Effects of human herpesvirus 6B reactivation on cognitive function in cord blood transplant recipients: a prospective multicenter study.

This prospective multicenter study aimed to determine the effects of human herpesvirus-6B (HHV-6B) reactivation on central nervous system (CNS) function in cord blood transplant (CBT) recipients. Our focus was to track HHV-6B reactivation and evaluate its association with delirium and cognitive function, specifically in the domains of verbal memory, attention/processing speed, and quality of life (QOL). A cohort of 38 patients participated in this study. Of the 37 patients evaluated, seven (18.9%) developed delirium, with six of these cases emerging after HHV-6B reactivation (median lag, 7 days). Evaluation of verbal memory showed that the final trial score for unrelated words at 70 days after transplantation was significantly lower than that before preconditioning (P = 0.004) among patients (n = 15) who experienced higher-level HHV-6B reactivation (median or higher maximum plasma HHV-6 DNA load for participating patients). Patients without higher-level reactivation did not show significant declines in verbal memory scores. QOL was assessed using the 36-item Short-Form Health Survey, and the social functioning score 1 year post-transplantation was significantly lower in patients who experienced higher-level HHV-6B reactivation than in those who did not. Our findings suggest that higher-level HHV-6B reactivation can detrimentally affect certain cognitive functions in CBT recipients.

Aortitis after administration of pegfilgrastim to a healthy donor for peripheral blood stem cell collection.

A 45-year-old man who was a sibling donor for allogeneic peripheral blood stem cell transplantation (allo-PBSCT) was administered 7.2 mg of pegfilgrastim for stem cell collection. Peripheral blood stem cells were collected 4 days after administration of pegfilgrastim (Day 4) and 4.32 × 106 /kg of CD34-positive cells per recipient body weight were obtained. Fever of 38 ℃ or higher and left submandibular pain appeared on Day 6. Ultrasonography and contrast-enhanced computed tomography (CT) showed wall thickening of the carotid artery and the abdominal aorta. We carefully excluded the possibilities of cardiovascular and autoimmune diseases by thorough examination, and ultimately diagnosed pegfilgrastim-induced aortitis. The patient's fever resolved rapidly after treatment with prednisolone (PSL) 1 mg/kg. We began to taper PSL after eight days. Sixty-one days after starting PSL, we confirmed that abdominal aortic wall thickening had improved by contrast-enhanced CT. We continued to taper off PSL and stopped 141 days later with no relapse thereafter. This is the first case report of pegfilgrastim-induced aortitis in an allo-PBSCT donor. Careful monitoring is warranted when administering pegfilgrastim to donors even without past medical history.

Risk factors and outcome of Stenotrophomonas maltophilia infection after allogeneic hematopoietic stem cell transplantation: JSTCT, Transplant Complications Working Group.

Stenotrophomonas maltophilia (S. maltophilia) is an aerobic nonfermenting Gram-negative bacillus widely distributed in the environment that has inherent multidrug resistance to beta-lactam and carbapenem antibiotics. S. maltophilia infection (SMI) is known as an important fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT), but its clinical characteristics have not been well clarified. A retrospective study to identify the incidence, risk factors, and outcomes of SMI after allogeneic HSCT was performed using the database of the Japanese nationwide registry, including 29,052 patients who received allogeneic HSCT in Japan between January 2007 and December 2016. A total of 665 patients developed SMI (sepsis/septic shock, 432; pneumonia, 171; other, 62). The cumulative incidence of SMI at 100 days after HSCT was 2.2%. Among risk factors identified for SMI (age ≥ 50 years, male, performance status 2-4, cord blood transplantation [CBT], myeloablative conditioning, Hematopoietic Cell Transplant-Comorbidity Index [HCT-CI] score 1-2, HCT-CI score ≥ 3, and active infectious disease at HSCT), CBT was the strongest risk factor (hazard ratio, 2.89; 95%CI, 1.94-4.32; p < 0.001). The survival rate at day 30 after SMI was 45.7%, and SMI before neutrophil engraftment was significantly associated with poor survival (survival rate 30 days after SMI, 40.1% and 53.8% in patients with SMI before and after engraftment, respectively; p = 0.002). SMI is rare after allogeneic HSCT, but its prognosis is extremely poor. CBT was a strong risk factor for SMI, and its development prior to neutrophil engraftment was associated with poor survival.

Treatment of T-Cell Prolymphocytic Leukemia with Central Nervous System Involvement Using Intrathecal Alemtuzumab Administration.

T-cell prolymphocytic leukemia (T-PLL) is a rare hematologic cancer with a dismal prognosis. Although a small number of patients have central nervous system (CNS) involvement, a standard treatment approach for these patients has not been established. Herein, we present a case of T-PLL with CNS involvement that was treated with a higher dose of intrathecal alemtuzumab than that previously reported. A 66-year-old man who had T-PLL with CNS involvement was admitted to our hospital. Intravenously administered alemtuzumab, a monoclonal antibody against the CD52 antigen, successfully reduced leukemia cells in peripheral blood; however, intrathecal treatment with methotrexate, cytarabine, and prednisone had a limited effect on the CNS involvement. Therefore, we intrathecally injected alemtuzumab as an experimental treatment. Although we escalated the dose of intrathecal alemtuzumab up to 5 mg, no adverse reaction was noted; however, this treatment did not completely clear the leukemia cells from the patient's cerebrospinal fluid (CSF). We performed whole brain and whole spinal irradiation therapies and subsequently performed allogeneic transplantation from a human leukocyte antigen-matched sibling donor with a conditioning regimen containing total body irradiation. At 21 days after transplantation, leukemia cells remained in his CSF. Although intrathecal alemtuzumab did not eliminate the CNS-invading leukemia cells, it was well-tolerated in our case. Further accumulation of similar cases is needed to determine the benefits and safety of intrathecal alemtuzumab administration.

Cat Rearing: A Potential Risk of Fulminant Sepsis Caused by Capnocytophaga canimorsus in a Hemodialysis Patient.

Capnocytophaga canimorsus is a commensal organism colonized in oral flora of dogs and cats and causes severe sepsis through bite wound in immunocompromised patients. To date, hemodialysis has not been reported as a risk of C. canimorsus infection. A 75-year-old woman with end-stage renal disease secondary to hypertension suddenly developed septic shock. She reared 6 cats in her home, but no bite or scratch wound was found on her body. She was empirically treated with piperacillin-tazobactam and temporally received continuous hemodiafiltration. On the fifth day after sampling, blood culture revealed C. canimorsus as the cause of sepsis. After 4 weeks of antibiotic therapy targeting this organism, she recovered from the sepsis and was discharged on the 109th hospitalization day. Hemodialysis patients may be vulnerable to invasion into the blood stream by C. canimorsus due to the presence of punctures in their skin and the impaired immune function associated with uremia. Physicians should consider this organism as a cause of sepsis in hemodialysis patients who rear dogs or cats even in the absence of apparent bite wounds.

Pharmacokinetics of dasatinib in a hemodialysis patient with chronic myeloid leukemia and chronic kidney disease.

Until now, no studies have addressed the use of dasatinib in hemodialysis patients. Herein, we report the case of a 73-year-old hemodialysis patient with chronic myeloid leukemia (CML) who was treated with dasatinib. For 5 years prior, the patient had received nilotinib for the treatment of CML. Regular hemodialysis was initiated due to progression of hypertensive nephrosclerosis, whereupon nilotinib was discontinued and the patient began receiving 100 mg dose of dasatinib once daily. On dialysis days, dasatinib was administered immediately after completion of dialysis. Four months after starting dasatinib, we performed a pharmacokinetic study. The plasma concentrations of dasatinib before, immediately, and 2 h after the completion of hemodialysis were 7.4, 6.1, and 59.5 ng/mL, respectively. Ultrasound cardiography revealed a gradual decline in ejection fraction during dasatinib therapy. Because the patient's dasatinib trough concentration was higher (6.1 ng/mL) than the target level (1.5 ng/mL), we suspected the development of dasatinib-related heart dysfunction; thus, dasatinib was discontinued 6 months after its initiation. We concluded that hemodialysis patients are potentially vulnerable to the cardiotoxic effects of dasatinib; monitoring of cardiac function and plasma drug concentration may thus be useful in assessing their condition.

Hematopoietic Stem Cell Transplantation in Solid Organ Recipients with Emphasis on Transplant Complications: A Nationwide Retrospective Survey on Behalf of the Japan Society for Hematopoietic Stem Cell Transplantation Transplant Complications Working Group.

Little is known about stem cell transplantation in solid organ transplantation (SOT) recipients. We conducted a nationwide retrospective survey of Japan Society for Hematopoietic Stem Cell Transplantation centers. A total of 19 patients who underwent 22 hematopoietic stem cell transplantations (HSCTs) after SOT were identified: 5 autologous HSCTs and 17 allogeneic HSCTs were performed. Patients who underwent autologous HSCT received a liver (n = 4) or kidney (n = 1) transplant. All 5 patients achieved neutrophil engraftment, and 2 of 3 patients with hepatoblastoma were alive at 1 year after HSCT. Allogeneic HSCT was performed in 16 patients (7 liver transplant recipients and 9 kidney transplant recipients). Among these, 2 donors were identical for both transplantations. All but 1 patient achieved neutrophil engraftment. The 5-year overall survival rate was 41.7%, but that in patients with malignant disease (n = 13) was much lower than the overall rate (23.1%). Only 1 patient with malignant disease underwent allogeneic HSCT in nonremission. In allogeneic HSCT after kidney transplantation, post-transplantation (1 year) kidney function in 5 evaluable patients was significantly lower than that before allogeneic HSCT, and 3 patients experienced renal rejection. However, no severe hepatic rejection was noted. In SOT recipients, HSCT is a potentially curable treatment for hematologic disorders, but it must be performed with caution, especially in patients with malignancy.

Impact of pretransplant donor-specific anti-HLA antibodies on cord blood transplantation on behalf of the Transplant Complications Working Group of Japan Society for Hematopoietic Cell Transplantation.

Graft failure (GF) remains a major complication of cord blood transplantation (CBT). Although the presence of pretransplant, donor-specific anti-HLA antibodies (DSA) was reported to be associated with an increased risk of GF after CBT, data are still limited. Thus, we conducted a retrospective analysis of recipients of single-unit CBT with pretransplant anti-HLA antibodies using the database of Japan Society for Hematopoietic Cell Transplantation (JSHCT). Data for recipients of single-unit CBT with pretransplant anti-HLA antibodies from 2010 to 2014 were obtained. In total, 343 patients who received CBT and who had detailed information about anti-HLA antibodies were included. The median age was 51 years (range, 0-71). Regarding DSA, 25 patients had a mean fluorescence intensity (MFI) ≥ 1000 (DSA-positive group) and 318 patients had a MFI <1000 (DSA-negative group). The cumulative incidence of neutrophil engraftment at 60 days after CBT was 75.7% (95% CI, 70.6-80.1) in the DSA-negative group and 56.0% (95% CI, 34.1-73.1) in the DSA-positive group (P = 0.03). In conclusion, pretransplant DSA with a MFI ≥ 1000 was associated with an increased risk of GF in single-unit CBT.

Resolved versus Active Chronic Graft-versus-Host Disease: Impact on Post-Transplantation Quality of Life.

The aim of this study was to determine whether impaired quality of life (QOL) persisted among patients who experienced resolved chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Eligible participants were patients who were relapse-free for 3 years after allo-HCT who were age ≥16 years at the time of transplantation and age ≥20 years without relapse at the time of the survey. The Medical Outcomes Study's 36-Item Short-Form Survey (SF-36), the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and a visual analog scale (VAS) were administered to assess QOL. Physicians evaluated the current status of chronic GVHD at survey using National Institutes of Health (NIH) criteria, and pretransplantation characteristics and history of GVHD were extracted from the national transplant registry database. Patients without currently active GVHD but with a history of chronic GVHD were categorized as having "resolved GVHD." Of 1250 patients informed of the study, 1216 provided consent and 1130 were included in the final analysis. A total of 745 patients (66%) had currently active chronic GVHD, 149 (13%) had resolved chronic GVHD, and 236 (21%) never had chronic GVHD after allo-HCT. Multivariable analyses showed that compared with patients with resolved or no chronic GVHD, those with active chronic GVHD reported significantly poorer QOL. The QOL scores were similar in patients with resolved chronic GVHD and those without chronic GVHD. Greater between-group differences were observed in SF-36 Physical component and VAS scores in patients age ≥50 years, but the differences were not statistically significant. Our data indicate that only currently active chronic GVHD has a significant impact on physical, mental, and social QOL in allo-HCT survivors, whereas previous chronic GVHD does not impair QOL if it has been resolved.

Favorable effect of bortezomib in dense deposit disease associated with monoclonal gammopathy: a case report.

BACKGROUND: Complement component 3 (C3) glomerulopathy, which includes dense deposit disease (DDD) and C3 glomerulonephritis, is caused by dysregulation of the alternative complement pathway. In most cases, C3 glomerulopathy manifests pathologically with membranoproliferative glomerulonephritis-like features. An association between C3 glomerulopathy and monoclonal gammopathy was recently reported in several cases, raising the possibility that C3 glomerulopathy is the underlying pathological process in monoclonal gammopathy of renal significance. CASE PRESENTATION: We herein report a case of monoclonal gammopathy-induced DDD that improved histologically and clinically with chemotherapy including bortezomib. Our case is the first in which treatment response can be linked to the histological response. Potential pathological insights are also discussed. CONCLUSIONS: Rapid and efficient chemotherapy has the potential to limit renal damage in monoclonal gammopathy-associated DDD.

Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group.

Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90 mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n = 63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 104 copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P < .001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation. The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P = .14). The cumulative incidences of grades II to IV and grades III to IV aGVHD at 60 days after CBT were not different between the groups (grades II to IV aGVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P = .96; grades III to IV aGVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P = 1.00). In the setting of this study foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of aGVHD.

Quality of Life after Allogeneic Hematopoietic Cell Transplantation According to Affected Organ and Severity of Chronic Graft-versus-Host Disease.

Knowing the impact of chronic graft-versus-host disease (GVHD) on quality of life (QoL) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by GVHD type and severity is critical for providing care to transplant survivors. We conducted a cross-sectional questionnaire study to examine the relationship between patient-reported QoL as measured by the Medical Outcomes Study 36-Item Short-Form Health Survey, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, and visual analogue scale (VAS) and chronic GVHD defined by the National Institutes of Health (NIH) criteria. Recipients of allo-HCT for hematologic disease between 1995 and 2009 aged ≥ 16 years at transplant and ≥20 years at the time of the survey who were relapse-free were eligible. A total of 1140 pairs of patient and physician questionnaires were included in the analysis. By NIH global severity score, QoL scores in all aspects were significantly lower in patients with higher global and organ-specific severity grades, independent of background variables. Compared with patients without GVHD symptoms, those with mild symptoms had impaired physical and general QoL according to global severity score and organ-specific scores except for the genital tract. Mild symptoms in the lungs, gastrointestinal tract, and joints and fascia were associated with clinically meaningful deterioration of physical QoL. VAS scores provided by physicians were generally higher than those provided by patients. Differences between scores reported by patients and physicians were larger for patients with no or mild GVHD symptoms. Our findings based on more than 1000 long-term survivors after HCT enabled us to identify a target of care, informing survivorship care protocols to improve post-transplantation QoL.