Publications by authors named "Takehiko Mori"

301 Publications

Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors.

Cancer Sci 2021 Jun 7. Epub 2021 Jun 7.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).
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http://dx.doi.org/10.1111/cas.15009DOI Listing
June 2021

Allogeneic hematopoietic stem cell transplantation for adult patients with B-cell acute lymphoblastic leukemia with high hyperdiploidy: a retrospective nationwide study.

Leuk Lymphoma 2021 May 12:1-7. Epub 2021 May 12.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

We compared the transplant outcomes of adult patients with B-cell acute lymphoblastic leukemia characterized by high hyperdiploidy (HeH; 51-65 chromosomes) ( = 29) and those with a normal karyotype ( = 87) by propensity score-matched analysis. There were no significant differences among groups in 3-year probabilities of overall survival (OS, 63.5% vs. 55.3%,  = .553), cumulative relapse incidence (28.6% vs. 28.7%,  = .982), and non-relapse mortality (10.9% vs. 21.4%,  = .303). Three-year OS was significantly worse in HeH patients with third or later complete remission (CR) or non-CR compared with those in first CR (19.0% vs. 69.9%,  = .010). Frequently gained chromosomes +21 (75.9%), +4 (69.0%), +6 (69.0%), +10 (69.0%), and +1 (69.0%) had no significant prognostic impact on the OS of patients with HeH in multivariate analyses. Patients with HeH who may benefit from allogeneic hematopoietic stem cell transplantation should be further analyzed.
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http://dx.doi.org/10.1080/10428194.2021.1924374DOI Listing
May 2021

Prognostic Impact of the Fractionation of Total Body Irradiation for Patients with Acute Myeloid Leukemia Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 Feb 13;27(2):185.e1-185.e6. Epub 2020 Dec 13.

Aichi Cancer Center, Nagoya, Japan. Electronic address:

Fractionated total body irradiation (TBI) at a total dose of 12 Gy is widely used for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT); however, there is limited information regarding the optimal number of fractions. To address this issue, Japanese nationwide transplantation registry data were analyzed. Because it was found that TBI was delivered almost exclusively in 4 (n = 1215, 30%) or 6 fractions (n = 2697, 67%), we focused on comparing 4- versus 6-fraction TBI. Compared to 6-fraction TBI, the 4-fraction version was associated with reduced risk of overall mortality (P = .002) and relapse (P = .018), while there was no difference in the risk of nonrelapse mortality (P = .422). The 4-fraction version did not aggravate acute graft-versus-host disease (GVHD), interstitial pneumonia, or sinusoidal obstruction syndrome of the liver. Chronic GVHD developed more frequently with the use of 4-fraction TBI, although the incidence of extensive chronic GVHD was similar. Subgroup analyses revealed that the 4-fraction version provided benefits for patients in non-complete remission (non-CR) but not for those in CR at transplantation. These findings suggest the advantage of 4-fraction over 6-fraction TBI for patients with AML undergoing allogeneic HCT in non-CR.
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http://dx.doi.org/10.1016/j.jtct.2020.10.018DOI Listing
February 2021

Impact of Specific Antibody Level on Human Herpesvirus 6 Reactivation after Allogeneic Stem Cell Transplantation.

Transplant Cell Ther 2021 Feb 11;27(2):174.e1-174.e5. Epub 2020 Dec 11.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

The majority of adults are seropositive for human herpesvirus 6 (HHV-6). HHV-6 reactivation can occur after allogeneic hematopoietic stem cell transplantation (HSCT) and lead to life-threatening central nervous system disorders. In this prospective study, we evaluated the relationship between HHV-6 reactivation and anti-HHV-6 IgG antibody levels in recipients of allogeneic HSCT. The HHV-6 viral load in the plasma was quantitatively measured weekly after allogeneic HSCT by real-time polymerase chain reaction. The level of anti-HHV-6 IgG antibody was measured by enzyme-linked immunosorbent assay before and serially after transplantation. In 28 of the 56 evaluated patients (50%), HHV-6 reactivation was detected after transplantation. In a multivariate analysis, cord blood as the stem cell source was the only significant factor associated with HHV-6 reactivation (odds ratio, 8.6; 95% confidence interval, 2.3 to 32.6; P < .01). When evaluated in the recipients of cord blood transplantation (CBT), the anti-HHV-6 antibody level before transplantation was significantly lower in the patients with HHV-6 reactivation compared with those without (sample positivity index: median, 2.04 [range, 0.95 to 5.98] versus 4.15 [range, 3.93 to 5.65]; P < .05). The anti-HHV-6 antibody level was significantly decreased at 3 months post-transplantation compared with before transplantation (P < .01). Such differences were not observed in other stem cell sources. Our results demonstrate that the low anti-HHV-6 antibody level before transplantation was associated with the reactivation of HHV-6 after CBT, and that the anti-HHV-6 antibody level was significantly decreased specifically after CBT. These results suggest that HHV-6-specific humoral immunity plays a role in HHV-6 reactivation after CBT.
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http://dx.doi.org/10.1016/j.jtct.2020.10.011DOI Listing
February 2021

Impact of event-free survival status after stem cell transplantation on subsequent survival of patients with lymphoma.

Blood Adv 2021 03;5(5):1412-1424

Department of Oncology and Hematology, Shimane University Hospital, Izumo, Japan.

We evaluated the impact of event-free survival (EFS) status at 24 months (EFS24) and 60 months (EFS60) after hematopoietic stem cell transplantation (HSCT) using registry data. Patients who underwent their first autologous HSCT (auto-HSCT) or allogeneic HSCT (allo-HSCT) for lymphoma between 1981 and 2018 were included. Overall survival was compared with that of the age-, sex, and calendar period-matched general population. A total of 14 977 patients, including 10 964 and 4013 who underwent auto-HSCT and allo-HSCT, respectively, were analyzed. Although patients who achieved EFS24 and EFS60 had favorable outcomes, most had significantly poorer survival rates than the general population. The standardized mortality ratios (SMRs) of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were significantly higher than that of the general population even after achieving EFS24 or EFS60. The SMRs of those after auto-HSCT were 2.5 to 3.5 and 2.7 to 3.7, respectively. The SMR was consistently highest in Hodgkin lymphoma (HL) patients after HSCT. By contrast, subsequent survival of patients with primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, or peripheral T-cell lymphoma, not otherwise specified, who achieved EFS60 after auto-HSCT, and those with extranodal natural killer/T-cell lymphoma who achieved EFS60 after allo-HSCT did not significantly differ from that of the general population, with SMRs of 1.6, 1.2, 1.8, and 1.3, respectively. Our results suggest that EFS24 and EFS60 were clinically useful end points after HSCT for lymphoma patients. Furthermore, patients with certain lymphoma subtypes who achieved EFS had a comparable prognosis with that of the general population and were potentially cured after HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2020003735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948259PMC
March 2021

Phase 1 study of plerixafor in combination with total body irradiation-based myeloablative conditioning for allogeneic hematopoietic stem cell transplantation.

Int J Hematol 2021 Jun 1;113(6):877-883. Epub 2021 Mar 1.

Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Plerixafor, a CXCR4 inhibitor, has the potential to mobilize leukemic cells, which may contribute to their chemosensitization. This phase 1 study evaluated the safety of myeloablative conditioning combined with plerixafor for allogeneic hematopoietic stem cell transplantation (HSCT). Patients with high-risk leukemia undergoing allogeneic HSCT after total body irradiation (TBI, 12 Gy)-based myeloablative conditioning were eligible; 9 patients were enrolled. The study was performed using a 3 + 3 design with an escalating total dose of plerixafor. Plerixafor was given subcutaneously 8 h before TBI and chemotherapeutic agents. Plerixafor was successfully escalated to the maximum dose (0.72 mg/kg) without dose-limiting toxicities. Underlying diseases were acute myelogenous and lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. As adverse events, plerixafor administration was associated with transient Grades 2-3 diarrhea (n = 7) and abdominal pain (n = 4). In 6 patients, leukemic cell mobilization into the peripheral blood by plerixafor was confirmed by a morphological or molecular method. All patients achieved neutrophil engraftment and 5 were alive in remission at a follow-up after 30-40 months. Plerixafor-combined myeloablative conditioning for allogeneic HSCT was well tolerated. Leukemic-cell mobilization into peripheral blood was observed in half of the patients. Further study is required to evaluate the efficacy and safety of this concept.
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http://dx.doi.org/10.1007/s12185-021-03109-7DOI Listing
June 2021

Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation.

Genes Immun 2021 May 24;22(1):35-43. Epub 2021 Feb 24.

Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.
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http://dx.doi.org/10.1038/s41435-021-00122-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903020PMC
May 2021

Management of generalized severe periodontitis using full-mouth disinfection and systemic antibiotics in a leukemic patient before stem cell transplantation: A case report.

Clin Case Rep 2021 Feb 3;9(2):644-649. Epub 2020 Dec 3.

Department of Dentistry and Oral Surgery Keio University School of Medicine Tokyo Japan.

The full-mouth disinfection protocol implemented in this case can be integrated into established protocols for treating severe periodontitis in the context of a hematological malignancy, without any interference with the cancer treatment.
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http://dx.doi.org/10.1002/ccr3.3604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869351PMC
February 2021

[Early recurrence of pneumocystis pneumonia post trimethoprim-sulfamethoxazole therapy that developed after chemotherapy for follicular lymphoma].

Rinsho Ketsueki 2021 ;62(1):42-46

Division of Hematology, Department of Medicine, Keio University School of Medicine.

A 75-year-old man was treated with bendamustine-containing chemotherapy for follicular lymphoma. Trimethoprim-sulfamethoxazole (TMP-SMX) for pneumocystis pneumonia (PCP) prophylaxis was discontinued at the last course of the chemotherapy. However, the patient developed PCP 6 months after the last course, and treatment with TMP-SMX (480 mg/day) was initiated. The TMP-SMX dose was reduced after 3 weeks of treatment. However, PCP recurred 6 days after dose reduction. Increasing the TMP-SMX dose to the therapeutic dose improved PCP. The dose was reduced to a maintenance dose after 7 weeks of the therapeutic dose of TMP-SMX treatment, and PCP did not recur thereafter. This case demonstrated that the early recurrence of PCP after appropriate treatment duration in immunocompromised conditions after chemotherapy, including bendamustine, may require prolonged treatment.
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http://dx.doi.org/10.11406/rinketsu.62.42DOI Listing
February 2021

[Spontaneous remission of relapsed skin lesions of ALK-positive anaplastic large cell lymphoma after autologous stem cell transplantation].

Rinsho Ketsueki 2021 ;62(1):25-29

Division of Hematology, Department of Medicine, Keio University School of Medicine.

A 44-year-old woman was diagnosed with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) with clinical stage IVA (nodal and bladder involvement). Complete response (CR) was achieved after the CHOP chemotherapy; however, 12 months after the last course of chemotherapy, ALCL relapsed in the form of skin lesions without nodal involvement. After achieving a second CR with chemotherapy, autologous stem cell transplantation was performed. Two months after transplantation, the disease again relapsed as multiple skin lesions. Electron beam irradiation was performed; however, other skin lesions appeared thereafter and spontaneously disappeared. At present, 3.4 years after the transplantation, the patient is free from disease. ALK-positive ALCL relapsing as skin lesions may behave differently from the nodal relapse. An accumulation of cases is required to elucidate ALCL characteristics relapsing as skin lesions.
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http://dx.doi.org/10.11406/rinketsu.62.25DOI Listing
February 2021

Germline RUNX1 translocation in familial platelet disorder with propensity to myeloid malignancies.

Ann Hematol 2021 Jan 18. Epub 2021 Jan 18.

Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.

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http://dx.doi.org/10.1007/s00277-021-04430-1DOI Listing
January 2021

Stopping tyrosine kinase inhibitors started after allogeneic HCT in patients with Philadelphia chromosome-positive leukemia.

Bone Marrow Transplant 2021 Jun 8;56(6):1402-1412. Epub 2021 Jan 8.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

For patients with Philadelphia chromosome (Ph)-positive leukemia, there is no consensus regarding how long tyrosine kinase inhibitors (TKI) should be given or whether TKI could be stopped if TKI is administrated after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed relapse-free survival (RFS) in 92 allo-HCT patients who received TKI for >3 months after allo-HCT, and aimed to develop a novel indicator, called as current TKI- & relapse-free (cTRFree) achievement. TKI after allo-HCT was started as planned in 39 patients, based on measurable residual disease (MRD) in 53 at a median of 152 days after allo-HCT. There was no difference in post-TKI RFS between the planned and MRD-based starting groups (P = 0.69). Second-generation TKIs were associated with superior RFS in Ph-positive acute leukemia (HR 2.71, P = 0.031). TKI was stopped before relapse in 48 patients. Stopping TKI as a time-dependent covariate was not associated with subsequent hematological relapse (HR 1.18, P = 0.72). In the TKI-stop group, TKI administration for >6 months tended to be associated with superior RFS (HR = 0.30, P = 0.08). As an indicator of transplant success, cTRFree was 35% 5 years after starting TKI. TKI could be stopped for recipients with sustained undetectable MRD. However, further prospective studies will be required to establish clinical recommendations.
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http://dx.doi.org/10.1038/s41409-020-01206-5DOI Listing
June 2021

Absence of HOMO/LUMO Transition in Charge-Transfer Complexes of Thienoacenes.

J Phys Chem A 2021 Jan 3;125(1):146-153. Epub 2021 Jan 3.

Department of Materials Science and Engineering, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552, Japan.

In charge-transfer complexes, transition from the donor highest occupied molecular orbital (HOMO) to the acceptor lowest unoccupied molecular orbital (LUMO) gives the charge-transfer absorption. However, in tetracyanoquinodimethane (TCNQ) complexes of thienoacenes, comparison of the observed and calculated charge-transfer absorption demonstrates that the HOMO/LUMO transition is absent in the solid state owing to the orbital symmetry, and the first near-infrared band comes from the transition from the donor next HOMO to the TCNQ LUMO. Maps of the oscillator strength in rotated and translated molecular geometries are calculated on the basis of the time-dependent density functional theory, in which the absence of the HOMO/LUMO transition is approximately maintained even in the general molecular geometry.
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http://dx.doi.org/10.1021/acs.jpca.0c08925DOI Listing
January 2021

Cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation under cytomegalovirus antigenemia-guided active screening.

Bone Marrow Transplant 2021 Jun 12;56(6):1266-1271. Epub 2020 Dec 12.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Although cytomegalovirus (CMV) remains a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), the incidence of CMV retinitis is considered to be lower than the incidence of CMV infection in other organs following allogeneic HSCT. In this study, the incidence and characteristics of CMV retinitis were retrospectively evaluated in recipients of allogeneic HSCT. Ophthalmological screening was performed at the development of ocular symptoms or positive CMV infection using peripheral blood evaluated by pp65 antigenemia or polymerase chain reaction. Of the 514 patients, 13 patients developed CMV retinitis. The median onset of CMV retinitis was day 34 (range, 21-118) post transplant, and the cumulative incidence was 2.5% (95% CI, 1.6-4.2) at 6 months after transplantation. Five patients presented ocular symptoms at the onset. In the remaining eight asymptomatic patients, the diagnosis of CMV retinitis was made by the screening guided by positive CMV infection. All evaluable patients responded to antiviral treatment but three showed incomplete improvement with ocular sequela. Our results suggest that the incidence of CMV retinitis after allogeneic HSCT is not negligible and active ophthalmological screening based not only on symptoms but also positive CMV infection monitoring contributes to the early diagnosis of CMV retinitis.
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http://dx.doi.org/10.1038/s41409-020-01176-8DOI Listing
June 2021

Toxoplasmosis after allogeneic hematopoietic stem cell transplantation: Impact of serostatus-based management.

Transpl Infect Dis 2020 Nov 10:e13506. Epub 2020 Nov 10.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

Toxoplasmosis caused by Toxoplasma gondii (T. gondii) is a serious infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). The incidence of toxoplasmosis varies widely because of the variabilities of seroprevalence among patient populations. The incidence and the optimal management of toxoplasmosis after allogeneic HSCT in a patient population with a low seroprevalence have not been fully evaluated. We conducted a single-center retrospective study evaluating toxoplasmosis in Japanese patients who underwent allogeneic HSCT. Of the 728 evaluable patients, only 5 developed toxoplasmosis with a median onset of day 60 post-transplant (range, day 55-393). The cumulative incidence was 0.7% (95% CI: 0.3%-1.5%) at day 500 post-transplant. Four of the five patients succumbed due to toxoplasmosis. The more recently treated 220 patients (not the earlier 508 patients) were screened for the T. gondii serostatus, and prophylactic treatment with trimethoprim/sulfamethoxazole was applied. All five patients with toxoplasmosis were in the unscreened group, and there was no case of toxoplasmosis after the introduction of the screening and prophylactic treatment. Our results suggest that toxoplasmosis after allogeneic HST is rare but can develop as a life-threatening complication even in the populations with low seroprevalence, and that prophylactic treatment for seropositive patients could effectively prevent toxoplasmosis.
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http://dx.doi.org/10.1111/tid.13506DOI Listing
November 2020

[Chronic active Epstein-Barr virus infection with multiple vascular lesions successfully treated by cord blood transplantation].

Rinsho Ketsueki 2020 ;61(10):1502-1507

Division of Hematology, Department of Medicine, Keio University School of Medicine.

An 18-year-old woman presented with fever and liver dysfunction. Computed tomography showed lymphadenopathy, hepatosplenomegaly, and vascular lesions such as aneurysms and irregularities at multiple arteries, including coronary arteries. Based on the high copy number of Epstein-Barr virus (EBV)-DNA in the peripheral blood, EBV-infected CD4T cells, and the proliferation of EBER-positive cells in the bone marrow, chronic active EBV infection (CAEBV) was diagnosed. Although the fever and liver dysfunction improved as a result of the initial immunosuppressive therapy and multiagent chemotherapy, EBV-DNA remained high. Moreover, she experienced repeated episodes of angina pectoris due to coronary arterial lesions. Therefore, cord blood transplantation was performed after reduced-intensity conditioning. EBV-DNA decreased quickly after initiating the conditioning and became undetectable at day 7 after the transplant. Vascular lesions did not progress after the transplant, and the patient's angina pectoris resolved. At 2.5 years after the transplant, she is alive without disease recurrence. The prognosis of CAEBV with vascular lesions is especially poor. Although the indication for allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to determine in such cases, the clinical course of our case suggests that allogenic HSCT could be safely performed under appropriate management and could successfully control not only CAEBV but also vascular lesions.
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http://dx.doi.org/10.11406/rinketsu.61.1502DOI Listing
January 2021

[Two serial events of delayed hemolytic transfusion reactions due to different primary immune response-induced irregular antibodies].

Rinsho Ketsueki 2020 ;61(10):1482-1486

Division of Hematology, Department of Medicine, Keio University School of Medicine.

A 74-year-old woman with a history of pregnancies, but without previous transfusions, received a red blood cell transfusion for aplstic anemia. She lost consciousness due to severe anemia two weeks later and was transported by ambulance to our hospital. Delayed hemolytic transfusion reaction (DHTR) was diagnosed based on the detection of anti-E antibody and positive E antigen of the previously transfused product. A transfusion of E antigen-negative red cell products was performed. However, DHTR due to anti-c antibody developed 16 d after the transfusion of a c antigen-positive product. Based on the onset of ≥14 d after the transfusions and the detection of a causative IgM-type antibody, DHTR due to a primary immune response was diagnosed. Because the incidence of DHTR is low, physicians rarely experience it in clinical practice. However, in our case, DHTR due to a primary immune response, which is even rarer in DHTR cases, developed twice within a short period. A history of transfusion and pregnancy as well as preexisting irregular antibodies have been identified as risk factors for DHTR. Thus, more attention should be paid to the risk of DHTR redevelopment by repeated transfusions.
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http://dx.doi.org/10.11406/rinketsu.61.1482DOI Listing
January 2021

Long-term remission of cryopyrin-associated periodic syndrome after allogeneic haematopoietic stem cell transplantation.

Ann Rheum Dis 2020 Nov 6. Epub 2020 Nov 6.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1136/annrheumdis-2020-218695DOI Listing
November 2020

Detection of residual disease in chronic myeloid leukemia utilizing genomic next generation sequencing reveals persistence of differentiated Ph B cells but not bone marrow stem/progenitors.

Leuk Lymphoma 2021 03 26;62(3):679-687. Epub 2020 Oct 26.

Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

Persistence of leukemic stem cells (LSCs) results in the recurrence of chronic myeloid leukemia (CML) after the administration of tyrosine kinase inhibitors (TKIs). Thus, the detection of minimal residual disease (MRD) with LSC potential can improve prognosis. Here, we analyzed 115 CML patients and found that CD25 was preferentially expressed on the phenotypic stem and progenitor cells (SPCs), and TKI therapy decreased the number of CD25-positive cells in the SPC fraction. To detect MRD harboring fusion DNA, we developed a highly-sensitive method using patient-specific primers and next-generation sequencing. By using this method, we identified that in patients who achieved molecular remission, almost all residual CD25-positive SPCs were -negative. Moreover, in some patients was detectable in peripheral B cells but not in SPCs. We conclude that CD25 marks LSCs at diagnosis but does not mark MRD following TKI treatment and that analysis of peripheral B cells can allow sensitive detection of MRD.
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http://dx.doi.org/10.1080/10428194.2020.1837366DOI Listing
March 2021

Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation.

Aging Cell 2020 11 23;19(11):e13251. Epub 2020 Oct 23.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Damage to the genome can accelerate aging. The percentage of aneuploid cells, that is, cells with an abnormal number of chromosomes, increases during aging; however, it is not clear whether increased aneuploidy accelerates aging. Here, we report an individual showing premature aging phenotypes of various organs including early hair loss, atrophic skin, and loss of hematopoietic stem cells; instability of chromosome numbers known as mosaic variegated aneuploidy (MVA); and spindle assembly checkpoint (SAC) failure. Exome sequencing identified a de novo heterozygous germline missense mutation of c.856C>A (p.R286S) in the mitotic activator CDC20. The mutant CDC20 showed lower binding affinity to BUBR1 during the formation of the mitotic checkpoint complex (MCC), but not during the interaction between MCC and the anaphase-promoting complex/cyclosome (APC/C)-CDC20 complex. While heterozygous knockout of CDC20 did not induce SAC failure, knock-in of the mutant CDC20 induced SAC failure and random aneuploidy in cultured cells, indicating that the particular missense mutation is pathogenic probably via the resultant imbalance between MCC and APC/C-CDC20 complex. We postulate that accelerated chromosome number instability induces premature aging in humans, which may be associated with early loss of stem cells. These findings could form the basis of a novel disease model of the aging of the body and organs.
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http://dx.doi.org/10.1111/acel.13251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681047PMC
November 2020

Negative Impact of Cytomegalovirus Reactivation on Survival in Adult Patients with Aplastic Anemia after an Allogeneic Hematopoietic Stem Cell Transplantation: A Report from Transplantation-Related Complication and Adult Aplastic Anemia Working Groups of the Japan Society for Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 Jan 9;27(1):82.e1-82.e8. Epub 2020 Oct 9.

Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.

Cytomegalovirus (CMV) infection is a major infectious complication following an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent large-scale retrospective studies reported that CMV reactivation is an independent risk factor for poor post-transplant outcomes, although the development of CMV end-organ disease is suppressed by the CMV antiviral preemptive therapy, which has been mainly analyzed for hematopoietic malignancies, such as acute leukemia. However, it remains unclear whether CMV reactivation also has a negative effect on post-transplant outcomes in aplastic anemia (AA). Therefore, we evaluated the clinical relevance of CMV reactivation in patients with AA using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Adult patients with AA who underwent their first allo-HSCT between 2005 and 2017 and who survived with neutrophil engraftment until 100 days post-transplantation were analyzed (n = 672). Patients were monitored using pp65 antigenemia since the time of engraftment, and CMV reactivation in the analysis of this study was defined as the beginning of CMV preemptive or definitive therapy within 100 days post-transplantation. CMV reactivation occurred in 372 (55%) patients, including 19 with CMV end-organ disease. In time-dependent multivariate analysis, patients aged ≥40 years (hazard ratio [HR], 1.89; P = .003) who underwent transplantation from HLA-matched related peripheral blood stem cells (HR, 2.85; P = .008), HLA-matched unrelated bone marrow (BM) (HR, 2.01; P = .036), and other stem cell sources (HR, 2.32; P = .007) compared to HLA-matched related BM, CMV reactivation (HR 1.65; P = .042), grade II to IV acute graft-versus-host disease (HR 1.73; P = .013), and secondary graft failure (HR 7.09; P < .001) had independent risk factors that significantly decreased overall survival, indicating that CMV reactivation, one of the early events at post-transplantation, had a significant negative impact on the long-term prognosis at post-transplantation. This effect was more pronounced in patients aged ≥40 years who received a graft from other than HLA-matched related BM. Comparing the causes of death with and without CMV reactivation, no significant difference in the frequency of each cause of death was observed between the 2 groups (P = .453). Improvement of post-transplant CMV management that effectively suppresses CMV reactivation in the early stage at post-transplantation will be required to improve post-transplant outcomes, especially in high-risk patients.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.001DOI Listing
January 2021

Individual HLAs influence immunological events in allogeneic stem cell transplantation from HLA-identical sibling donors.

Bone Marrow Transplant 2021 Mar 9;56(3):646-654. Epub 2020 Oct 9.

Central Japan Cord Blood Bank, Seto, Japan.

In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the effects of patient and donor human leukocyte antigen (HLA) matching status on graft-versus-host disease (GVHD) have been extensively elucidated, but the effects of specific HLAs on acute GVHD remain unclear. Using data from a Japanese registry, we retrospectively analyzed 4392 patients with leukemia or myelodysplastic syndrome who received transplants from HLA-identical sibling donors to investigate the effects of HLAs on acute GVHD. From unbiased searches of HLA-A, -B, and -DR, HLA-B60 was significantly associated with an increased risk of grades II-IV acute GVHD (HR, 1.34; 95% CI, 1.13-1.59; P = 0.001). In contrast, HLA-B62 was significantly associated with a decreased risk of grades II-IV (HR, 0.73; 95% CI, 0.62-0.87; P < 0.001) and III-IV acute GVHD (HR, 0.63; 95% CI, 0.46-0.87; P = 0.005). The risk of leukemia relapse was significantly higher in HLA-B62-positive patients than in HLA-B62-negative patients (HR, 1.23; 95% CI, 1.05-1.43; P = 0.01). Both HLA-B60 and -B62 did not affect overall survival. The findings of this study may by implication suggest the possibility that the effects of specific HLAs on transplant outcomes may reflect inherent biological features, and thus consideration of specific HLAs may be helpful to predict transplant outcomes.
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http://dx.doi.org/10.1038/s41409-020-01070-3DOI Listing
March 2021

Cyclosporine/methotrexate versus tacrolimus/methotrexate with or without anti-thymocyte globulin as GVHD prophylaxis in adult patients with aplastic anemia.

Ann Hematol 2021 Jan 9;100(1):217-228. Epub 2020 Oct 9.

Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.

The impact of calcineurin inhibitor types and anti-thymocyte globulin (ATG) in conditioning on overall survival (OS) and GVHD-free, relapse-free survival (GRFS) has not yet been analyzed in detail for aplastic anemia. We herein examined 517 adult patients with aplastic anemia who underwent BMT from HLA-matched sibling donors (MSD, n = 255) and unrelated donors (UD, n = 262) and were treated with cyclosporine A (CSA) + methotrexate (MTX) (n = 258) and tacrolimus (TAC) + MTX (n = 259). In total, 330 patients received ATG in conditioning. CSA + MTX versus TAC + MTX did not have a significant impact on acute and chronic GVHD, OS, or GRFS in each donor type. The use of ATG in conditioning reduced the risk of grade II-IV acute GVHD in the MSD and UD cohorts (HR 0.42, P = 0.014, and HR 0.3, P < 0.001, respectively); however, a differential impact on GRFS was identified, namely, better GRFS in MSD recipients (HR 0.56, P = 0.016), but not in UD recipients (HR 1.1, P = 0.657). In conclusion, CSA + MTX and TAC + MTX were similar as GVHD prophylaxis regardless of the donor type, and ATG in conditioning increased GRFS in MSD transplants, but not in UD transplants.
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http://dx.doi.org/10.1007/s00277-020-04290-1DOI Listing
January 2021

Seroprevalence of Toxoplasma gondii among Japanese adults with hematological diseases.

Int J Hematol 2020 Nov 6;112(5):755-756. Epub 2020 Oct 6.

Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

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http://dx.doi.org/10.1007/s12185-020-03017-2DOI Listing
November 2020

Clinical Benefits of Preconditioning Intervention in Patients with Relapsed or Refractory Acute Myelogenous Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation: A Kanto Study of Group for Cell Therapy Multicenter Analysis.

Transplant Cell Ther 2021 Jan 30;27(1):70.e1-70.e8. Epub 2020 Sep 30.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

A multicenter retrospective study was conducted to evaluate the clinical significance of preconditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) not in remission. The study cohort consisted of 519 patients classified according to the intensity (intensive/moderate) of PCI and their response to PCI. The group treated with PCI had higher blast counts in the peripheral blood (PB) and had a lower overall survival (OS) rate (P < .001) and higher nonrelapse mortality (NRM) rate (P = .035) compared with those without PCI (no PCI group). Approximately 40% of the patients (68 of 236) achieved a good response to PCI (good PCI group), and those patients had lower blast counts in the PB compared with the group with poor response to PCI (poor PCI group). OS in the good PCI group was comparable to that in the no PCI group and significantly better than that in the poor PCI group (hazard ratio, .54; 95% confidence interval, .39 to .77; P < .001). However, OS was significantly lower in patients with intensive/moderate PCI compared with the no PCI group. These results suggest that PCI increases NRM without decreasing the post-transplantation relapse rate, but may be beneficial for patients with lower blast counts in PB irrespective of its intensity.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.025DOI Listing
January 2021

[Efficacy of photocatalytic air purifiers in reducing dimethyl sulfide malodor following cryopreserved peripheral blood stem cell infusion].

Rinsho Ketsueki 2020 ;61(8):885-887

Division of Hematology, Department of Medicine, Keio University School of Medicine.

Dimethyl sulfoxide (DMSO) is used as a cryoprotectant for peripheral blood stem cells (PBSC) preservation. Dimethyl sulfide (DMS) is a metabolite of DMSO secreted through patients' breath after PBSC infusion. It possesses malodor causing an unpleasant environment. We evaluated the efficacy of a photocatalyst environment purifier, which has the potential to lyse toxic substances, in reducing DMS malodor. High DMS concentration in the air after PBSC infusion rapidly decreased after operating the device. Our results suggest that photocatalytic reaction has the potential to reduce the DMS odor associated with PBSC infusion.
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http://dx.doi.org/10.11406/rinketsu.61.885DOI Listing
October 2020

[Systemic varicella-zoster infection during ixazomib-containing multiagent chemotherapy for multiple myeloma].

Rinsho Ketsueki 2020 ;61(8):870-873

Division of Hematology, Department of Medicine, Keio University School of Medicine.

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.
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http://dx.doi.org/10.11406/rinketsu.61.870DOI Listing
October 2020

Effects of Acute and Chronic Graft-versus-myelodysplastic Syndrome on Long-term Outcomes Following Allogeneic Hematopoietic Cell Transplantation.

Clin Cancer Res 2020 12 6;26(24):6483-6493. Epub 2020 Sep 6.

Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Purpose: Potent graft-versus-tumor (GVT) effects associated with graft-versus-host disease (GVHD) might be dependent on hematologic disease type and status. However, the data regarding the impact of GVHD on transplant outcomes for patients with myelodysplastic syndrome (MDS) are limited.

Experimental Design: We retrospectively evaluated the impact of acute and chronic GVHD on transplant outcomes for a large cohort of adult patients with a low-risk ( = 1,193) and high-risk ( = 1,926) MDS treated by first allogeneic hematopoietic cell transplantation between 2001 and 2017.

Results: The multivariate analysis, in which development of GVHD was treated as a time-dependent covariate, showed that acute and chronic GVHD at any grade or severity did not improve overall mortality, relapse, or nonrelapse mortality (NRM) in low-risk MDS. For patients with high-risk MDS, development of limited chronic GVHD was significantly associated with lower overall mortality [HR, 0.66; 95% confidence interval (CI), 0.50-0.86; = 0.002]. This is probably due to that the reduced risk of relapse with grade III-IV acute GVHD (HR, 0.41; 95% CI, 0.25-0.65; = 0.0002), or limited (HR, 0.57; 95% CI, 0.39-0.83; = 0.003) or extensive (HR, 0.56; 95% CI, 0.41-0.77; = 0.0004) chronic GVHD was offset by increased NRM with grade III-IV acute GVHD or extensive chronic GVHD in high-risk MDS.

Conclusions: These data demonstrated a survival benefit of the graft-versus-MDS effect is present only in high-risk MDS patients with limited chronic GVHD..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1104DOI Listing
December 2020

Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with paroxysmal nocturnal hemoglobinuria.

Int J Hematol 2021 Jan 5;113(1):122-127. Epub 2020 Sep 5.

Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.

The safety and efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for paroxysmal nocturnal hemoglobinuria (PNH) remain unclear. Therefore, we retrospectively analyzed the outcomes of 42 adult patients with PNH who underwent allogeneic HSCT using the registry database of the Japan Society for Hematopoietic Cell Transplantation. The median patient age was 32.5 years. The number of packed red cell (PRC) transfusions was < 20 times in 19 patients and ≥ 20 times in 16; 7 patients had missing data. Stem cell sources were bone marrow (N = 15) or peripheral blood (N = 13) from a related donor or bone marrow (N = 11) and cord blood (N = 3) from an unrelated donor. The cumulative incidence of neutrophil engraftment at day 40 was 81%. Six patients died before engraftment, and the 6-year overall survival (OS) was 74%. The OS of patients with < 20 pretransplant PRC transfusions was significantly higher than that of patients with ≥ 20 pretransplant PRC transfusions (95% vs. 63%; P < 0.05). Moreover, the OS of patients aged < 30 years was significantly higher than that of patients aged ≥ 30 years (90% vs. 59%; P < 0.05). Allogeneic HSCT for PNH could provide favorable survival; however, pretransplant transfusion burden and patient age should be considered when deciding the timing of allogeneic HSCT.
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http://dx.doi.org/10.1007/s12185-020-02982-yDOI Listing
January 2021