Autotaxin is a potential predictive marker for the development of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT), and stratification of the high-risk group before transplantation is significant. Serum autotaxin (ATX) levels have been reported to increase in patients with liver fibrosis caused by metabolic inhibition from liver sinusoidal endothelial cells. Considering that the pathophysiology of VOD/SOS begins with liver sinusoidal endothelial cell injury, an increase in serum ATX levels may precede the onset of VOD/SOS. A retrospective study with 252 patients, including 12 patients with VOD/SOS, who had received allo-HCT was performed. The cumulative incidence of VOD/SOS was higher in the group with serum ATX levels before conditioning (baseline ATX) above the upper reference limit (high ATX group, p < 0.001), and 1-year cumulative incidences were 22.7% (95% confidence interval [95%CI], 3.1-42.4%) and 3.5% (95%CI, 1.1-5.8%), respectively. In the multivariate analysis, elevated baseline ATX was identified as an independent risk factor for VOD/SOS development and showed an additive effect on the predictive ability of known risk factors. Furthermore, the incidence of VOD/SOS-related mortality was greater in the high ATX group (16.7% vs. 1.3%; p = 0.005). Serum ATX is a potential predictive marker for the development of VOD/SOS.

Impacts of Posttransplant Cyclophosphamide Dose on Graft-versus-leukemia Effects via HLA-B Leader in HLA-haploidentical Peripheral Blood Stem Cell Transplantation.

INTRODUCTION: The graft-versus-leukemia effect of HLA-B leader dimorphism, i.e. methionine (M) or threonine (T) at position -21 of the leader sequence, has been observed in HLA-haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy-haplo). However, the biological mechanism has been unclear, and the contributions of HLA-B leader genotype to risk reduction of relapse might be dependent on posttransplant cyclophosphamide (PTCy) doses. METHODS: To investigate whether the effect of HLA-B leader dimorphism was modified by the PTCy dose, we retrospectively analyzed 99 patients who received PTCy-haplo. RESULTS: In the low-dose PTCy group, the patient M+ HLA-B leader genotype did not significantly affect the cumulative incidence of relapse (CIR) but negatively impacted the overall survival (OS) compared to the M- genotype. In contrast, in the high-dose PTCy group, patients with the M+ genotype had a decreased CIR, but no significant difference in the OS was observed between patients with the M+ and M- genotypes. Regardless of PTCy doses, the patient M+ genotype had detrimental effects on nonrelapse mortality. CONCLUSION: Our findings suggest that the effect of the patient HLA-B leader genotype is modified by the PTCy dose, providing immunological insight into the PTCy dosage and supporting further studies to investigate the underlying mechanisms.

Comparison of long-term outcomes after first HLA-mismatched unrelated donor transplantation with single unrelated cord blood transplantation using reduced-intensity or reduced-toxicity conditioning.

BACKGROUND: No comparative data have shown significant survival differences between HLA-mismatched unrelated donor (MMUD) transplantation and cord blood (CB) transplantation, each with reduced-intensity/reduced-toxicity conditioning (RIC/RTC). However, advances in graft-versus-host disease (GVHD) prophylaxis might help update current strategies. METHODS: We retrospectively compared the outcomes of first allogeneic hematopoietic cell transplantation from MMUDs (n = 15) or single unrelated CB (n = 35) after RIC/RTC. RESULTS: The median age was 60 years. The MMUD group had a numerically lower 100-day incidence of grade III-IV acute GVHD (7% vs. 29%, P = 0.079) and non-relapse mortality (0% vs. 40%, P = 0.12). Eight MMUD recipients received anti-thymocyte globulin, bortezomib, or posttransplant cyclophosphamide for GVHD prophylaxis. They did not develop grade III-IV acute GVHD. The MMUD group had significantly better 5-year overall survival than the CB group (62% vs. 31%, P = 0.021), although relapse rates were similar. A multivariable analysis and sensitivity analysis also showed trends toward higher overall survival in the MMUD group. CONCLUSION: MMUD with better GVHD prophylaxis might be preferred over CB in patients with older age and comorbidities.

Invasive fungal infection caused by Blastobotrys mokoenaii in an immunocompromised patient with acute myeloid leukemia: A case report.

Blastobotrys is a genus of rare yeast that is increasingly recognized as a cause of fungal infections in humans. However, there have been no reports of fungal infections in humans caused by Blastobotrys mokoenaii. We describe a case of invasive fungal infection (IFI) caused by B. mokoenaii in an immunocompromised patient with acute myeloid leukemia (AML). A 46-year-old man with relapsed/refractory AML underwent a second allogeneic peripheral blood hematopoietic stem cell transplantation (allo-PBSCT) during remission. The patient had prolonged neutropenia and received systemic steroid therapy for graft-versus-host disease before the second allo-PBSCT. Uncommon yeast was isolated from the blood cultures obtained on day 4. We initially suspected that the uncommon yeast was Trichosporon spp. based on its morphology. However, unlike Trichosporon spp., in vitro antifungal susceptibility tests showed that this yeast isolate was resistant to micafungin, caspofungin, voriconazole, itraconazole, and fluconazole. We performed DNA sequencing and identified it as B. mokoenaii. B. mokoenaii was persistently isolated from blood cultures taken during combination therapy with liposomal amphotericin B and voriconazole. The patient died of multiorgan failure on day 24. B. mokoenaii can cause severe IFI in immunocompromised patients; however, it may not be correctly identified by routine clinical microbiology testing in a hospital laboratory and DNA sequencing is useful for diagnosis.

The safety of the combination therapy of recombinant factor VIIa and plasma-derived factor VIIa and factor X for refractory hemorrhage in acquired hemophilia A.

Acquired hemophilia A (AHA) is a rare, life-threatening hemorrhagic disease caused by autoantibodies against factor VIII (FVIII), and bypassing agents (BPA) are used to control bleeding. However, some cases need a change of BPA or BPAs given sequentially or in combination for refractory bleeding. A 71-year-old man was admitted with subcutaneous hemorrhage. Laboratory investigations showed prolongation of activated partial thromboplastin time (APTT) and low-coagulation FVIII activity and FVIII inhibitor; we, therefore, diagnosed AHA. He was treated with recombinant factor VIIa (rFVIIa) BPA and prednisolone. However, his symptoms did not improve sufficiently, thus we switched BPA to activated prothrombin complex concentrate. Unfortunately, this was not effective and he suffered hemorrhagic shock. Therefore, we selected rFVIIa, with plasma-derived FVIIa and factor X (pd-FVIIa/FX) as combination therapy, and hemostasis was achieved without thrombosis. This case suggests that the combination of rFVIIa and pd-FVIIa/FX short-term can be well tolerated for refractory hemorrhage in AHA.

Sinusoidal obstruction syndrome associated with disseminated toxoplasmosis involving the liver after allogeneic hematopoietic stem cell transplantation: A case report.

Sinusoidal obstruction syndrome (SOS) is a fatal complication after hematopoietic stem cell transplantation (HSCT). Only a few complications after HSCT have been reported as risk factors for SOS, including sepsis. Here, we report the case of a 35-year-old male diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent peripheral blood HSCT from a human leukocyte antigen-matched unrelated female donor in remission. Graft-versus-host disease prophylaxis contained tacrolimus, methotrexate, and low-dose anti-thymoglobulin. The patient was treated with methylprednisolone for engraftment syndrome from day 22. On day 53, he presented worsening fatigue, breathlessness, and abdominal pain in the right upper quadrant that had persisted for 4 days. Laboratory tests showed severe inflammation, liver dysfunction, and positive for Toxoplasma gondii PCR. He died on day 55. An autopsy showed SOS and disseminated toxoplasmosis. Hepatic infection with T. gondii was identified in zone 3 of the liver, which overlapped with the pathological features of SOS. In addition, the timing of the exacerbation of hepatic dysfunction coincided with the onset of systemic inflammatory symptoms and T. gondii reactivation. This rare case of toxoplasmosis is the first to suggest that hepatic infection with T. gondii is strongly associated with SOS after HSCT.

Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil.

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m2) and FM140 (melphalan dose: 140 mg/m2), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.

Immunomodulatory and direct activities of ropeginterferon alfa-2b on cancer cells in mouse models of leukemia.

Although ropeginterferon alfa-2b has recently been clinically applied to myeloproliferative neoplasms with promising results, its antitumor mechanism has not been thoroughly investigated. Using a leukemia model developed in immunocompetent mice, we evaluated the direct cytotoxic effects and indirect effects induced by ropeginterferon alfa-2b in tumor cells. Ropeginterferon alfa-2b therapy significantly prolonged the survival of mice bearing leukemia cells and led to long-term remission in some mice. Alternatively, conventional interferon-alpha treatment slightly extended the survival and all mice died. When ropeginterferon alfa-2b was administered to interferon-alpha receptor 1-knockout mice after the development of leukemia to verify the direct effect on the tumor, the survival of these mice was slightly prolonged; nevertheless, all of them died. In vivo CD4+ or CD8+ T-cell depletion resulted in a significant loss of therapeutic efficacy in mice. These results indicate that the host adoptive immunostimulatory effect of ropeginterferon alfa-2b is the dominant mechanism through which tumor cells are suppressed. Moreover, mice in long-term remission did not develop leukemia, even after tumor rechallenge. Rejection of rechallenge tumors was canceled only when both CD4+ and CD8+ T cells were removed in vivo, which indicates that each T-cell group functions independently in immunological memory. We show that ropeginterferon alfa-2b induces excellent antitumor immunomodulation in hosts. Our finding serves in devising therapeutic strategies with ropeginterferon alfa-2b.

Invasive pulmonary aspergillosis caused by Aspergillus terreus diagnosed using virtual bronchoscopic navigation and endobronchial ultrasonography with guide sheath and successfully treated with liposomal amphotericin B.

Invasive aspergillosis is a significant cause of mortality in patients with hematological malignancy. Early diagnosis of invasive pulmonary aspergillosis (IPA) by bronchoscopy is recommended but is often difficult to perform because of small lesion size and bleeding risk due to thrombocytopenia. A 71-year-old woman had received initial induction therapy for acute myeloid leukemia. On day 22 of chemotherapy, she had a high fever, and the chest computed tomography scan revealed a 20-mm-sized nodule with a halo sign. Bronchoscopy assisted by virtual bronchoscopic navigation (VBN) and endobronchial ultrasonography with a guide sheath (EBUS-GS) was performed, and Aspergillus terreus was identified from the culture of obtained specimens. A. terreus is often resistant to amphotericin B; thus, voriconazole is usually recommended for treatment. However, the obtained A. terreus isolate showed minimal inhibitory concentrations of 2 µg/mL for voriconazole and 0.5 µg/mL for amphotericin B. Therefore, the patient was successfully treated with liposomal amphotericin B. For patients suspected of having IPA, early diagnosis and drug susceptibility testing are very important. This case suggests that bronchoscopy using VBN and EBUS-GS is helpful for accurate diagnosis and successful treatment even if the lesion is small and the patient has a bleeding risk.

Characterization of readmission after allogeneic hematopoietic cell transplantation.

To elucidate the incidence, causes, and risk factors associated with readmission due to transplant-related complications, we studied 213 consecutive patients who were discharged without progression of primary disease after their first allogeneic hematopoietic cell transplantation at our center between 2013 and 2016. The median patient age was 50 years (range, 18-71 years). Eighty-three patients had AML or MDS, 66 had lymphoma, 28 had ALL, 23 had ATL, and 13 had other diseases. The median duration of hospitalization for transplantation was 56 days (range 27-325 days). The cumulative incidences of readmission due to transplant-related complications were 8% at 30 days, 16% at 100 days, and 25% at 1 year after discharge. The most frequent cause of readmission was infection, followed by graft-versus-host disease throughout the first year. In multivariate analysis, steroid use at discharge was the only risk factor associated with readmission within 30 days, and steroid use at discharge, absolute lymphocyte count < 500/µl at discharge, and documented bacterial infection during admission were risk factors associated with readmission within 1 year. Our results indicated that factors during hospitalization or discharge, but not at transplantation, were associated with readmission. Patients with these risk factors should be monitored carefully after discharge.

Acquired Factor V Inhibitor with Hemorrhagic Symptoms after Prasugrel Hydrochloride Treatment.

Acquired factor V inhibitor (AFVI) is a rare coagulopathy. It may be triggered by specific antigens such as antibiotics. We herein report the first case of AFVI after treatment with prasugrel hydrochloride (prasugrel) in an 80-year-old male who underwent percutaneous coronary intervention because of angina pectoris 6 years ago and was initiated on aspirin and ticlopidine hydrochloride. He was switched from ticlopidine hydrochloride to prasugrel before undergoing percutaneous coronary intervention for myocardial infarction. Fifteen days later, he developed sudden nasal hemorrhage, hematuria, and systemic purpura. Coagulation tests revealed prolonged prothrombin time-international normalized ratio (11.35) and activated partial thromboplastin time (170 s). The coagulation factor profile revealed a decreased FV activity (1%). The Bethesda assay for FV inhibitor was positive. AFVI was diagnosed; prasugrel was immediately discontinued, and administration of recombinant activated factor VII and prednisolone were initiated. Hemorrhagic symptoms immediately disappeared; FV activity improved, and the FV inhibitor titer was normalized.

Prognostic significance of low pre-transplant skeletal muscle mass on survival outcomes in patients undergoing hematopoietic stem cell transplantation.

Little is known about the prognostic significance of muscle loss for allogeneic hematopoietic stem cell transplantation (allo-HCT). We retrospectively analyzed consecutive patients who received allo-HCT from 2013 to 2015. All patients underwent computed tomography (CT) imaging and bioelectrical impedance analysis (BIA) within 30 days before allo-HCT. Skeletal muscle area (cm2) at the third lumbar vertebra level on CT imaging and skeletal muscle mass (kg) measured by BIA were normalized by height in meters squared (m2) to calculate the skeletal muscle area index (SMI) and skeletal muscle mass index (SMMI). SMI and SMMI were significantly correlated (r = 0.744; P < 0.001). The cumulative incidence of 1-year non-relapse mortality (NRM) was significantly higher in patients with low SMI than high SMI (17% versus 0%, respectively; P = 0.023). Overall survival was shorter in patients with low SMI than high SMI (56% versus 93%, respectively; P < 0.001). In univariate analysis, low SMI was associated with increased risk of NRM (HR 7.46; 95% CI 1.05-52.98; P = 0.044), and in multivariate analysis it was associated with higher overall mortality (HR 5.35; 95% CI 1.71-16.72; P = 0.004). These results suggest that low muscle mass is an independent predictor of mortality after allo-HCT.

Combination of Frailty Status and Comorbidity Score Improves the Stratification of Survival in Patients With Myelodysplastic Syndrome Owing to Good Predictive Capability for Infection-related Mortality.

BACKGROUND: We investigated the prognostic effects of frailty and its association with comorbidity in patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: This retrospective analysis included 118 consecutive patients diagnosed with MDS. Frailty was evaluated using the clinical frailty scale (CFS). Comorbidity was classified using the Charlson comorbidity index (CCI) and MDS comorbidity index (MDS-CI). RESULTS: On multivariate analysis, CFS (≥ 5 vs. < 5; hazard ratio [HR], 3.37; P = .002), CCI (≥ 2 vs. < 2; HR, 2.59; P = .002), and Revised International Prognostic Scoring System (IPSS-R) category (HR, 2.1; P = .009) were independently predictive of overall survival (OS). One-year OS of patients with CFS ≥ 5 or CCI ≥ 2 were significantly worse compared with those with CFS < 5 or CCI < 2 (55% vs. 91%; P < .001; 46% vs. 91%; P < .001, respectively). OS was clearly stratified into 3 groups according to CFS (≥ 5 vs. < 5) and CCI (≥ 2 vs. < 2; P < .001). When comparing these 3 groups, the incidence of infection-related mortality progressively increased with CFS ≥ 5 and/or CCI ≥ 2 (P < .001). This effect was more obvious in patients with lower IPSS-R. CONCLUSION: The present study suggests frailty and comorbidity may be patient-related, independent predictive factors of poor prognosis. This could probably be attributed to increasing infection-related mortality with frailty and comorbidity. Combining the evaluation of frailty and comorbidity with IPSS-R might aid in more precise prediction of OS, especially in patients with low risk of MDS.

Lymphocyte-depleted classical Hodgkin lymphoma accompanied by myelofibrosis.

A 91-year-old male with fever of unknown origin was referred to our department. 18F-FDG PET/CT scan revealed a high FDG uptake in abdominal lymph nodes and multiple bones. The bone marrow biopsy showed fibrosis and atypical megakaryocytes, which were consistent with myelofibrosis. The patient died 28 days after admission and an autopsy was performed. The lymph nodes and bone marrow specimens revealed scattered Reed-Sternberg cells and a dearth of lymphoid cells with fibrosis. A final diagnosis of lymphocyte-depleted classical Hodgkin lymphoma (LDCHL) with bone marrow involvement was made. It is necessary to identify LDCHL during differential diagnosis for bone marrow fibrosis accompanied by lymphadenopathy.

Prognostic Effect of Low Subcutaneous Adipose Tissue on Survival Outcome in Patients With Multiple Myeloma.

BACKGROUND: Increasing evidence suggests that decreased skeletal muscle mass (sarcopenia) or adipose tissue assessed using computed tomography (CT) predicts negative outcomes in patients with solid tumors. However, the prognostic value of such an assessment in multiple myeloma (MM) remains unknown. PATIENTS AND METHODS: Consecutive patients with newly diagnosed symptomatic MM were retrospectively analyzed. The cross-sectional area of skeletal muscles and subcutaneous or visceral adipose tissue was measured using CT. Body composition indexes (skeletal muscle index, subcutaneous adipose tissue index [SAI], and visceral adipose tissue index) were calculated. The association between these indexes and overall survival (OS) was examined. RESULTS: Of 56 evaluable patients, 37 (66%) had sarcopenia. The 2-year OS in patients with SAI < median was 58% compared with 91% in those with SAI ≥ median (P = .006). In multivariate analyses, SAI < median was significantly associated with poor OS (hazard ratio, 4.05; P = .02). Sarcopenia was not associated with OS. The maximum value of the standardized uptake value was significantly higher in patients with SAI < median (P = .02). CONCLUSION: The findings of this study suggest that low subcutaneous adipose tissue at baseline predicts poor survival outcome in patients with MM.