-relapse mortality (21% versus 19%, P = 0.403), respectively, which were confirmed with multivariate analysis. These results indicate that both procedures should be considered viable options for patients lacking a matched donor.

Although the hematopoietic cell transplantation (HCT)-comorbidity index (HCT-CI) score is associated with an increased risk of mortality after allogeneic HCT, it remains unclear how pre-HCT liver dysfunction affects clinical outcomes. We retrospectively compared clinical HCT outcomes among four groups stratified according to the presence of HCT-CI liver and other organ scores, using a Japan transplant registry database between 2010 and 2020. Of the 14235 recipients, 1527 tested positive for an HCT-CI liver score including HBV or HCV hepatitis (n = 503). The 5-year overall survival (OS) was significantly lower in the HCT-CI liver(+) other(+) and HCT-CI liver(-) other(+) groups compared to the HCT-CI liver(+) other(-) and HCT-CI liver(-) other(-) groups [49.9% vs. 59% vs. 66.5% vs. 68.3%, p < 0.001]. A multivariate analysis showed that both the HCT-CI liver(+) other(+) [HR 1.62, p < 0.001] and HCT-CI liver(-) other(+) groups [HR 1.21, p < 0.001] were significantly associated with inferior OS. Similarly, both the HCT-CI liver(+) other(+) [HR 1.89, p < 0.001] and liver(-) other(+) groups [HR 1.26, p < 0.001] were significantly associated with an increased risk of NRM. On the other hand, the HCT-CI liver(+) other(-) group was not associated with either OS or NRM. Separately analyzing the subcohorts with or without HCT-CI other scores, the presence of an HCT-CI liver score alone did not affect survival, while the co-presence of pretransplant liver dysfunction seemed to synergistically increase the adverse impact on OS and NRM among recipients with other organ comorbidities. Further studies will be needed to identify optimal strategies for recipients with pretransplant liver dysfunction.

Rapid tapering of cyclosporine (CsA) in the early phase after allogeneic transplantation may induce a potent graft-versus-leukemia/lymphoma (GVL) effect. We retrospectively reviewed the outcomes of patients with high-risk hematological malignancies who underwent their first transplantation at our institution. The blood CsA concentration was maintained at around 300 ng/ml. Our planned schedule for tapering CsA in patients without graft-versus-host disease (GVHD) or with limited GVHD was to reduce the dose by 10% per week starting from day 30 for related HSCT or from day 50 for unrelated HSCT. In total, we began tapering CsA in 36, and classified them into 2 an "On-schedule group" or "Delayed group" based on the timing of starting tapering. The cumulative incidences of grade II-IV acute GVHD overall were 33.8% and 39.4% (P = 0.746) in the On-schedule and Delayed groups. The On-schedule group showed no significant difference in non-relapse mortality, but showed a trend toward a higher relapse rate, resulting in significantly worse overall survival (55.6% vs 72.2% at 1y, P = 0.025) and worse disease-free survival (38.9% vs 66.7% at 1y, P = 0.059). These findings suggest that early CsA tapering after HSCT in high-risk patients was not effective.

Talaromyces columbinus was previously reported in two patients with lung infections under the name Penicillium piceum and one case of dual infection with Aspergillus calidoustus was recently reported.; currently, no treatment has been established. We identified a 61-year-old woman with fatal pneumonia with repeated detection of T. columbinus that developed two years after haploidentical transplantation using alemtuzumab for chronic myeloid leukemia in the blast phase. Seven months after transplantation, her minimal residual disease (MRD) turned positive. Thus, ponatinib was restarted, which resulted in MRD becoming negative again. Nine months after transplantation, she developed autoimmune hemolytic anemia (AIHA); treatment with prednisone (PSL) 35 mg was started. PSL was discontinued one year ten months after transplantation, but was resumed at 5 mg after relapse one year eleven months after transplantation. Two years after transplantation, she developed cough, and a CT scan showed bilateral pulmonary infiltrates. Initiation of antibiotics, voriconazole (VRCZ), posaconazole (PSCZ) and liposomal amphotericin B (L-AMB) did not improve her condition. Sputum culture detected Penicillium species, which was identified as T. columbinus by polymerase chain reaction (PCR). Since the minimal inhibitory concentration (MIC)/minimal effective concentration (MEC) ratio was lower for echinocandins, micafungin (MCFG) was added to L-AMB. However, the patient died of respiratory failure on day 38 of admission. This is the first reported case of T. columbinus infection in Japan. Managing this infection is challenging due to the lack of established diagnostic methods and treatments. Proactive diagnostic testing and case accumulation are needed.

We previously reported that the area under the curve of log-transformed cytomegalovirus antigenemia (CMV-AUC) until 100 days after allogeneic hematopoietic cell transplantation (allo-HCT) was associated with an increased risk of non-relapse mortality. We applied a risk-adapted letermovir (LTV) prophylaxis strategy guided by a risk score that predicts a higher CMV-AUC. First, we retrospectively analyzed 278 allo-HCT recipients between 2007 and 2017 (Period 1). We scored risk factors for higher CMV-AUC by odds ratios: malignant lymphoma including adult T cell leukemia/lymphoma (1 point), an unrelated or haploidentical donor (1 point), and recipient/donor CMV serostatus (+/+; 2 points, +/-; 3 points). We have administered LTV to patients with a total score of ≥ 4 points. We then focused on 143 patients who underwent allo-HCT when we applied this strategy (Period 2). Forty patients (28%) in Period 2 received LTV prophylaxis. Two patients (5.4%) exhibited higher CMV-AUC among 37 patients in the higher-risk group (≥ 4 points). However, as many as 33% of the patients with 3 points in Period 2 experienced higher CMV-AUC. Notably, in the lower-risk patients of Period 2, 68% of patients who received systemic steroids for acute graft-versus-host-disease (GVHD) developed higher CMV-AUC. Our risk-adapted LTV prophylaxis strategy effectively prevented higher CMV-AUC in the higher-risk group and reduced the use of LTV. Additionally, including the use of systemic steroids for acute GVHD in this risk-adapted approach is preferable.

BACKGROUND: A change in empirical antibiotics or the addition of glycopeptide antibiotics is often applied in cases of persistent febrile neutropenia (FN) despite the administration of broad-spectrum antibiotics. However, the clinical benefit of these approaches remains unclear. METHODS: We conducted a retrospective study to evaluate the effectiveness of a change in antibiotics or the addition of glycopeptide antibiotics for persistent FN after autologous hematopoietic cell transplantation (auto-HCT). We retrospectively reviewed the records of 208 patients who received auto-HCT at our institution between 2007 and 2019. FN that lasted for 4 days or longer was defined as persistent FN. We compared the time to defervescence between patients whose initial antibiotics were changed and/or who additionally received glycopeptide antibiotics, and those without these antibiotic modifications. RESULTS: Among patients who fulfilled the criteria of persistent FN (n = 125), changes in antibiotics were not significantly associated with the time to defervescence in a multivariate analysis (hazard ratio [HR] 0.72, p = 0.27). On the other hand, the addition of glycopeptide antibiotics was paradoxically associated with a delay in defervescence (HR 0.56, p = 0.033). CONCLUSIONS: Although there may be differences in patient backgrounds, no significant differences were observed in either a univariate or multivariate analysis. Since neither a change in antibiotics nor the addition of glycopeptide antibiotics was associated with earlier defervescence in persistent FN after auto-HCT, routine antibiotic modifications might not be necessary in this setting.

The recent progress with ruxolitinib treatment might improve quality of life as well as overall survival in patients with primary myelofibrosis. Therefore, the optimal timing of allogeneic hematopoietic cell transplantation (HCT) in the ruxolitinib era remains to be elucidated. We constructed a Markov model to simulate the 5-year clinical course of transplant candidates with primary myelofibrosis and compared outcomes between those who underwent immediate HCT and those whose HCT was delayed until after ruxolitinib failure. Since older age was associated with an increased risk of mortality, we analyzed patients aged <60 and ≥60 years separately in subgroup analyses. Life expectancy was consistently longer in the groups undergoing delayed HCT after ruxolitinib failure regardless of the patients' age. Regarding quality-adjusted life years, a baseline analysis showed that immediate HCT was inferior to delayed HCT after ruxolitinib failure (2.19 vs. 2.26). In patients aged <60 years, immediate HCT was equivalent to delayed HCT after ruxolitinib failure (2.31 vs. 2.31). On the other hand, in patients aged ≥60 years, immediate HCT was inferior to delayed HCT after ruxolitinib failure (1.98 vs. 2.21). A one-way sensitivity analysis showed that the utility of being alive without chronic graft-versus-host disease after immediate HCT was the most influential parameter for quality-adjusted life years, and that a value higher than 0.836 could reverse the superiority of delayed HCT after ruxolitinib failure. As a result, delayed HCT after ruxolitinib failure is expected to be superior to immediate HCT, especially in patients aged ≥60 years, and is also a promising strategy even in those aged <60 years.

We report the case of a 65-year-old man who was diagnosed with Bickerstaff brainstem encephalitis prior to central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL). He was diagnosed with DLBCL of the paranasal sinus in June 2022. After treatment with 6 cycles of R-GCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone) and 2 cycles of high-dose methotrexate (HD-MTX), complete remission was confirmed. In June 2023, the patient developed dizziness and was admitted to our hospital. MRI showed FLAIR high-intensity areas extending from the medial part of each thalamus to the pons. Cerebrospinal fluid (CSF) showed increased mononuclear cells, but they were predominantly T-cells. Impairment of consciousness progressed, and thus the patient was treated with HD-MTX based on a presumptive diagnosis of CNS relapse of DLBCL. However, there was no improvement. An anti-GQ1b IgG antibody test was positive, leading to a diagnosis of Bickerstaff encephalitis, and 6 sessions of plasma exchange were performed. Neurological symptoms improved after these treatments, but 2 months later, the left blepharoptosis and ophthalmoparesis reappeared. CSF analysis revealed B-cell clonality, and the patient was diagnosed with CNS relapse. Autoimmune encephalitis should be considered as a differential diagnosis even in patients with lymphoma who are at high risk of CNS invasion.

Clinical research regarding the impact of pretransplantation physical function on transplantation outcomes in older adults remains limited. We retrospectively reviewed the charts of 150 consecutive patients age >55 years who underwent their first allogeneic hematopoietic cell transplantation (HCT) at our center between 2010 and 2021. We evaluated the clinical impact of pretransplantation physical function, including hand grip strength (HGS), knee extension strength (KES), and distance covered in a 6-minute walk test (6MWT), along with other clinical factors, on transplantation outcomes such as overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of disease relapse (CIR). There was no difference in OS, NRM, or CIR among the 3 age groups studied (56 to 60 years, 61 to 65 years, and 66 to 70 years). With regard to physical function tests, we divided the study patients into 2 groups based on the median HGS, KES, and 6MWT values: higher physical function and lower physical function groups. Because there were significant differences in HGS and KES between male and female patients, sex-specific threshold values were used. In a univariate analysis, OS tended to be better in the higher physical function group compared with the lower physical function group (4-year OS, 42.0% versus 32.0% in HGS, P = .14; 44.8% versus 37.8% in KES, P = .17; 46.7% versus 30.5% in 6MWT, P = .099). NRM was significantly lower in the higher physical function group (4-year NRM, 25.5% versus 39.9% in HGS, P = .045; 17.7% versus 38.0% in KES, P = .005; 22.5% versus 43.4% in 6MWT, P = .033). There was no significant difference in CIR between the higher and lower physical function groups (4-year CIR, 34.6% versus 28.7% in HGS, P = .38; 38.5% versus 25.8% in KES, P = .20; 33.0% versus 27.0% in 6MWT, P = .42). In multivariate analysis, the higher KES group (hazard ratio [HR], .54; 95% confidence interval [CI], .32 to .90) was significantly associated with better OS, as were female sex (HR, .48; 95% CI, .26 to .89) and low/intermediate Disease Risk Index (HR, 3.59; 95% CI, 2.04 to 6.31). Higher KES (HR, .37; 95% CI, .17 to .83) and female sex (HR .36; 95% CI, .13 to .998) were significantly associated with a reduced risk of NRM. Higher HGS and higher 6MWT tended to be associated with a reduced risk of NRM, but this trend was not statistically significant. Pretransplantation physical function, particularly the strength of the lower extremities, but not chronological age, is associated with NRM and OS after allogeneic HCT in adults age >55 years.

Combination of calcineurin inhibitors (CIs) with short-term methotrexate is a standard prophylactic regimen for graft-versus-host disease (GVHD). However, it is sometimes difficult to continue CIs due to adverse effects, such as renal impairment and fluid overload. In such cases, we replace CIs with corticosteroids, considering that full dose of CIs is equivalent to prednisolone (PSL) at 1 mg/kg. We retrospectively evaluated the clinical significance of replacement of CIs with corticosteroids after allogeneic hematopoietic cell transplantation (HCT). We evaluated 42 patients switched from CIs to corticosteroids within 90 days among the 479 patients who underwent allogeneic HCT at our center between 2007 and 2019. Renal impairment (n = 33), fluid overload (n = 13), and thrombotic microangiopathy (n = 3) were the main reasons for switching. Although creatinine and body weight returned to baseline at 4 weeks after switching, 100-day non-relapse mortality was high (57.1%). Grade II-IV acute GVHD was seen in 10 (24.4%) patients who did not have it before switching treatment (n = 41). In conclusion, CIs were switched to corticosteroids in patients with severe clinical conditions. The incidence of acute GVHD was acceptable. Although the short-term mortality rate was high, improvement of renal function or fluid overload was observed in a certain proportion of the patients.

Several biofluid-based biomarkers for traumatic brain injury show promise for use in diagnosis and outcome prediction. In contrast, few studies have investigated biomarkers for non-traumatic brain injury. We focused on ubiquitin C-terminal hydrolase-L1 (UCH-L1), which has been proposed as a screening tool for traumatic brain injury, and investigated whether the plasma UCH-L1 level could also be a useful biomarker in patients with non-traumatic brain injury. We measured UCH-L1 in 25 patients who had experienced neurological complications after allogeneic hematopoietic cell transplantation (HCT) and 22 control patients without any complications or graft-versus-host disease. Although UCH-L1 levels before HCT did not differ significantly (P = 0.053), levels after HCT were higher in patients with neurological complications compared with the control group (P < 0.001). At a UCH-L1 cutoff value of 0.072 ng/ml, sensitivity was 68.0% and specificity was 100%. The statistical power of UCH-L1 for neurological complications seemed to be higher than that of CT and comparable to that of MRI. Thus, increased levels of UCH-L1 might reflect the presence of neurological damage even in patients with non-traumatic brain injury. Further large cohort investigations are warranted.

Fatal cardiac complications can occur from the early to late phases after hematopoietic cell transplantation (HCT). Herein, the Japanese transplant registry database was used to retrospectively analyze health records of 33,791 allogeneic HCT recipients to elucidate the pathogenesis and risk factors involved. Overall, 527 patients died of cardiac complications at a median of 130 (range 0-3924) days after HCT. The cumulative incidence of fatal cardiac complications was 1.2% (95% confidence interval [CI]: 1.0-1.3) and 1.6% (95% CI: 1.5-1.8) at 1 and 5 years after HCT, respectively. Fatal cardiovascular events were significantly associated with an HCT-specific comorbidity index (HCT-CI) score of ≥1 specific to the three cardiovascular items, lower performance status, conditioning regimen cyclophosphamide dose of >120 mg/kg, and female sex. Cardiovascular death risk within 60 days after HCT was associated with the type of conditioning regimen, presence of bacterial or fungal infections at HCT, and number of blood transfusions. Contrastingly, late cardiovascular death beyond 1 year after HCT was associated with female sex and older age. Lower performance status and positive cardiovascular disease-related HCT-CI were risk factors for cardiac complications in all phases after HCT. Systematic follow-up may be necessary according to the patients' risk factors and conditions.

Adult T-cell leukaemia/lymphoma (ATL) is an aggressive malignancy of peripheral T cells caused by human T-cell lymphotropic virus type-1 (HTLV-1). Tax is the most important regulatory protein for HTLV-1. We aimed to reveal a unique amino acid sequence (AA) of complementarity-determining region 3 (CDR3) of the T-cell receptor (TCR)β and TCRα chains of HLA-A*02:01-restricted Tax11-19 -specific cytotoxic T cells (Tax-CTLs). The gene expression profiles (GEP) of Tax-CTLs were assessed by the next-generation sequence (NGS) method with SMARTer technology. Tax-CTLs seemed to be oligoclonal, and their gene compositions were skewed. The unique motifs of 'DSWGK' in TCRα and 'LAG' in TCRβ at CDR3 were observed in almost all patients. Tax-CTL clones harbouring the 'LAG' motif with BV28 had a higher binding score than those without either of them, besides a higher binding score associated with longer survival. Tax-CTLs established from a single cell showed killing activities against Tax-peptide-pulsed HLA-A2+ T2 cell lines. GEP of Tax-CTLs revealed that genes associated with immune response activity were well preserved in long-term survivors with stable status. These methods and results can help us better understand immunity against ATL, and should contribute to future studies on the clinical application of adoptive T-cell therapies.

Allogeneic hematopoietic cell transplantation between female donors and male recipients (female-to-male allo-HCT) is a well-established risk factor for inferior survival outcomes due to a higher incidence of graft-versus-host disease (GVHD). However, a clinical significance of anti-thymocyte globulin (ATG) in the female-to-male allo-HCT has not been elucidated. In this study, we retrospectively evaluated male patients who underwent allo-HCT between 2012 and 2019 in Japan. In the female-to-male allo-HCT cohort (n = 828), the use of ATG was not associated with a decreased risk of GVHD (HR of acute GVHD 0.691 [95% CI: 0.461-1.04], P = 0.074; HR of chronic GVHD 1.06 [95% CI: 0.738-1.52], P = 0.76), but was associated with favorable overall survival (OS) and a decreased risk of non-relapse mortality (NRM) (HR of OS 0.603 [95% CI: 0.400-0.909], P = 0.016; HR of NRM 0.506 [95% CI: 0.300-0.856], P = 0.011). The use of ATG in female-to-male allo-HCT resulted in survival outcomes that were almost equivalent to those in the male-to-male allo-HCT group. Therefore, GVHD prophylaxis with ATG might overcome the inferiority of survival outcomes in female-to-male allo-HCT.

BACKGROUND: In autologous hematopoietic cell transplantation (HCT), myelosuppression and mucosal damage are more severe than those in conventional chemotherapy because of high-dose chemotherapy, but the duration of neutropenia is shorter due to stem cell rescue. METHODS: We retrospectively evaluated febrile neutropenia (FN) and bloodstream infection (BSI) in 208 patients who underwent their first autologous HCT at our institution between 2007 and 2019. They were compared to those in patients who underwent intensive chemotherapy for acute myeloid leukemia (AML) (130 induction/salvage and 191 consolidation). RESULTS: The median neutropenic period in autologous HCT, AML induction/salvage and consolidation was 9, 26.5, and 19 days, respectively. The incidence of FN was 93.8%, 92.3%, and 81.7%, and that of BSI in initial FN was 7.2%, 7.5% and 26.3%, respectively. The incidence of oral mucositis (≥ grade 2) was 63.1%, 9.2% and 12.2%, and that of diarrhea (≥ grade 2) was 53.3%, 9.2% and 6.4%, respectively. Although there were significant differences in the incidence of shaking chills, the degree of fever and the value of CRP between patients with and without BSI in initial FN of AML chemotherapy, no significant risk factors or predictive factors for BSI were identified in autologous HCT. CONCLUSIONS: The profile of infectious complications in autologous HCT was characterized by a high incidence of FN maybe due to mucosal damage. On the other hand, the incidence of BSI was lower compared to that in AML consolidation chemotherapy.

Acute myeloid leukemia (AML) is a malignancy that requires immediate treatment. However, the factors that predict very early mortality are not well known. We retrospectively analyzed 70 patients who were newly diagnosed with AML at our institution between 2014 and 2020. Very early death within 30 days after the initial consultation with a hematologist occurred in eight patients, including seven men. They were older than 30-day survivors (70.5 vs. 47 years, P < 0.01). In addition, four patients with a low score on the Glasgow Coma Scale (GCS) at diagnosis died within 30 days, and half of the early death group died due to cerebral hemorrhage. We next tried to predict early death using a ROC curve. Age, hemoglobin (Hb), estimated glomerular filtration rate (eGFR) and the international normalized ratio of prothrombin time (PT-INR) all had an area under the curve of greater than 0.8 for predicting very early death. A multivariate analysis revealed that older age (OR = 1.14, P = 0.033), Hb (OR = 0.48, P = 0.05), and low GCS (OR = 140.0, P = 0.0073) were significantly associated with very early death. Further studies will be needed to confirm which patients are at high risk for early death and to improve the treatment strategy for such patients.

Chronic active Epstein-Bar virus infection (CAEBV) is known to cause various symptoms. Although pulmonary artery hypertension (PAH) has been reported as a cardiovascular complication of CAEBV, the mechanisms of PAH and the effects of treatment have not been fully elucidated. We experienced 4 adult patients with CAEBV complicated by PAH. All of them received treatment for PAH with a vasodilator followed by chemotherapy with or without allogeneic hematopoietic cell transplantation for CAEBV. In all of these patients, the transtricuspid pressure gradient improved under treatment with vasodilator, and further improvement was observed under treatment for CAEBV in 3 patients. Autopsy was performed in 2 patients, which revealed EBER-positive cells and a change in the pulmonary artery at each stage in the pathology. In conclusion, EBV-infected cells can cause vasculitis and finally PAH. However, PAH complicated with CAEBV can be improved by PAH medication and treatment of CAEBV.

A 34-year-old man with KMT2A-MLLT1 acute myeloid leukemia in first complete remission underwent allogeneic peripheral blood stem cell transplantation from his HLA-matched sister after conditioning with busulfan/cyclophosphamide. He did not have severe graft-versus-host disease, but he developed interstitial pneumonia six months after transplantation when his oral cyclosporine A (CsA) dose was reduced to 10 mg/day. He was given prednisolone (PSL), which temporarily improved his respiratory condition, but he quickly deteriorated when PSL was reduced. Anti-MDA5 antibody was found to be positive after additional testing, and a three-drug combination of intravenous cyclophosphamide+PSL+CsA was initiated for anti-MDA5 antibody positive rapidly progressive interstitial lung disease, which was effective for interstitial pneumonia. He received a successful living-donor lung transplant from his younger brother and sister. We present a case of rapidly progressive anti-MDA5 antibody positive interstitial lung disease in which the patient's respiratory condition improved after triple therapy and subsequent living-donor lung transplantation.

We report a case of FLT3-mutated APL who developed disease relapse despite all-trans retinoic acid (ATRA) + chemotherapy, and re-induction chemotherapy with arsenic trioxide (ATO) and high-dose (HD) cytarabine (Ara-C) therapy failed to yield complete remission. Because the leukemic cells were resistant to all the aforementioned therapies, we started the patient on monotherapy with gilteritinib, a selective FLT3-inhibitor, as an alternative re-induction treatment option rather than further intensive chemotherapy. The patient showed complete hematologic remission in response to this therapy. This case serves as supporting evidence for the use of single-agent therapy with gilteritinib as a bridge to transplantation in patients with refractory FLT3-mutated APL.

A 76-year-old woman with a past history of diabetes mellitus and Hashimoto's disease, in regard to her personal history, she did not smoke or drink alcohol. In March, year X-1, she became aware of cervical lymphadenopathy. Based on the findings of lymph node biopsy, she was diagnosed as having diffuse large B-cell lymphoma(DLBCL). An upper gastrointestinal endoscopy(U-GIE)revealed white granular prominences in the gastric fornix, and biopsy of these lesions revealed the diagnosis of Russell body gastritis(RBG). Neither lymphoma infiltration nor other malignant findings were found. Diagnostic tests for Helicobacter pylori were negative. The clinical stage of the DLBCL was determined as stage ⅢA, and the International Prognostic Index was"high intermediate". She received 6 cycles of R-CHOP therapy, with concomitant use of a proton pump inhibitor. Complete remission was confirmed in November, year X-1. An U-GIE performed again no longer showed the white granular prominences in the gastric fornix. The present report is the first of DLBCL complicated by RBG; our findings suggested that the two diseases were associated with each other.

Idiopathic pneumonia syndrome (IPS) is a fatal pulmonary complication after allogeneic hematopoietic stem cell transplantation (allo-HCT). However, it is often difficult to diagnose IPS, since a considerable number of IPS patients are critically ill, which makes it difficult for them to undergo bronchoscopy. In this study, we explored the risk factors of IPS based on two definitions. Definite IPS was diagnosed based on the results of bronchoscopy, whereas clinical IPS was diagnosed based on the clinical condition and bronchoscopy was not mandatory. Among 444 allo-HCT recipients at our center, 30 definite IPS and 54 clinical IPS were identified. In a multivariable analysis, a high ferritin level was associated with a higher incidence of definite IPS, whereas clinical IPS was frequently associated with older age, MAC, high ferritin level, low %DLCO and second allo-HCT due to graft failure. These risk factors may contribute to the accurate and early diagnosis of IPS.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is one of auto-immune antibodies which is associated with a rare subtype of dermatomyositis (DM), and MDA5-DM is well-characterized by rapid progressive interstitial lung disease (ILD) which in part resembles pulmonary complications after allogeneic hematopoietic cell transplantation (allo-HCT). However, previous studies about anti-MDA5 antibody after allo-HCT were extremely limited. Here, we present 4 cases of ILD with anti-MDA5 antibody after allo-HCT. All of the cases showed rapidly progressive clinical course and 3 of 4 cases died despite intensive immunosuppressive therapies which included prednisolone, cyclophosphamide and calcineurin inhibitor. Additionally, 3 of 4 cases had tested positive for anti-MDA5 antibody by using cryopreserved plasma which were collected about 2-3 months before the diagnosis of MDA5-DM-ILD. It suggests that an inflammatory condition due to MDA5-DM-ILD might have sub-clinically occurred before the development of respiratory failure. The current cases suggest that the clinical feature was relatively similar to classical MDA5-DM-ILD, although it is difficult to distinguish MDA5-DM-ILD from chronic GVHD and other pulmonary complications after allo-HCT. Since clinical courses of MDA5-DM-ILD is considerably aggressive, it is important to discriminate MDA5-DM-ILD from other complications after allo-HCT.

In general, the initial systemic treatment for chronic graft-versus-host disease (cGVHD) is 0.5 to 1 mg/kg of prednisolone (PSL). However, patients without high-risk features are sometimes treated with a calcineurin inhibitor (CI) or PSL at lower doses. Here we retrospectively evaluated patients with cGVHD who were treated with low-intensity immunosuppressive therapy (IST), defined as CI with or without PSL at <.25 mg/kg. The primary outcome was failure-free survival (FFS), and we evaluated current FFS (cFFS) considering the state transition between low-intensity IST and high-intensity IST defined as the administration of >.25 mg/kg of PSL or immunosuppressants other than CI or PSL. Fifty-four patients were evaluated, few of whom had a low performance status and intestinal or lung involvement. FFS at 24 months after treatment was 50.0% (95% confidence interval [CI], 36.0% to 62.3%). Risk factors for failure were use of IST before 6 months post-transplantation (hazard ratio [HR], 2.16; 95% CI, 1.05 to 2.16; P = .036) and transplantation from a female donor to a male recipient (HR, 2.65; 95% CI, 1.29 to 5.48; P = .008). At 6 months, 44.0% of patients had achieved a complete or partial response without a change in treatment. cFFS at 36 months was 67.0% (95% CI, 51.8 to 79.4%), which was greater than simple FFS (43.2%; 95% CI, 36.6% to 52.8%). There was no difference in simple FFS according to the National Institutes of Health global score. However, cFFS at 3 years varied according to the global score (mild, 91.7%; moderate, 64.0%; severe, 43.8%; P = .036). Low-intensity IST for cGVHD was effective in patients without high-risk features.

BACKGROUND: Pancreatic atrophy after allogeneic hematopoietic cell transplantation (HCT) is one of the symptoms associated with chronic graft-versus-host disease (GVHD). Although pancreatic atrophy has been considered to cause exocrine insufficiency and weight loss, it is not yet clear what kinds of recipients can be expected to recover their body weight (BW) or pancreatic thickness. In addition, the effect of pancreatic atrophy on the prognosis has not been clarified. METHODS: We retrospectively analyzed 170 recipients who received allogeneic bone marrow transplantation or peripheral blood stem cell transplantation, and evaluated them using the CT scan images obtained closest to 1, 2, 3, and 4 years after HCT. RESULTS: Fifty-five recipients (32.4%) demonstrated pancreatic atrophy, and 11 (20%) of them recovered their pancreatic thickness. While recipients without pancreatic atrophy gradually recovered their BW (P < 0.001), those with atrophy did not (P = 0.12). Moderate and severe chronic GVHD tended to be slightly more common in the atrophy group (47.3% vs 38.3%), whereas the pancreatic thickness tended to recover in these recipients (30.8% vs 10.3%). HCT from a female donor to a male recipient showed superior pancreatic recovery compared to other donor and recipient sex combinations. Pancreatic atrophy treated as a significantly associated with inferior survival (HR 4.91, P < 0.001) and an increased risk of non-relapse mortality (HR 8.75, P < 0.001). CONCLUSIONS: These results suggest that it is important to monitor pancreatic thickness after HCT. Further prospective investigations are warranted to clarify the significance of pancreatic atrophy on clinical outcomes.

In general, the recipient's ABO blood type changes to the donor's ABO blood type after ABO-incompatible allogeneic hematopoietic stem cell transplantation (HSCT). However, we experienced a 26-year-old male with acute myelogenous leukemia (AML) who underwent ABO-incompatible HSCT twice and persistently showed his original blood type even after demonstrating complete donor-type chimerism. Based on the results of various examinations, we considered that the antigen of the recipient's original blood type persistently synthesized in the recipient's non-hematopoietic organs was secreted and adsorbed on the surface of donor-derived RBCs. We should therefore perform detailed examinations to determine the precise blood type after ABO-incompatible HSCT.

Disease relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) and the mechanisms of relapse remain unclear. We encountered a 58-year-old man with chronic myelomonocytic leukemia (CMML) that relapsed after haploidentical HCT from his daughter. Peripheral blood samples collected at HCT and at relapse were analyzed, and CD14+/CD16- monocytes that typically accumulate in CMML were isolated by flow cytometry. Whole-exome sequencing of the monocytes revealed 8 common mutations in CMML at HCT. In addition, a PHF6 nonsense mutation not detected at HCT was detected at relapse. RNA sequencing could not detect changes in expression of HLA or immune-checkpoint molecules, which are important mechanisms of immune evasion. However, gene set enrichment analysis (GSEA) revealed that a TNF-α signaling pathway was downregulated at relapse. Ubiquitination of histone H2B at lysine residue 120 (H2BK120ub) at relapse was significantly decreased at the protein level, indicating that PHF6 loss might downregulate a TNF-α signaling pathway by reduction of H2BK120ub. This case illustrates that PHF6 loss contributes to a competitive advantage for the clone under stress conditions and leads to relapse after HCT.

Chromosome analysis is a powerful prognostic tool in myeloid malignancies. Recipients who experience relapse after allogeneic hematopoietic cell transplantation (allo-HCT) often show chromosomal changes between diagnosis and relapse. However, the clinical impact of chromosomal changes and the efficacy of post-relapse treatment according to chromosomal changes have not been fully investigated. We retrospectively analyzed 72 recipients who had experienced relapse after allo-HCT for acute myeloid leukemia or myelodysplastic syndrome. We categorized them into two groups: with or without clonal chromosomal changes at relapse after allo-HCT. Post-relapse survival was shorter in the clonal chromosomal change group (median 117 days vs 275 days, P = 0.019). Moreover, acquisition of chromosome 7 abnormality or complex changes tended to be associated with inferior survival in a univariate analysis (median 92 days vs median 173 days, P = 0.043), and this adverse impact was confirmed in a multivariate analysis (hazard ratio 2.07, P = 0.024). The patterns of chromosomal changes from diagnosis to relapse after allo-HCT were heterogenous, and further investigations are required to clarify the effect of individual chromosomal changes.

TEMPI syndrome is a rare disease associated with plasma cell neoplasms. Although previous studies have reported that bortezomib is effective as a first-line treatment for TEMPI syndrome, some cases are refractory to this treatment. Pomalidomide, a kind of immunomodulatory drug, is widely used for the treatment of relapsed or refractory multiple myeloma and could be administered without dose modification in patients with renal dysfunction. We present a case of bortezomib-refractory TEMPI syndrome with renal insufficiency that was successfully treated with a combination of pomalidomide and low-dose dexamethasone with minimal adverse effects, followed by autologous hematopoietic stem cell transplantation (ASCT). To the best of our knowledge, this is the first case of TEMPI syndrome that was successfully treated with pomalidomide. Pomalidomide may be suitable for patients who do not respond to a proteasome inhibitor-based treatment. In addition, a subsequent ASCT could also be effective for achieving a further treatment response.

Chronic graft-versus-host disease (cGVHD) of the liver is often observed in allogeneic hematopoietic stem cell transplantation (allo-HSCT) during tapering or after stopping calcineurin inhibitors (CI). We conducted a retrospective analysis of 242 allo-HSCT recipients whose CI dose was reduced to less than 40 mg of cyclosporin A or 0.4 mg of tacrolimus to clarify the clinical characteristics of liver GVHD in patients on low-dose CI. Sixty patients (25%) developed clinically suspected liver cGVHD while on low-dose CI. Multivariate analysis showed that donor age ≥ 40 years [hazard ratio (HR) 2.20], myeloablative conditioning (HR 2.19), female donor to male recipient (HR 2.53) and recipient seropositivity for herpes simplex virus (HR 2.52) were significant risk factors for liver cGVHD during low-dose CI period. Peak aspartate aminotransferase and alanine aminotransferase levels were higher in patients with liver GVHD during low-dose CI period than in other periods. Twenty-seven patients were initially treated with resumption of CI or a CI dose increase and 21 responded. Among the 18 patients treated with corticosteroids, total bilirubin was a risk factor for failure of corticosteroid therapy. The results of this study clarified the clinical characteristics of liver GVHD in patients on low-dose CIs.

Cytomegalovirus reactivation is still a critical concern following allogeneic hematopoietic cell transplantation, and cellular immune reconstitution of cytomegalovirus-specific cytotoxic T-cells is necessary for the long-term control of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation. Here we show the features of repertoire diversity and the gene expression profile of HLA-A24 cytomegalovirus-specific cytotoxic T-cells in actual recipients according to the cytomegalovirus reactivation pattern. A skewed preference for BV7 genes and sequential "G" amino acids motif is observed in complementarity-determining region-3 of T cell receptor-β. Increased binding scores are observed in T-cell clones with complementarity-determining region-3 of T cell receptor-β with a "(G)GG" motif. Single-cell RNA-sequence analyses demonstrate the homogenous distribution of the gene expression profile in individual cytomegalovirus-specific cytotoxic T-cells within each recipient. On the other hand, bulk RNA-sequence analyses reveal that gene expression profiles among patients are different according to the cytomegalovirus reactivation pattern, and are associated with cytokine production or cell division. These methods and results can help us to better understand immune reconstitution following hematopoietic cell transplantation, leading to future studies on the clinical application of adoptive T-cell therapies.

BACKGROUND: We assessed the kinetics of cytomegalovirus (CMV) reactivation using the area under the curve (AUC), which simultaneously reflects both the viral load at each time point and the duration of CMV antigenemia (CMV-AG). METHODS: We performed a single-institute retrospective analysis in patients who received allogeneic hematopoietic stem cell transplantation (HSCT) between 2007 and 2017 and survived more than 100 days after HSCT. The AUC of CMV-AG (CMV-AUC) was calculated by a trapezoidal method using the number of CMV-AG tested by the C10/C11 method after logarithmic transformation, and plotted weekly up to day 100. RESULTS: CMV reactivation was observed in 195 cases and the median CMV-AUC for CMV-reactivated patients was 8.7 (range 0.5-30.7). Older age, corticosteroid administration, CMV-seropositive transplant recipients, HSCT from an unrelated donor, and underlying diseases were independent predictive factors for higher CMV-AUC. Higher CMV-AUC was associated with poor overall survival (OS) with borderline significance in a univariate analysis (p = .07), but was not significant in a multivariate analysis. Older age, high-risk disease status, and female gender were identified as significant factors associated with poor OS in this study. On the other hand, CMV-AUC (hazard ratio: no reactivation reference, low 0.98, high 2.49, p < .01), older age, HCT-CI ≥3, and corticosteroid administration were identified as significant factors associated with increased incidence of non-relapse mortality (NRM). CONCLUSIONS: The kinetics of CMV reactivation in terms of CMV-AUC reflect both the severity and duration of CMV reactivation. High CMV-AUC was associated with an increased incidence of NRM in survivors over 100 days.

Recipient cytomegalovirus (CMV) seropositivity is known to be a risk factor for CMV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HCT). We explored the association of CMV-IgG titer of recipients with CMV reactivation after allo-HCT and developed a model for predicting CMV reactivation for the purpose of identifying a high-risk group. In addition, we evaluated the impact of CMV-IgG titer on survival outcomes and acute graft-versus-host disease (GVHD). We retrospectively analyzed 309 patients who achieved neutrophil engraftment after allo-HCT and evaluated whether pretransplantation recipient CMV-IgG titer was associated with transplantation outcomes, including CMV reactivation. Using the best cutoff value determined by a receiver operating characteristic curve analysis, we divided the study cohort into 3 groups: high-titer, low-titer, and negative. CMV reactivation occurred most frequently in the high-titer group, followed by the low-titer and negative groups (81%, 37%, and 16%, respectively, at 180 days after allo-HCT; P < .01). In a multivariate analysis, recipient CMV-IgG titer was significantly associated with subsequent CMV reactivation (hazard ratio [HR], 9.31 in the high-titer group [P < .01] and 2.91 in the low-titer group [P = .023]). CMV diseases were observed exclusively in the high-titer group. Overall survival (OS) was lower in the high-titer group compared with the other 2 groups (2-year OS, 56%, 60%, and 80%, respectively; P = .075), whereas the cumulative incidences of grade II-IV acute GVHD, nonrelapse mortality (NRM), and relapse were not significantly different among the 3 groups. In multivariate analyses, CMV-IgG titer was not associated with increased risks of these outcomes, although CMV reactivation itself was identified as a risk factor for NRM (HR, 3.05; P = .002). Our data demonstrate that a higher titer of recipient CMV-IgG is predictive of CMV reactivation after allo-HCT. Further investigation is needed to determine how to apply these results to prophylactic or preemptive strategies against CMV, considering recipient CMV-IgG titer for effective risk stratification.

Large outbreaks of measles or rubella occasionally occur around the world, and measles infection can be severe and even fatal in transplant patients. However, limited data are available on immunity to measles, mumps, and rubella (MMR) in adult patients after allogeneic stem cell transplantation (allo-HCT). The aim of this study was to evaluate the immune status against MMR and the effects of vaccination against MMR in adult patients after allo-HCT. A total of 135 adult patients who were alive without relapse and new malignancy at 2 years after allo-HCT were included in this study. We measured IgG antibody to MMR before allo-HCT and annually thereafter. The probabilities of being seropositive to measles, mumps or rubella after allo-HCT were estimated according to the Kaplan-Meier method and compared among groups with the log-rank test. The probability of being seropositive at 2 years after allo-HCT in patients who were seropositive before allo-HCT was 60.6% for measles, 39.7% for mumps, and 52.2% for rubella. History of chronic graft-versus-host disease tended to be a risk factor for the loss of immunity against measles (hazard ratio [HR] 1.69, P = .064) and rubella (HR 1.75, P = .056). To predict the loss of immunity against MMR at 2 years after allo-HCT, we defined the following cutoff values for the IgG index before HCT: 18.2 for measles, 5.3 for mumps, and 21.4 for rubella using a receiver-operating characteristics curve. The lower-IgG groups experienced a significant loss of seropositivity at 2 years (39% versus 82% for measles, P < .001; 13% versus 59% for mumps, P < .001; and 33% versus 90% for rubella, P < .001). After this loss of immunity, 25 patients received a single vaccination against MMR. The seroconversion rates were 64%, 36%, and 72% for measles, mumps, and rubella, respectively. Loss of immunity to MMR commonly occurs in the first several years after transplantation. In the patients who lose the immunity, the seroconversion rate after 1 dose of MMR vaccine given at ≥2 years after transplantation is suboptimal.

Most acute leukemia patients receive consecutive intensive chemotherapy, which usually takes several months before allogeneic hematopoietic stem cell transplantation (allo-HCT). Intensive chemotherapy often induces gastrointestinal adverse events. These adverse events leave patients in a state of malnutrition, leading to a reduction in body weight. In this study, we analyzed the impact of body weight loss before allo-HCT on survival outcomes of acute leukemia patients (acute myeloid leukemia, acute lymphoid leukemia and mixed phenotype acute leukemia). A loss of body weight (LBW), which was a reduction of body weight from diagnosis or relapse to transplantation, was calculated in 182 acute leukemia patients who received first allo-HCT at our center between June 2006 and September 2019. A receiver operating characteristics curve for nonrelapse mortality (NRM) was plotted for defining the cut-off value of LBW. The cutoff value of LBW was defined as 13.2%. A higher LBW was significantly associated with inferior NRM and overall survival (OS) (2-year [2y] NRM 36.1% versus 11.5%, P = .0025; 2y-OS 39.9% versus 65.8%, P = .020). The adverse impact of LBW was also confirmed in multivariate analyses for NRM and OS (HR of NRM 2.74 [1.25-6.03], P = .0012; HR of OS 2.06 [1.00-3.07], P = .0049). The main cause of death included disease progression (n = 34) and infection (n = 35). Death cause by infection was more frequently observed in the high-LBW group (15 cases [35.7%] versus 20 cases [14.3%]; P = .0035). In addition, subgroup analyses based on a combination of the body mass index at diagnosis and LBW were performed. When the non-overweight-low LBW group (body mass index [BMI] ≤25 and LBW ≤13.2%) was used as a reference in multivariate analysis, the overweight-high LBW group (BMI >25 and LBW >13.2%) showed an increased risk of poor survival outcomes (HR of NRM 4.27 [95% confidence interval {CI}, 1.82-10.0], P < .001; HR of OS 1.93 [95%, CI 1.00-3.71], P = .050). High LBW was significantly associated with inferior survival outcomes, and the adverse effect of malnutrition might be greater than the favorable effect of the reduction in overweight.

BACKGROUND: We retrospectively compared the impact of the areas over and under the lymphocyte curve (L_AOC vs L_AUC) on cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Among 394 consecutive patients who underwent their first allogeneic HSCT at our center between 2007 and 2018, 301 patients met the inclusion criteria. L_AOC was calculated as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count [ALC] <700/μL). We calculated L_AOC and L_AUC from day 0 to day 15 (L_AOC15, L_AUC15) and from day 0 to day 30 (L_AOC30, L_AUC30). RESULTS: CMV antigenemia was defined as more than 3 cells/2 slides by the C10/11 method and detected in 204 cases (CMV reactivation) at a median of 39 days after HSCT. Although there were significant differences in L_AOC15, L_AOC30, L_AUC15, and L_AUC30 between patients with and without CMV reactivation, there was no difference in accuracy for predicting CMV reactivation between L_AOC and L_AUC. In a multivariate analysis, L_AOC15 and L_AUC15 were each identified as independent predictive factors for CMV reactivation, along with advanced age and CMV serostatus. However, ALC at day 14 or day 21 was as accurate as area-based indexes such as L_AOC15 and L_AUC15. L_AOC15 and L_AUC15 were significantly associated with longer duration of anti-CMV antiviral therapy while ALC was not. CONCLUSIONS: L_AOC15 and L_AUC15 had similar impacts on CMV reactivation. Although these area-based indexes were not superior to ALC for predicting CMV reactivation, they might predict patients who need longer duration of antiviral therapy more accurately.

BACKGROUND: We retrospectively evaluated the association between the D-index, which reflects both the depth and duration of neutropenia, and proven/probable invasive fungal disease (IFD) early after allogeneic hematopoietic stem cell transplantation (HSCT) at our center (n = 394). METHODS: The D-index was defined as the area over the neutrophil curve during neutropenia. The cumulative D-index from the start of neutropenia until the development of infection (c-D-index) was also evaluated as a real-time assessment of neutropenia. RESULTS: There were 19 cases of early proven/probable IFD before and within 1 week after engraftment. Fifteen cases (78.9%) were seen as breakthrough infection while on empiric (n = 7), preemptive (n = 4) or prophylactic (n = 4) antifungal administration with mold-active agents. The c-D-index and lower performance status were identified as independent significant predictive factors for IFD. A receiver operating characteristic (ROC) curve analysis showed that the D-index and c-D-index were more accurate than the simple duration of neutropenia and as accurate as the duration of profound neutropenia for predicting IFD. The sensitivity, specificity, and positive and negative predictive values of the c-D-index using an appropriate cutoff (CO) value (10 644) determined by ROC curve analysis were 73.1%, 63.2%, 9.1%, and 97.9%, respectively. The advantage of the c-D-index to cumulative days of neutropenia in terms of positive and negative predictive values seemed to be small. CONCLUSIONS: The appropriate CO value for the c-D-index for predicting IFD was as high as 10 644 in allogeneic HSCT with a more frequent use of empiric antifungal therapy. The c-D-index is useful for assessing the risk of breakthrough IFD.

The pulmonary function test (PFT) is an important test for risk stratification before allogeneic transplantation (allo-HCT). However, it might be preferable to avoid PFT as much as possible in the recent era of coronavirus disease 2019 (COVID-19), because PFT requires forced expirations and might produce aerosols, increasing the risk of COVID-19 transmission. Therefore, we tried to predict normal PFT results before allo-HCT based on computed tomography (CT) findings. This study included 390 allo-HCT recipients at our center for whom lung CT images and PFT results before allo-HCT were available. Abnormal CT findings were less likely to be observed in the normal PFT group (47.0% versus 67.4%, P = .015), with a high negative predictive value of 92.9%. In a multivariate analysis, normal CT was significantly associated with normal PFT (odds ratio, 2.47; 95% confidence interval, 1.22 to 4.97; P = .012). A model for predicting normal PFT was constructed based on the results of a multivariate analysis, and the area under the curve of the receiver operating characteristic analysis was 0.656, which gave a sensitivity of 45.5% and a specificity of 86.0%. The relatively high specificity of the model suggested that PFT can be omitted in patients with normal CT findings before allo-HCT.

Autologous hematopoietic recovery after allogeneic hematopoietic cell transplantation (allo-HCT) is rare in patients who receive myeloablative conditioning (MAC). Autologous hematopoietic recovery suggests graft rejection, leading to concerns about subsequent disease relapse. We herein report a rare case of a patient with acute leukemia who experienced autologous hematopoietic recovery after cord blood transplantation (CBT) with total body irradiation-based MAC. Chromosomal abnormalities were repeatedly detected without any disease relapse for eight months. The accumulation of similar cases is required to accurately assess the incidence and clinical outcomes of autologous hematopoietic recovery after CBT with MAC.

BACKGROUND: We evaluated the clinical impact of cytomegalovirus (CMV) reactivation calculated in terms of the area under the curve of CMV antigenemia (CMV-AUC) on the development of invasive mold infection (IMI) in the post-engraftment phase after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Among 394 consecutive patients who underwent their first allogeneic HSCT at our center between 2007 and 2018, 335 were included after excluding patients with a past history of invasive fungal disease (IFD), the development of IFD before engraftment, engraftment failure, or early death within 30 days. CMV antigenemia (CMV-AG) was monitored weekly after engraftment and 3 or more cells/2 slides were regarded as positive. CMV-AUC was calculated by the trapezoidal method using the number of CMV-AG after logarithmic transformation and the duration in weeks and was added until negative conversion. Patients with CMV reactivation were divided into low and high CMV-AUC groups using the median value of CMV-AUC as a threshold. RESULTS: There were 17 proven/probable IMIs including one mucormycosis and 16 probable invasive aspergillosis, and the 2-year cumulative incidence was 1.0% in the negative CMV-AUC group (n = 136), 3.3% in the low CMV-AUC group (n = 98) and 13.8% in the high CMV-AUC group (n = 101) (P = .001). In a multivariate analysis, grade II-IV acute GVHD (HR 3.74) and CMV-AUC (HR low 1.25, high 5.91) were identified as independent significant factors associated with a higher incidence of IMI. CONCLUSIONS: Cytomegalovirus kinetics evaluated in terms of CMV-AUC were significantly associated with the development of IMI in the post-engraftment phase after allogeneic HSCT.

While the dose of ganciclovir (GCV) is decided base on patients' body weight (BW), that of valganciclovir (VGCV) is fixed as 900 or 1800 mg/d regardless of the patient's BW in preemptive therapy for cytomegalovirus (CMV) reactivation in hematopoietic stem cell transplantation. We analyzed the impact of the patient's BW on the effectiveness and adverse events (AEs) of VGCV. From March 2004 to February 2017, 27 patients received VGCV as a first-line treatment for CMV reactivation. As a historical control group, we extracted 17 patients who started to receive GCV at a similar timing. We used the following definitions of outcomes: speed of reduction of CMV antigenemia (CMV-AG) as a measure of effectiveness, ratios of baseline and minimum value for white blood cell (WBC) and platelet counts, and ratio of baseline and maximum values for serum creatinine (sCr) as measures of AEs. As a result, there was no significant correlation between average daily dose of VGCV with or without adjusting for the patient's BW and speed of reduction of CMV-AG. On the other hand, the decreases in WBC and platelets and the increase in sCr were significantly correlated with the cumulative dose of VGCV. However, the absolute values of the correlation coefficients did not increase when we analyzed the correlations between the BW-adjusted cumulative dose of VGCV and factors associated with adverse events. There were no significant differences in efficacies or AE parameters between the GCV and VGCV groups. In conclusion, the patient's BW did not significantly affect the effectiveness or adverse events of VGCV.