Intensive oral care can reduce bloodstream infection with coagulase-negative staphylococci after neutrophil engraftment in allogeneic hematopoietic stem-cell transplantation.

PURPOSE: Bloodstream infection (BSI) is a major complication of allogeneic hematopoietic stem-cell transplantation (allo-SCT). There are several causes of BSI; in particular, severe oral mucositis (OM) can induce BSI due to coagulase-negative staphylococci (CoNS). The OM severity may be reduced with intensive oral care. Thus, we evaluated whether the type of oral care affects the BSI incidence eventually. METHOD: We performed retrospective analysis on 206 recipients who underwent allo-SCT from 2006 to 2017 at our institute. Intensive oral care by a dental specialist was performed for 111 recipients (intensive-care group) and self-oral care was performed by 95 recipients (self-care group). Incidence of BSI was assessed by type of the oral care, before neutrophil engraftment (pre-E-BSI) and after neutrophil engraftment (post-E-BSI) period until 180 days after allo-SCT. RESULT: A total of 112 BSI occurred in 90 of the 206 recipients and 120 bacteria were identified, with CoNS being the most prevalent. There was no significant difference in the incidence of pre-E-BSI between the self-care and intensive-care groups (30.8% and 30.6%, respectively; P = 0.508). Meanwhile, the incidence of post-E-BSI was significantly lower in the intensive-care group than in the self-care group (14.3% and 28.6%; P = 0.008). In addition, the intensive-care group had significantly lower incidence of post-E-BSI with CoNS than the self-care group (8.5% and 21.5%, respectively; P = 0.009). CONCLUSION: Intensive oral care through the period of allo-HCT can significantly reduce the post-E-BSI occurrence, especially due to CoNS.

A multicenter phase II study of intrabone single-unit cord blood transplantation without antithymocyte globulin.

To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 107/kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0-85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 109/L on day 60 was 80.6% (68.2-88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L on day 100 were 75.8% (62.6-84.9%) and 72.6% (59.4-82.1%), respectively, with median time to platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.

Marker chromosome is a strong poor prognosis factor after allogeneic HSCT for adverse-risk AML patients.

INTRODUCTION: Chromosome analysis is necessary for the risk classification of acute myeloid leukemia (AML). Marker chromosome (MC) is a fragmented chromosome whose origin cannot be identified from other chromosomes and originates from marked genomic instability. Although AML with MC (MC+) has a poor prognosis even after intensive chemotherapy, its influence on the outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. OBJECTIVE AND METHODS: We retrospectively analyzed 162 AML patients after allo-HSCT. To evaluate the significance of MC, we compared it with other chromosomal abnormalities. RESULT: Marker chromosome was detected in 14 (8.6%, MC+) patients (vs MC-, n = 158). The 2-year overall survival (OS) in MC+ vs MC- was 26.8% vs 62.2% (P = .0098). The 2-year cumulative incidence of relapse (CIR) in MC+ vs MC- was 80.4% vs 35.5% (P = .0004). Among adverse-risk AML (AD-AML, n = 36), AD-AML/MC+ (n = 11) demonstrated a poorer 2-year OS (9.1%, vs AD-AML/MC- n = 25, 58.3%, P = .0031) and higher 2-year CIR (89.6%, vs AD-AML/MC- 44.7%, P = .002). In multivariate analysis, MC (HR 3.08, 95% CI; 1.02-9.29, P = .046) and HCT-CI (HR 3.23, 95% CI; 1.00-10.4, P = .049) were independent risk factors for CIR among AD-AML. CONCLUSION: Our study suggests MC as a new independent factor for chromosome risk classification to further classify AD-AML.

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.

Phase II study of intrabone single unit cord blood transplantation for hematological malignancies.

The outcomes of cord blood transplantation with non-irradiated reduced-intensity conditioning for hematological malignancies need to be improved because of graft failure and delayed engraftment. Intrabone infusion of cord blood cells has the potential to resolve the problems. In this phase II study, 21 adult patients with hematological malignancy received intrabone transplantation of serological HLA-A, B, and DR ≥4/6 matched single cord blood with a median number of cryopreserved total nucleated cells of 2.7 × 107 /kg (range, 2.0-4.9 × 107 /kg) following non-irradiated fludarabine-based reduced-intensity conditioning. Short-term methotrexate and tacrolimus were given as graft-versus-host disease prophylaxis, and granulocyte colony-stimulating factor was given after transplantation. No severe adverse events related to intrabone injection were observed. The cumulative incidences of neutrophils ≥0.5 × 109 /L, reticulocytes ≥1%, and platelets ≥20 × 109 /L recoveries were 76.2%, 71.4%, and 76.2%, respectively, with median time to recoveries of 17, 28, and 32 days after transplantation, respectively. The probability of survival with neutrophil engraftment on day 60 was 71.4%, and overall survival at 1 year after transplantation was 52.4%. The incidences of grade II-IV and III-IV acute graft-versus-host disease were 44% and 19%, respectively, with no cases of chronic graft-versus-host disease. The present study showed the safety of direct intrabone infusion of cord blood. Further analysis is required to confirm the efficacy of intrabone single cord blood transplantation with non-irradiated reduced-intensity conditioning for adult patients with hematological malignancy. This study was registered with UMIN-CTR, number 000000865.

Donor Killer Immunoglobulin-Like Receptor Haplotype B/x Induces Severe Acute Graft-versus-Host Disease in the Presence of Human Leukocyte Antigen Mismatch in T Cell-Replete Hematopoietic Cell Transplantation.

Natural killer cells have been identified as a mediator of alloimmune reactions in allogeneic hematopoietic stem cell transplantation (HSCT). Killer immunoglobulin-like receptors (KIRs) are an important determinant of natural killer cell function. The relationship between KIR genotypes/haplotypes and clinical outcomes of allogeneic HSCT is complex and inconsistent among several reports. We assessed the clinical impact of KIR haplotype on T cell-replete allogeneic HSCTs performed in a single Japanese center for hematological malignancies (n = 106). A comparison of 2 groups, donor haplotypes A/A and B/x, revealed no significant differences in overall survival, relapse, and nonrelapse mortality. However, grade III to IV acute graft-versus-host disease (GVHD) occurred significantly more frequently in the KIR haplotype B/x group (A/A versus B/x: 4.9% versus 20.0%; P = .02). This was even more evident when HLA mismatch was present. The highest incidences of grade II to IV and grade III to IV acute GVHD were observed in patients who received allografts from HLA-mismatched donors with KIR haplotype B/x. These data highlight the importance of KIR genotyping in donor matching, especially when HLA mismatch allogeneic grafting is planned.

The Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation.

Evaluation methods, such as scoring systems for predicting complications in advance, are necessary for determining the adaptation of allogeneic hematopoietic cell transplantation (HCT) and selecting appropriate conditioning regimens. The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), which is based on functions of main organs, is a useful tool for pre-transplant risk assessments and has been widely applied in determining treatment strategies for patients with hematological diseases. However, as allogeneic HCT is performed on patients with diverse backgrounds, another factor, which reinforces the HCT-CI, is required to evaluate pre-transplant risk assessments. The Glasgow Prognostic Score (GPS), which assesses the combined C-reactive protein and albumin, was reported to predict survival of patients with solid-organ malignancies independently of receiving chemo/radiotherapy and stages of cancer. In this study, we applied the GPS for pre-transplant risk assessments for allogeneic HCT. The GPS successfully stratified the patients into three risk groups of overall survival (OS) and non-relapse mortality (NRM). Moreover, the GPS could predict outcomes independently of the HCT-CI for OS and NRM in multivariate analysis. The GPS is considered to be a useful tool and reinforces the HCT-CI for determining adaptation of allogeneic HCT for patients with hematopoietic neoplasms.

Successful umbilical cord blood hematopoietic stem cell transplantation in a patient with adult T-cell leukemia/lymphoma initially achieving complete remission with anti-CC chemokine receptor 4 antibody combined chemotherapy.

A 62-year-old man with CHOP refractory adult T-cell leukemia/lymphoma (ATLL) received anti-CC chemokine receptor 4 antibody (mogamulizumab) combined with CHOP and achieved complete remission. At 71 days after the final administration of mogamulizumab, he received umbilical cord blood transplantation (CBT) using reduced intensity conditioning. Umbilical cord blood engraftment was confirmed on day16. Grade II acute graft-versus-host disease (GVHD) was diagnosed on day60 and was controlled by administration of methylprednisolone. There was no evidence of relapse at 9 months after CBT. Ratios of regulatory T cells in CD4 positive T cells were remarkably low during all of these periods. Since mogamulizumab reduces regulatory T cells, the frequency and severity of acute GVHD were reported to be increased in patients administered mogamulizumab before allogenic stem cell transplantation. Further experiences are needed for selecting optimal donor sources, the portability period and GVHD prophylaxis for patients using mogamulizumab before allogeneic stem cell transplantation.

Decade-long WT1-specific CTLs induced by WT1 peptide vaccination.

INTRODUCTION: The peptide-based cancer vaccine targeting Wilms' tumor 1 (WT1) is a promising immunotherapeutic strategy for hematological malignancies. It remains unclear how long and to what extent the WT1-specific CD8 + cytotoxic T cell (CTL) persist after WT1 peptide vaccination. METHODS: The WT1 peptide vaccine was administered with written consent to a patient with CML in the chronic phase who did not respond well to imatinib, and the patient was followed for 12 years after vaccination. Immune monitoring was performed by specific amplification of WT1-specific CTLs using a mixed lymphocyte peptide culture. T-cell receptors (TCRs) of amplified WT1-specific CTLs were analyzed using next-generation sequencing. This study was approved by the Institutional Review Board of our institution. RESULT: WT1-specific CTLs, which were initially detected during WT1 peptide vaccination, persisted at a frequency of less than 5 cells per 1,000,000 CD8 + T cells for more than 10 years. TCR repertoire analysis confirmed the diversity of WT1-specific CTLs 11 years after vaccination. CTLs exhibited WT1 peptide-specific cytotoxicity in vitro. CONCLUSION: The WT1 peptide vaccine induced an immune response that persists for more than 10 years, even after cessation of vaccination in the CML patient.

Genetic manipulation resulting in decreased donor chondroitin sulfate synthesis mitigates hepatic GVHD via suppression of T cell activity.

Donor T cell activation, proliferation, differentiation, and migration are the major steps involved in graft-versus-host disease (GVHD) development following bone marrow transplantation. Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and causes immune modulation by interacting with cell growth factors and inducing cell adhesion. However, its precise effects on immune function are unclear than those of other proteoglycan families. Thus, we investigated the significance of CS within donor cells in acute GVHD development utilizing CSGalNAc T1-knockout (T1KO) mice. To determine the effects of T1KO, the mice underwent allogenic bone marrow transplantation from major histocompatibility complex-mismatched donors. While transplantation resulted in hepatic GVHD with inflammatory cell infiltration of both CD4+ and CD8+ effector memory T cells, transplantation in T1KO-donors showed milder cell infiltration and improved survival with fewer splenic effector T cells. In vitro T-cell analyses showed that the ratio of effector memory T cells was significantly lower via phorbol myristate acetate/ionomycin stimulation. Moreover, quantitative PCR analyses showed significantly less production of inflammatory cytokines, such as IFN-γ and CCL-2, in splenocytes of T1KO mice. These results suggest that reduction of CS in donor blood cells may suppress the severity of acute GVHD after hematopoietic stem cell transplantation.

[Successful treatment of acute promyelocytic leukemia complicated with autoimmune hepatitis-induced portal hypertension with all-trans retinoic acid].

A 35-year-old man admitted to the hospital for oral hemorrhage was diagnosed with acute promyelocytic leukemia (APL). Remission from APL was achieved by induction therapy with all-trans retinoic acid (ATRA); the PML/RARA fusion gene was not detected on PCR analysis. Despite complete molecular remission, severe persistent pancytopenia, massive ascites, and renal failure were observed. The liver surface appeared rough and irregular on computed tomographic images. On the basis of the liver biopsy results, we diagnosed his condition as portal hypertension due to autoimmune hepatitis. Indocyanine green test showed good residual function of the liver, and therefore, 2 courses of consolidation therapy were administered; chemotherapy was stopped because of severe pancytopenia due to portal hypertension. Instead of continuing the consolidation therapy, maintenance therapy involving 8 rounds of ATRA monotherapy (45 mg/m(2), days1∼14) was initiated. Portal hypertension did not progress further with this maintenance therapy and therefore it was continued. The patient has been in remission from APL ever since, and no relapses have occurred since the past 5 years. These results suggest that ATRA can be used for long-term therapy in such cases.

[Cardiogenic shock due to takotsubo cardiomyopathy during induction therapy for acute myeloid leukemia].

A 61-year-old man admitted for pancytopenia was diagnosed with acute myeloid leukemia. On day 26 of induction therapy, the patient suddenly developed cardiogenic shock. The ultrasound cardiogram showed imaging features typical of takotsubo cardiomyopathy. Cardiogenic shock caused by takotsubo cardiomyopathy is rare in patients with hematological malignancies but is a severe complication during chemotherapy.

DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction.

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.

WT1-specific CD8 + cytotoxic T cells with the capacity for antigen-specific expansion accumulate in the bone marrow in MDS.

Wilms' tumor 1 (WT1) is a tumor-associated antigen and immunotherapy target in myelodysplastic syndrome (MDS). Further information is needed on the characteristics of WT1-specific CD8 + T cells to develop immunotherapeutic strategies for MDS. To clarify the frequency, distribution, and phenotype of WT1-specific CD8 + T cells, which occur innately in MDS patients, we analyzed paired peripheral blood (PB) and bone marrow (BM) samples from 39 patients with MDS or acute myeloid leukemia with myelodysplasia-related changes. The median frequency of WT1 tetramer-binding CD8 + T cells in the CD8 + T cell population was 0.11% in PB and 0.18% in BM. A further tetramer assay combined with mixed lymphocyte peptide culture (MLPC assay) was used to detect functional WT1-specific CD8 + T cells that could respond to the WT1 peptide. Functional WT1-specific CD8 + T cells were detected in BM in 61% of patients, which was significantly higher than in PB (23%, p = 0.001). The frequency of these cells estimated by the MLPC assay was tenfold higher in BM than in PB. The majority of WT1 tetramer-binding CD8 + T cells in BM had a unique phenotype with co-expression of CD39 and CXCR4. These findings will facilitate the development of novel immunotherapeutic strategies for MDS.

Hypereosinophilia-related liver pseudotumor with elevated interleukin-5 levels preceding T-cell lymphoma.

A 61-year-old woman with hypereosinophilia and elevated interleukin (IL)-5 level was admitted to our hospital after detection of multiple liver tumors. Liver biopsy demonstrated that the tumor consisted of scar tissue with remnants of eosinophilic infiltration, suggesting that it had formed by massive eosinophilic infiltration. The hypereosinophilia was treated mainly by prednisolone, and thereafter, the liver tumors disappeared. However, 10 months postadmission, CD4+ T-cell lymphoma, which can produce IL-5, was detected in the nasopharynx and oropharynx. Therefore, we believe that this is a rare case of hypereosinophilia-related liver pseudotumor induced by presumed by IL-5 elevation.

Gemcitabine, Dexamethasone, and Cisplatin Regimen as an Effective Salvage Therapy for High-grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements.

A 61-year-old woman exhibited right inguinal lymphadenopathy and right lower limb edema approximately 1 month prior to hospitalization. She was diagnosed with high grade B-cell lymphoma, and a lymph node biopsy and fluorescence in situ hybridization indicated MYC, BCL2, and BCL6 rearrangements (triple-hit lymphoma). She had progressive disease that was CD20-negative after two courses of rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine (R-CODOX-M/IVAC) therapy. Subsequent etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (EPOCH) therapy was not effective. However, after two cycles of gemcitabine, dexamethasone, and cisplatin (GDP) therapy, she achieved a complete response and was able to undergo autologous peripheral blood stem cell transplantation. GDP therapy may be effective as salvage therapy for chemotherapy-resistant triple-hit lymphoma.

Anaplastic large cell lymphoma, with 1,25(OH)2D3-mediated hypercalcemia: A case report.

Hypercalcemia due to malignant tumors including malignant lymphomas is relatively common. Among cancer patients with hypercalcemia, humoral hypercalcemia of malignancy is the most common and accounts for about 80% of all cases with hypercalcemia. 1,25-dihydroxyvitamin D3(1,25(OH)2D3)-mediated hypercalcemia is relatively rare. Although malignant lymphoma has been also reported to cause 1,25(OH)2D3-mediated hypercalcemia, it is not known whether there is any association between 1,25(OH)2D3-mediated hypercalcemia and any specific histological type of malignant lymphoma. We herein report a case of an anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) -negative with 1,25(OH)2D3-mediated hypercalcemia, which has never been previously reported. An 80-year-old Japanese man was admitted to our department due to acute exacerbation of hypercalcemia. He was diagnosed with ALCL, ALK-negative. Serum 1,25(OH)2D3 level was high and seemed to be associated with the lymphoma because the serum calcium and 1,25(OH)2D3 levels improved in response to chemotherapy. Histological findings showed that many CD68 positive macrophages were observed in the microenvironment of tumor cells. Lymphoma cells or tumor microenvironmental cells may produce 1,25(OH)2D3 because several previous reports showed the source of 1,25(OH)2D3 can be either lymphoma or tumor microenvironmental cells. Moreover, because 1,25(OH)2D3-mediated hypercalcemia has been reported regardless of the specific histological type of lymphoma, tumor microenvironmental cells may be involved in this condition. However, we could not identify the source of 1,25(OH)2D3 in this case. The association between 1,25(OH)2D3 production and prognosis in malignant lymphomas is yet unknown; further studies are needed to elucidate the clinical characteristics of malignant lymphoma with 1,25(OH)2D3-mediated hypercalcemia.

Myeloablative and reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide.

We conducted two parallel prospective, multicenter, phase II studies to evaluate the safety and efficacy of HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) following myeloablative conditioning (MAC, n = 50) and reduced-intensity conditioning (RIC, n = 77). Event-free survival (EFS) at 1-year as for primary endpoint was 64% and 43% in the MAC and RIC groups, respectively. Neutrophil engraftment was achieved in 98% and 94% in the MAC and RIC groups, respectively. The incidences of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 18% and 8% in the MAC group, and 14% and 5% in the RIC group, respectively. Those of all grade and moderate to severe chronic GVHD at 2-year were 36% and 20% in the MAC group, and 27% and 20% in the RIC group, respectively. Overall survival (OS), EFS, nonrelapse mortality, and relapse rate at 2-year were 68%, 54%, 10%, and 36% in the MAC group, and 44%, 35%, 20%, and 45% in the RIC group, respectively. Notably, 83% and 86% of patients who survived without relapse stopped immunosuppressant at 2-year in the MAC and RIC groups, respectively. Our results indicate that both MAC and RIC are valid options for PTCy-haploPBSCT for adults with hematological malignancies.