Early-onset herpes simplex encephalitis type 1 triggered by COVID-19 disease: A case report.

Coronavirus disease 2019 (COVID-19) causes a systemic inflammatory response and a temporary immunosuppression of hosts. Several reports have showed that reactivation of herpes simplex virus type 1 (HSV-1) is strongly associated with COVID-19. We present a case of a 66-year-old female, who developed HSV-1 encephalitis, showing impaired consciousness and typical MRI findings such as hyperintense lesions in the temporal lobe, insular cortices, bilateral medial frontal lobe on diffusion-weighted imaging, 7 days after the onset of COVID-19 symptoms. The number of cases of encephalitis in patients with COVID-19 is increasing. However, there has been limited reports of HSV-1 encephalitis following COVID-19, especially for cases with an interval of 7 days or less from the onset of COVID-19 symptoms to the onset of HSV-1 encephalitis. Our case highlights the importance of considering HSV-1 encephalitis in the differential when managing a patient with COVID-19-associated neurologic complications, even if it is in the early stages of COVID-19.

Myeloid leukemoid reaction after initial azacitidine therapy for chronic myelomonocytic leukemia.

The development of myeloid leukocytosis in leukemia patients during antileukemic treatment requires a differential diagnosis between myeloid leukemoid reaction and leukemia progression. We herein report the case of an 80-year-old Japanese man with chronic myelomonocytic leukemia (CMML) who developed marked myeloid leukocytosis (36.3 × 109/L) with 32.5% monocytes and 48% neutrophils about 4 weeks after the initial 5-azacitidine (AZA) treatment. The leukocytosis was unlikely to be attributed to infection and adverse drug reaction. As it resolved in a few days without any interventions, the transient myeloid leukocytosis was confirmed to be a myeloid leukemoid reaction. After four cycles of AZA treatment, leukemic blasts in the bone marrow decreased and the patient became transfusion-independent. Interestingly, levels of serum G-CSF showed a similar trend to the myeloid leukocytosis, while those of serum GM-CSF and IL-17 were undetectable throughout the clinical course, suggesting that a differentiation response to AZA treatment might lead to the myeloid leukemoid reaction. Our case implies that a marked but transient myeloid leukemoid reaction mimicking CMML progression can develop during AZA treatment, which requires careful clinical monitoring and differential diagnosis.

[Multiple extramedullary plasmacytomas responding to a reduced dose of carfilzomib following drug-induced thrombotic microangiopathy].

Herein, we report the findings of a 79-year-old male patient who presented with multiple extramedullary plasmacytomas following a relapse of primary plasma cell leukemia. He developed thrombotic microangiopathy (TMA) while receiving carfilzomib, lenalidomide, and dexamethasone (KLd) therapy. He was diagnosed with plasma cell leukemia 3 years ago; he demonstrated a very good partial response (VGPR) after undergoing two regimens, including either bortezomib or lenalidomide, and he had been followed up without any other treatment due to complications of infection. Following relapse, KLd was initiated. On day 7 of KLd, TMA developed; therefore, the treatment was discontinued. The TMA improved only with the discontinuation of KLd. A reduced dose of KLd was readministered; the TMA did not relapse. He demonstrated VGPR after three courses of reduced-KLd; he has since remained in remission through ten courses. Therefore, carfilzomib therapy may be useful in relapsing and refractory cases. Drug-induced TMA has been reported to be caused by either immune-mediated or dose-dependent toxicity mechanisms. In patients who develop dose-dependent TMA with carfilzomib, dose reduction could be considered in cases showing an effective response to the treatment.

Does time of CCI measurement affect the evaluation of platelet transfusion effectiveness?

The measurement of corrected count increment at 1-h post-transfusion (CCI-1 h) of platelet concentrate (PC) transfusion is recommended, but in the revised Japanese Guideline (2017) it was changed to "after 10-min to 1-h", following the revision of the guidelines from Western countries. Here, we aimed to investigate on the feasibility to apply the CCI measured at 10-min or 30-min post-transfusion as the surrogate of CCI-1 h. Peripheral blood was collected at 10-min, 30-min and 1-h post-transfusion of PC and the effectiveness of the transfusion was analyzed based on the CCI. In the period from December 2017 to February 2020, 8 patients, who received multiple PC transfusion (total 208) at our institution, were analyzed. We performed the univariate analyses to examine the relationship between CCI value and the categorical variables, p-value <0.1 was obtained for gender (p = 2.91 × 10-19), fever after transfusion (p = 0.0163). The qualitative variables, namely measurement time (p = 0.0553), also showed p-value <0.1. Using these factors as covariates in the mixed effect model, we found that the measurement time (p = 0.0007) had a significant effect on the CCI value when looking at fixed effects. Although there is a tendency for decreased CCI values with time progression, the slope of the change in the mixed model was -0.00307, indicating that the CCI difference among the 3 measurements was small. Here we provide evidence that CCI measured at 10-min and 30-min post-transfusion give results comparable to those measured at 1-h post-transfusion, under the Japanese practice of platelet transfusion, which relies on 100 % single-donor apheresis PC, and ABO-identical whenever possible.

Azacitidine-associated haemorrhagic enteritis in a case of myelodysplastic syndrome: A case report.

WHAT IS KNOWN AND OBJECTIVE: 5-Azacitidine (AZA) is an agent widely used to treat myelodysplastic syndrome (MDS). CASE DESCRIPTION: We herein report an 83-year-old woman diagnosed with MDS who was treated with AZA. She tolerated the first cycle of AZA; however, severe adverse events involving haemorrhagic enteritis with multiple intestinal ulcers developed after the second and third cycles. Additionally, the interval between the administration of AZA and the development of haematochezia shortened with each cycle of AZA. WHAT IS NEW AND CONCLUSION: We herein report as-yet-undescribed potential side effects, AZA-associated haemorrhagic enteritis that should be kept in mind.

Multiple HLA-matched platelet transfusions for a single patient with broad anti-HLA antibodies: a case report.

The efficacy of 30 platelet concentrate (PC) products transfused to a patient with myelodysplastic syndrome (MDS) was evaluated by calculating the 1-hour post-transfusion corrected count increment (1h-CCI). Of the 30 transfusions, all HLA-A/B-matched, the cross-match (CM) test was negative in 23 (CM(-)-PC) and weakly positive (CM(+)-PC) in 2, and the CM test was not conducted in 5 (non-CM-PC). The effective rate was higher with CM(-)-PC compared to non-CM-PC (82.6% vs 60%), but statistical significance was not achieved, which suggested that the CM test of PC may still be a not satisfactorily effective predictor of PC refractoriness. Studies are ongoing in Japan to confirm on the importance of CM test of PC.

Leukemic mature B-cell neoplasm observed during the treatment with romiplostim in patient with thrombocytopenia and liver cirrhosis.

We report here a new adverse event of romiplostim which is a protein analog of thrombopoietin. Leukemic mature B-cell neoplasm was observed during the treatment of thrombocytopenia in a patient with liver cirrhosis. Their relationship was suggested clinically but the mechanism of leukemic expansion of lymphoma cells was not clarified.

Phase II study of imatinib-based chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia.

This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib-combined chemotherapy for newly diagnosed BCR-ABL-positive ALL in adults. Sixty-eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients >55 years of age. Sixty-five patients achieved CR (95.6%). The estimated 2-year event-free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo-SCT) at initial CR was performed in 43 patients. Thirty-five of 39 patients <55 years and 8 of 26 patients >55 years underwent allo-SCT at first CR. The 3-year OS in patients <55 years receiving allo-SCT at first CR, patients >55 years receiving allo-SCT at first CR, patients <55 years not receiving allo-SCT at first CR, and patients >55 years not receiving allo-SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P = 0.058). The three-year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P = 0.150). A high CR rate was observed with imatinib-based chemotherapy allowing allo-SCT in a high proportion of patients, particularly those <55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo-SCT. This trial was registered with the UMIN (000001226).

An autopsy case that manifested no convincing histological changes of severe renal failure after hematopoietic stem cell transplantation.

A 48-year-old Japanese woman, who had been diagnosed with smoldering adult T-cell leukemia, was admitted to our hospital for hematopoietic stem cell transplantation (HSCT) because of an acute exacerbation of her disease. After myeloablative conditioning procedures, comprising cytarabine with cyclophosphamide and total body irradiation, the HLA-matched unrelated bone marrow stem cells were infused (day 0). Her serum creatinine concentration, having been 0.6 mg/dL at baseline, began to increase from day 1 and was 2.3 mg/L on day 7. Hemodialysis was required to treat fluid overload and worsening uremia on days 8 and 9. On day 10, she presented with refractory hypotension and died due to multi-organ failure on day 12. Renal pathology at autopsy showed no specific histological changes to which her clinically severe acute kidney injury (AKI) was attributable. This case suggests that post-HSCT AKI is not necessarily accompanied by apparent renal histologic damage, even if it is clinically serious.

Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP): Subset analysis of the DASISION trial with 2-year follow-up.

Dasatinib is a highly potent BCR-ABL kinase inhibitor with established efficacy and safety in imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. In the global phase III DASISION trial in patients with newly diagnosed chronic phase CML (CML-CP), dasatinib was found to have an acceptable safety profile and demonstrated significantly faster and higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. Here, we report the results of a subset analysis of Japanese patients enrolled in the DASISION trial, showing safety and efficacy profiles generally consistent with patients enrolled worldwide, including higher response rates (CCyR, MMR) with dasatinib compared with imatinib and similar high rates of progression-free and overall survival with both therapies. However, the small sample size of the present study limits the strength of these conclusions, and further exploration is needed to confirm any differences observed in Japanese patients compared with the total treated population. These findings support the use of dasatinib 100 mg QD as a first-line treatment in Japanese patients with newly diagnosed CML-CP.

The recipient CXCL10 + 1642C>G variation predicts survival outcomes after HLA fully matched unrelated bone marrow transplantation.

CXCL10 is a chemoattractant for immune cells that is involved in several immune-inflammatory disorders. This study retrospectively examined the impact of a single nucleotide variation (rs3921, +1642C>G) in the CXCL10 gene on transplant outcomes in a cohort of 652 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies. The recipient C/G or G/G genotype was found to be associated with a significantly better 5-year overall survival (OS) rate and a lower transplant-related mortality (TRM) rate than the recipient C/C genotype. The recipient C/G or G/G genotype also predicted a reduced incidence of death due to organ failure. The multivariate analysis showed the recipient C/G or G/G genotype to exhibit statistical trends toward beneficial effects on OS but not on TRM. CXCL10 genotyping could therefore be useful in predicting prognoses and creating therapeutic strategies for improving the final outcomes of patients who undergo allogeneic BMT.

Recipient PTPN22 -1123 C/C genotype predicts acute graft-versus-host disease after HLA fully matched unrelated bone marrow transplantation for hematologic malignancies.

PTPN22 is a critical negative regulator of T cell responses. Its promoter gene variant (rs2488457, -1123G>C) has been reported to be associated with autoimmune diseases. This study analyzed the impact of the PTPN22 variant on transplantation outcomes in a cohort of 663 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The recipient C/C genotype versus the recipient G/G genotype resulted in a lower incidence of grade II-IV acute graft-versus-host disease (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.29-0.85; P = .01), as well as a higher incidence of relapse (HR, 1.78; 95% CI, 1.10-2.90; P = .02), as demonstrated on multivariate analysis. In patients with high-risk disease, the recipient C/C genotype was associated with significantly worse overall survival rates than the recipient G/G genotype (HR, 1.60; 95% CI, 1.02-2.51; P = .04), whereas this effect was absent in patients with standard-risk disease. In addition, the donor G/C genotype was associated with a lower incidence of relapse (HR, 0.58; 95% CI, 0.40-0.85), which did not influence survival. Our findings suggest that PTPN22 genotyping could be useful in predicting prognoses and creating therapeutic strategies for improving the final outcomes of allogeneic BMT.

Poor outcome of myeloablative conditioned allogeneic bone marrow transplantation for myelofibrosis.

OBJECTIVE: This study retrospectively analyzed clinical outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelofibrosis (MF) in a single institution. METHODS: During the past 20 years, 6 patients with MF have undergone allo-HSCT in our institution. We investigated the clinical characteristics and follow-up course of these patients. PATIENTS: Median age was 47 years (range, 40-52 years). The median interval between diagnosis and allo-HSCT was 12.5 months (range, 5-97 months). RESULTS: Among these 6 patients, 4 patients were categorized in the high-risk group according to the International Prognostic Scoring System. All 6 patients received myeloablative conditioning regimens, but most of them eventually died of relapse. CONCLUSION: In this small series, allo-HSCT resulted in dismal outcomes. Our experience clearly indicates the need for studies with a larger series of patients to evaluate the efficacy of this modality.

Second allogeneic transplantation for relapsed acute leukemia after initial allogeneic hematopoietic stem cell transplantation.

We retrospectively reviewed the medical records of 45 patients with relapsed acute leukemia after initial allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among 45 patients, a total of 11 patients eventually underwent second allo-HSCT (HSCT-2). Median survival after relapse was 294 days (range, 135-942 days) for HSCT-2. Multivariate analysis showed significantly better survival for recipients of second allo-HSCT than for other patients (hazard ratio, 4.38; 95 % confidence interval, 1.45-13.2; P = 0.009). Although outcomes for patients with relapsed leukemia were generally poor, our results suggest that second HSCT could offer a survival advantage over other conventional salvage strategies.

Clinical impact of pre-transplant pulmonary impairment on survival after allogeneic hematopoietic stem cell transplantation.

We retrospectively analyzed the clinical outcomes of patients with pulmonary impairment before undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for the first time. Among 297 evaluable patients who underwent their first HSCT, 23 had restrictive, obstructive or mixed ventilatory impairment (n = 9, 13 and 1, respectively). Males predominated among the patients with pulmonary impairment (p = 0.037) and received a reduced intensity conditioning (RIC) regimen more frequently, although the difference did not reach statistical significance (p = 0.05). Among 23 patients with pulmonary impairment, 9 underwent post-transplant pulmonary function tests and obstructive ventilatory impairment progressed only in 2 patients, both of whom developed bronchiolitis obliterans. Kaplan-Meier estimates of 3-year overall (OS) among patients with and without pulmonary impairment were 57% and 47%, respectively, and those of relapse-free survival (RFS) were 70%, and 68%, respectively, with no significant differences between the groups (OS, p = 0.235; RFS, p = 0.287). The rates of non-relapse mortality also did not significantly differ (p = 0.835). Our results suggest that allogeneic HSCT is safe for patients with pulmonary impairment. The lower frequency of fatal pulmonary complications after HSCT and the RIC regimen might contribute to favorable survival rates.

A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation.

Interleukin IL-17 is a proinflammatory cytokine that has been implicated in the pathogenesis of various autoimmune diseases. The single nucleotide polymorphism (SNP), rs2275913, in the promoter region of the IL-17 gene is associated with susceptibility to ulcerative colitis. When we examined the impact of rs2275913 in a cohort consisting of 438 pairs of patients and their unrelated donors transplanted through the Japan Marrow Donor Program, the donor IL-17 197A allele was found to be associated with a higher risk of acute graft-versus-host disease (GVHD; hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.00 to 2.13; P = 0.05). Next, we investigated the functional relevance of the rs2275913 SNP. In vitro stimulated T cells from healthy individuals possessing the 197A allele produced significantly more IL-17 than those without the 197A allele. In a gene reporter assay, the 197A allele construct induced higher luciferase activity than the 197G allele, and the difference was higher in the presence of T cell receptor activation and was abrogated by cyclosporine treatment. Moreover, the 197A allele displayed a higher affinity for the nuclear factor activated T cells (NFAT), a critical transcription factor involved in IL-17 regulation. These findings substantiate the functional relevance of the rs2275913 polymorphism and indicate that the higher IL-17 secretion by individuals with the 197A allele likely accounts for their increased risk for acute GVHD and certain autoimmune diseases.

Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies.

Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41-0.89; P = 0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27-0.86, P = 0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47-0.99; P = 0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35-1.06; P = 0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT.