玉置 雅治

BACKGROUND: Sex-mismatched allogeneic hematopoietic cell transplantation (allo-HCT), particularly with female donors and male recipients (FtoM), is known to be associated with an increased risk of chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM). This adverse effect of FtoM allo-HCT is considered to result from allo-immunity against Y-chromosome antigens. However, it has not been elucidated whether the adverse impact of FtoM allo-HCT varies by recipient age. OBJECTIVE: This study aims to examine the effect of sex-mismatch on clinical outcomes in allo-HCT from human leukocyte antigen (HLA)-matched donors, stratified by recipient age group. STUDY DESIGN: Using a Japanese transplantation registry database, we analyzed 10392 patients (n = 2169, 2573, and 5650 in FtoM, MtoF, and sex-matched allo-HCT, respectively) with standard-risk hematological malignancies who had undergone their first allo-HCT from HLA-matched related or unrelated donors without in vivo T-cell depletion between 2008 and 2022. The impact of sex-mismatch on clinical outcomes was separately assessed by recipient age groups: ≤ 15, 16-39, and ≥ 40 years. The primary endpoint was overall survival (OS). Secondary endpoints included disease-free survival, NRM, and the cumulative incidences of acute and chronic GVHD. RESULTS: In recipients aged ≥ 40 years, OS and NRM at 5 years post-HCT were significantly worse in the FtoM group compared with the MtoF and sex-matched groups (5-year OS 49.5% vs 59.6% vs 57.1%, P < 0.001; 5-year NRM 27.9% vs 21.9% vs 23.0%, P < 0.001), while no differences were observed among the FtoM, MtoF, and sex-matched groups in recipients aged ≤ 15 years or 16-39 years. Multivariate analyses confirmed that FtoM allo-HCT was significantly associated with increased mortality only in recipients aged ≥ 40 years (hazard ratio [HR] for OS 1.31, P < 0.001; HR for NRM 1.44, P < 0.001). The FtoM group in recipients aged ≥ 40 years frequently experienced fatal infection and fatal non-infectious pulmonary complications. In addition, we confirmed that the adverse effect of FtoM allo-HCT on OS similarly appeared only in recipients aged ≥ 40 years in both sub-cohorts divided by a median of donor age (40 years). CONCLUSION: The adverse impact of FtoM allo-HCT on survival outcomes differed according to recipient age. Our findings suggest that female donors should be avoided, especially in older male recipients undergoing allo-HCT.

Previous studies have shown that the pre-transplant C-reactive protein (CRP)/platelet ratio (CP ratio) is a predictor of survival. The aim of this multicenter retrospective study was to evaluate the clinical significance of CP ratio in patients with malignant lymphoma (ML) who underwent allogeneic hematopoietic stem cell transplantation (alloHCT). The cohort included patients with ML who underwent first alloHCT from 2007 to 2021. CP ratio was defined as CRP [mg/dL]/platelet [104/μL] and evaluated prior to alloHCT. The cutoff value for CP ratio was set at 0.05 based on previous studies. A total of 311 cases were analyzed, of which 134 were mature B cell lymphoma, 177 were T/NK cell lymphoma (including 70 cases of adult T-cell leukemia/lymphoma), and 17 were Hodgkin's lymphoma. The median age was 53 years (range: 17-69 years). High CP ratio was associated with status of disease, presence of infections, poor performance status at alloHCT, and high transfusion volume received prior to alloHCT. Overall survival (OS) at 2 years according to CP ratio (low vs. high) was 61.1% versus 30.1% (p < 0.001), non-relapse mortality (NRM) was 21.4% versus 40.7% (p = 0.001), and the relapse rate was 23.7% versus 32.6% (p = 0.061), respectively. In multivariate analysis, the high CP ratio group was associated with poor OS (HR = 2.20, 95% CI: 1.61-3.02, p < 0.001) and higher NRM (HR = 1.90, 95% CI: 1.28-2.81, p = 0.0014). High CP ratio was found to be associated with poor post-transplant OS and NRM, and was a suitable prognostic biomarker for stratifying the risk of patients with ML who are candidates for alloHCT.

Although second allogeneic hematopoietic cell transplantation HCT (HCT2) is a potentially curative treatment for patients relapsing after their first HCT (HCT1), it is associated with higher non-relapse mortality (NRM) compared with HCT1. Furthermore, while reduced-intensity conditioning (RIC) in HCT2 might decrease NRM, there is no consensus on which patients may benefit from RIC. We retrospectively analyzed 2478 patients who underwent HCT2 for relapse of hematologic malignancies after HCT1. In a multivariate analysis, older recipient age, short duration between HCT1 and HCT2, RIC in HCT1, HCT-CI ≥ 2, and ECOG PS ≥ 2 were associated with an increased risk of NRM. RIC in HCT2 was associated with better NRM compared to myeloablative conditioning (MAC) (hazard ratio [HR] 0.83, 95% confidence interval [CI]: 0.72-0.97; p = 0.018), but was not significantly associated with overall survival (OS) (HR 0.91, 95% CI: 0.82-1.01; p = 0.075). We observed a significant interaction for NRM between extensive cGVHD in HCT1 and the conditioning intensity of HCT2 (interaction p < 0.001), meaning that the benefit of RIC in HCT2 was seen in patients with extensive cGVHD in HCT1, but not in those without cGVHD. RIC in HCT2 was also associated with superior OS in patients with extensive cGVHD in HCT1 (HR 0.68, 95% CI: 0.49-0.93; p = 0.02), with significant interaction between the conditioning intensity and the prior history of extensive cGVHD (interaction p = 0.01). This study suggests that RIC in HCT2 reduces NRM for HCT2 and improves OS, especially in patients with a history of extensive cGVHD.

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.

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.

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.

Allogeneic hematopoietic stem cell transplantation from a female donor to a male recipient (female-to-male allo-HCT) is a well-established risk factor for chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM). The inferior outcomes of female-to-male allo-HCT are considered to be due to allo-immunity against H-Y antigens. However, the influence of minor histocompatibility antigens in haplo-identical allo-HCT remains to be elucidated. We investigated the impact of female-to-male allo-HCT according to the haplo-HCT subtype. In the post-transplant cyclophosphamide (PTCY) cohort (n = 660), a female-to-male sex-mismatch was significantly associated with a decreased risk of relapse (HR: 0.70 [95% CI: 0.49-0.99], P = 0.045), but not with overall survival (OS) or NRM (HR: OS 0.89 [95% CI: 0.68-1.16], P = 0.40; NRM 0.98 [95% CI: 0.68-1.41], P = 0.90). On the other hand, in the non-PTCY cohort (n = 219), a female-to-male sex-mismatch was associated with inferior risks of OS and NRM, but was not associated with relapse. These results suggested that the survival impact of the haplo-HCT subtype differed according to the presence of a sex-mismatch. PTCY might be feasible for overcoming the inferiority of female-to-male allo-HCT and might preserve a GVL effect against H-Y antigens.

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

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.

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

BACKGROUND: Monitoring of HBV-DNA and HBV-DNA-guided preemptive therapy using nucleos(t)ide analogues (NAs) are recommended for preventing the development of hepatitis due to HBV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in recipients with resolved HBV infection. However, little is known about the appropriate duration of NA treatment and the outcomes of NAs cessation on recurrence of HBV reactivation. OBJECTIVE: To clarify the consequences of NAs cessation in recipients with resolved HBV infection who experienced HBV reactivation following allo-HSCT. STUDY DESIGN: We retrospectively reviewed the clinical records of recipients with resolved HBV infection (HBsAg-negative, anti-HBc-positive) before allo-HSCT who had been diagnosed as having HBV reactivation (HBsAg-positive and/or HBV-DNA detectable) after allo-HSCT during the period from January 2010 to December 2020. RESULTS: A total of 72 patients from 16 institutes were registered (median age of the patients, 60 years; age range, 27-73 years; 42 males and 30 females). Initial HBV reactivation was observed on day 10 to day 3034 (median, 513 days) after allo-HSCT. Anti-HBs were lost in more than 80% of the patients at the time of HBV reactivation. All 72 patients received preemptive NAs and no fatal HBV reactivation-related hepatitis was observed. There was continuous detection of HBV-DNA without hepatitis in 5 patients during the follow-up period. Administration of NAs was discontinued in 24 (33%) of 72 patients by each physician's decision. Second HBV reactivation occurred in 11 (46%) of the 24 patients in whom administration of NAs was discontinued. Duration of NA treatment were not significantly different between patients with or without second HBV reactivation. The frequency of further HBV reactivation tended to be lower in patients with anti-HBs titer of more than 10 mIU/mL at the time of NA cessation. CONCLUSION: Multiple reactivation of HBV after NA discontinuation was common in patients with HBV reactivation who received allo-HSCT despite the long duration of NA. Careful monitoring of HBV-DNA is important even after the discontinuation of NA in the case with HBV reactivation after allo-HSCT because multiple reactivations could occur. Active immunization by HB vaccine might be effective for suppressing further HBV reactivation after cessation of NAs.

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.

BACKGROUND AIMS: Allogeneic hematopoietic stem cell transplantation from female donors to male recipients (female-to-male allo-HCT) is a well-established risk factor for a greater incidence of non-relapse mortality (NRM) and chronic graft-versus-host disease (GVHD). In contrast, unrelated cord blood transplantation (UCBT) is associated with a lower incidence of chronic GVHD. In this study, survival outcomes were compared between the UCBT and unrelated female-to-male bone marrow transplantation (UFMBMT) groups. METHODS: We evaluated male allo-HCT recipients who underwent UCBT or UFMBMT between 2012 and 2020 in Japan. There were 2517 cases in the UCBT group, 456 cases in the HLA-matched UFMBMT group and 457 cases in the HLA-mismatched UFMBMT group. RESULTS: HLA-mismatched UFMBMT was significantly associated with a decreased risk of relapse (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.57-0.98], P = 0.033) and HLA-matched UFMBMT had the tendency of a decreased risk of relapse (HR 0.78; 95% CI 0.61-1.01, P = 0.059). HLA-matched UFMBMT was also associated with favorable OS (HR 0.82; 95% CI 0.69-0.97, P = 0.021). The relationship between the donor sources and relapse was similarly observed in the lymphoid malignancy cohort. CONCLUSIONS: The difference of graft-versus leukemia effect by H-Y immunity according to donor sources might contribute to the difference in clinical impact. It might be desirable for patients who could sufficiently wait for donor coordination to select BMT rather than UCBT, even if only unrelated female donors are available for male recipients.

Abstract 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.

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.

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.

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.

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.

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.

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.

TEMPI syndrome is a rare disease associated with plasma cell neoplasms. Although previous studies have reported that bortezomib is effective as a 1st-line treatment for TEMPI syndrome, some cases are refractory to this treatment. Pomalidomide, a kind of immunomodulatory drugs, 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. 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.

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.

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.

The graft-versus-leukemia (GVL) effect is one of the curative mechanisms of allogeneic hematopoietic stem cell transplantation (allo-HCT). H-Y antigens, which are encoded by Y chromosome, are important targets of the GVL effect. Thus, deletion of the Y chromosome (del[Y]) might cause the GVL effect to deteriorate in a transplantation involving a female donor and male recipient, although the clinical significance of the del(Y) group remains to be elucidated. In this study, we evaluated adult male patients who underwent allo-HCT between 2010 and 2019 in Japan. There were 155 cases in the del(Y) group and 4149 cases without del(Y) who underwent female-to-male allo-HCT. Del(Y) was significantly associated with inferior overall survival (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.00-1.53; P = .049) and an increased risk of relapse (HR, 1.40; 95% CI, 1.08-1.80; P = .0098) in multivariate analyses. There was no significant difference in nonrelapse mortality between recipients with and without del(Y) (HR, 1.08; 95% CI, 0.769-1.51; P = .67). In contrast, del(Y) was not significantly associated with any clinical outcomes in the cohort of male-to-male allo-HCT. A higher incidence of relapse might have been caused by attenuation of the GVL effect resulting from a lack of H-Y antigens. Because a GVL effect resulting from sex mismatch may not be expected in men with del(Y) who undergo allo-HCT with a female donor, additional post-allo-HCT strategies might be required to prevent disease relapse.

BACKGROUND: It has been reported that prolonged neutropenia during post-remission chemotherapy is associated with a reduced risk of disease relapse in pediatric acute myeloid leukemia (AML) patients. METHODS: We retrospectively reviewed the charts of adult AML patients in first complete remission (CR1) who underwent consolidation chemotherapy with high-dose cytarabine. Those receiving allogeneic hematopoietic cell transplantation in CR1 were excluded. We calculated the D-index, which is an area-based neutropenia index. The patients were divided into 2 groups using the median value of the D-index during the first cycle of consolidation chemotherapy (C#1). RESULTS: Fifty-six patients were included. The 2-year cumulative incidence of relapse was 54.8% (95% confidence interval (CI): 37.5-73.8) in patients with a D-index < 5,118 and 62.0% (95%CI: 42.7-81.4) in those with a D-index ≥ 5,118 (P = 0.56). In a multivariate analysis, intermediate / adverse cytogenetic risk (HR 2.76), performance status ≥ 2 (HR 5.55) and 2 cycles of induction chemotherapy required to achieve CR1 (HR 4.29) were identified as significant factors associated with relapse. The D-index at C#1 did not have a significant impact. CONCLUSIONS: In contrast to pediatric patients, the severity of neutropenia is not associated with a risk of disease relapse in adult AML patients.

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.

There is a matter of debate about the clinical impact of cytomegalovirus (CMV) reactivation on the development of late-onset invasive aspergillosis (IA), which occurs 40 days or later after allogeneic hematopoietic stem cell transplantation (HSCT). Using a Japanese transplant registry database, we analyzed the risk factors for the development of late-onset IA in 21,015 patients who underwent their first allogeneic HSCT between 2006 and 2017. CMV reactivation was defined as the initiation of preemptive anti-CMV antiviral therapy. Overall, there were 582 cases of late-onset IA, which occurred at a median of 95 days after HSCT. The 2-year cumulative incidence was 3.4% (95% confidence interval (CI), 3.0-3.9) in patients with CMV reactivation within 40 days after HSCT and 2.5% (95% CI, 2.3-2.8) in those without it (P < 0.001). In a multivariate analysis, CMV reactivation as a time-dependent covariate was significantly associated with the development of late-onset IA (hazard ratio (HR) 1.40, P < 0.001), as well as grade II-IV acute GVHD, age > 50 and HCT-CI ≥ 3 in the entire cohort. If we focus on the subgroup without grade II-IV acute GVHD, which is generally an indication for systemic corticosteroid therapy (n = 12,622), CMV reactivation was still a significant factor for the development of late-onset IA (HR 1.37, P = 0.045) as well as age > 50 years, HCT-CI ≥ 3, and cord blood transplantation. In conclusion, CMV reactivation was associated with an increased risk of late-onset IA after allogeneic HSCT independently of acute GVHD. Close monitoring for late-onset IA is necessary for patients who develop CMV reactivation even without grade II-IV acute GVHD.