The hepatic niche leads to aggressive natural killer cell leukemia proliferation through the transferrin-transferrin receptor 1 axis.

Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associated with Epstein-Barr virus, with a disastrously poor prognosis. Owing to the lack of samples from patients with ANKL and relevant murine models, comprehensive investigation of its pathogenesis including the tumor microenvironment (TME) has been hindered. Here we established 3 xenograft mice derived from patients with ANKL (PDXs), which enabled extensive analysis of tumor cells and their TME. ANKL cells primarily engrafted and proliferated in the hepatic sinusoid. Hepatic ANKL cells were characterized by an enriched Myc-pathway and proliferated faster than those in other organs. Interactome analyses and in vivo CRISPR-Cas9 analyses revealed transferrin (Tf)-transferrin receptor 1 (TfR1) axis as a potential molecular interaction between the liver and ANKL. ANKL cells were rather vulnerable to iron deprivation. PPMX-T003, a humanized anti-TfR1 monoclonal antibody, showed remarkable therapeutic efficacy in a preclinical setting using ANKL-PDXs. These findings indicate that the liver, a noncanonical hematopoietic organ in adults, serves as a principal niche for ANKL and the inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL.

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.

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.

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.

Updated Clinical Outcomes of Hematopoietic Stem Cell Transplantation Using Myeloablative Total Body Irradiation with Ovarian Shielding to Preserve Fertility.

Myeloablative conditioning regimens are associated with severe gonadal toxicity. To preserve ovarian function, we have been investigating ovarian shielding during total body irradiation (TBI) with a myeloablative dose. In this report, we update the clinical outcomes. Female patients with standard-risk hematologic diseases, aged 40 years or younger, who desired to have children, were included (n = 19). The conditioning regimen consisted of TBI at 12 Gy with ovarian shielding and cyclophosphamide (120 mg/kg) or cytarabine (24 g/m2). Ovarian shielding reduced the actual irradiation dose applied to the ovaries from 12 Gy to 2 to 3 Gy. The median age at hematopoietic stem cell transplantation (HSCT) was 24 years (range, 19 to 33 years). With a median follow-up period of 1449 days (range, 64 to 3694) after HSCT, 5-year overall survival and 1- and 5-year relapse rates were 67%, 17%, and 31%, respectively. Only 2 of 14 patients with acute myeloid or lymphoid leukemia in remission have relapsed thus far. The 6-month and 1-year cumulative rates of menstrual recovery were 42% and 78%, respectively. In all patients with menstrual recovery, menstruation recovered within 1 year. The serum anti-Müllerian hormone (AMH) level tended to gradually increase after menstrual recovery. Three patients with extensive chronic graft-versus-host disease experienced delayed recovery of menstruation and serum AMH. Five pregnancies in 3 patients resulted in normal delivery in 1, selective cesarean operation in 1, current pregnancy in 1, and natural abortion in 2. These results suggest that a myeloablative TBI regimen with ovarian shielding could preserve fertility after HSCT without an apparent increase in relapse in standard-risk patients. Because serum AMH recovered gradually over time, the AMH level during the early phase after HSCT may have little value as a marker of ovarian reserve.

Haploidentical transplantation using low-dose alemtuzumab: Comparison with haploidentical transplantation using low-dose thymoglobulin.

OBJECTIVES: To establish the optimal strategy for haploidentical hematopoietic stem cell transplantation (HSCT). METHODS: We performed a prospective study on haploidentical HSCT using low-dose alemtuzumab. Alemtuzumab was added at 0.25 mg/kg for 2 days. The primary outcome measure was the survival rate with the engraftment of donor cells and without grade III-IV acute graft-vs-host disease (GVHD) at 60 days after transplantation. RESULTS: Fourteen adult patients with advanced hematological disease were enrolled. The primary outcome measure was achieved in 86% of the patients. Six patients experienced relapse/progression. Non-relapse death was observed in three patients, and all of them had a history of previous allogeneic HSCT. Overall survival and progression-free survival rates at 1 year were 51% and 43%, respectively. Four patients were suspected to have herpes simplex virus infection and three had aseptic meningitis under the use of acyclovir at 200 mg. There were no deaths due to viral infection. Compared to those who underwent haploidentical HSCT using thymoglobulin, patients with alemtuzumab showed a slower recovery of CD8+ T-cells and lower incidences of GVHD and EB virus reactivation. CONCLUSIONS: Haploidentical HSCT using low-dose alemtuzumab can be performed safely. We need to overcome the high relapse/progression rate in non-remission patients.

Association between Activated Partial Thromboplastin Time and the Amount of Infused Heparin at Bone Marrow Transplantation.

The actual heparin concentration of harvested allogeneic bone marrow varies among harvest centers. We monitor the activated partial thromboplastin time (APTT) of the patient during bone marrow infusion and administer prophylactic protamine according to the APTT. We retrospectively reviewed the charts of consecutive patients who underwent bone marrow transplantation without bone marrow processing at our center between April 2007 and March 2016 (n = 94). APTT was monitored during marrow transfusion in 52 patients. We analyzed the relationship between the APTT ratio and several parameters related to heparin administration. As a result, the weight-based heparin administration rate (U/kg/hour) seemed to be more closely related to the APTT ratio (r = .38, P = .005) than to the total amount of heparin. There was no significant correlation between the APTT ratio and renal or liver function. Bleeding complications during and early after infusion were seen in 3 of 52 patients, and included intracranial, nasal, and punctured-skin bleeding. The APTT ratio during transfusion was over 5.88 in the former 2 patients and 2.14 in the latter. All of these patients recovered without sequelae. In conclusion, slow bone marrow infusion is recommended to decrease the weight-based heparin administration rate when the heparin concentration per patient body weight is high.

Refractory Graft-Versus-Host Disease-Free, Relapse-Free Survival as an Accurate and Easy-to-Calculate Endpoint to Assess the Long-Term Transplant Success.

The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo-HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation.

A Unique T-Cell Receptor Amino Acid Sequence Selected by Human T-Cell Lymphotropic Virus Type 1 Tax301-309-Specific Cytotoxic T Cells in HLA-A24:02-Positive Asymptomatic Carriers and Adult T-Cell Leukemia/Lymphoma Patients.

We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax301-309-specific CD8+ cytotoxic T cells (Tax301-309-CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02+) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donor-derived PDR+ CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax301-309-CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-ß chain of Tax301-309-CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax301-309-CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax301-309-CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax301-309-CTLs, 1,458 Tax301-309-CTLs and 140 clones were identified in this cohort. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-ß CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR+ CTL frequencies and HTLV-1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA-A*24:02+ HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR+ CTL response in the progression from carrier state to ATL.IMPORTANCE ATL is an aggressive T-cell malignancy caused by HTLV-1 infection. The HTLV-1 regulatory protein Tax aggressively promotes the proliferation of HTLV-1-infected lymphocytes and is also a major target antigen for CD8+ CTLs. In our previous evaluation of Tax301-309-CTLs, we found that a unique amino acid sequence motif, PDR, in CDR3 of the TCR-ß chain of Tax301-309-CTLs was conserved among ATL patients after allo-HSCT. Furthermore, the PDR+ Tax301-309-CTL clones selectively expanded and showed strong cytotoxic activities against HTLV-1. On the other hand, it remains unclear how Tax301-309-CTL repertoire exists in ACs. In this study, we comprehensively compared Tax-specific TCR repertoires at the single-cell level between ACs and ATL patients. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-ß CDR3, was conserved in all ACs and ATL patients, regardless of clinical subtype in HTLV-1 infection.

Delayed platelet recovery after allogeneic hematopoietic stem cell transplantation: Association with chronic graft-versus-host disease and survival outcome.

Delayed platelet recovery (DPR) despite prompt neutrophil engraftment is frequently observed after allogeneic hematopoietic stem cell transplantation (HSCT). However, few studies have evaluated the risk factors and long-term outcome. Therefore, we retrospectively analysed 219 adult patients who underwent their first allogenic HSCT with neutrophil engraftment. Of these 219 patients, 50 (22.8%) had DPR that was defined as relapse-free survival at day 60 after HSCT without primary platelet recovery despite neutrophil engraftment. The results of a multivariate analysis showed that a high-risk underlying disease (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.04-5.48; P = .041) and human leukocyte antigen-mismatched HSCT (OR, 2.63; 95% CI, 1.28-5.43; P = .009) were associated with an increased risk of DPR. In univariate analyses, the occurrence of DPR was significantly associated with inferior overall survival, high nonrelapse mortality, and a low incidence of chronic graft-versus-host disease (GVHD), despite a comparable relapse rate. In multivariate analyses, DPR was associated with inferior overall survival (hazard ratio [HR], 2.00; 95% CI, 1.23-3.27; P = .005) and a low incidence of chronic GVHD (HR, 0.42; 95% CI, 0.22-0.78; P = .002). In conclusion, DPR was a strong predictor of shorter survival but also less frequent chronic GVHD.

Safety of avoiding systemic corticosteroid administration for grade II acute graft-versus-host disease limited to the skin.

We hypothesized that systemic corticosteroid administration would be safely avoided not only in grade I acute graft-versus-host disease (GVHD) but also in selected patients with grade II acute GVHD limited to the skin (grade IIs GVHD). We retrospectively evaluated risk factors for subsequent GVHD progression, defined as the involvement of other organs or progression to grade III to IV GVHD, in 50 patients with acute GVHD of grade IIs at its onset. Sixteen patients received systemic corticosteroid administration before GVHD progression. The cumulative incidence of GVHD progression at 28 days from the onset of grade IIs GVHD was 24%. Twenty-five patients did not require systemic corticosteroid administration throughout the entire episode of acute GVHD. Systemic corticosteroid administration before GVHD progression did not affect GVHD progression, chronic GVHD, or non-relapse mortality. Early onset (less than 26 days from transplantation) of grade IIs GVHD was identified as the only statistically significant risk factor for GVHD progression (hazard ratio 6.73, 95% confidence interval 1.5-31.1, P = 0.01). In conclusion, avoiding systemic corticosteroid administration for selected patients with grade IIs GVHD before GVHD progression did not compromise the transplantation outcomes. Patients with early-onset grade IIs GVHD were at high risk for GVHD progression.

Outcome of gastrointestinal graft-versus-host disease according to the treatment response.

The optimal treatment strategy for gastrointestinal graft-versus-host disease (GI-GVHD) after allogeneic hematopoietic cell transplantation remains to be established. We retrospectively analyzed 68 cases of GI-GVHD at our institution between 2007 and 2017. The survival outcomes were significantly inferior in patients who did not respond to the first-line treatment (1-year overall survival 27.3 vs 69.2%, P = 0.0017; non-relapse mortality 50.0 vs 18.6%, P = 0.026). After subsequent treatments, 18 patients were refractory to all steroid-based treatments such as steroid pulse therapy and oral beclomethasone dipropionate (BDP). However, these steroid-refractory cases showed a gradual increase in the response rate after the initial diagnosis of steroid refractoriness. This result may be explained by the problem of evaluating the response based solely on the volume of diarrhea, i.e., severe mucosal damage due to refractory GI-GVHD may require a long recovery and sometimes be complicated with other diseases. In conclusion, patients with GI-GVHD who failed to respond to the first-line treatment had inferior survival. However, later improvement may be observed without additional immunosuppressant other than steroid among patients who initially do not respond to steroid therapy. It is important to repeat colonoscopy in patients with refractory GI-GVHD to monitor the activity of GVHD.

Positive Cytotoxic Crossmatch Predicts Delayed Neutrophil Engraftment in Allogeneic Hematopoietic Cell Transplantation from HLA-Mismatched Related Donors.

Although a positive cytotoxic crossmatch (XM) has been reported to predict graft failure, mainly in solid organ transplantations, its significance in allogeneic hematopoietic cell transplantation (HCT) remains to be elucidated. We retrospectively assessed the impact of positive XM on neutrophil engraftment in 41 patients who underwent HCT with an HLA-mismatched related donor. XM was positive in 22 patients. Six of these 22 patients were also positive for anti-HLA antibody, whereas only 1 was positive for donor-specific anti-HLA antibody. The cumulative incidence of engraftment at day +28 was 89.5% in patients with negative XM versus 59.1% in those with positive XM (P = .08). In particular, positive B cell warm XM was significantly associated with a lower probability of engraftment at day +28 (46.7% versus 88.5%; P = .04). In a multivariate analysis, both positive XM and positive B cell warm XM were significantly associated with delayed engraftment (hazard ratio [HR], .46; P = .02 and HR, .41; P = .01, respectively). There was no significant difference in the achievement of engraftment between those with and without detection of anti-HLA antibodies. In conclusion, positive XM might be associated with a delayed neutrophil engraftment after HCT from HLA-mismatched related donors.