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  • 1
    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 102, No. 5 ( 2023-05), p. 1239-1246
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
    In: International Journal of Hematology, Springer Science and Business Media LLC, Vol. 116, No. 6 ( 2022-12), p. 966-972
    Type of Medium: Online Resource
    ISSN: 0925-5710 , 1865-3774
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 3
    In: International Journal of Hematology, Springer Science and Business Media LLC, Vol. 119, No. 5 ( 2024-05), p. 573-582
    Type of Medium: Online Resource
    ISSN: 0925-5710 , 1865-3774
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2024
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  • 4
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5747-5747
    Abstract: Background & Aim: Recombinant human soluble thrombomoduline alpha (rhTM) is a novel anticoagulant agents and approved for disseminated intravascular coagulation (DIC) in Japan. Although several case reports suggested its therapeutic potential for sinusoidal obstructive syndrome/hepatic veno-occlusive disease (SOS/VOD), no information is available in large cohort. The aim of the study is to evaluate the therapeutic potential of rhTM for SOS/VOD. Patients & Methods: We retrospectively studied 878 times of allogeneic hematopoietic cell transplantation (HCT) in Toranomon Hospital from June 2008 to June 2015. We extracted the patients who used rhTM for DIC and satisfied the diagnostic criteria of SOS/VOD around the same time, because the use of rhTM for SOS/VOD alone is off-label. We excluded the patients who were already treated with rhTM before the emergence of the first symptom or sign of SOS/VOD, who used rhTM only in the short period (within 2 days), and who started rhTM over 30 days after the emergence of the first symptom or sign of SOS/VOD. To diagnose classical SOS/VOD (≤ 21 days after transplantation), we used two classical criteria of the modified Seattle (McDonald et al. Ann Intern Med 1993) and the Baltimore (Jones et al. Transplant 1987). For late-onset SOS/VOD ( 〉 day 22 of transplantation), we used the criteria which was recently published from the EBMT group (Mohty et al, Bone Marrow Transplant 2016). We considered the atrophic change of the liver in a long-term clinical course as an evidence of SOS/VOD, in a patient who was not evaluated the portal flow. We defined as severe SOS/VOD, if the patients had renal (Cr ≥ 2 times of baseline at transplant), respiratory (SpO2 ≤ 90% and/or the need for positive pressure) or central nervous system failure (confusion, lethargy and/or delirium) until 2 weeks after the diagnosis of SOS/VOD. Complete response (CR) of SOS/VOD was defined as the resolution of all the symptoms and the signs of SOS/VOD diagnostic criteria. We prioritized the date of Baltimore criteria, when we fixed the date of diagnosis. Results: A total of 39 patients used rhTM for DIC and concurrent SOS/VOD. The median age was 60 years (range, 27 - 72) and 27 patients (69%) was male. Hematologic diseases were as follows; AML (n=25), ALL (n=5), lymphoma (n=3), CML (n=2), MDS (n=2) and CMML (n=2). Donor cell sources were UCB (n=34) and UBM (n=5). Most of the prophylaxis regimen at the time of transplantation was the combination of ursodeoxycholic acid and dalteparin in 36 patients (92%). Classical SOS/VOD was diagnosed in 3 (8%) and 8 patients (21%) by the criteria of the modified Seattle and the Baltimore at the median day of 14 (range, 11 - 14) and 16 (range, 11 - 20), respectively. Twenty-eight patients (72%) were diagnosed as late-onset SOS/VOD at the median day of 44 (range, 22 - 89). In a total of 39 patients, severe SOS/VOD developed in 33 patients (85%) (renal, n=32; respiratory, n=7; central nervous system, n=15). The elevation of transaminase (2x upper limit of normal range) was observed in 18 patients (46%). The median interval from the emergence of the first symptom or sign of SOS/VOD to rhTM administration was 7 days (range, 0 - 23). The median duration of rhTM administration was 11 days (range, 3 - 63). RTM was used alone in 20 patients (51%), in combination with dalteparin in 7 (18%), with antithrombin III (ATIII) in 5 (13%), with dalteparin & ATIII in 3 (8%), with ATIII & prostaglandin E1 (PGE1) in 2 (5%), and with PGE1 in 2 (5%). Corticosteroid was used with rhTM concomitantly in 32 patients (82%). Finally, 13 patients achieved CR of SOS/VOD. The cumulative incidence of CR of SOS/VOD was 33.3 % at 1 year after the administration of rhTM (95% confidence interval, 18.5 - 48.9%) (Figure 1). The median interval from the administration of rhTM to CR of SOS/VOD was 51 days (range, 6 - 141). At 1 year after transplantation, overall survival was 25.6% (95% confidence interval, 13.3 - 69.9%) (Figure 2). From the administration of rhTM to 2 weeks after the cessation of rhTM, 23 hemorrhagic adverse events were observed. Seven out of 23 events were at grade 3-5, and 5 out of 7 events were fatal (intra-abdominal n=2, gastro-intestinal n=1, lung n=1, and brain n=1). Conclusion: We concluded that rhTM had a possible therapeutic potential for SOS/VOD. Its safety and efficacy should be evaluated in a prospective study in the future. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Izutsu: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 5
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4482-4482
    Abstract: & lt;Introduction & gt; Delayed immune reconstitution after allogeneic transplantation increases the risk of treatment-related mortality, and chronic GVHD. Previous reports showed that absolute lymphocyte count at day 30 (ALC30) was a significant prognostic factor of transplantation, and lower numbers of total CD4+ T cells and naïve CD4+ T cells in particular were associated significantly with higher mortality. However, there is little knowledge about the factors associated with low lymphocyte recovery, especially in cord blood transplantation (CBT). The cut-off value of lymphocyte recovery for statistical significance has not been determined yet. & lt;Methods & gt; We retrospectively analyzed the outcome of 579 consecutive patients who underwent single cord blood transplantation (CBT) for the first time at Toranomon Hospital between January 2011 and 2018. Patients with active infection at transplantation (n=40), in poor ECOG PS (3 or more) (n=36), or lacked information about CT before CBT (n=1) were excluded from this study. & lt;Results & gt; Five hundred and two patients (n=317 male; n=185 female) were included in this study. The median age at transplantation was 57 years (range, 16-77), with a median HCT-CI score of 2 (0-10). Underlying diseases were AML (307), MDS (43), MPN (20), ALL (50), mature lymphoid malignancies (54), and others (28). Median spleen index (SI) before transplantation was 60.2 (16.5-319.7). Three hundred and ninety eight patients (79%) were not in remission at transplant. MAC regimens were selected in 400 (80%). TAC alone was used in 132 (26%) as GVHD prophylaxis. Median number of TNC and CD34+ cells infused were 2.62 (1.57-6.85) x 107/kg and 0.86 (0.29-3.77) x 105/kg, respectively. 194 (39%) were positive for anti-HLA antibodies, but none had donor-specific. With a median follow-up of 32 (range, 3-99) months, cumulative incidence of neutrophil engraftment (NE), the 3-year probabilities of overall survival (OS), relapse rate (RR) and non-relapse mortality (NRM) for entire population were 92.8%, 40.6%, 23.5%, and 35.3%, respectively. Underlying disease (myeloid malignancy), disease status at SCT (non-CR), poor PS (PS=2), GVHD prophylaxis (TAC+MMF), low CD34-positive cell dose ( & lt;0.8 x 105/kg), and splenomegary (SI ≥ 40) were significantly associated with inferior NE in multivariate analysis. Disease status at SCT (non-CR), poor PS (PS=2), Higher HCT-CI (PS ≥ 3), and GVHD prophylaxis (TAC+MMF) were significantly associated with higher NRM in multivariate analysis. We analyzed the relationship between ALC30 and transplantation outcome. Median number of ALC30 was 231 (3.5-1503), and the 25th percentile was 144. We divided the cohort into two groups, ALC30 low group ( & lt;150, n=123), ALC30 high group (≥150, n=346). High number of ALC30 (≥150) was associated with better survival (48.1% vs. 29.5%, p & lt; 0.01) and lower NRM (26.9% vs. 41.9%, p & lt; 0.01) due to reduced incidence of lethal infection (7.1% and 23.4% of total death in ALC30 high and low, respectively, p & lt; 0.01), but was not associated with RR (25.5% vs. 25.1%, p = 0.59). High ALC30 (≥150), as well as younger age ( & lt;60), underlying disease (myeloid malignancy), better PS (0-1), and disease status at SCT (CR) showed a superior OS in multivariate analysis. We then assessed factors associated with ALC30, and higher infused dose of CD34-positive cells was the only factor associated with high ALC30, (p=0.03, t-test). Other factors, such as infused TNC dose, type of conditioning, or GVHD prophylaxis did not show significant association with ALC30. & lt;Conclusion & gt; This retrospective study demonstrated that low ALC30 after CBT had negative impact on survival because of higher NRM rate. High CD34-positive cell dose was the only factor associated with high ALC30. Not CD34-positive cell dose, but ALC30 had significant impact on OS in multivariate analysis, so we need to take lymphocyte recovery into account, in an attempt to improve transplantation outcome. Figure Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 6
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 26, No. 9 ( 2020-09), p. 1689-1696
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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  • 7
    In: Mycopathologia, Springer Science and Business Media LLC, Vol. 182, No. 9-10 ( 2017-10), p. 847-853
    Type of Medium: Online Resource
    ISSN: 0301-486X , 1573-0832
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
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    detail.hit.zdb_id: 2003647-4
    SSG: 12
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  • 8
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3390-3390
    Abstract: BACKGROUND: We previously reported higher incidence of central nervous system complications (CNSCs) after cord blood (CB) than after bone marrow or peripheral blood transplantation (Kageyama K, et al. ASH 2016). Infectious complications such as human herpes virus type 6 (HHV-6) associated limbic encephalitis and/or myelitis have been the major cause of CNSCs. In this study, we now focused on non-infectious myelopathy and peripheral neuropathy (NIMPN) for which the main diseased focus located outside of cerebrum or cerebellum, since there has been little information available about them. The aim of the study is to clarify the incidence and the outcome of NIMPN after CBT. METHODS: We retrospectively studied medical records of 459 patients who underwent CBT as the first transplantation at Toranomon Hospital between July 2012 and March 2018. NIMPNs were diagnosed when the patients developed myelopathy or peripheral neuropathy without detection of pathogens tested in cerebrospinal fluid (CSF) or without radiological findings indicating hemorrhage, ischemia, or focal lesions suggestive of infections. We excluded the patients whose ECOG performance status scale was 3 or 4, and who had neurological symptoms before transplantation. Institutional review board of Toranomon Hospital approved the study (research number #1205-H) RESULTS: NIMPNs developed in 8 patients within 2 years after transplantation (2 myelopathies and 6 peripheral neuropathies [PN]). Their characteristics are as follows: the median age, 53 years (range, 37 - 62); 5 males and 3 females; AML-NOS (n = 5), AML with MRC (n = 1), therapy-related MDS or AML (n = 2). All except one were not in remission before transplantation. The combination of fludarabine, busulfan, and melphalan with or without high-dose cytarabine was used as conditioning regimen. Tacrolimus (Tac) alone (n = 2), Tac and mycophenolate mofetil (n = 5), and Tac and methotrexate (n = 1) were used as GVHD prophylaxis. The cumulative incidence of NIMPNs was 1.74% at 2 years after transplantation (95% confidence interval, 0.54 - 3.93). The median onset day of NIMPNs was 90 days after transplantation for all patients (range, 25 - 255); 40 days for myelopathy, and 100 days for PN. All had varying degree of hypesthesia or paresis and were unable to walk by themselves at diagnosis. All developed neurological symptoms after engraftment. Grade 2 - 3 of acute GVHD preceded NIMPNs in all patients. At diagnosis, the following pathogens were confirmed to be negative by PCR in CSF; HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, BKV, toxoplasma. CSF cell count and protein level did not increase in all of them. Myelin basic protein level in CSF was elevated in 3 out of 6 patients (519 ng/L and 1358 ng/L for myelopathies, 1321 ng/L for PN), which suggested demyelinating changes. Oligoclonal bands were not detected. Spinal MRI study performed in 4 patients showed no abnormality. In line with previous reports, axonal degeneration was confirmed by nerve biopsy in 2 patients with PN. After the diagnosis of NIMPNs, all patients were treated with high dose intravenous immunoglobulin (IVIG) (400 mg/kg for 5 days). The median interval from diagnosis to treatment was 28 days (range, 5 - 71). IVIG was administered monthly for the median of 2 courses (range, 2 - 5). In 2 patients, rituximab or steroid pulse therapy was added on IVIG, respectively. After these treatments, symptoms improved in 6 out of 8 patients and they finally were able to walk by themselves (1/2 of myelopathy and 5/6 of PN). The remaining one died of severe liver acute GVHD and another one is hospitalized until now without recovery. The median follow-up days of survivors was 498 days (range, 74 - 2190). Seven out of 8 patients are currently alive. CONCLUSION: NIMPNs were observed after CBT with low incidence. Although all patients presented severe neurological symptoms at diagnosis, IVIG and immunosuppressive therapy had a therapeutic benefit, and their prognosis with respect to neurological symptoms and survival was not dismal. Disclosures Yamamoto: Bristol-Myers Squibb: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 9
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5382-5382
    Abstract: INTRODUCTION: Allogeneic hematopoietic cell transplantation provides an opportunity for a cure of myeloproliferative neoplasms (MPNs). Although several studies showed its efficacy even for leukemic transformation (LT) from MPNs, no direct evidence exists which compared the long-term outcome of patients in chronic phase (CP) and LT in a same cohort. METHODS: We retrospectively studied allogeneic hematopoietic cell transplantation for MPNs between 1999 and 2017 in Toranomon Hospital. LT was defined according to the WHO classification in 2016. Risk stratification was according to the dynamic international prognostic scoring system (DIPSS). The spleen index was defined as the measurement of spleen on CT scan. The day of neutrophil and platelet engraftment was defined as the first 3 consecutive days on which the patient's absolute neutrophil and platelet count was 〉 0.5 x 109/L and 〉 20 x 109/L without platelet transfusion, respectively. The study was approved by the ethics committee of Toranomon Hospital (research number #1796), and conducted in accordance with the Declaration of Helsinki. RESULTS: A total of 36 patients were extracted. At transplantation, the disease status of MPN was CP in 16 patients (44%) and LT in 20 (56%). Median spleen index was significantly lower in LT than CP (104 cm2 vs. 150 cm2, p 〈 0.01), and more CP patients received splenic irradiation before transplantation (p = 0.04). At the start of conditioning regimen, a half of the patients in LT was not in remission even after chemotherapy. Most patients in CP used bone marrow or peripheral blood stem cells, whereas umbilical cord blood (U-CB) was preferred for patients in LT (p 〈 0.001). Among these 2 cohorts, the cumulative incidence of neutrophil and platelet engraftment was comparable at day 60 and at 1 year after transplantation, respectively (neutrophil engraftment: 87.5% in CP vs. 80.0% in LT, p = 0.11; platelet engraftment: 68.8% in CP vs. 65.0% in LT, p = 0.70). Overall survival (OS) was significantly superior for patients in CP to ones in LT (p = 0.02) (Figure). OS rate at 5 and 10 years after transplantation for patients in CP and LT were 56.2% (95% confidence interval [CI], 1.0 - 35.4) vs. 11.2% (95% CI, 29.5 - 76.2), and 45.0% (95% CI, 17.8 - 69.1) vs. 0%, respectively. Median survival was 7.5 and 0.9 years for patients in CP and LT, respectively. Median follow up of survivors in CP and LT was 1652 days (range, 980 - 5395) and 906 days (range, 522 - 1014), respectively. At 10 years after transplantation, the cumulative incidence of relapse was significantly higher for patients in LT than ones in CP (6.2% in CP vs. 38.0% in LT, p = 0.04). In LT patients, disease recurrence occurred within 3 years after transplantation and 7 out of 17 patients (41%) died of relapse after transplantation. CONCLUSION: To achieve a long-term relapse-free survival, it is crucial for MPN patients to undergo transplantation in chronic phase, not after the development of LT. Delayed decision to transplant may be critical for patients who are at high risk for LT. Figure Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 10
    In: Blood, American Society of Hematology, Vol. 142, No. Supplement 1 ( 2023-11-02), p. 6931-6931
    Abstract: [Background] Although the standard treatment for relapsed or refractory large B-cell lymphoma (LBCL) is high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT), the prognosis of relapsed or refractory LBCL is poor. The chimeric antigen receptor (CAR) T-cell therapy showed efficacy against relapsed or refractory LBCL. However, little real-world data on lisocabtagene maraleucel (liso-cel) were reported. Therefore, we report our data on liso-cel for relapsed or refractory LBCL in our institution. [Methods] We retrospectively analyzed clinical characteristics of patients who underwent leukapheresis to manufacture liso-cel between August 2021 and March 2023 at Toranomon Hospital. Overall survival (OS), progression-free survival (PFS), and duration of response (DOR) were calculated using the Kaplan-Meier method. OS was defined as the time from infusion of liso-cel to the date of death or last follow-up. PFS was defined as the time from infusion of liso-cel to progression of disease or death. DOR was defined as the time from first complete response or partial response to disease progression or death. The Cox proportional hazards model was used to determine the significance of multiple variables. [Results] Leukapheresis for the manufacture of liso-cel was performed in 25 cases. Of these 25 cases, liso-cel could not be manufactured in only one patient, and the other 24 patients received liso-cel infusion. Of the 24 patients who received liso-cel, 14 were men and the median age was 64.5 years (range, 29-78). Twenty-one patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; the other 3 had a PS of 2. The other clinical characteristics were as follows: Stage III/IV in 21 (87.5%); Bulky mass in 6 (25%); extranodal involvement & gt; 1 in 9 (38%); international prognostic index (IPI) & gt; 2 in 13 (54%); and elevated LDH in 11 (46%). Histological diagnoses were diffuse large B-cell lymphoma (n=13), transformed follicular lymphoma (n=6), primary mediastinal large B-cell lymphoma (n=3), and high-grade B-cell lymphoma (n=2), respectively. Secondary central nervous system (CNS) involvement was detected in 4 cases. The number of patients with primary refractory disease or relapse within 12 months after first-line chemotherapy is 10 (42%) and 10 (42%), respectively. Since 10 patients with primary refractory disease required immediate chemotherapy until leukapheresis was performed, liso-cel was used as a third-line or later in all cases. Patients had received a median of 4 (range, 2-9) previous lines of chemotherapy. Six patients (25%) had received a previous autologous HSCT, and two (8%) had received a previous allogeneic HSCT, respectively. The median time from leukapheresis to liso-cel arrival at our institution was 42 (range, 37-45) days. Bridging chemotherapy after leukapheresis was performed in all cases, with polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) being the most common with 13 cases (54%). Eight cases (33%) had achieved complete response (CR), and 8 cases (33%) had achieved partial response (PR) before lymphodepleting chemotherapy. The median follow-up of survivors was 7.7 months (range, 2.5-14.5). The median OS, PFS, and DOR were 11.5 months (95% confidence interval [CI] : 8.9 to not applicable, NA), 8.5 months (95% CI: 2.1 to NA), and 8.9 months (95% CI: 3.3 to NA), respectively. The overall response rate was 71%, with 54% achieving CR. Cytokine release syndrome (CRS) and neurological events (NEs) occurred in 21 (88%) and 2 patients (8%); grade 3 or worse CRS and NEs occurred in 1 (4%) and 2 patients (8%). Grade 3 or worse neutropenia, anemia, and thrombocytopenia were occurred in 23 (96%), 14 (50%), and 17 cases (71%), respectively. Prolonged Grade 3 or worse neutropenia was seen in 12 cases (50%) at 28 days after liso-cel infusion. No treatment-related death was not observed. Six patients died, and the causes of death were LBCL (n=3), pneumonia (n=2), and COVID-19 (n=1). In the multivariate analysis, independent risk factors for PFS were PS of 2 (hazard ratio [HR], 56.39; 95% CI, 8.31 to 382.7; p & lt;0.001) and disease status (stable disease/progressive disease) before lymphodepleting chemotherapy (HR, 6.14; 95% CI, 1.07 to 35.06; p=0.04). [Conclusion] In our cohort, liso-cel has shown high response in relapsed or refractory LBCL. Disease status before lymphodepleting chemotherapy is significant for better prognosis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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