Utility of the refined EBMT diagnostic and severity criteria 2023 for sinusoidal obstruction syndrome/veno-occlusive disease.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Early diagnosis of SOS/VOD is associated with improved clinical outcomes. In 2023, the refined European Society for Blood and Marrow Transplantation diagnostic and severity criteria (refined EBMT criteria 2023) have been advocated. The revision has introduced new diagnostic categories, namely; probable, clinical, and proven SOS/VOD. In addition, the Sequential Organ Failure Assessment (SOFA) score has been newly incorporated into the SOS/VOD severity grading. We performed a retrospective analysis to evaluate the utility of these criteria. We analyzed 161 cases who underwent allogeneic HSCT. We identified 53 probable, 23 clinical, and 4 proven SOS/VOD cases. Probable SOS/VOD was diagnosed a median of 5.0 days earlier (interquartile range: 2-13 days, P < 0.001) than that of clinical SOS/VOD. The development of probable SOS/VOD alone was associated with a significantly inferior survival proportion compared to non-SOS/VOD (100-day survival, 86.2% vs. 94.3%, P = 0.012). The SOFA score contributed to the prediction of prognosis. Consequently, the refined EBMT criteria 2023 demonstrated the utility of SOS/VOD diagnosis and severity grading. Further investigations and improvements in these criteria are warranted.

Early diagnosis of sinusoidal obstruction syndrome after hematopoietic stem cell transplantation, with modified diagnostic criteria including refractory thrombocytopenia.

Sinusoidal obstruction syndrome (SOS) is a fatal complication of hematopoietic stem cell transplantation (HSCT). Early diagnosis for SOS can improve clinical outcomes significantly. Here, we performed a retrospective study to investigate the Cairo diagnostic criteria, in which SOS was defined as the development of two or more in seven events, including transfusion-refractory thrombocytopenia. Among 154 cases of allogeneic HSCT, 10 cases of SOS using the European Society for Blood and Marrow Transplantation criteria (EBMT16) as the reference standard were identified. The original Cairo criteria could diagnose SOS 5 days earlier than any other established criteria, with some false-positive results (sensitivity = 100.0%; specificity = 72.2%). When the cutoff was set to three events for the Cairo criteria, the diagnosis of SOS could be made 3 days earlier than that using the EBMT16 criteria, with comparable precision (specificity = 86.1%). The accuracy of the Cairo criteria improved further when the cutoff point was set to four (specificity = 93.8%). The fulfillment of the Cairo criteria was associated with high mortality. Based on our results, the Cairo criteria were also considered clinically useful, especially at three or four cutoff points. Further studies are required to validate and refine the criteria.

Safety and Accuracy of Professional Continuous Glucose Monitoring in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Hyperglycemia in the early days following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-known risk factor for acute graft-versus-host disease (GVHD) and non-relapse mortality. The FreeStyle Libre Pro, a factory calibrated continuous glucose monitoring (CGM) device, has been used for the retrospective analysis of glucose testing in patients with diabetes. We assessed the safety and accuracy of the device in patients undergoing allo-HSCT. We recruited eight patients who underwent allo-HSCT between August 2017 and March 2020. They wore the FreeStyle Libre Pro on the day before or on the day of transplantation until 28 days after transplantation. Adverse events, especially bleeding and infection, were monitored to assess safety, and blood glucose levels were measured and compared with the device values. None of the eight participants experienced bleeding that was difficult to stop from the sensor site or local infection that required antimicrobial administration. The device value was well correlated with blood glucose (correlation coefficient r=0.795, P<0.01); however, the overall mean absolute relative difference was 32.1%±16.0%. Our study demonstrated the safety of FreeStyle Libre Pro in allo-HSCT patients. However, the sensor results tended to be lower than the blood glucose levels.

Efficacy and Safety of Synbiotics in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Randomized, Double-blinded, Placebo-controlled Pilot Study.

Objective High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective treatment option for relapsed and refractory aggressive malignant lymphoma. However, patients frequently experience treatment-induced gastrointestinal symptoms. Synbiotics, including live microorganisms and nondigestible food ingredients, reportedly ameliorate chemotherapy-induced mucosal damage. In this study, we assessed the efficacy and safety of synbiotics in patients undergoing auto-HSCT. Methods This randomized, double-blinded study included patients with malignant lymphoma eligible for auto-HSCT. The patients were randomly assigned to either a synbiotic group receiving Bifidobacterium longum (BB536) and guar gum or a placebo group receiving a placebo containing dextrin. The supplements were administered twice daily from the start of conditioning chemotherapy up to 28 days after auto-HSCT. The primary endpoint was the duration of total parenteral nutrition (TPN). Results In total, 12 patients were included and randomized. The median duration of TPN was 15 (range, 12-33) days in the synbiotic group and 17.5 (range, 0-32) days in the placebo group. The median duration of grade ≥3 diarrhea was shorter in the synbiotic group than in then placebo group (2.5 vs. 6.5 days), as was the duration of hospital stay (31.5 vs. 43 days). The oral intake and quality of life regarding diarrhea and anorexia improved in the synbiotic group after engraftment. Synbiotic infections, including bacteremia, were not observed. Conclusion Synbiotics may reduce gastrointestinal toxicity, thereby reducing nutritional problems and improving the quality of life of patients undergoing auto-HSCT, without severe adverse events.

Global longitudinal strain is superior to ejection fraction for long-term follow-up after allogeneic hematopoietic stem cell transplantation.

Global longitudinal strain (GLS), a new cardiac parameter measured by the speckle-tracking method, is reportedly more sensitive than ejection fraction (EF) in detecting slight cardiac dysfunction in heart failure patients. We validated the utility of GLS in allogeneic hematopoietic stem cell transplantation (HSCT) patients during a long-term follow-up. Medical records of patients who underwent allogeneic HSCT between 2013 and 2020 were reviewed retrospectively. We evaluated the last echocardiography performed before transplantation and those performed annually during the 5 years after transplantation. We also investigated newly diagnosed cardiac events, which developed after HSCT. Among 85 patients, 22 used cardioprotective drugs. The median follow-up duration in surviving patients was 54.1 months (range, 2.9-92.6 months). GLS significantly decreased year by year, and patients taking cardioprotective agents tended to have a better GLS at 5 years than at 3 years, while EF did not change. Fifteen patients developed newly diagnosed cardiac events. Multivariate analysis revealed that low GLS and high serum ferritin levels at baseline were independently associated with the development of cardiac events. Therefore, we need a continuous follow-up of cardiac function by GLS and prescription of cardioprotective drugs might be considered for HSCT patients with low GLS. Further research is warranted.

A Third Dose COVID-19 Vaccination in Allogeneic Hematopoietic Stem Cell Transplantation Patients.

We previously reported that a second dose of BNT162b2 was safe and effective for allogeneic hematopoietic stem cell transplantation (HSCT) patients. Here, we investigated the safety and efficacy of a third dose of COVID-19 mRNA vaccine in allogeneic HSCT patients. Antibody titers against the S1 spike protein were measured using the QuaResearch COVID-19 Human IgM IgG ELISA kit. The previous study included 25 allogeneic HSCT patients who received two doses of BNT162b2. Following the exclusion of three patients because of the development of COVID-19 (n = 2) and loss to follow-up (n = 1), the study evaluated 22 allogeneic HSCT patients who received a third dose of COVID-19 mRNA vaccine (BNT162b2 [n = 15] and mRNA-1273 [n = 7]). Median age at the time of the first vaccination was 56 (range, 23-71) years. Five patients were receiving immunosuppressants at the third vaccination, namely calcineurin inhibitors (CI) alone (n = 1), steroids alone (n = 2), or CI combined with steroids (n = 2). Twenty-one patients (95%) seroconverted after the third dose. None of our patients had serious adverse events, new-onset graft-versus-host disease (GVHD), or GVHD exacerbation after vaccination. A third dose of the BNT162b2 and mRNA-1273 COVID-19 vaccines was safe and effective for allogeneic HSCT patients.

Human herpesvirus 6 encephalitis in patients administered mycophenolate mofetil as prophylaxis for graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Human herpesvirus 6 (HHV-6) encephalitis is a known life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, few studies have focused on the occurrence of HHV-6 encephalitis in patients receiving mycophenolate mofetil (MMF) combined with a calcineurin inhibitor as prophylaxis for graft-versus-host disease (GVHD). This study aimed to investigate the impact of MMF administered for GVHD prophylaxis in the occurrence of HHV-6 encephalitis after allo-HSCT and the characteristics of this condition. METHODS AND RESULTS: We retrospectively analyzed 73 patients who underwent allo-HSCT (83 transplants) at our hospital between April 2010 and December 2015. MMF (2-3 g/d) was administered along with a calcineurin inhibitor. Seven patients (8.0%) developed encephalitis due to HHV-6. The median period from allo-HSCT to the onset of HHV-6 encephalitis was 23 days (range, 17-98 days). The cumulative incidence of HHV-6 encephalitis on day 100 after treatment was 12% and 6% in patients who underwent cord blood transplantation (CBT) and non-CBT (ie, bone marrow transplantation and peripheral blood stem cell transplantation), respectively (P = 0.344). Neurological symptoms of encephalitis were more severe in non-CBT cases than those in CBT cases. All patients diagnosed with HHV-6 encephalitis were treated with ganciclovir or foscarnet. None of the enrolled patients died from HHV-6 encephalitis. CONCLUSIONS: Mycophenolate mofetil may have the potential to increase the frequency of severe HHV-6 encephalitis in patients undergoing CBT and non-CBT. Thus, MMF should be administered with caution, and patients should be monitored closely for HHV-6 encephalitis even those who did not undergo CBT.

Successful Bridging Chemotherapy with Gemcitabine, Carboplatin, and Dexamethasone before Unrelated Stem Cell Transplantation for Hepatosplenic T-cell Lymphoma.

A 45-year-old woman was diagnosed with hepatosplenic T-cell lymphoma (HSTCL), a rare subtype of peripheral T-cell lymphoma. She received different types of chemotherapy, but disease progression was observed. To reduce the tumor burden before an unrelated bone marrow transplantation, combination chemotherapy consisting of the gemcitabine, carboplatin, and dexamethasone (GCD) was administered as bridging therapy, resulting in a reduction in the number of lymphoma cells. We were then able to perform bone marrow transplantation. Although she experienced some adverse events, she successfully achieved long-term remission. We herein report a successful case of HSTCL treated with unrelated stem cell transplantation following the GCD regimen as bridging chemotherapy.

Discontinuation of sorafenib can lead to the emergence of FLT3-ITD-positive acute myeloid leukemia.

A 69-year-old woman who had been diagnosed with unresectable papillary thyroid cancer was referred to our hospital. We initially treated her with sorafenib, but she subsequently developed erythema multiforme, which was suspected to be a drug rush due to sorafenib; therefore, sorafenib was discontinued. At the time of discontinuation, immature blast cells were detected in her peripheral blood. Approximately two weeks later, her skin rash improved substantially, but the proportion of blasts in the peripheral blood increased. We performed a bone marrow examination, and she was diagnosed with FLT3-ITD-positive acute myeloid leukemia. FLT3-ITD expression is found in 20-25% of AML and is a known independent poor prognostic factor. To overcome the poor prognosis associated with FLT3-ITD, molecular drugs targeting FLT3-ITD are attracting much attention. Sorafenib, a multi-kinase inhibitor, also has an effect on FLT3-ITD. Although primary disease flares after tyrosine kinase inhibitor discontinuation have been reported, this is the first report to describe discontinuation of sorafenib treatment as a potential trigger of FLT3-ITD-positive acute myeloid leukemia in papillary thyroid cancer.

Invasive Scopulariopsis alboflavescens infection in patient with acute myeloid leukemia.

Scopulariopsis alboflavescens is a soil saprophyte that is widely distributed in nature. Recently, there have been increasing number of reports of invasive infections with Scopulariopsis species in immunocompromised patients. In this report, we described an adult woman with acute myeloid leukemia and who developed S. alboflavescens pneumonia. Liposomal amphotericin B and voriconazole combination therapy was unsuccessful and the patient died because of pneumonia. Scopulariopsis is highly resistant to available antifungal agents and almost invariably fatal. This case report should alert clinicians to the importance of listing Scopulariopsis as a pathogenic fungus in immunocompromised patients.

Pharmacokinetics of intravenous mycophenolate mofetil in allogeneic hematopoietic stem cell-transplanted Japanese patients.

PURPOSE: Mycophenolate mofetil (MMF) is increasingly used among Japanese patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Because pharmacokinetic data for MMF in the Asian population are limited, we conducted this investigation. METHODS: Intravenous MMF (1000 mg/dose) was administered to 10 patients along with cyclosporine or tacrolimus for 10 days after allo-SCT; it was administered every 8 h in peripheral blood stem cell- and bone marrow-transplanted patients, and every 12 h in cord blood-transplanted patients. MMF was administered orally at the same dose from day 11. Plasma concentrations of mycophenolic acid (MPA) were measured by high-performance liquid chromatography. RESULTS: The MPA AUC0 - tau was 31.9 ± 3.4, 26.2 ± 2.4, and 21.0 ± 2.2 µg*h/mL, the mean Ctrough was 0.25, 0.35, and 0.37 µg/mL, and the Cmax was 10.8, 9.2, and 5.5 µg/mL on days 2, 9, and 16, respectively. The AUC0 - tau and Cmax were significantly higher after intravenous MMF dosing than after oral MMF dosing. All patients exhibited successful neutrophil engraftments in a median time of 18 days. Grade II acute graft-versus-host disease (GvHD) of the skin was observed in two patients, and one patient developed limited chronic GvHD. Individual cases of transient and curable grade III oral mucositis and diarrhea were observed; however, MMF was not discontinued. No other severe complications or infections were observed. CONCLUSIONS: Intravenously administered MMF was safe and possibly effective in achieving higher MPA plasma concentrations for GvHD prophylaxis after allo-SCT in Japanese patients.

Early lymphocyte recovery predicts clinical outcome after HSCT with mycophenolate mofetil prophylaxis in the Japanese population.

Immune reconstitution affects clinical outcomes after allogeneic hematopoietic stem cell transplantation (HSCT), and it has been suggested that lymphocyte recovery affects survival after HSCT. However, few studies have examined lymphocyte recovery in Asian patients who received mycophenolate mofetil (MMF) prophylaxis for graft-versus-host disease. We retrospectively evaluated early lymphocyte recovery after HSCT among Japanese adults who received MMF prophylaxis. Patients were divided into two groups according to their median absolute lymphocyte count (ALC) on day 28 after HSCT as follows: the "low ALC group" (≤ 0.22 × 109 cells/L) and the "high ALC group" (> 0.22 × 109 cells/L). With a median follow-up of 317 days, the high ALC group showed significantly better overall survival than the low ALC group (at 1 year: 62 vs. 46%, P = 0.02). The high ALC group also tended to have better non-relapse mortality than the low ALC group (at 1 year: 13 vs. 23%, P = 0.08). There was no significant difference in relapse rate between the high and low ALC groups (at 1 year: 29 vs. 35%, P = 0.2). We conclude that among Japanese patients who received MMF prophylaxis, ALC on day 28 after HSCT was effective in predicting overall survival and non-relapse mortality.

A Case of Classical Hodgkin Lymphoma with Total Lymph Node Infarction.

Lymph node infarction is very rare, and is frequently associated with neoplasms, such as malignant lymphoma and non-neoplastic disease, or interventions such as fine-needle aspiration (FNA). A 76-year-old-man presented with cervical lymph node swelling. Although FNA was performed, the findings were insufficient for a definitive diagnosis. Consequently, surgical biopsy of the cervical lymph node was performed, which revealed total infarction; a diagnosis of classical Hodgkin lymphoma was made later. Both lymphoma itself and FNA may cause total lymph node infarction, which makes diagnosis confusing. Therefore, it is important to repeat the biopsy rather than repeat FNA to correctly diagnose malignant lymphoma, including Hodgkin lymphoma.

Tiotropium Attenuates Refractory Cough and Capsaicin Cough Reflex Sensitivity in Patients with Asthma.

BACKGROUND: Asthmatic cough is often refractory to standard treatments such as inhaled corticosteroids (ICS) and long-acting ß2 agonists (LABA). Tiotropium may modulate cough reflex sensitivity of acute viral cough, but its efficacy in asthmatic cough remains unknown. OBJECTIVE: To evaluate whether tiotropium improves cough and cough reflex sensitivity in patients with asthma refractory to ICS/LABA. METHODS: Seventeen consecutive patients with asthma with chronic cough despite the use of ICS/LABA (13 women; 43.4 ± 19.0 years; average ICS dose, 651 ± 189 µg/d; fluticasone equivalent) were additionally treated with tiotropium (5 µg/d) for 4 to 8 weeks to examine its effects on pulmonary function and capsaicin cough reflex sensitivity (cough thresholds C2 and C5). Cough severity, cough-specific quality of life, and asthma control were also evaluated using cough visual analog scales (VASs), the Japanese version of Leicester Cough Questionnaire (J-LCQ), and Asthma Control Test (ACT), respectively. Patients with an improved cough VAS score of 15 mm or more were considered responders to tiotropium. RESULTS: Tiotropium significantly improved cough VAS, J-LCQ, and ACT scores, but not FEV1. Changes in cough VAS score correlated with those in C2 (r = -0.58; P = .03), C5 (r = -0.58; P = .03), and ACT scores (r = -0.62; P = .02), but not in FEV1 in the overall patients. When analyses were confined to the 11 responders, tiotropium significantly improved capsaicin cough reflex sensitivity within the subgroup (C2: P = .01 and C5: P = .02) and versus the nonresponders (C2: P = .004 and C5: P = .02). CONCLUSION: Tiotropium may alleviate asthmatic cough refractory to ICS/LABA by modulating cough reflex sensitivity but not through bronchodilation.

Combined measurements of fractional exhaled nitric oxide and nasal nitric oxide levels for assessing upper airway diseases in asthmatic patients.

BACKGROUND: Despite the close linkage between rhinitis, chronic rhinosinusitis (CRS) and asthma, relevant biomarkers of both upper and lower airway inflammation are rare. METHODS: Patients with asthma (without upper airway disease [UAD; n = 24], with rhinitis [n = 25], CRS [n = 24], and nasal polyps [n = 2]), isolated rhinitis (n = 13), isolated CRS (n = 13), and 10 healthy controls were prospectively recruited. Fractional exhaled nitric oxide (NO) levels at 50 mL/s (FeNO50), nasal NO levels, Lund-Macay-scores of sinus computed tomography and an asthma control questionnaire (ACQ) were evaluated. RESULTS: Asthma was associated with higher FeNO50 levels irrespective of the UAD category. FeNO50 levels were higher in asthmatics with CRS (median: 54.0 ppb) than those with rhinitis (35.2 ppb, p = 0.02) and those without UAD (34.3 ppb, p = 0.002). Nasal NO levels were higher in rhinitis patients than other UAD categories, irrespective of the asthma concomitance. Nasal NO levels were higher in asthmatics with rhinitis (112.8 ppb) than those without UAD (67.2 ppb, p = 0.001) and those with CRS (57.6 ppb, p < 0.0001). A receiver-operating-characteristic curve analysis for detecting comorbid allergic rhinitis (AR) in asthmatics showed a high area under the curve (0.87). Nasal NO levels were positively correlated with FeNO50 levels (ρ = 0.56, p = 0.003) in asthmatics with rhinitis. In contrast, they were negatively correlated with the Lund-Macay (ρ = -0.46, p = 0.03) and ACQ scores (ρ = -0.52, p = 0.009) in asthmatics with CRS. CONCLUSIONS: Higher nasal NO levels reflect the presence of AR, irrespective of asthma concomitance. Higher FeNO50 levels reflect the presence of CRS and asthma. These NO measurements are useful for assessing comorbid UAD in asthmatics.

Optimal cut-off value and clinical usefulness of the Adherence Starts with Knowledge-12 in patients with asthma taking inhaled corticosteroids.

BACKGROUND: Non-adherence to inhalation regimens is common in asthmatic patients. The Adherence Starts with Knowledge-12 (ASK-12) survey was developed to detect and address patient-specific barriers to medication adherence. Our objective is to investigate the clinical usefulness of the ASK-12 for assessing and addressing adherence to inhalation therapy in asthma. METHODS: The ASK-12 was administered to 138 asthmatic patients. Using pharmacy-refill data, we examined the cut-off value of the ASK-12 to identify patients who were non-adherent to inhalation regimens and identify factors associated with non-adherence. To verify the usefulness of the ASK-12, inhalation regimens were prospectively switched to less-expensive and simpler (once-daily) dosing regimens in eight non-adherent asthmatic patients who reported specific-barriers in "inconvenience of twice-daily inhaler use" and "cost". RESULTS: Valid responses were received from 114 (82.6%) patients. A significant correlation was found between pharmacy-refill rates and the ASK-12 total score (r=-0.55, P<0.0001). The optimal cut-off value of the ASK-12 total score to discriminate non-adherent patients (defined by pharmacy-refill rate <80%) was 23, with 71.4% specificity and 93.3% sensitivity. Using this value, 52 (45.6%) patients were classified as non-adherent. Univariate followed by multivariate analysis identified younger age as a predictor of non-adherence to inhalation regimens (odds ratio, 2.67; 95% CI, -0.95 to -0.06; P=0.027). Switching inhaled medicines in eight patients resulted in significant improvements in both ASK-12 scores and asthma control. CONCLUSIONS: The ASK-12 is a brief, practical, and clinically useful measure for assessing and addressing adherence to inhalation regimens in asthma.

Serum Periostin as a Biomarker for Comorbid Chronic Rhinosinusitis in Patients with Asthma.

RATIONALE: Periostin is a matricellular protein that is involved in the pathophysiology of allergic rhinitis, chronic rhinosinusitis, and asthma. Associations of serum periostin with systemic and airway eosinophilic inflammation and comorbid chronic rhinosinusitis in patients with asthma have been demonstrated. Although serum periostin is positioned as a marker of helper T cell 2 immune responses, its implication regarding the presence of comorbid upper airway diseases in patients with asthma remains unclear. OBJECTIVES: To investigate the utility of serum periostin as a diagnostic biomarker for upper airway disease in patients with asthma. METHODS: We prospectively enrolled 65 patients with stable asthma, 20 without upper airway disease, 22 with rhinitis, and 23 with chronic rhinosinusitis (13 with nasal polyps, 10 without). Serum periostin, eotaxin, total IgE, fractional exhaled nitric oxide, and blood and sputum eosinophil levels were measured and compared between upper airway disease subtypes. We evaluated the utility of each biomarker in detecting upper airway disease, associations among the biomarkers, and severity of upper airway disease as measured by the Lund-Mackay score for sinus computed tomography. RESULTS: Serum periostin levels were higher in patients with asthma who had chronic rhinosinusitis (109.6 ± 47.4 ng/ml) than in those without upper airway disease (83.2 ± 22.9 ng/ml) (P = 0.04). Serum periostin levels in patients with asthma who had chronic rhinosinusitis and nasal polyps were significantly higher (130.0 ± 46.6 ng/ml) than in those without nasal polyps (87.9 ± 37.7 ng/ml) (P = 0.001). Serum periostin levels were not associated with the presence or the severity of rhinitis. In contrast, receiver operating characteristic curve analyses showed moderate diagnostic accuracy for detecting chronic rhinosinusitis (area under the curve, 0.71; P = 0.01) and high accuracy for chronic rhinosinusitis with nasal polyps (area under the curve, 0.86; P = 0.0002). When we compared patients with asthma who had comorbid chronic rhinosinusitis and nasal polyps with patients with asthma without these comorbidities, we found serum periostin to be the sole biomarker among those tested for detecting the presence of nasal polyps. Serum periostin was also the sole biomarker that significantly correlated with Lund-Mackay score in patients with chronic rhinosinusitis (r = 0.44; P = 0.04). CONCLUSIONS: Serum periostin is useful for detecting chronic rhinosinusitis with nasal polyps and predicting radiological chronic rhinosinusitis severity in patients with asthma. Clinical trial registered with the UMIN Clinical Trials Registry (UMIN000017533).