Decision analysis for transplant candidates with primary myelofibrosis in the ruxolitinib era.

The recent progress with ruxolitinib treatment might improve quality-of-life as well as overall survival in patients with primary myelofibrosis (PMF). Therefore, the optimal timing of allogeneic hematopoietic cell transplantation (HCT) remains to be elucidated in the ruxolitinib era. We constructed a Markov model to simulate the 5-year clinical course of transplant candidates with PMF, and compared outcomes between immediate HCT and delayed HCT after ruxolitinib failure. Since older age was associated with an increased risk of mortality, we analyzed patients aged < 60 and ≥ 60 separately in subgroup analyses. The expected life years was consistently longer in delayed HCT after ruxolitinib failure regardless of patient age. Regarding quality-adjusted life years (QALYs), a baseline analysis showed that immediate HCT was inferior to delayed HCT after ruxolitinib failure (2.19 versus 2.26). In patients aged < 60, immediate HCT was equivalent to delayed HCT after ruxolitinib failure (2.31 versus 2.31). On the other hand, in patients aged ≥ 60, immediate HCT was inferior to delayed HCT after ruxolitinib failure (1.98 versus 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 QALYs, 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, and is also a promising strategy even in those aged < 60.

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

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

Clinical impact of a change in antibiotics or the addition of glycopeptide antibiotics for persistent febrile neutropenia after autologous stem cell transplantation.

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.

Gene expression and TCR amino acid sequences selected by HLA-A02:01-restricted CTLs specific to HTLV-1 in ATL patients.

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)ß 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 TCRß 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.

Unrelated female-to-male bone marrow transplantation would be preferred over cord blood transplantation in male 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.

Risk factors for fatal cardiac complications after allogeneic hematopoietic cell transplantation: Japanese Society for Transplantation and Cellular Therapy transplant complications working group.

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.

Clinical features of febrile neutropenia and bloodstream infection in autologous hematopoietic cell transplantation: Comparison to those in intensive chemotherapy for acute myeloid leukemia.

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.

Chronic active Epstein-Bar virus infection complicated by pulmonary artery hypertension.

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.

[Anti-MDA5 antibody-positive rapidly progressive interstitial lung disease after allogeneic hematopoietic cell transplantation successfully treated with triple immunosuppressive therapy].

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.

Successful Treatment of the TEMPI Syndrome with Pomalidomide Plus Dexamethasone Followed by Autologous Stem Cell Transplantation.

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.

Cytomegalovirus reactivation is associated with an increased risk of late-onset invasive aspergillosis independently of grade II-IV acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation: JSTCT Transplant Complications Working Group.

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.

Association of the areas over and under the lymphocyte curve with cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.

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.

Association between the kinetics of cytomegalovirus reactivation in terms of the area under the curve of cytomegalovirus antigenemia and non-relapse mortality after allogeneic hematopoietic stem cell transplantation.

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.

Pre-Hematopoietic Stem Cell Transplantation Lung Computed Tomography as an Alternative to the Pulmonary Function Test during the COVID-19 Pandemic.

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.

Effect of Smoking on Outcomes of Allogeneic Transplantation: A Single-Center Analysis.

Pulmonary complications are fatal adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). On the other hand, smoking is a well-known risk factor for various pulmonary diseases and also increases the incidence of pulmonary complications and overall mortality in allo-HCT recipients. In this study, we retrospectively assessed the impact of smoking intensity on survival outcomes. This study included consecutive allo-HCT recipients at our center between June 2007 and May 2019 whose smoking profiles were available (n = 408); they were divided into high (pack-years >10, n = 171) and low (pack-years ≤10, n = 231) pack-years groups. In univariate analyses, nonrelapse mortality (NRM) and overall survival (OS) were significantly inferior in the high pack-years group (1-year NRM 26.6% versus 13.9%, P < .001; 1-year OS 58.4% versus 70.1%, P = .0067). However, this association was not observed in multivariate analyses. In subgroup analyses according to sex, the survival outcomes in the high pack-years group were significantly inferior in males (NRM hazard ratio [HR], 2.24 [95% confidence interval (CI), 1.23 to 4.07], P = .0082; OS HR, 1.54 [95% CI, 1.04 to 2.28], P = .031), but not in females (NRM HR, 0.587 [95% CI, 0.241 to 1.43], P = .24; OS HR, 0.689 [95% CI, 0.400 to 1.19], P = .18). In summary, high pack-years were associated with inferior survival of allo-HCT recipients, especially in males.

Impact of blood pressure early after allogeneic hematopoietic cell transplantation on clinical outcomes.

Allogeneic hematopoietic transplantation (allo-HCT) is still associated with significant morbidity and mortality, and risk stratification is critical. In this study, we analyzed the relationship between blood pressure control early after allo-HCT and survival outcomes. All patients who survived longer than 28 days after allo-HCT at our center between June 2007 and June 2018 (n = 353) were included, and the average systolic blood pressure (asBP) from 1 to 28 days after allo-HCT was calculated. According to the results of a ROC curve analysis, an asBP of 131 mmHg was defined as a cut-off value between high and low asBP groups. Non-relapse mortality (NRM) and OS were significantly inferior in the high asBP group (2-year-NRM 28.0% vs 11.1%, P < 0.001; 2-year-OS 46.7% vs 65.7%, P = 0.001). In addition, baseline asBP before commencement of the conditioning regimen and elevation of asBP (asBP - baseline asBP) were both associated with inferior NRM. While these results were also observed in the younger patients (≤ 50 years), no relationship was observed in the older patients (> 50 years). High blood pressure within 28 days after allo-HCT was associated with inferior survival outcomes, especially in patients younger than 50 years.

Impact of neutropenia evaluated in terms of the D-index on invasive fungal disease while on empiric or preemptive antifungal treatment strategy in the early phase after allogeneic hematopoietic stem cell transplantation.

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.

Impact of the patient's body weight on the efficacy and adverse events of valganciclovir for cytomegalovirus reactivation after hematopoietic stem cell transplantation.

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.

Association between the kinetics of cytomegalovirus reactivation evaluated in terms of the area under the curve of cytomegalovirus antigenemia and invasive mold infection during the post-engraftment phase after allogeneic hematopoietic stem cell transplantation.

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.

Surgical resection for persistent localized pulmonary fungal infection prior to allogeneic hematopoietic stem cell transplantation: Analysis of six cases.

OBJECTIVE: Although invasive fungal disease (IFD) is an important complication in allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of surgery, including the role of surgical resection for persistent pulmonary fungal disease prior to allogeneic HSCT in the current era with a variety of available antifungal agents, is controversial. We investigated the role of surgical resection. METHODS: We retrospectively investigated six patients who underwent surgical resection of suspected pulmonary fungal disease prior to allogeneic HSCT between April 2007 and June 2016 at our medical center. RESULTS: We present six patients who underwent surgical resection of suspected pulmonary fungal disease prior to allogeneic HSCT. In our case series, three of four patients who were given a presurgical diagnosis of possible IFD were given a proven diagnosis after surgery, including two cases of invasive aspergillosis (IA) and one case of mucormycosis. All surgeries were performed by video-assisted thoracic surgery (VATS) for lobectomy without major complications. Recurrence of IFD was not observed after allogeneic HSCT in any of the six patients. CONCLUSION: Our experience indicated that surgical resection of persistent localized pulmonary lesions of IFD before allogeneic HSCT was helpful for obtaining a definitive diagnosis and might be useful for reducing recurrence after HSCT.